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Fluoride: The Ultimate Cluster-Flux

And the Players Involved

A Compilation of Documents and Articles


Relating to Fluoride

This collection is dedicated to those who wrote the original works and
made them available on the internet. I have spent countless hours
searching for information on fluoride and it is my wish, by assembling
these works, to enable others to save time looking and make available
more time for them to ‘do’.

If you are sickened and appalled by the approved use of fluoride in


food, beverage and other consumer products then I ask that you spread
this knowledge on to others and contact your local representatives in the
hopes that one day fluoride will be more strictly regulated or, banned
altogether.

These documents are listed in roughly the order I found them. It would
be nearly impossible to group them in some kind of order since they are
all linked together – a cluster-flux of monumental proportions.

I would like to thank (or curse) Christopher Bryson whose excellent


book, The Fluoride Deception, opened my eyes to fluoride and started
me on this journey of uncovering the truth.

For more information on fluoride, I would recommend the Fluoride Action


Network (FAN) http://www.fluoridealert.org/ as a good place to start.

NOTICE

In accordance with Title 17 U.S.C., section 107, some material on this web site is provided without
permission from the copyright owner, only for purposes of criticism, comment, news reporting,
teaching, scholarship and research under the "fair use" provisions of federal copyright laws. These
materials may not be distributed further, except for "fair use" non-profit educational purposes,
without permission of the copyright owner.
http://gulfwarcouncil.com/gulf_war_illness_explained_in_th.htm

Gulf War Illness Explained in the Simplest Terms

Gulf War Illness Explained in the Simplest Terms

By: Jim Phelps


Copyright 2005

The 1991 Persian Gulf War still affects hundreds of thousands of


American Veterans from the "toxic soup" that cut some 30 years
off many of their life-spans. There has been much discussion of
the toxic soup's components that have taken the terrible toll on
those exposed. The significant toxic exposures were aluminum
and mercury in vaccines, the Depleted Uranium from munitions,
the oil well fires, the nerve gases that hydrolyses to hydrogen
fluoride, DEET, PB, high chlorine in drinking water, methanol from
"Nutrasweet" soft drinks, and other insecticides.

All these varied toxic materials leave many people mystified as to


what are the main components driving the long term illnesses
showing up in many of the hundreds of thousands of people sent
into the Gulf War zone and others that never entered the war zone
who also became sick from only the vaccines. The question
becomes what is the common factor that connects all these
persons leading to this similar illness pattern. There were some
immediate effects due to consumption of high amounts of
Nutrasweet beverages in the hot climates that put many soldiers
well over the safe levels of methanol, which began some of the
nervous system damage. This was made worse by damage to
repair enzymes like SOD, due to varied chemical exposures that
lowered this essential enzyme.

The common factor that connects to all the illness is not a mystery
and is a well known effect, but one that is suppressed. The
common mechanism is the loss of enzymes in the human body
and the main two involved are glurathione (GSH) and SuperOxide
Dimutase (SOD). Glutathione is the main enzyme that clears many
toxic metals from the body and without it being at full potential
toxic metals concentrations rise in the body leading to increases in
free radical damage to cells via reactive oxygen damage (ROS).
SOD is responsible for repair of the ROS damage to the cells. So,
the main problem is both the loss of the mechanism that clears the
toxic material and the loss of the mechanism that repairs the
damage due to rise in the toxic materials driving high rates of ROS
damage.

The other key enzyme is one called RNase L which is damaged by


the high free radical effects from the toxic metals interaction with
cell mitochondria. The RNase L enzyme is the key one that
controls viral infections (and also mycoplasma, bacteria) within
cells. High radiation generation of free radicals also damages this
same enzyme class and results in viral infections that are typically
controlled with these enzymes. Inner cell infections like
mycoplasmas can appear that require antibiotics to control.

GSH and SOD also care for the brain and pass easily into the brain
tissues. The GSH clears the brain of toxic metals, like mercury and
lead, and the SOD tries to heal the damage caused by the toxic
metals substituting into cell processes that lead to ROS damage.
The "brain fog" or "foggy thinking" that associates with Gulf War
Illness is a direct result of lowered levels of GSH and SOD in the
body and is a first order sign for this type mechanism being of
prime importance.

The prime causes of reduced GSH and SOD are toxic materials like
HF (hydrogen fluoride), AlFx, DEET, mercury, PCB, chlorine,
insecticides, and a lack of vegetables and fruits in diets. Everyone
in the US today has some degree of GSH and SOD suppression
and the problem worsens with age. Many of these toxic materials
highly retain in the body and the leading problems come from
mercury, PCBs, and fluorides. The mercury component and the
bad diets lead many vets to get many of the Gulf War Illness
symptoms just due to the many killed vaccines they received that
employed mercury.
The reduction of the clearance of toxic metals due to GSH is easily
observed in the population as it plays a direct role in why hair
turns gray. Grey hair is caused principally by rising levels of Hg or
mercury in the body being incorporated into the hair follicles
causing the loss of pigment from the higher cellular ROS
problems. Grey hair has higher levels of mercury in it than
pigmented hair strands and the effect helps to pull some mercury
from tissues. Grey hair for many people begins in areas of the chin
and face, where the highest concentrations of mercury tend to
accumulate in tissues from mercury dental fillings. With increasing
age the gray hair can affect most of the head's hair. This is a
common example of the effects of reduced GSH and SOD enzymes
that happens with age and rise of internal retention of PCB,
pesticides, HF, and Hg that act to damage GSH and SOD
production.

The enzyme GSH removes toxic metals from the brain and tissues
by combining the toxic metals with sulfur and then an excretion
pathway via the bile into the feces and out of the body. As GSH
levels in the body fall from chemical poisoning effects it places
more of a load on the kidney pathway of excretion. The toxic
metals loading on the kidney can become too large easily and
damage the renal tubule cells leading to less excretion rate and an
acid shift of the blood that enhances the toxic metals retention
problems. The failure of the GSH pathway to remove metals from
the body and the damage of the kidney pathway to remove metals
from the body produces a rise in toxic metal retention in the body,
high ROS levels, and very high risk for cancer and all the immune
linked illnesses. The failure of the kidney pathway to remove toxic
metals generally shows with porphyria in the urine.

Vets that came to the war zone were exposed to HF from nerve gas
demolition plumes of hydrogen fluoride enzyme system poisons
drifting into their breathing air space that damaged the GSH and
SOD levels. Vets were also exposed to DEET, oil hydrocarbons,
and insecticide sprays the also damaged GSH and SOD levels. The
net result of this long term poisoning effect is a slow rise in the
toxic metals (Hg, Pb, Al, Cd, etc.) concentrations in the body and a
slow decline of the beneficial trace metals (Zn, Mg, Se, Cu, etc.) in
the body that support the formation of GSH and SOD. One can
even look at the recovery regimen that GWI researcher named Dr.
Garth Nicholson recommends and find he recommends minerals
and other factors that boost these beneficial trace elements and
GSH and SOD. Nicholson was the first to spot mycoplasma effects
in GWI, and the mycoplasma problems are also common to
radiation exposures due to high levels of ROS damage to RNase L
cellular enzymes in the body generated by high radiation.

This basic mechanism for illness is common to the Chronic


Fatigue Syndrome (CFS) and the illnesses of the DOE gas diffusion
plant workers. The most damage to the GSH and SOD in these
cases is due to the rise of fluoride and HF exposures that lead to
the upset of the metals metabolism in the body. The health damage
is due to high levels of ROS that lead to health problems that look
like they are caused by internal radiation free radical damage. The
rise of the toxic metals and the acid pH shifts in the blood lead to
kidney cell damage that has the appearance of DU type heavy
metals poisoning. When the body's pH goes into the acid domain
the metals retention is high and the ROS damage to cells extreme
and usually results in cancer virus activation.

In areas like Oak Ridge where high levels of chemicals like HF kill
off the GSH and SOD enzyme clearance of mercury from the body
one finds higher rates of thyroid damage. High levels of mercury
are well associated with hypothyroidism and Hashimoto's
Thyroiditis. Sometimes the thyroid effects in Oak Ridge have the
appearance of hyperthyroidism when there is too much cadmium
and the high free radical damage due to loss of SOD. It is a very
similar effect that damages the kidneys that potentiates toxic
metals retention.

The worst effect from GWI comes from the fluoride and aluminum
vaccine effects that spontaneously form AlFx compounds that
mimic the pituitary hormone TSH. The AlFx compound then
determines the levels of thyorid gland and liver T-3 and T-4, which
program the energy levels in the mitochondria of every cell in the
body. It is this effect that results in the depletion of the GSH levels
needed in all the cells of the body. This effect causes the night
sweats that are common to both people with CFS and GWS. It also
causes the loss of restful sleep and the inability to sleep because
the cells won't power down like they would under the control of the
pituitary gland.
It is this thyroid hormone mimic problem that lies at the very heart
of GWI, because so little of a chemical can cause such a global
effect on all cells in the body. The effect that is produced is like
that of hyperthyroidism, which leaves people very tired, often
sleepless, and will little cellular GSH. The standard thyroid test
using TSH results in misdiagnosis of hypothyroidism because
these persons will test low for TSH and be uncommonly tired. This
effect leads to the confusion on GWS by many doctors and it also
leads to ways to cover up the health problems by testing only for
TSH. Only the Thyroid Panel tests begin to show the T-3 and T-4
high level problems that the AlFx compound causes in the GWI
equation.

The key to the AlFx TSH hormone mimic effect is that AlFx
compounds don't follow the night and day amplitude and pulse
fluctuations of the normal pituitary TSH. The AlFx compounds
have drastically different bonding characteristics to TSH receptor
sites of cells due to the fact that highly electronegative fluorine is
involved in the site bonding. This effect results in a nearly
permanent bond to the receptor sites for TSH, which highly upsets
the normal thyroid hormone regulation process. It is this effect that
depletes the GSH in every cell in the body and why the Al and F
contamination effects are often the worst on GSH levels and the
illness processes.

The bottom line is that 10 days of war took 30 plus years off the
lives of hundreds of thousands of US soldiers that entered this
conflict. Hundreds of thousands of Vets were exposed to some of
the most retained chemical poisons on the planet that killed their
GSH and SOD levels leading to health problems about like those of
a 60-year-old female. Some have brain injury so severe from the
toxic metals effects on the brain that look like the seizures of
Minimata Disease. Gone was their prime of life and health and 20-
30 year old people were suddenly given the health of life outlook
for an elderly person. If one considers the typical life span these
days as being 75 years, then the loss of 30 years from the life span
of each of the 800,000 people in the Gulf War means 400,000
people effectively died from this toxic soup war zone.

The American Government appears interested in offering up DU as


the principle reason for all the rise of cancers in Iraq after the war.
This benefits the US because it conceals the main issue of wide
ranging chemical damage effects from blown up oil wells and oil
refineries that used HF and the oil products that damage the GSH
and SOD in the human body. There is no possible way that the use
of DU in Iraq has caused the wide spread illness effects in the
civilian populations. On the other hand, there is little doubt that DU
is directly involved in affecting the health of persons that cleaned
up DU hits on vehicles, those that stirred up the DU dusts hunting
war souvenirs, and some of the Iraq population in close proximity
to high level DU contamination. DU oxide dusts of the nano-meter
size particles easily gain entry to the body via skin and via lung
and has toxic characteristics similar to mercury. The DU issue is
being politicized to hide the very much larger problems of
chemical effects on GSH and SOD. The chemical damage factor to
GSH and SOD causes the DU retention time in the body (or the
biological half-life) and ROS damage to be greater, and the same
effect applies to all other toxic metals.

All of the studies for DU's biological half life is done on healthy
animals with normal levels of GSH and SOD, and without the
mercury toxicity effect on renal cells. When chemical damage to
the GSH and SOD levels in the body is included for the increased
toxic metals damage to kidney calls, the biological half-life of DU
and other metals is made much longer. The use of mercury in
vaccines helped to impair kidney cells and the damage is high as
mercury also suppresses GSH and SOD. All the GWI studies that
use the single challenge DU exposure for the biological half-life
numbers that don't include the chemical damage to the enzyme
clearance of toxic metals are in error. With the reduction of GSH
and the bile pathway comes high loading of the renal cells with DU,
Hg, and other toxic metals that damage these cells and set up
higher levels of toxic metals retention in the body due to highly
impacted losses of the two main clearance mechanisms.

The DU armor on US tanks is sandwiched between sheets of


aluminum and when the material is hit, not only DU dusts come off
but Aluminum dusts do also. The aluminum dusts pose an even
worse health risk than the DU, because they form the AlFx
compounds in the body that upset the TSH pituitary regulation
process and the prime factor that triggers GWS via GSH depletion.
These exposures would add on top of the aluminum in the vaccine
exposures.
The War in Iraq also is one of political affectations, rather than any
real threats against the US. Bush-41 holds a huge interest in the
Kuwait oil fields and he was the first US operation to open up
Kuwait's oil fields. Iraq was considered a threat to Israel and the
Jews. Government engineered the Iraq conflicts for Israel's
interests and not those of the US. In so doing, persons have killed
some 400,000 effective lives in the US and cost the US trillions of
dollars for the interests of a foreign power that has little interest in
the US other than trickery to promote their own group
aggrandizement interests. Big oil person Condi Rice, who was
trained by Madeline Albright's father in Denver, Co., is part of the
Jewish problems. Oil is being used by Israel to leverage US into
doing their bidding. Even the 911 event was about Israel's agents
helping to facilitate the WTC attacks and helping the Arab factions
pull off the attacks. The pattern that has gone on since the times of
JFK's death fits the Mossad Logo that Reads: "By Way Of
Deception Thou Shalt Do War"

The Persian Gulf Wars are all about the concepts of deceit and
treachery and this method is being used to conceal the main
health effects of GSH and SOD damage via chemical effects on
enzymes. The effect is most pronounced for hydrogen fluoride
systemic poisoning effects on enzymes using metals. This simple
and very basic of effects is the principle damage vector to most all
persons health in the US and the very roots of the system of
profits for the AMA based medical system. When this very basic
system for cause and effect on health becomes exposed, large
parts of the medical system in the US will be tossed aside as being
too expensive and insensible. Again, the main cause of Gulf War
Illness and the very war itself is about politics and money and not
about any mystery causation.

The very roots of the GOP dominated industry is on the very verge
of being found out for the degrees to which they have abandoned
citizens health to favor making uranium, aluminum, and other
strategic metals to gain control via wars. Long ago the US decided
to cover up this major cause of ill health in the US and use AMA
medicines to mask the symptoms and control the damage factors.
The Rockefeller based AMA and big oil is right in the middle of the
cover-ups. Even religion, which is highly GOP oriented, is being
used to help cover up the health associations from toxic emissions
that appear in the biblical times.

The very same diversion tactics have been used in Oak Ridge to
conceal the HF dominated health damage to workers and area
residents health. In Oak Ridge radiation and heavy metals are
played up as the direct cause for what is causing everyone's health
problems. The real problem is a two step progression due to
chemical damage from HF, PCB, and Hg to enzymes GSH and SOD
leading to factors that look like radiation damage effects to cell
enzymes that regulate viruses and cause the rise of toxic metal
retention. Oak Ridge uses deception to protect themselves from
the massive lawsuits and the Govt. payout for the health damage
their operations have caused to a large area in and around Oak
Ridge. The local medical system uses the large-scale cover up of
the problems as a reason to make great profits treating all the
additional illnesses and dispensing large amounts of drugs to
those affected. Oak Ridge has long had an understanding with the
local medical community that they won't disclose the main causes
of illnesses or diseases, if they associate in any way to the DOE
operations in Oak Ridge. It is this same system of ultimate deceit
and treachery used to fool the citizens that has been extended to
those veterans of the Gulf Wars and the people of Iraq and other
sites where the toxic soup factors have become extreme.

Both GSH and SOD are liver oriented enzymes and required in
every cell to work properly. GWI's prime cause and effect leads off
with chemical damage to the liver's production of GSH and SOD.
When this liver enzyme system is chemically poisoned the body's
toxic metal load begins to increase and as this occurs these toxic
metals interact with the cell mitochondria that then causes the
increase in the ROS levels within the cells. It makes perfect since
that these two areas would become the first affected, as these are
the most vulnerable areas for chemical and metal poisoning
effects on the body. The very same effect occurs with aging, as
levels of these enzyme poisons rises in the body with age.

Even the factors of high rates of ALS seen in the GW vets is


directly associated with the GSH and SOD enzymes. ALS is
associated with upsets of copper and manganese that form these
enzymes. The problems of Mad Cow and Prion linked illnesses are
caused by these same factors. Mad Cow effects come from a
systemic shift toward Mn-SOD from the Cu-Zn-SOD, and loss of Mn
dependent enzymes that cleave viral RNA within cells. When sulfur
bearing compounds like DMSO are applied to Mad Cow affected
brain tissues, the plaques dissipate, and DMSO appears to act as
GSH in supplying the sulfur to remove the toxic metals from the
brain that attract the SOD needed for myelin repair.

For those of you who want to look more deeply into the issues of
how GWI and CFS are well association let me recommend reading
this better documented piece at:
"http://www.doewatch.com/cfs.html"
and see this for more fluorine details:
"http://www.doewatch.com/f.html"

This health problem's main vector from damage to GSH and SOD
has been long known back in time and is part of the story of
Prometheus and damage to the liver from exposure to volcanic
emissions, HF. Hercules rescued Prometheus from liver damage
problems is the heart of this same health damage vector. If one
notes, the Prometheus figure is part of Rockefeller Center in New
York City, and this same mechanism is what makes the doctors of
the Rockefeller AMA based system their wealth. The main problem
of GWI is the greed of GOP oriented system of AMA profiteering by
suppression of how industry poisons the GSH and SOD liver
enzymes leading to immune related illnesses in the population.

The Prometheus story is the Greek version of health effects from


nature's emission of toxic materials, but versions of the same
theme carry back in time to the stories of Noah and Moses, and
their very similar volcanic associated health effects. The major
problem blocking the real story on GWI being told by the US Govt.
is all about near total corruption in US politics and the US version
of religion based on alterations from the truths of the old biblical
narratives.

This is an effort to make the real story public, as we survive in


each other's care. The real story here is about being dutiful toward
the people of the US and not its corrupted operations that attempt
to deceive the people from the truth. It is these untruths in religion
and cover ups in health that are at the very roots of the terrorism
equation, which Israel and the GOP exploit to the harm of every
citizen in the US.
The People of America have never been so disenfranchised from
control of their Govt. nor the US Constitution as threatened as now
from this corrupted political and religion process. The entire US
system is at risk from these cover-ups in health linked to industry
emissions and racketeering process used to hide the massive
problems.

REFERENCE CITATIONS:

Title
Role of glutathione and hepatic glutathione S-transferase in the
biliary excretion of methyl mercury, cadmium and zinc: a study
with enzyme inducers and glutathione depletors.

Author
Gregus Z; Varga F

Source
Acta Pharmacol Toxicol (Copenh), 56(5):398-403 1985 May

Abstract
The effect of hepatic glutathione (GSH) depletion and enzyme
induction on hepatic glutathione S-transferase (GST) activity,
biliary excretion of GSH, methyl mercury, cadmium and zinc was
studied in rats. The GSH depletors, methyl iodide and diethyl
maleate, did not influence hepatic GST activity but, depending on
the substrate used, benzo(a)pyrene, phenobarbital, pregnenolone-
16 alpha-carbonitrile (PCN) and trans-stilbene oxide (TSO)
increased it by 16-33, 44-89, 53-97 and 208-279%, respectively.
GSH depletors decreased (-88%), benzo(a)pyrene and TSO did not
affect, phenobarbital and PCN increased (+113 and +149%) the
transport of GSH into bile. The biliary excretion of methyl mercury,
cadmium and zinc was reduced by GSH depletors (-97, -74 and -
93%), and enhanced by phenobarbital (+139, +280 and +220%) and
PCN (+150, +121 and +160%). Treatment with benzo(a)pyrene and
TSO did not affect the excretion of methyl mercury and zinc into
bile, but decreased that of cadmium. These results do not provide
evidence for the role of hepatic GST but strongly support the
importance of biliary GSH excretion in the hepatobiliary transport
of methyl mercury, cadmium and zinc. It is assumed that
phenobarbital and PCN enhance the biliary excretion of these
metals by increasing the transport of GSH, the carrier molecule,
from liver to bile.

Title
Effect of lipoic acid on biliary excretion of glutathione and metals.

Author
Gregus Z; Stein AF; Varga F; Klaassen CD Address Department of
Pharmacology' University Medical School of P]ecs' Hungary.

Source
Toxicol Appl Pharmacol, 114(1):88-96 1992 May

Abstract
Several metals are excreted in bile as glutathione complexes' and
their biliary excretion is facilitated by increased hepatobiliary
transport of glutathione. The present study analyzed the effect of
lipoic acid (LA; thioctic acid; 37.5-300 mumol/kg' iv)' an
endogenous disulfide which can be reduced in vivo to a dithiol' on
the hepatobiliary disposition of glutathione-related thiols and the
biliary excretion of metals (10 mumol/kg' iv) in rats. Administration
of LA enhanced the biliary excretion of reduced glutathione in a
dose-dependent fashion. Despite increasing glutathione output' LA
(150 mumol/kg' iv) did not increase' but rather decreased' the
biliary excretion of methylmercury' cadmium' zinc' and copper'
which are transported into bile in a glutathione-dependent manner'
as indicated by a marked reduction in their biliary excretion after
diethyl maleate-induced glutathione depletion. In contrast' biliary
excretion of inorganic mercury' which is minimally affected by
glutathione depletion' was dramatically enhanced (12- to 37-fold)
by LA administration. Following inJection of LA' the
concentrations of endogenous disulfides in arterial blood plasma
(e.g.' cystine' glutathione disulfide' cysteine-glutathione' protein-
cysteine' and protein-glutathione mixed disulfides) were
considerably diminished' while the levels of endogenous thiols
(e.g.' glutathione and cysteine) were increased. This finding
indicates that LA' probably after enzymatic conversion to
dihydrolipoic acid' can reduce endogenous disulfides to thiols. It
appears that LA induces the transport of glutathione into bile by
the temporary formation of dihydrolipoic acid-glutathione mixed
disulfide' which after being translocated into bile is cleaved to LA
and reduced glutathione. Because the glutathione molecule thus
transported into bile cannot complex metals at the thiol group' this
might be the mechanism for the observed failure of the LA-induced
increase in biliary excretion of glutathione to enhance the
hepatobiliary transport of metals that are transported into bile as
glutathione complexes (i.e.' methylmercury' cadmium' zinc' and
copper). The observations also raise the possibility that
endogenous dihydrolipoic acid' by forming a stable complex with
mercuric ion' may play the role of a carrier molecule in the
hepatobiliary transport of inorganic mercury.
Title
Biliary secretion of glutathione and of glutathione-metal
complexes.

Author
Ballatori N; Clarkson TW

Source
Fundam Appl Toxicol, 5(5):816-31 1985 Oct

Abstract
As bile is the main route of elimination of many metals, a large
number of studies have been directed toward the characterization
of the hepatobiliary transport of both endogenous and exogenous
metals. Although some progress has been made, we still know
little of the basic mechanisms involved in the hepatocellular
uptake of metals, in their intracellular translocation and
metabolism, or in their transport into bile. Our recent studies have
focused on the last step in the hepatobiliary transport of mercury,
namely, the secretion of the metal from liver cells into bile. The
rate of secretion of methyl and inorganic mercury into bile was low
in suckling rats and rapidly increased to adult rates soon after
weaning. These changes closely followed similar developmental
changes in the biliary secretion of reduced glutathione (GSH).
When GSH secretion into bile was completely inhibited, without
changing hepatic levels of GSH or mercury, mercury secretion was
also completely blocked. mercury secretion paralleled individual
and sex-related differences in GSH secretion. At the same time, the
secretion of mercury was independent of bile flow, of the thiol and
mercury concentration gradients between bile and liver cells, and
of those between bile and plasma. Our results, therefore, indicate a
close coupling between the secretion of mercury and that of GSH.
These in vivo findings, along with in vitro studies by others in
vesicles isolated from the canalicular membrane of the liver cell,
indicate a carrier-mediated transport system for GSH, but the
nature of the linkage of this transport system with mercury
secretion is not yet fully established. Our data and those in the
literature are consistent with the involvement of at least two steps
in the movement of mercury from liver cells to bile--the formation
of a mercury-glutathione complex in the liver cell, followed by the
secretion of this complex through a process closely linked to GSH
secretion. The identification of GSH as an endogenous complexing
agent in the transport of metals between tissues and body fluids
now permits the design of therapeutic strategies aimed at
exploiting this transport vehicle to effect the removal of metals via
physiological routes of excretion. The present discussion
considers the role of GSH in the hepatobiliary transport of metals.
In doing so, a brief review is given of current understanding of
hepatic GSH metabolism and transport.

Diagnosis: Environmental Toxic Pathway Analysis and Immune


System Cytokine Modality Provide Key Insight into Chronic
Fatigue Syndrome Mechanism and Etiology of Varied Pathogen
Driven Illnesses.

By: J. E. Phelps Copyright 2005

Abstract:

The cytokine signature of chronic fatigue syndrome (CFS) is similar to that


seen in chemical injury, Gulf War Syndrome (GWS), and Human
Immunodeficiency Virus (HIV). CFS is shown to have a Th2 cytokine
humoral modality from the shut down of the Th1 cellular defense. Th2 is an
allergic antibody biased mode that takes precedence as the Th1 cellular
mode that regulates pathogen infection internal to cells is exhausted.
Illnesses for Department Of Energy gas diffusion plant workers have this
modality and many similarities to CFS due to similar toxic exposures. This
report investigates the stance that toxic materials drive disease and
presents an underlying common mechanism that has been overlooked and
more recently suppressed. The report will show that there are new highs in
toxic induced immune damage that lead to extreme free radical damage
from toxic metals retention, then a proliferation of unregulated pathogens
that further damage health. Analysis of the toxic pathways of nuclear
industry toxic metals point to cytokine signatures that offer key insight into
progression of these cytokine activations leading to long term CFS.
Beryllium metal cytokine factors are presented as a model for other toxic
metals and chemicals that form insoluble products in the lymph nodes due
to shut down of GSH and SOD clearance enzymes which then leads to long
term cytokine triggering and shutting down the macrophage pathogen
destruction function. The beryllium-fluoride G-protein model is then
expanded into a general model for other toxic metals and fluorides that
damage GSH and SOD and share biological concentration of cytokine
triggering toxic materials build up in the lymph nodes. This effect leads to
continual cytokine triggering and toxic damage to the macrophage cells
that perform pathogen destruction and antigen presentation function. The
discussion also takes into account the time line of scientific discoveries
that have allowed these insights into CFS since its recent popularized
discovery in the mid 1980's. Key points that will be considered are the G-
protein mimic effects of beryllium and aluminum when compounded with
fluorine that mode lock the lymph node dendritic cells when GSH and SOD
are suppressed. Then the effect of fluoride compound breakdown that
sequesters increasing fluorine atom concentrations in the bone marrow
that in turn robs immune cell formation of essential metals for enzyme
protection. The depletion of GSH will lead to discovery of problems with
the global sulfur cycle from ozone hole effects damaging the DMS levels
needed to support hepatic clearance of toxic metals and prevent
hypethyroid type shifts and metabolic acidosis leading to CFS and other
immune system illnesses. This report is a comprehensive and broad based
discussion illustrated with practical examples and referenced to peer
reviewed scientific journals to show the key effect in CFS and human
immune health.

The human immune system is a complex system of dynamic cells


with many cytokine feedback factors that have been explored in
the last decade to reveal many of the mechanisms for illness. The
immune defense takes on two distinct modes as set up by the
stimulation of T helper cells, as triggered from the lymph nodes.
The cellular Th1 immune system profile is one designed to control
pathogens internal to cells and the humoral Th2 system response
controls external cell pathogens.[1] Study of the cell factors and
cytokine signaling yields an understanding of how these factors
lead to and control many illnesses, including chronic fatigue
syndrome (CFS). This report outlines a cellular mechanism and a
toxic pathway for damage to the immune system by analysis of the
cellular cytokine response from toxic damage, which then leads to
more progressive disease factors from loss of pathogen
regulation.

This discussion will time line the discovery of CFS, correlate toxic
environmental factors with CFS, and connect the cell mechanisms
to the prime factors driving the CFS immune dysfunction process.
The nuclear weapon materials research offers key insight into the
toxic pathways and cellular responses that lead to these theories
and conclusions. This report reflects my research into viral and
immune system effects since 1980, with direct experience from the
Oak Ridge, Tennessee nuclear site. I, as an ORNL Sr. Staff,
proposed that fluoride in bone had an insoluble precipitate effect,
a metals speciation, on the essential trace metals for immune cells
formed in the bone mass. The effects of fluoride forming G-
proteins would lock up and shut down the lymph node immune
defense process. Fluoride is a potent enzyme poison due to its
affinity toward trace metals. This key effect has not been reported
by ORNL and has been suppressed since 1986 due to Oak Ridge
liabilities from toxic HF emissions. Presenting a key finding on
fluoride toxic effect and its cumulative mechanism in a public
forum is the purpose of this report.

This report is principally concerned with the lymph system, its


cytokine signaling, and how it responds to toxic exposure. Cell
and lymph system response is nothing new as even snake venom
toxin drives cytokine response and nitrogen oxide (NO)
generation.[2] Snake bites require light tourniquet pressure to
prevent circulation of snake venom in the lymph system and
around the body leading to death in some cases. Many biological
toxins are handled well by the lymph system, but many toxic
materials enter the same pathways and cause serious problems
due to insolubility problems of mineralization or turning to stone in
these critical zones. Oddly enough, it has been suggested that the
symbolic imagery connected with the Virgin Mary icon standing
with foot placed on a snake emanating from the Earth and the
snake biting the apple as symbolism for contamination from the
Earth's lower regions connected to disease and illness. Religion
symbolism from Noah is connected to the largest land mass
volcano on the Earth and the toxic emanations to health effects on
man and animals. Religion and Revelations even speak to the
asteroid called "wormwood" that poisoned the planet with volcanic
like toxins from the heat of interactions from land impacts, or
caused massive floods when they impacted oceans. This report
will take a multi-disciplined investigation, using volcanology,
asteroid terminal event toxic releases, history, religion, nuclear
plants, wars, and toxic research to look more deeply into these
health effects.

From the nuclear weapons production, Oak Ridge is one of the


most chemically impacted industry sites in the U.S. and many toxic
linked illness patterns are evident. The toxic material research
studies from the nuclear industry and Oak Ridge health problems
provide a clear and unique view for some of the mechanisms for
toxic driven immune activation in illnesses. These studies, that are
well known in the nuclear plants, will be used to illustrate and
prove the process of toxic induced immune illnesses. Toxic
material pathways into the human body, how they retain or
concentrate with time, and vector to different organ systems play
pivotal roles in disease etiology. Some of these toxic material
pathways directly affect the immune system resistance and lead to
viral disease etiology. Examining these patterns and how they
overlap CFS is the focus of this report.

The term "CFS" (or CFIDS) made its national appearance in the mid
1980's with the investigations of Dr. Paul Cheney concerning sick
persons in the area of Lake Tahoe, on the California and Nevada
border. Most of these CFS persons were fine one day and came
down with mononucleosis like illness the next, with flu like
symptoms persisting. In 1999, Cheney described the illness as one
that depleted glutathione, used much ATP, and showed a very
significant up regulation in an enzymatic pathway known as the 2-
5A RNase L.[3] Looking for toxic exposure factors, the waters of
Lake Tahoe are pristine, but the area is of volcanic origin that
contaminate some wells and soils with volcanic materials. Well
waters are often contaminated with higher levels of arsenic,
manganese, radium, radon, and fluoride than surface waters.
South Lake Tahoe has public water supplies from wells that have
metal contamination, often associated with volcanic zones or
mining. South Lake Tahoe water reports have specific caution for
immune compromised persons because of these pollutants.[4]

Cheney's CFS Tahoe cluster diagnosis was made possible by


detection of new chemical bio-markers, but CFS is not new as it
appears to be symptomatically reported in 1750 and in other terms
in earlier periods.[5] It is also speculated that the biblical story of
Jesus healing the person by the well is even earlier evidence of the
illness. The Cheney / Tahoe mononucleosis like illness is
associated with swollen lymph node from activation of EBV, HHV-
6, and other viral pathogens that are associated with follow on
disease factors, like MS.[6, 7] Glutathione (GSH) depletion is
associated with the cellular oxidant repair process and
detoxification of tissues and it is lowered by chemical and
pathogen damage to mitochondria of cells that manufacture
ATP.[8, 9] Lowered GSH can hasten cell apoptosis and is an
indicator in chronic disease, cancer, arthritis, and rapid aging.[10,
11, 12, 13, 14, 15] Glutathione is important in liver detoxification
and in maintaining the mucosa cells that line the intestine.[16, 17]
Selenium associated Glutathion depletion drives shifts in cytokine
mode from Th1 to Th2.[18]

The "2-5A RNase L" enzyme is part of the activation process for
the Th1 interferon cytokine that inhibits viral replication in
cells.[19] 2-5A RNase L is also important in the control of HIV
replication.[20] These bio-markers point out that control of viral
pathogens in the body have been compromised. The mechanism
from just these indicators is not well defined, but these are
indicators of immune cell toxic effects. There is a enzyme chimera
effect for CFS associated 2-5A RNase L where persons with CFS
produce a 37 kDa enzyme inside their white blood cells, where
normal persons produce a slower but more effective 83 kDa
enzyme. The lighter weight enzyme is faster in dissemination, but
less effective in killing viral components. The damage to the RNase
L enzyme follows damage to GSH and SOD, which clears toxic
metals that damage mitochondial function, produce excessive
ROS generation, and reduce ATP production.

The appearance of this lighter weight chimera of the 2-5A RNase L


enzyme sets up the factor for viral infections and in white cells not
being controlled. The 37 kDa enzyme does not kill viral presence
inside cells, nor does it kill many of the white cells. This is the key
to transmission for the viral spreading in the white cells of the
immune system and infecting many cells in the body. The rise in
the RNase L causes damage to the mitochondria and ATP
production. It also sets up the causation for the high levels of NO
in the cells that damage the mtDNA. This effect sets up the
debilitating fatigue connected with CFS that follows directly upon
the RNase L chimera. The principle question then becomes what
causes this enzyme of the white cells formed in the bone marrow
to mutate into a lesser effective enzyme.

The basic mechanism of cell enzymes that police viral and


pathogen infections inside the cells is also seen from high
radiation effects. Typically the high ROS produced by external
gamma radiation will result in cell infection problems that are
treated with antibiotics. Mycoplasma's, viruse's, and bacteria's
become problems when RNase L becomes less effective due to
high rates of ROS damage. The very same effect on RNase L can
be had from the loss of GSH and SOD due to chemical factors
acting on G-protein channels shutting down its production. In this
way, chemical induced free radical damage and radiation induced
free radical damage are the same and additive toward damage to
the RNase L. Cancer tumors occur from the activation of
endogenous DNA viruses and the mutations of those viruses the
radiation induces. Vaccines also included cancer viruse like SV-40,
which can become active when cells loose their RNase L enzyme
protection. When the Rnase L enzyme is impaired by free radical
damage, cancer viruses can proliferate and even produce their
own GSH and SOD to promote their growth. Cancer viruses also
promote cytokine TNFa which sets up higher blood circulation that
helps the tumors grow more rapidly. Cancer virus and tumors
proliferate only with ROS damage to the RNase L enzymes impair
the process that causes cell apoptosis or death AND when the
back up system of Th1 cytokine signaling impairs the macrophage
and T-cell protection system. Both failures often hinge on damage
to GSH and SOD from chemicals affecting the GSH G-protein
channel.

Cheney's patients were from an extinct volcanic zone with


contaminates in well water. From the study of volcanology, we
know volcanic zones have many of the toxic fluorides and metals
problems associated with mining and operation of Department Of
Energy (DOE) plants that emit metals and fluorides.[21, 22, 23]
Volcanoes have more explosive power from H2S than nuclear
weapons and produce toxic fallout and contamination problems
with acids, toxic metals, and toxic halogen compounds [i.e.:
calcium fluoride, hydrogen fluoride, hydrogen chloride]. Meteor
events also present toxic emissions like those from volcanoes and
these same factors play dominant roles in species survival.
Meteors that hit the oceans cause massive waves as in the times
of Moses flood, and those that hit the land mass produce huge
levels of very toxic acids like HF. The Earth, for many millennia,
was bathed in distilled waters from the heat of the sun that
produced a thin layer of less toxic soils on the planets surface and
clean surface waters. Mining, industry, and well drilling often
compromise this natural toxic isolation process and lead to health
problems in man.

Volcanoes and glacial effects have long been associated with


essential trace metals availability in soils. Soils in the US and other
areas have been highly depleted of these essential trace metals by
over farming, over grazing, and by acid rain effects. Before man's
energy needs the chemical speciation and solubility factors for
these trace metals was determined by sulfur from volcanic
emissions. As man's energy needs have become dominate; the
hydrochloric, carbonic, and nitric acid effects have grossly upset
the metals speciation from that of sulfur dominated. This highly
affects grazing animals health that are highly coupled to the soils
via the grass uptake of these trace metals. The change in metal
speciation puts more toxic and dangerous metals into the grazing
animal's diets and with this effect comes the "mad cow," scrappie,
and prion linked problems we see today. One can easily find cattle
being highly affected by toxic aluminum, increased manganese,
mercury, and other metals offset. In the US, the practice of feeding
cows bone meal had to be stopped because the bone sequestered
these toxic metals and fluorides and this was linked to the prion
formation.

Toxic emissions from volcanoes have been associated to bio-


markers such as porphirine and porphyrins, which are diagnostic
indicators of toxic cell damage effects from metals and
chemicals.[24] Porphyrin is the killing chemical inside NK cells and
when these cells are destroyed it releases higher rates of the
porphyrins in the blood. CFS causes lowered NK cell population
and this is a result of their porphyrin content and RNase L
ineffectivity toward viral infections. Persistent toxic gas emissions
of volcanoes kill animals and cause long term defoliation of
downwind areas. This is often connected to chemical damage
effects to GSH and SOD enzymes, which increases retention of
toxic metals and ROS damage in cells. Mining and smelting
operations often cause similar problems with acid run off
contaminating soil and water with metals and fluoride. It should be
noted that century's earlier volcanic zones were connected with
rapid spread of disease. An example is the Hawaiian Islands and
their native residents weakened immune resistance to measles,
syphilis, and other diseases, as Europeans traded and socialized
with them. It is noted in history that in this population disease
spread incredibly fast and devastated the islands inhabitants,
which suggested their immune resistance was degraded by their
volcanic environment. Volcanic eruptions are even postulated to
have caused the downfall of the Egyptian City of Memphis from
massive plagues. It was these early associations that connected
toxic material to the weakening of the immune protection system
making persons vulnerable to opportunistic infection and
endogenous viruses in the body, as well as exogenous viral
transmission. These early observations suggested CFS had
environmental and industrial linked toxic contamination origins.

In other centuries toxic metals such as arsenic, lead, and mercury


were associated with health effects. Lead was connected to the
neurological hearing illnesses that Beethoven experienced and
even associated with the demise of the Roman empire due to the
lead food storage methods.[25] Lead promotes a Th1 type cytokine
response and tumor necrosis factor alpha (TNFa) that will activate
the macrophage's and pull particulate into the lymph nodes.[26]
The leading Th1 cytokine called TNFa promotes macrophage
activation. Persistent triggering of Th1 inflammatory cytokines by
toxic materials is linked to CFS factors like headache, fever,
myalgia, fatigue, and are toxic in high doses. Here the pathway
was via food supply with absorption via stomach and gut and
retention of metal oxides in the local lymph nodes. Toxic metal
retention and damage to the immune system is associated with
cancer vulnerability.[27, 28, 29] The effects of arsenic in well water
are associated with the rising cancer rates in India. It was
attempted to improve the biologically polluted, surface public
water supplies in India via drilling wells, but this resulted in high
arsenic public water. Arsenic is well connected to lung, bladder,
and skin cancer, but is a treatment for liver cancer that impairs the
mitochondria of cancer cells.[30, 31] A similar attempt to avoid
biologically contaminated surface water in Africa presented wells
with high fluoride content. How these toxic materials distribute in
the body organs and inner cell effect is important to immune
resistance. A dominate factor for metals retention and lymph node
build up is linked to chemical damage to two essential enzymes,
GSH and SOD, which convert metals to sulfides and excrete them
via the liver's bile pathway.

A metal oxide analogy from the mining industry is connected to


the mechanism of a controversial anti-cancer drug called laetrile.
In special mining practices, cyanide chemicals are combined with
insoluble metal oxides in a process called in-situ mining to form
extractable soluble metal products. The cyanide radical makes
metal oxides soluble via replacement of the oxygen radical. The
cyanide radical is unique in its ability to render metal oxides
soluble and the effect is used in mining for various metals and in
the electroplating process. Some enzyme processes mimic this
effect in human chemistry. Cyanide radicals are also drawn into
the lymph nodes, where the increased probability to react with
metal oxides may reduce their concentration. Lessening the lymph
node concentrations of insoluble metals then linked to the anti-
cancer effect by restoring lymph node cell function. It is suggested
that the biblical symbolism of turning to stone is a version of these
metal oxide ore minerals forming stone and impairing the lymph
system. The function of the immune system is central to the
control of cancer viruses, yet many studies are done with only the
cancer tumor cells in mind. The laetrile studies omit the immune
system effects and the metal loading effects in the lymph nodes.
Many B vitamins are also cyanide involved compounds that may
play a role in the metal detoxification process. Vitamin B-17 and
laetrile share the cyanide radical. Many grains contain B-17 and
over processing of foods tend to denature the natural beneficial
content. These vitamin processes are highly controlled by the GSH
enzyme's availability. Food processing and cooking often deplete
food of vitamins, enzymes, and cyanide compounds. In the last 50
years, the industrial dominance of metals in immune damage has
been replaced by more dominant chemicals, such as fluorides.[32,
33] This makes the effects of laetrile of lesser benefit in cancer
treatment. When fluoride enters the picture, damage to the GSH
and SOD process become dominate in the toxic metal retention
and ROS cellular damage process.

These simple observations began my thesis for the mechanism for


disease from the impact of toxic metals on cells in the early 1980s.
These observations qualify that many toxic metals are linked to
disease, now it remains to determine what quantity and what
processes are involved. It was observed that many toxic heavy
metals damage cells and activates immune system response. The
toxic cell damage triggers cytokine production and T-cells that kill
the damaged cell with hyper-oxygen products and trigger
macrophage's, which clean up the material and process it with
hyper-oxygen reduction chemistry.[34] The process results in the
accumulation of insoluble metal oxides in the macrophage region
of lymph nodes and can be seen in data from many toxic metals.
This biological accumulation of toxic metals is seen in the
research data for beryllium, silicon, plutonium, uranium, and other
insoluble metal oxides.[35, 36, 37] The effect is very clear in
research for lung damage from airborne toxic metals pathways to
lung that activate the lung inflammatory immune response. Toxic
materials in the lung activate the cytokine production of TNFa that
promote macrophage's, and can be seen with radiation and for
toxic metals. [38, 39, 40] Cytokine TNFa is directly delivered to the
mitochondria of cells and involved in apoptosis / necrosis.[41] The
mitochondria of cells play important roles in cell energy
production and hormonal and cytokine messaging.

Beryllium is the most detailed studied toxic metal and makes an


excellent example for the model of how a toxic metal activates the
immune system.[42] Beryllium workers can become sensitive to
beryllium and become sensitized to breathing it as determined by a
lymphocyte proliferation test. With any addition exposures
persons can acquire a fatal disease called chronic beryllium
disease, where the lungs cells are damaged by continual
inflammation. This is often mediated with steroid inhaler
medication. The disease is often mis-diagnosed as asthma initially
due to similarity of symptoms. Beryllium is taken into the lymph
nodes via the action of macrophages and as the lymph
concentration builds it triggers the lymph nodes to make T-cells
and B-lymphocytes in response to the toxic beryllium metal.[43] As
the concentration in the lymph nodes builds the insoluble metal
oxides retain long term and keep the local lung lymph system
triggered long term in the Th1 inflammation mode. In this Th1 State
the lung uses much glutathione for cell repair processes.[44] The
key element for beryllium disease is that beryllium-fluoride
compounds are the worst and this effect is tied to the issue of their
BeFx G-protein effects toward shutting down GSH and SOD
production within cells. The effect shuts down the prime clearance
enzyme for the beryllium and the cell ROS repair process. The air
pathway for beryllium used in the nuclear weapons business is a
well developed model for the immune activation process, and
shows a local process that is highly related to indicators seen in
CFS. Sensitization to beryllium compounds happens after cells in
the lymph nodes undergo blast cell transformation. It is clear that
beryllium concentrations of beryllium toxic metal in lymph nodes
set up the cytokine triggering of the immune system.

Beryllium and fluoride can combine either in manufacturing


processes or spontaneously inside the human body. Beryllium and
fluorine combine to form dangerous BeFx and AlFx compounds
that mimic G-protein triggers for human immune cells. The fluorine
atom is the most electronegative of the elements and when bonded
to these cell sites it cannot be undone. The vaccine business uses
a similar technique with vaccine adjuvants made from aluminum
[aluminum hydroxide (alum), aluminum phosphate], which forms
an AlFx complex that also mimic the G-protein trigger effects.[45,
46, 47] Here the effect seeks to program the lymph node dendritic
cells for long term memory of the vaccine and shift to Th-2
cytokine dominance. It is this effect that tends to lock on the
immune system memory and set up long term immune sensitivity
to metals like beryllium, and cause the immune system's tolerance
for varied pathogens to become negatively affected.

Man's industrial effects have produced a systemic shift in the


nature of the planet's processes that have resulted in a serious
problem for the immune system. The rise of HCl in the
environment has freed more aluminum into the food chain, and
man uses aluminum in many places from salt and baking powder
to vaccines and toothpaste. Fluoride has risen in the environment
and into man due to similar aspects. Fluoride in the body tends to
spontaneously interact with trace metals and can form the AlFx
compounds that trigger the cellular G-protein channels that shut
down GSH and SOD production. Man has also introduced dioxin,
PCB, Hg, DDT and other chemicals that have risen in man's body
and that interfere with the G-protein channel that regulates GSH
and SOD cell production. 80% of the drugs make in the US are
directed at controlling G-protein channels in cells that correct for
these toxic induced effects on GSH and SOD. It is a multi-trillion
dollar industry, where one system pollutes and causes illnesses,
which the other attempts to correct for the toxic induced damages
using pharmacology methods.

Other toxic metals cause the same problems at concentrations


lower than that needed to kill the cells directly, as long term
cytokine activation causes serious health problems.[48] As the
metals concentrations build in the lymph nodes the TNFa cytokine
causes necrosis of the macrophage and other lymph nodes cells
and continual generation of activated T and B cells. If the lymph
node concentrations get too high this disables the pathogen
destruction function of macrophages. Beryllium oxide particles
principally involves the local lung lymph nodes, but other toxic
metals that are more soluble and enter the body via air or food
chain can impair lymph nodes near the intestine or all the lymph
nodes at once. As the macrophages are disabled it leaves cell
fragment products scattered around the tissues that then bias the
system toward a Th2 response in the long term. Th2 modality
excretes IL-10, which further shuts down the macrophage function
and exasperates the effect. This leaves the body vulnerable to
inner cell viruses and other pathogens such as mycoplasma.

Metal prosthetic joints in the body further illustrate the effect of


metal particulate concentrating into the lymph nodes and this
triggering inflammatory cells that loosen the bone with high levels
of peroxides.[49, 50] Metal particles of less than 1 micron can be
carried into the lymph nodes via the macrophage's and
concentrate there.[51] The lungs are sensitive to many different
metal particles that can also set up the Th1 inflammation mode.
The effect is intensified if the particles from airborne exposure
have an acid like coating that is insoluble. Regulations have
attempted to mediate these toxic particle exposures, but has made
further poor choices. Gasoline refining eliminated lead in the
1980's because of this effect on the population and replaced it with
hydrogen fluoride (HF), which has even worse cumulative factors
and time integral dose effect on the macrophage function. Rising
levels of pesticides in food and water, rising industrial emissions
of HF all combine to contribute to effects of GSH and SOD
reduction leading to toxic metal retention that trigger the cytokines
and lead to CFS cytokine Th2 modality in the long term. The
worsening environmental metal effects can be seen in even the
surface waters of the Great Lakes with their increasing levels of
toxic metals that can damage the immune system, produce allergy,
increases susceptibility to disease, and autoimmune disorders.[52]
Even pollution of rivers from fluorides added to public water
supplies harm salmon.[53] Animals and man can be highly affected
by toxic metals and their phagocytosis cell ability severely
impaired by low concentrations of metals, while NK cell activity is
not impaired.[54] It is these poorly controlled pollutants that drive
increasing rates of CFS, cancer, and many immune linked
illnesses.

The key etiology of the toxic accumulation effect can be


anticipated by the function of oxygen based chemistry of
stationary macrophage's in the lymph nodes acting with the mobile
macrophage's carrying toxic cell material from around the body to
these local lymph zones. This is an often overlooked important and
key effect to have build up of insoluble toxic material directly in the
critical signaling network of lymph nodes that keeps the immune
system cytokine triggered and supply high oxidative stress
directly in the lymph nodes. This effect can lead to toxic metals
damaging the ability of the body to control pathogens and even to
rising viral presence in the body from endogenous and exogenous
sources.[55, 56] For air pollutants the lungs nodes are most
affected and for food and water pollution the stomach and
intestine nodes are the principle effect zones. A pivotal role is
carried by the proper function of the lymph node pathogen
regulation mechanism. Simple local inflammatory activation of the
immune system results in increased glutathione to aid in DNA
repair, and long term global activation results in depletion of
glutathione. Decreased levels of glutathione promote cell
apoptosis / necrosis. Toxic's that damage the liver cause a lack of
glutathione for DNA repair.

The importance of a cell organelle called the mitochondria was


better defined with respect to disease mechanisms in the mid
1980's with its critical role as the cell energy mechanism and the
source of ATP.[57] These organelles were small cells within cells
with bacterial like DNA that were vulnerable to oxidation effect,
metals, and oxidative halogens.[58] GSH plays a strong role in the
production of ATP and mtDNA repair from oxidative damage.[59,
60] CFS is well connected to lowered ATP levels.[61] Mitochondrial
damage is connected to nerve damage and aging.[62, 63]
Mitochondria is how the body converts stored fat into energy and
damage to these areas of cells is linked to weight gain and obesity
factors that are high in the US. Fluorides have the capacity to
affect the thyroid T-3 hormone production and modify cellular ATP
production throughout the body as well as diminish mitochondrial
numbers in cells.[64] Depletion of ATP is connected to the Th1 to
Th2 switch seen in CFS and other diseases.[65] High
concentrations of toxic metals and fluorides in the lymph nodes
will highly impact the mitochondria of these cells. This leave little
doubt that the worst case for mitochondria damage due to toxic
concentrations is the lymph nodes and that this process is directly
connected to CFS and other immune dysfunction illnesses.

The role of GSH and SOD and the involvement with mitochondria
and ATP explains the issue of "radiation hormesis." Radiation
hormesis was seen in areas like Japan after the bombs were
dropped and it promoted more rapid tree growth as shown by tree
growth ring data. The increase in radiation in the area promoted
the cells and its feedback systems to call for more SOD to be
produced to handle the free radical damage effects. SOD and GSH
go hand in hand in plants and to increase SOD the GSH levels are
naturally increased as well. The high GSH levels cleared the toxic
metals from the cells to greater extents that promoted less
destructive mitochondria interaction from the metals and greater
amounts of ATP generation. The higher levels of ATP promoted
more rapid cell growth and is the interaction mechanism for
radiation hormesis.

The enzymes GSH and SOD are also the prime clearance and
repair mechanism for the brain. Altered levels of GSH and SOD are
tied to all of the mental illness problems, and also to factors of
Alzheimer's, Parkinson's, and etc. It is well known that the metal
lithium is used in the treatment for mental illnesses and what the
lithium drugs promote is higher levels of SOD being made in the
cells to repair the ROS damage to cells. The ROS damage to cells
stems from toxic metals like mercury or the combination of
aluminum and fluorine forming the AlFx type G-protein. The lithium
atoms are believed to interact with other metals in the G-protein
channels that direct the production of SOD by the cells. This
process of lithium on SOD appears to not up-regulate the GSH
levels needed to clear the brain of the toxic metals, so the lithium
drugs have to be used often to control the mental illness.

One of the prime CFS symptoms is that of frequent diarrhea and


this again is associated with the levels of GSH and SOD in the cells
of the gut walls. Persons with CFS and GWI generally have
impaired levels of GSH and SOD enzymes. This effect is made
much worse in the local area of the gut when these persons drink
excessive levels of sugar-laden colas or other sugary foods.
Processed sugar is a GSH and SOD antagonist and this promotes
high levels of free radical damage to the cells of the gut wall. The
high rates of free radical damage causes the gut cells to sluff-off
with lots of water much as a blister type effect from a burn. The
same type effect occurs from the radiation intestinal death effects
for acute radiation doses that make the same levels of ROS
damage to the cells. The extreme damage from the high levels of
ROS damage also cause damage to the blood vessels in the colon
and cause bleeding hemorrhoid problems and loss of blood and
essential trace metals. The high levels of ROS damage in these
local cells also damages the Mn dependent 2-5A RNase L enzyme
resulting in lots of local cells having active viral infection problems
that involve the local lymph system. The problems of reduction in
the cell production of GSH and SOD well define the mechanism of
problems like persistent diarrhea and even the issue of loss of
cognitive abilities from similar problems in the brain.

These intestinal effects are even spoken of in the Biblical Narrative


with recognition of guts like stinking sulfur bogs. The Biblical
Narratives also speak to the use of the plant called "Aloe Vera" as
a type of medicine. Aloe Vera has very high levels of both the
enzymes GSH and SOD. The high levels of SOD in the plant is why
it is often used so effectively to treat burns, as it corrects for the
free radical damage effects to cells. Persons seeking to correct for
the free radical damage of their intestinal tract often consume Aloe
Vera juice.

Another interesting association from the free radical effect


produced from the loss of GSH and SOD from toxic materials
exposures is that of nitric oxide production being increased.
Rising levels of nitric oxide (NO) in the tissues promote sexual
arousal and this is the effect produced by the drug called "Viagra."
When the Manhattan Project was begun in the 1940s the plants in
Oak Ridge had such a problem with workers having sex on the job
that all the plants office and lab area frosted glass were changed to
clear glass to cut down on these problems in the work force. The
NO effect was particularly strong at the plants that released large
amounts of hydrogen fluoride (K-25 and Y-12), that cuts GSH and
SOD production via the combination with aluminum forming the
AlFx G-protein. There is extensive evidence from the Manhattan
Project and from the US Dept. of Energy (DOE) on the problems
associated with toxic releases affecting the cellular levels of GSH
and SOD leading to illnesses.

Oak Ridge is an interesting place to study the effects of GSH and


SOD suppression via occupation chemical exposures, as it has so
many toxic materials that fall into this class of enzyme damaging
chemicals. Oak Ridge lost some 2 million pounds of mercury from
its lithium operations and this affects both workers and a large
area into which the mercury escaped. Oak Ridge lost huge
amounts of PCBs into area creek and burned PCBs to release
dioxin. Oak Ridge and the local TVA power plants released huge
amounts of hydrogen fluoride into plant and town areas. All of
these pollutants are well known to damage the production of GSH
and SOD, and often the workers in specific areas have health
problems from the particular workplace chemical toxic of interest.
The collective sum of all these chemical agents that damage GSH
and SOD is the reason the Oak Ridge area is highly affected by
chemical injury problems.

Toxic metal and fluoride releases are connected to the Oak Ridge
K-25 gas diffusion plant and a number of workers were noted to be
affected by symptoms similar to chronic fatigue syndrome. Gas
diffusion plant workers with CFS like symptoms number in the
hundreds. The K-25 gaseous diffusion plant lost huge amounts of
toxic hydrogen fluoride (HF) to the air of the plant and region and
was discovered by questioning workers about processes and
releases. Other HF releases from the X-10 "Molten Salt Reactor
Experiment" and the Y-12 UF-4 "Salt Shop" operations provided
similarly affected workers and correlation to HF toxic effect due to
cumulative low level exposures. The large losses of the K-25 plant
exposed not only workers, but also downwind residents of the
plant to fluorides. Fluorides were highly suspected as area pine
trees, which are very vulnerable to fluorides, were showing impact.
Fluorides damage the GSH and SOD enzymes of pine trees and
acts much like dioxin, which works via this enzyme process to
create ROS damage in plants. There was both air / lung pathway
effects, soil contamination / food pathways into the
gastrointestinal system, and ground and surface water pathways
into communities. These pathways for fluorides connected them
with the CFS like symptoms and asthma seen in workers and
communities. Asthma is directly connected to reduced GSH and
SOD. The workers had high levels of calcium that is indicative of
fluoride exposure.[66] They also had high retention of metals and
high porphyrin. Fluorides tend to be accumulated (integrated) over
a lifetime and the same net dose occurs from a ten-unit dose over
one year or that of a one unit dose over ten years.

Fluorides cause some of the worst damage to the immune system


with very low concentrations. Industrial fluoride emission in
Germany in the late 1800s was perhaps the first chemical to
produce worker and community health problems. Fluoride is
connected to renal stone formation via insoluble calcium fluoride
formation, much like what happens with metals in lymph
nodes.[67] Veterinarians warn against using fluoride toothpaste on
animals and with the knowledge of the lymph node effects fluoride
tooth pastes and fluoridated public water become dangerous to
public health. Industrial fluoride emission was linked to asthma
and to arthritis.[68, 69, 70] Fluoride workers also show their
cytokine response biased toward the Th2 in the long term.[71]
Fluorides impair the macrophage's at very low concentrations and
the effect is strongest in the lymph nodes from the insoluble
product effect that is often combined with metals and free radical
synergy effects.[72, 73, 74, 75] Fluorides cause swelling of the
mitochondria indicating damage to ATP processes.[76] Hydrogen
fluoride sets off inflammation in lungs.[77, 78] Fluorides toxic
effects set up the same mechanism as seen in the beryllium model.
Fluorides are pulled into the lymph nodes and the affinity of
fluoride for calcium produces an insoluble precipitate that is
similar to the effects caused by the insoluble metals. The effect
sets up TNFa and hyper-oxygen damage that locally lowers
glutathione in the lymph cells. TNFa promotes viral RNA
replication. Increasing viral infection in the type I macrophage's
promotes more TNFa and this is multiplied by the repeating effect
of cells in the lymph system. This activation of the Th1 process
also sets up a switch to Th2 mode slowly as the macrophage's
stop working and foreign cell products accumulate in the tissues
that trigger the Th2 mode. Th2 suppressor effects on Th1, impaired
ATP, glutathione, and other effects contribute to the mode
switch.[79] Th2 mode involves IL-10 that further depresses and
shuts down the macrophage action and locks in the Th2 mode.

This lymph node / mitochondria impact thesis became a toxic


pathway mechanism for immune dysfunction in 1986 that
explained the process for all immune linked diseases and even
aging / longevity factors. The thesis was that insoluble toxic
material, metals and fluoride predominately, accumulated in the
lymph nodes and disabled this pathogen destruction mechanism
and the toxic presence set up a continuous cytokine response in
the lymph system that keeps the immune system triggered and
allows pathogen presence.[80] In the early stages of viral
activation, a Th1 profile with TNFa is often seen and in a normal
immune response these levels control the virus.[81] Internal cell
viruses such as EBV, CMV, HHV-6, mycoplasma, cancer viruses,
HIV, and etc. can run out of control with a system biased toward
Th2. The toxic material concentrations triggered the inflammation
effects that cause cell apoptosis, necrosis, consume glutathione,
etc. Add in pathogenic components and the outcome is further
modified. HIV spends cell energy and promotes TNFa and IL-10,
which helps in the demise of T-cells as the disease progresses due
principally to the loss of macrophage activity from the IL-10.[82]

The 1991 Gulf War exposed thousands of veterans to various toxic


materials that have long retention in the body and set up the same
conditions as the toxic metal effects in the lymph nodes. Many of
these Gulf War Veterans experience the symptoms of CFS and
multiple chemical sensitivity (MCS).[83] Gulf War persons were
exposed to HF via hydrolysis of sarin and soman nerve gases, to
glutathione depleting insecticides and oil emissions, and to toxic
metals from vaccines (Al and Hg) and DU. They also are biased
toward the Th2 profiles because of the similarity to the industrial
pollution that drives CFS. They were exposed to toxic metals in the
form of DU and mercury preservative in Th2 promoting vaccines.
They were exposed to halogens in the form of bromine from PB
tablets, excessive chlorides from water treatment, various
pesticides, and fluorides from nerve gases.[84] Recent studies
have shown that those exposed to chemicals have brain
damage.[85] CFS affected persons also show brain damage.[86]
Gulf War Syndrome (GWS) persons also have fibromyalgia similar
to CFS.[87] The pain is driven by loss of sodium channel and ATP
in nerve cells, and the calcium rich myelin of nerves is high in
fluoride and metal retention that drives this effect. It is not a single
chemical factor analysis that solves the illness toxic driven
equation, but various toxins acting in the same pathway to disable
the lymph system's critical enzymes (GSH, SOD, RNase L) that
best explains GWS. This war was the toxic equivalent of hell that
dosed many there with 30 years of industrial and environmental
pollutants that aged them with health effects to 60 years old
females. There is one central etiology mechanism involving
chemical damage to GSH and SOD levels leading to increased
toxic metals retention in the lymph nodes and cells triggering the
cytokine response. The immune dysfunction comes from multiple
contaminates acting via a common mechanism that allow varied
illness outcomes as determined by exogenous and endogenous
viral predisposition's and other opportunistic pathogens.

Food processing and preparation play a strong role in the vitamin


and free radical effects in the intestine that affect these cells and
their local lymph nodes. Foods processing and cooking destroy
most of the nutrients in food. Raw and uncooked living vegetable
foods supply more vitamins, as compared to cooked vegetables or
fried food.[88, 89, 90] Cooked food has long been associated with
delivery of free radicals from foodstuffs to the stomach and
intestines and this effect causes some excess production of white
blood cells, called digestive leukosis. High temperature fried food
supplies the most free radical content and highest toxic exposure
due to bio-concentration in the food chain. Raw and uncooked
foods don't produce these free radical effects and provide better
delivery of enzymes and vitamins, as well as fiber to detoxify the
system. Raw food diets aid in mediation of CFS, cancers, and other
immune illnesses because of these vitamin and reduced free
radical factors. Raw vegetables supply glutathione that helps to
keep the metals clearance of tissues and brain working to avoid
the build up of toxic metals due to increased biological half-life of
the toxic metals from glutathione impairment.

The raw food verses cooked food is also involved with the biblical
issues of Genesis. Animal foods add a level of bio-concentration of
toxic material from airborne contamination of the animal food
chain. Cooking vegetables or animal products produces free
radicals from the pollutants and pesticides that can retain more
easily in the body. Vegan diets also make the intestine more basic,
which results in less immune activation and less absorption of
toxic metals. A shift of the blood pH toward acid contributes to
higher toxic metals retention because it impairs the rate of metals
clearance by the kidney. Because of these effects, the raw
uncooked vegan diet is connected toward effective intervention for
fibromyalgia, rheumatoid, heart, and cancer.[91, 92, 93, 94, 95, 96]
Vegan diets also alter the fecal bacteria levels and bacterial fatty
acid generation.[97, 98] The toxic load and nutrient supply in the
intestines is highly associated with immune illnesses and long
term effects result in leaking gut syndromes. The quick heating
pasteurization of milk also produces toxic effect.[99] Raw food
diets promote illness recovery. One must acknowledge that most
produce in the US is still short of the needed beneficial trace
metals that have been depleted by poor farming methods, even in
the organic farming realms. Serious persons should shift diets to
include sea vegetables to enhance their essential trace metals
nutrients.
Raw and uncooked vegetables promote better coupling of the
human nutrient absorption systems for uptake of the essential
trace metals (selenium, zinc, copper), which help to form the
immune repair system with enzymes (GSH, SOD, RNase L) and
also helps to remove fluorine from the body and bone mass. Soils
in the US have become increasing depleted of these essential trace
metals due to acid rain and over-farming without replacement of
these metals. Glacial and volcanic effects placed these essential
trace elements there, and the effects of industrial acid rains
remove or worsen their availability to the food chain. The depletion
of these trace metals sets up a rise in the rate of fluorine retention
in the bone masses, where the immune system cells are formed.
This effect starves the immune system cells formed in the bone
mass of the essential metals needed for proper cell DNA repair and
resistance against pathogen infections. This effect of fluorine
rising in the bone mass is directly connected to the HIV infection
process via loss of manganese. The effect also sets up the
shrinkage of the thymus gland from these metals depletion effects
on the immune cells.

Plant cells and enzymes closely match those in animals and


humans, and prove useful in helping return some of the enzyme
functions in fluoride affected persons. It sometimes takes 10 years
of toxic exposures from materials like fluoride to set up the cellular
stress conditions that make for CFS. It also takes around 10 more
years to turn around the bone burden of fluoride and get the
cellular damage and enzyme processes back up to near normal.
The bone retention of fluoride sets up a very long recovery period
for those that chose to successfully modify their nutrition and
healthy eating habits.

There is more that supports the conclusion that the toxic loading
in the lymph nodes shut down the monocytes / macrophage's and
is the pivotal problem with HIV.[100] HIV transmission and
infections appear most prevalently in the intestine and its local
lymph system. Here the toxic load of the food and water chain
come into play with cytokine factors and lymph node effect. The
intestinal region is the most affected from cooked food free
radicals and the uptake of toxics in the food and water chain.
Regions in Africa with the highest fluoride in well water and food
have the largest problem with HIV transmission.[101, 102, 103, 104,
105, 106] Many of the high fluoride regions follow the east African
Rift Valley zone that is lined with volcano and seismic zones. In
many of these areas the persons have frosty white teeth from
dental fluorosis and many are disabled by age 40. This is
significant because fluoride toxic effects set up cytokine profiles
that HIV transmission and growth require with TNFa in the lymph
nodes and loss of macrophage / monocyte performance driving
Th2 bias in the intestines and body as a whole.[107] The TNFa
cytokine promotes the viral proliferation of HIV.[108]

The rise of fluorides in the body is the principle trigger for HIV
infections due to the fluoride in the bone mass upsetting the
beneficial trace metal concentrations for cellular enzymes. HIV
affects the 2-5A RNase L enzyme pathway in cells, so the fatigue
associated with CFS is altered when HIV enters the equation.
Fluoride in the bone mass robs the immune cells that form there of
the essential metal manganese that is needed to block reverse
transcripion of HIV in cells.[109] This effect sets up the high rates
of infectivity in the lymph systems immune cells by HIV, with the
virus setting up the higher rates of TNFa that promote rapid
growth. HIV is highly sequestered in the lymph nodes of the gut
region, where the highest exposure due to fluorides and metals
affects the lymph nodes and bone mass. The high level of mtDNA
damage from metals promotes excessive NO production and
damage factors.

HIV, as it infects more cells in the body, sets up its own cytokine
signatures that become the additional factors on top of the toxic
effects that keep it from being regulated. HIV also produces IL-10,
which suppresses macrophage action.[110] Impaired monocyte /
macrophage function is highly associated to HIV progression and
pathology for other viral infection.[111] Rising IL-10 levels that
suppress macrophage action directly connect to the loss of CD-4+
T cells.[112] These T-cells are preferentially attacked due to the
gp120 bonding site on T-cells that promotes HIV cellular
transmission into these cells. The early AZT treatment acted more
to destroy cell mitochondria than to oppose HIV replication.[113,
114] HIV always involves activation of other viruses and these can
worsen the cytokine activation and AIDS progressions.[115] HHV-7
is often activated in HIV infected persons and the lymph nodes are
seen to be the site of reactivation.[116] This leaves little doubt that
the failing lymph node effects play a central role in HIV
proliferation. This can also be seen in the case of cancer viruses
where the failing lymph node cellular regulation allows cancer
metastasis of lymph nodes and helps to spread the cancer viral
infection. The same effect also spreads HIV and other viruses,
rather than regulate and destroy them. The HAART treatment for
HIV lowers the AZT dose and avoids using TNFa mechanisms that
promotes HIV transcription and this has almost rendered HIV a
chronic survivable disease, with many having near normal life-
span with non-detectable HIV in their blood. The principle problem
with HIV and the immune system is that TNFa triggers it and loss
of manganese sustains its replication. The key factor is
macrophage and monocyte enzyme performance for regulation of
HIV, with the exposure to fluorides dominating this performance in
many countries.

The dominate effects of the fluorine atom's affinity toward metals


in the body is easily established via the fluorine deposition rates in
the bone mass and other calcium rich tissues. Fluoride absorbs
into the calcium phosphate or hydroxyapatite of the bone mass, as
well as the hydroxyapatite in the pineal gland, where the serotonin
/ melatonin hormone process is antagonistically affected.

Fluorides rise in the bone mass contributes to the depletion of


selenium needed for making the enzyme Se-glutathione and the
copper and zinc needed to produce Cu-Zn superoxide dismutases
or SOD. [117, 118, 119] Fluoride antagonism toward selenium also
upsets the thyroid autoimmune hormone process. [120, 121] The
depletion of these enzymes contributes toward the retention of
toxic metals (Hg, Cd, Al) from acid rain effects on soil and food
chain uptake. The retention of these toxic metals damages the
cellular mtDNA and ATP production levels of cells due to the
mutated enzyme RNase L. Fluoride's affinity toward beneficial
trace metals damages literally 100s of enzyme processes that lead
eventually toward poor health, illness, and death.

GSH or Se-glutathione supplies a sulfur atom for toxic metals to


bind that renders to them the same solubility factors as were
dominate when the Earth's metals were formed from volcanic
dominated sulfur releases. The effects of HCl dominated Acid Rain
are upsetting the soils metals speciation and increasing the levels
of metals availability from the change from the sulfur domination.
This results in damage to the Cu-Zn SOD as metallic elements like
manganese compete against the copper-zinc. The combination of
rising fluoride and acid rain set up loss of GSH and change of
metals speciation for the SOD that sets up the problems leading to
prion and mad cow problems. Chemicals like DMSO that supply
sulfur atoms to bind metals deep into tissues and the brain have
been shown to reverse the manganese amyloid plaques associated
with prion diseases.

The UV and Ozone Hole problem has severely upset the global
sulfur cycle upon which the Se-GSH system depends for adequate
sulfur. The ocean plankton levels have been reduced which causes
an increase in the global CO-2 levels and a loss of DMS that is
formed from the process that regulates cloud formation. The loss
of cloud seeding by the DMS causes the bulk of the global
warming problem via loss of reflective clouds for the IR radiation
reflection. Plankton are the world's largest CO-2 sink and the
largest system that places sulfur into the human and animal food
chain. When the DMS is impacted by UV radiation, it lowers the
DMS, DMSO, and MSM pathway into the human chain to supply the
levels of sulfur needed by GSH in the liver and cells to remove
toxic metals from the body. This systemic loss of sulfur stores
causes a metabolic acidosis and hyperthyroid shift in the
population that results in CFS and many other immune illnesses.

Mad Cow or BSE is characterized by plaques with high levels of


manganese. The mitichondria when under toxic stress makes Mn-
SOD, that is the reason for these plaques and tangles in the brain.
The high levels of toxic metals in the brain due to loss of GSH
stimulates the increased Mn-SOD variant. The mitochondrial
processes taking up all the cellular manganese depletes that
needed to make the enzymes to protect the cell from internal viral
activation. Viral protective enzymes like 2-5A RNase L require
manganese to do their job as does interferon that protects cells
from viral infection.

The fluoride damage to the enzyme processes like Se-glutathione


(GSH) and others like it set up factors that result in retention of the
toxic metals such as mercury, cadmium, lead, nickel, and others.
[122] This results in the appearance of persons with high fluorine
effects having heavy metal poisoning. The fluoride effect driving
the retention of metals like mercury add dramatically toward the
nervous system damage and loss of T-cells. The loss of GSH and
other clearing enzymes results in a see-saw like effect where the
beneficial trace elements such as selenium, zinc, magnesium, and
copper are depleted and the harmful metals like mercury, lead,
cadmium are increased. [123, 124, 125] Such observations often
lead to chelation type therapy, which needs to be done carefully
with reintroduction of beneficial mineral cocktails and keeping
GSH levels preserved or increasing. This type effect is readily seen
in the DOE K-25 gas diffusion plant workers exposed to HF
associated with Oak Ridge, Tennessee.

Hydrogen Fluoride (and other fluoride compounds) taken into the


body will spontaneously form aluminum compounds that are
similar to the pesticide called cryolite. Cryolite insecticide works
by upsetting the trace metals metabolism within cells. Every man,
woman, and child on this planet is being affected by this chemical
insecticide forming inside the bodies and damaging their metals
metabolism and in the long term. It is a dominant effect that results
in death by a process like the novel called "Arsenic and Old Lace."
Placing a safer metal into the blood circulation by adding titanium
dioxide to the food chain is being used to offset this formation of
the Al-F compound effect on human and animal health.

The reduction of GSH for removing toxic metals via the bile
pathway shifts toxic metals into the kidneys and slows the
clearance of all toxic metals due to the pH effects on clearance of
metals by kidney cells, which promotes blood pH shifts toward
metabolic acidosis. Kidney damage and heart damage go hand in
hand because of this relationship with build up of toxic metals
within the body due to loss of GSH levels. Heart disease and
kidney disease always go hand in hand, as high blood pressure
from arterial disease causes renal failure. The cholesterol build up
on arteries is directly associated with toxic metals / fluorides
adhering to the arterial walls and the cholesterol repair mechanism
attempting to repair the problems. These are processes that are
the normal outcome of old age, but the onset of these old age
factors is a direct function of the GSH impairment from both
natural and industrial exposures. Cancers and the neurological
outcomes are the outcome of the same process of loss of GSH and
SOD with age due to environmental accumulation.
Heart disease yields an interesting association with salt, because
doctors recommend to stop to control blood pressure. The
problem with table salt is that it has aluminum silicate added to
keep it flowing. The blood has a high concentration of salt on the
order of seawater concentration, so dietary salt is not going to be
what causes the high blood pressure reaction. Aluminum will
combine with fluoride in the blood making the AlFx compound that
lowers GSH and provokes the build up of metals in heart cell
mitochondria and high rates of ROS production. The
administration of nitro-glycerin for heart pain promotes the
production of SOD in the heart cells and the neutralization of the
ROS within the cells. A very similar effect happens in the brain
with metals accumulation that causes increased ROS and the
metal lithium being used to trigger increased SOD to counter
mental disorders. Ending the use of salt with aluminum hydroxide
acts to lower the kidney stress factors from toxic metals
accumulation and lowers blood pressure. This effect is very telling
of the sensitivity of the body to aluminum / fluoride affecting GSH
levels.

The aluminum in salt and aluminum in baking power observations


began to break the secrets of CFS in the 1980s at ORNL. CFS and
GWI symptoms like "night sweats" are easily explained once one
finds that the AlFx G-protein effect mimics the TSH hormone
generated by the pituitary gland. When the AlFx levels formed from
the foods a person consumed during the day exceed the levels of
TSH hormone from the pituitary then the cells can't power down at
night from the dynamic control of the mitochondria by the pituitary
TSH and thyroid process. Likewise, other symptoms like inability
to sleep or get rested sleep could be explained. What they were
experiencing was the effect of hyperthyroidism, which involves
extreme tiredness, inability to sleep, and loss of GSH. It is this
running full power 24 hours a day that exhausts the supply of GSH
in cells. The body intentionally powers down at night to replenish
GSH and do cell repair processes and this cannot happen when
TSH mimic compounds like AlFx take control over thyroid
hormone levels.

The characteristics of the AlFx compound in the mimic of TSH is a


very destructive method, as the fluorine component of the
compound causes a bond that does not clear as does the normal
TSH. The highly electronegative effects of fluorine causes the AlFx
to bond long term to receptor sites of cells. This process highly
upsets the normal pulse and amplitude processes of the pituitary
control via TSH on the thyroid hormone generation. The
characteristics of the AlFx compounds to form almost permanent
bonds to the receptor sites for TSH highly damages the cellular
repair processes and GSH levels within cells. The heart of the
problems with the AlFx compound is that it doesn't follow day and
night variation of normal TSH and the fluorine component of AlFx
forms a nearly permanent bond to TSH receptor sites, which
causes severe thyroid hormone regulation problems. This is why
the AlFx compounds play a dominant role in cellular GSH
depletion throughout the body and human health.

One of the problems in detection and diagnosis of this effect is


that doctors will only run simple TSH tests for thyroid function,
which will often show up as low when the AlFx compounds are
driving the over production of thyroid hormones. When the doctor
sees a low TSH he declares the person as having hypothyroidism,
when just the direct opposite is the case. The doctors need to run
the "Total Thyroid Panel" type test to get a better idea of what is
happening with T-3 and T-4 and see if things like AlFx and other
thyroid affecting chemicals are causing problems. This is part and
parcel for how the AMA doctors avoid exposing the industry that
poison people via this process.

The American population has been poisoning itself with this low
level of aluminum and fluoride in the food chain. The incidence of
common colds, flu, and fever are strongly correlated with high
much flour and salt with aluminum content enters their diets. The
duration of colds, flu, and fever was correlated with diet and the
time of clearance of these materials from the gut. This effect was
similar to the night sweat effects seen in CFS and GWS, which
stemmed from the highly abnormal thyroid hormone mimic effect
of AlFx compounds. It was found that fever and sudden recovery
would trace the elimination of these food materials from the gut. It
was also found that persons that consumed too much aluminum in
flour and salt exhibited higher rates of heart problems. They
exhibited early brown spots on their skin similar to liver spots that
warn of liver damage, and they had degenerative mental problems
that resembled ADD and dyslexia. It became clear there were ways
to avoid colds and flu, and that Americans have been poisoning
themselves chronically from the rising Al and F effect in their food
chain.

Environmental legislation has slowed some of the toxic effects


from the chemicals that damage GSH and SOD enzyme levels. The
Government has not been clear as to why DDT, PCB, Dioxin, and
varied chemicals have been banned, but the major reason has
been to slow down the toxins that damage GSH and SOD enzymes.
It is a case of not enough or soon enough, as the problems
continue to mount. Eating fish has been suggested to be limited to
once a week over the same problems with mercury. The current
trend is that industry is being protected, while the citizens have
been increasing affected. The systemic health problems due to
these many chemicals and damage GSH and SOD enzymes show
up clearly in areas like Oak Ridge and the HF toxic releases and Al
vaccine problems from the Gulf War.

The analysis of the trace metals factors leads again to the metals
speciation shifts due to fluorine's presence in the body and bone
marrow. Here the issues of the Old World belief in the trace metal
copper being linked to eternal life come into play. Copper is
grouped with silver and gold in the valence column of the Periodic
Table. Examination of the elemental gold reveals that in its Gold +0
metallic state that it very non-reactive with most ions, with
exceptions being mercury via the amalgam effect and fluorine due
to the high electronegative effect. Gold colloid particles would
become a sort of "teflon bullet" and be able to migrate past brain
and cellular membranes and become effective in the removal of
mercury from the tissues and brain, as well as aid in the removal of
fluorine itself. This concept stems from ancient alchemical texts
and the science arts from Egypt and plays a strong role in early
religious beliefs and practices leading toward higher brain
functioning and longevity. Similar concepts called "acupuncture"
for pain therapy using metallic needles of copper, silver, and gold
inserted into tissues are associated with the same fluorine and
mercury removal concept. These concepts are applicable toward
treatment for CFS and other fluorine induced illnesses.

It is these factors that set the stage for the appearance of CFS in
volcanic zones like the Lake Tahoe region, as found by Cheney.
The loss of ATP, the depletion of GSH, and the appearance of
multiple endogenous viruses in the body are the direct result of
the synergistic effects of rising fluorides on the beneficial trace
metals needed for the proper functioning of the human immune
system. Fluorides in the body cause the loss of the beneficial trace
metals required for proper enzyme protection of cells, and the rise
of the toxic metals that damage mtDNA and ATP production. The
effects set up increased rates of cellular damage from NO and
other oxidation effects (ROS). The net result is called Chronic
Fatigue Syndrome. The mechanism is common too not only CFS,
but to HIV infectivity and the process leading to cancers. Fluoride
causes acidosis of the body and with this comes even greater loss
of ability to clear toxic metals by the kidneys and the high levels of
metals damage that set up cancer by loss of immune system
regulation.

This analysis process leads to a new more inclusive model for


total oxidative stress for cells that involves radiation induced
oxidative stress directly, chemicals that alter thyroid hormones
and lower GSH and SOD, and exposures to toxic metals that set up
high rates of mitochondria malfunction and production of ROS.
The total oxidative stress model for cells predicts that the AlFx and
mercury interaction as thyroid hormones and the GSH and SOD
depletion with age dominated pre-industry health effects. The
postindustrial effects must include the PCBs, DDT, Dioxin, Hg, and
others that similarly alter thyroid response and reduce the GSH
and SOD protective enzymes. When the "Total Oxidative Stress
Model" is used, which includes the loss of GSH and SOD and its
clearance mechanism for toxic metals in the body, then the
biological sciences correctly models the cellular protective
enzyme health mechanism. This process then accurately models
the failure mechanisms for CFS, Cancer, AIDS, MS, BSE / mad cow,
Scrapie, Alzheimer's, Kidney / Heart Disease, and etc.

In Conclusion, immune system diseases are caused by poor


environmental, industrial, and agricultural practices bringing toxic
material into contact with the air, food and water chain leading to
animals and humans. The principle toxic offenders are fluorides
(HF) and its halogen family relatives, closely followed by toxic
metals (Hg), and chemicals (dioxin, PCB, DDT) that impact GSH
and SOD. The leading damage vector is via GSH and SOD enzymes
leading to toxic metals damage to the cell mitochondria of lymph
node macrophage cells of the Th1 driven cellular defense immune
system. The failing of the Mn dependent RNase L enzyme leaves
cells infected with the pathogens seen in chemical plant workers,
CFS, GWS, MCS, and HIV. The critical or processional pivotal event
leading to this is the accumulation of toxic products in the lymph
nodes and fluoride in the bone mass that robs the immune cells of
essential DNA and mtDNA repair enzymes. This effect produces
the net aging effect of the body, as it sets the net cellular
degradation from unregulated pathogens. The effect is largely
being driven by the loss of the Global Sulfur Cycle and the DMS,
DMSO, and MSM availability to the food chain leading to not only a
rise in CFS, but all immune illnesses globally.

References:

1. Kuby, J., (1994) Immunology, W. H Freeman and Co., ISBN 0-


7167-2643-2 p 297-321.

2. Petricevich, V. L., Teixeira, C. F., Tambourgi, D. V., Gutiérrez, J.


M.,. (2000) Increments in serum cytokine and nitric oxide levels in
mice injected with Bothrops asper and Bothrops jararaca snake
venoms. Toxicon, 2000 09, 38: 9, 1253-1266.

3. CFS Radio Program February 28th, 1999 Roger G. Mazlen, M.D.,


Host withDr. Paul Cheney, WEVD Radio New York City,
Transcribed by Carolyn Viviani.

4. South Lake Tahoe Public Utility District, 1999 Annual Water


Quality Report.

5. Manningham, R., (1750) The symptoms, nature, causes and cure


of the febricula or little fever: commonly called the nervous or
hysteric fever; the fever of spirits; vapours, hypo, or spleen. 2nd
edition. J Robinson, London, pp 52-53.
6. Hernán1, M. A., Zhang, S. M., Lipworth, L., Olek, M. J.., Ascherio,
A., (2001) Multiple Sclerosis and Age at Infection with Common
Viruses, Epidemiology 2001;12:301-306.

7. Ablashi, D. V., Eastman, H. B., Owen, C. B., Roman, M. M.,


Friedman, J., Zabriskie, J. B., Peterson, D. L., Pearson, G. R.,
Whitman, J. E., Frequent HHV-6 reactivation in multiple sclerosis
(MS) and chronic fatigue syndrome (CFS) patients. J Clin Virol,
2000 05, 16: 3, 179-191.

8. Valentine, W. N., Paglia, D. E. (1980), Syndromes with increased


red cell glutathione, Hemoglobin, 1980 01, 4:5-6, 799-804.

9. Parke, D.V., (1982), Mechanism of chemical toxicity-a unifying


hypothesis, Regul Toxicol Pharmacol, 1982, 12, 4, 267-286.

10. Slater, A. F., Stefan, C., Nobel, I., Van den Dobbelsteen, D. J.,
Orrenlus, S., (1995), Signaling mechanisms and oxidative stress in
apoptosis, Toxicol Lett, 1995 12, 82-83, 149-153.

11. Lang, C. A., Mills, B. J., Mastropaolo, W., Liu, M. C., (2000),
Blood glutathione decreases in chronic diseases, J Lab Clin Med,
2000-05, 135:5, 402-405.

12. Pawowicz, Z., Zachara, B. A., Trafikowska, U., Maciag, A.,


Marcheluk, E., Nowicki, A., (1991), Blood selenium concentration
and glutathione peroxidase activities with breast cancer and with
advanced gastrointestional cancer, J Trace Elem Electrolytes
Health Dis., 1991 12, 5: 4, 275-277.

13. Tarp, U., Hansen, J. C., Overvad, K., Thorlling, E. B., Tarp, B. D.,
Graudal, H., (1987), Glutathoine peroxidase activity in patients with
rhumatoid arthritis and in normal subjects: effect of long-term
selenium supplementation, Arthritis Rheum, 1987 10, 30: 10, 1162-
1166.

14. Hazelton, G. A., Lang, C. A., (1980), Glutathione contents of


tissues in the aging mouse, Biochem J, 1980 00, 188: 1, 25-30.

15. Hussain, S., Slikker, W. Jr, All, S. F., (1995), Age-related


changes in antioxidant enzymes, superoxide dismutase, catalase,
glutathione peroxidanse and glutathione in different regions of the
mouse brain, Int J Dev. Neurosci. 1995 12, 13: 8, 811-817.

16. Batt, A. M., Ferrari, I., (1995), Manifestation of chemically


induced liver damage, Clin Chem, 1995 12, 41: 12 Pt 2, 1882-1887.

17. Naito, Y., Yoshikawa, T., Boyu, Y., Fujii, T., Masui, Y., Tanaka,
Y., Fujita, N., Yoshida, N., Kondo, M., (2000), Protective role of
glutathione against nitric oxide-induced necrosis in rat gastric
mucosal cells, Aliment Pharmacol Ther., 2000 04, 14 Suppl 1: 145-
152.

18. Peterson, J., Proc Natl Acad Sci., March 1998, Immunology
Magazine.

19. Suhadolnik, R. I., Peterson, D. L., O'Brien, K., Cheney, P. R.,


Herst, C. V. T., Reichenbach, N. L., Kon, N., Horvath, S. E., Iacono,
K. T., Adelson, M. E., De Meirleir, K, De Becker, P., Charubala, R.,
Pfleiderer, W., {1997) Biochemical Evidence for a Novel Low
Molecular Weight 2-5A-Dependent RNase L in Chronic Fatigue
Syndrome, Journal of Interferon and Cytokine Research, 17:377-
385 (1997).

20. Sobol, R.W., (1992) A structural and functional characterization


of the 2-5A synthesis/RNase L antiviral pathway and its role in HIV-
1 regulation: the pivotal role of 2-5A, Diss Abstr Int 52(7):3590
1992.

21. McGee, K. A., Doukas, M. P., Kessler, R., Gerlach, T. M., (1997)
Impacts of Volcanic Gases on Climate, the Environment, and
People, U.S. Geological Survey Open-File Report 97-262, May 1997.

22. Rubin, C. H., Noji, E. K., (1994). Evaluating a Fluorosis Hazard


After a Volcanic Eruption, Archives of Environmental Health,
Sep/Oct94, Vol. 49 Issue 5, p395, 7p, 2 charts, 3 graphs Health,
September, 1994.

23. Independent Investigation of the East Tennessee Technology


Park, Volume 1 (October 2000). DOE Office of Oversight,
Environment, Safety and Health.
24. Podkletnov, N. E., Markhinin, E. K., (1981) New data on
Abiogenic synthesis of prebiological compounds in volcanic
processes, Orig Life 1981 12, 11:4, 303-315.

25. Yamawaki, M., Ariga, T., Gao, Y., Tokuda, A., Yu, J. S.,
Sismanis, A., Yu, R.K.. (1998) Sulfoglucuronosyl glycolipids as
putative antigens for autoimmune inner ear disease. J
Neuroimmunol 1998 Apr 15;84(2):111-116.

26. Krocova, Z., Macela, A., Kroca, M., Hernychova, L., (2000) The
immunomodulatory effect(s) of lead and cadmium on the cells of
immune system in vitro. Toxicol Vitr, 2000 02, 14: 1, 33-40.

27. Axelson, O., (1980) Arsenic compounds and cancer. J Toxicol


Environ Health, 1980 00, 6: 5-6, 1229-1235.

28. Dodd, N. J., Silcock, J. M., (1976) Electron spin resonance


study of changes during development of solid yoshida tumour. II.
Paramagnetic metal ions. Br J Cancer, 1976 11, 34: 5, 556-565.

29. Germolec, D. R., Yoshida, T., Gaido, K., Wilmer, J. L.,


Simeonova, P. P., Kayama, F., Burleson, F., Dong, W., Lange, R. W.,
Luster, M. I., (1996) Arsenic induces overexpression of growth
factors in human keratinocytes. Toxicol Appl Pharmacol, 1996 11,
141: 1, 308-318.

30. Shen, Z. Y., Shen, J., Cai, W. J., Hong, C., Zheng, M. H., (2000)
The alteration of mitochondria is an early event of arsenic trioxide
induced apoptosis in esophageal carcinoma cells. Int J Mol Med,
2000 02, 5: 2, 155-158.

31. Akao, Y., Yamada, H., Nakagawa, Y., (2000) Arsenic-induced


apoptosis in malignant cells in vitro. Leuk Lymphoma, 2000 03, 37:
1-2, 53-63.

32. Bryson, C., (1998) The Donora Fluoride Fog: A Secret History of
America's Worst Air Pollution Disaster Fall 1998 Earth Island
Journal

33. Glasser, G., (1998) - Fluoride And The Phosphate Connection,


Earth Island Journal Special Report "Fluorides And The
Environment", (1998)
34. Clark, W. R., (1986) The Experimental Foundation of Modern
Immunology, John Wiley and Sons. p 418-421.

35. Harley, N. H., Foulkes, E. C., Hilborne, L. H., Hudson, A.,


Anthony, C. R., (1999). A Review of the Scientific Literature As It
Pertains to Gulf War Illness, Volume 7, Depleted Uranium. RAND
report.

36. Kniazhev, V. A., Umnikova, N. M., (1975), Toxicology of high-


fired beryllium oxide inhaled by rodents. II. Metabolism and early
effects, Arch Environ Health 30(11): 546-551.

37. Kathren, R. L., Strom, D.J., Sanders, C. L., Filipy, R. E., McInroy,
J. F., Bistline, R. E., (1993) Distribution of Plutonium and
Americium in Human Lungs and Lymph Nodes and Relationship to
Smoking Status, Radiation Protection Dosimetry, Vol. 48(4): p 307-
315.

38. McKinney, L. C., Aquilla, E. M., Coffin, D., Wink, D. A.,


Vodovotz, Y., (October 1998). Ionizing radiation potentiates the
induction of nitric oxide synthase by IFN-g and/or LPS in murine
macrophage cell lines: role of TNF-a. Journal of Leukocyte
Biology, Volume 64 459-466.

39. Morales, A., Miranda, M., Sánchez Reyes, A., Biete, A.,
Fernández Checa, J.C., (1998) Oxidative damage of mitochondrial
and nuclear DNA induced by ionizing radiation in human
hepatoblastoma cells. Int J Radiat Oncol Biol Phys, 1998 Aug, 42:1,
191-203.

40. Tinkle, S. S., Schwitters, P. W., Newman, L. S., (1996). Cytokine


Production by Bronchoalveolar Lavage Cells in Chronic Beryllium
Disease. Environ Health Perspect 104(Suppl 5):969-971.

41. Ledgerwood, E. C., Prins, J. B., Bright, N. A., Johnson, D. R.,


Wolfreys, K., Pober, J. S., O'Rahilly, S., Bradley, J. R., (1998).
Tumor Necrosis Factor Is Delivered to Mitochondria Where a
Tumor Necrosis Factor-Binding Protein Is Localized. Lab Invest
1998, 78:1583-1589.

42. Deodhar, S.D., Barna, B.P., (1991) Immune mechanisms in


beryllium lung disease. Cleve Clin J Med, 1991 Mar, 58:2, 157-160.
43. Sawyer, R.T. Kittle, L.A., Hamada, H., Newman, L.S., Campbell,
P.A., (2000) Beryllium-stimulated production of tumor necrosis
factor-alpha by a mouse hybrid macrophage cell line. Toxicology,
2000 00, 143: 3, 235-247.

44. Comhair, S.A., Lewis, M. J., Bhathena, P. R., Hammel, J. P.,


Erzurum, S. C., (1999) Increased glutathione and glutathione
peroxidase in lungs of individuals with chronic beryllium disease.
Am J Respir Crit Care Med, 1999 Jun, 159:6, 1824-1829.

45. Li L., (2003) The biochemistry and physiology of metallic


fluoride: action, mechanism, and implications. Rit Rev Oral Biol
Med 2003: 14(2):100-14

46. Strunecka, Anna, Pharmacological implications of


aluminofluoride complexes, Department of Physiology and
Developmental Physiology, Faculty of Sciences, Charles
University, Vinièná 7, 128 00, Prague 2, Czech Republic.

47. Strunecka, Anna, Patocka, Jiri, Schuld, Andreas, AlFx: the


useful tool in laboratory investigations, but potential danger for
humans. Department of Physiology and Developmental Biology,
Czech Republic.

48. Slifka, M. K., Whitton, J. L., (2000) Clinical implications of


dysregulated cytokine production. J Mol Med, 2000 01, 78: 2, 74-80.

49. Tucci, M., Baker, R., Benghuzzi, H., Hughes, J., (2000) Levels of
hydrogen peroxide in tissues adjacent to failing implantable
devices may play an active role in cytokine production. Biomed Sci
Instrum, 2000 01, 36: , 215-220.

50. Urban, R. M., Jacobs, J.J., Tomlinson, M. J., Gavrilovic, J.,


Black, J., Peoch, M., (2000) Dissemination of wear particles to the
liver, spleen, and abdominal lymph nodes of patients with hip or
knee replacement, J Bone Joint Surg Am, 2000 04, 82: 4, 457-476.

51. Azuma, Y., Kaji, K., Katogi, R., Takeshita, S., Kudo, A., Tumor
necrosis factor-alpha induces differentiation of and bone
resorption by osteoclasts. J Biol Chem, 2000 00, 275: 7, 4858-4864.
52. Bernier, J., Brousseau, P., Krzystyniak, K., Tryphonas, H.,
Fournier, M., (1995) Immunotoxicity of heavy metals in relation to
Great Lakes. Environ Health Perspect, 1995 12, 103 Suppl 9: , 23-
34.

53. Foulkes, R. G., Anderson, A. C., (1994), Impact of Artificial


Fluoridation on Salmon Species in The Northwest USA and British
Columbia, Canada, Fluoride Vol.27 No.4 220-226 1994.

54. De Guise, S., Bernier, J., Lapierre, P., Dufresne, M. M., Dubreuil,
P., Fournier, M., (2000) Immune function of bovine leukocytes after
in vitro exposure to selected heavy metals. Am J Vet Res, 2000 03,
61: 3, 339-344.

55. Christensen, M. M., Ellermann Eriksen, S., Rungby, J.,


Mogensen, S. C., (1996) Influence of mercuric chloride on
resistance to generalized infection with herpes simplex virus type
2 in mice. Toxicology, 1996 00, 114: 1, 57-66.

56. Soltýs, J., Borosková, Z., Dvoroznáková, E., (1997) Effects of


concurrently administered copper and mercury on phagocytic cell
activity and antibody levels in guinea pigs with experimental
ascariasis. J Helminthol, 1997 12, 71: 4, 339-344.

57. Graff, C., Clayton, D. A., Larson, N.G., (1999) Mitochondrial


medicine-recent advances, J Intern Med., 1999 Jul, 246:1, 11-23.

58. Treem, W. R., Sokol, R. J., (1998) Disorders of the mitochondria,


Semin Liver Dis., 1998, 18:3, 237-253.

59. Morales, A., Miranda, M., Sanchez, Reyes A., Biete, A.,
Fernandez Checa J. C., (1998) Oxidative damage of mitochondrial
and nuclear DNA induced by ionizing radiation in human
heptoblastoma cells, Int J Radiat Oncon Biol Phys, 1998 Aug, 42:1,
191-203.

60. Yakes, F. M., Van Houten, B., (1997) Mitochonrail DNA damage
is more extensive and persists longer than nuclear DNA damage in
human cells following oxidative stress, Proc Natl Acad Sci USA,
1997 Jan, 94:2, 514-519.
61. J. Alexander Bralley, J. A., Lord, R. S., (1994). CFS, Journal of
Applied Nutrition, 46(3):74-78.

62. Tritschler, H. J., Packer, L., Medori, R., (1994) Oxidative stress
and mitochondrial dysfunction in neurodegeneration, Biochem Mol
Biol, 1994 Aug, 34:1, 169-181.

63. Lenaz, G., (1998) Role of mitochondria in oxidative stress and


ageing. Biochim Biophsy Acta, 1998 Aug, 1366:1-2, 53-67.

64. Bachinskii, P. P., Gutsalenko, O. A., Naryzhniuk, N.D., Sidora, V.


D., Shliakhta, A. I., (1985) Action of the body fluorine of healthy
persons and thyroidopathy patients on the function of
hypophyseal-thyroid the system, Probl Endokrinol (Mosk) 1985
Nov-Dec;31(6):25-29.

65. Hasko, G., Kuhel, D. G., Salzman, A. L., Szabo, C., (2000) ATP
suppression of IL-12 and TNFa release from macrophages. Br J
Pharmacol, 2000 03, 129: 5, 909-914.

66. Hynczak, A. J., Adamowicz, A., Fabisz, L., Kosmider, K., Suska,
M., Wnuczynaki, K., Wozniak, Z., (1980), Calcium and magnesium
in the blood serum of workers exposed to fluoride compounds, in
relation to age and duration of employment, Med Pr. 1980 01, 31:5,
345-349.

67. Trace Elements in Human and Animal Nutrition (Fifth Edition)


Edited by Walter Mertz, U. S. Dept. of Agriculture, Agricultural
Research Service, Beltsville Human Nutrition Research Center,
Beltsville, Maryland, 1987 p371.

68. Waldbott George L, (1998) The Preskeletal Phase of Chronic


Fluoride Intoxication, Fluoride 31(1) 1998, pp 13-20.

69. Fluoride, The Aging Factor, Dr. John Yiamouyiannis, Health


Action Press, 1993.

70. Roholm, K., (1937) Fluorine Intoxication, A Clinical-Hygiene


Study, With a Review of the Literature and Some Experimental
Investigations. H.K. Lewis & Co., Ltd., London, 1937.
71. Balabolkin, M.I., Mikhailets, N.D., Lobovskaia, R. N.,
Chernousova, N. V., (1995), The interrelationship of the thyroid and
immune statuses of workers with long-term fluorine exposure Ter
Arkh, 1995, 67:1, 41-42.

72. Curnette, J., et al (1979) Fluoride-mediated Activation of the


Respiratory Burst in Human Neutrophils, Journal of Clinical
Investigation, Vol. 63, pp. 637-647.

73. Zhan, Y., Du, L., Zhan, C., (1995) A study on human dental
embryology in an endemic high fluorosis region, Zhonghua Bing Li
Xue Za Zhi 24(1):36-8 (1995) (www.ncbi.nlm.nih.gov id=7781114)
Department of Histology and Embryology, Guiyang Medical
College.

74. Gabler, W. L., Leong, P. A., (1979) Fluoride Inhibition of


Polymorphonumclear Leukocytes, Journal of Dental Research, Vol.
48, No. 9, pp. 1933-1939.

75. Gabler, W. L., et al. (1985) Effect of Fluoride on the Kinetics of


Superoxide Generation by Fluoride, Journal of Dental Research,
Vol. 64, p. 281.

76. Kozlyuk, A. S., et al. (1987) Immune Status of Children in


Chemically Contaminated Environments, Zdravookhranenie, Issue
3, pp. 6-9.

77. Lund, K., Boe, J., Refsnes, M., Sandström, T., Söstrand, P.,
Kongerud, J., (1996) Acute inflammatory markers in
bronchoalveolar lavage fluid from subjects exposed to hydrogen
fluoride European respiratory journal, vol. 9, suppl. 23, 1996, s.
438s ; ISSN 0106-433 9.

78. Lund, K., Boe, J., Refsnes, M., Söstrand, P., Schwarze, P.,
Sandström, T., (1996) Experimental hydrogen fluoride exposure
induces airway inflammation in normal subjects American journal
of respiratory and critical care medicine, vol. 153, no. 4, pt 2, 1996,
s. A484 ; ISSN 1073-449X

79. Visser, J.T., De Kloet, E.R., Nagelkerken, L,. (2000). Altered


glucocorticoid regulation of the immune response in the chronic
fatigue syndrome. Ann N Y Acad Sci 2000;917:868-875.
80. Nosik, N.N., (2000) Cytokines in viral infections Vopr Virusol,
2000 00, 45: 1, 4-10.

81. Rentenaar, R.J., Gamadia, L.E., van DerHoek, N., van_Diepen,


F.N., Boom,R., Weel, J.F., Wertheim van Dillen, P.M., van Lier, R.A.,
ten Berge, I.J., (2000) Development of virus-specific CD4(+) T cells
during primary cytomegalovirus infection. J Clin Invest, 2000 02,
105: 4, 541-548.

82. Lane, B. J., Provost, Craig, M. A., Resting energy expenditure in


asymptomatic HIV-infected females. J Womens Health Gend Based
Med, 2000 04, 9: 3, 321-327.

83. Reid, S., Hotopf, M., Hull, L., Ismail, K., Unwin, C., Wessely, S.,
(2001) Multiple chemical sensitivity and chronic fatigue syndrome
in british gulf war veterans. Am J Epidemiol 2001 Mar
15;153(6):604-609.

84. Roland, P. S., Haley, R. W., Yellin, W., Owens, K., Shoup, A. G.,
(2000) Vestibular dysfunction in Gulf War syndrome. Otolaryngol
Head Neck Surg, 2000 03, 122: 3, 319-329.

85. Haley, R.W., Marshall, W.W., McDonald, G.G., Daugherty, M.A.,


Petty F., Fleckenstein, J.L., (2000) Brain abnormalities in Gulf War
syndrome: evaluation with 1H MR spectroscopy. Radiology, 2000
06, 215: 3, 807-817.

86. Cook, D. B., Lange, G., DeLuca, J., Natelson, B.H., (2001)
Relationship of brain and mri abnormalities and physical
functional status in chronic fatigue syndrome, Int J Neurosci 2001
Mar: 107 (1-2): 1-6.

87. Buskila, D., Fibromyalgia, (2000) chronic fatigue syndrome, and


myofascial pain syndrome. Curr Opin Rheumatol, 2000 03, 12: 2,
113-123.

88. Rauma, A.L., Torronen, R., Hanninen, O., Verhagen, H.,


Mykkanen, H., (1995) Antioxidant status in long-term adherents to
a strict uncooked vegan diet. Am J Clin Nutr, 1995 Dec, 62(6):1221-
1227.
89. Rauma, A. L., Torronen, R., Hanninen, O., Mykkanen, H., (1995)
Vitamin B-12 status of long-term adherents of a strict uncooked
vegan diet ("living food diet") is compromised. J Nutr, 1995 Oct,
125(10):2511-2515.

90. Donaldson, M.S., (2000) Metabolic vitamin B-12 status on a


mostly raw vegan diet with follow-up using tablets, nutritional
yeast, or probiotic supplements, Annals of Nutrition & Metabolism.
44(5-6):229-234, 2000 Sep-Dec.

91. Rauma, A.L., Nenonen, M., Helve, T., Hanninen, O., (1993) Effect
of a strict vegan diet on energy and nutrient intakes by Finnish
rheumatoid patients. Eur J Clin Nutr 1993 Oct;47(10):747-749.

92. La Puma, J., (1999) Vegan Diet and Rheumatoid Arthritis.


Internal Medicine Alert, April 15, 1999 v21 i7 p52(1).

93. Nenonen, M.T., Helve, T.A., Rauma, A.L., Hanninen, O.O., (1998)
Uncooked, lactobacilli-rich, vegan food and rheumatoid arthritis.
Br J Rheumatol 1998 Mar;37(3):274-281.

94. Peltonen, R., Nenonen, M., Helve, T., Hanninen, O., Toivanen,
P., Eerola, E., (1997) Faecal microbial flora and disease activity in
rheumatoid arthritis during a vegan diet. Br J Rheumatol 1997
Jan;36(1):64-68.

95. Hanninen, O., Rauma, A. L., Kaartinen, K., Nenonen, M., (1999)
Vegan diet in physiological health promotion. Acta Physiol Hung
1999;86(3-4):171-180.

96. Kaartinen, K., Lammi, K., Hypen, M., Nenonen, M., Hanninen, O.,
Rauma, A.L.,. (2000) Vegan diet alleviates fibromyalgia symptoms.
Scand J Rheumatol 2000;29(5):308-313

97. Ling, W.H., Hanninen, O., (1992) Shifting from a conventional


diet to an uncooked vegan diet reversibly alters fecal hydrolytic
activities in humans. J Nutr 1992 Apr;122(4):924-930.

98. Peltonen, R., Ling, W-H., Haenninen, O., Eerola, E., (1992) An
uncooked vegan diet shifts the profile of human fecal microflora:
Computerized analysis of direct stool sample gas-liquid
chromatography profiles of bacterial cellular fatty acids. Applied
and Environmental Microbiology [APPL. ENVIRON. MICROBIOL.],
vol. 58, no. 11, pp. 3660-3666, 1992.

99. "Milk - The Deadly Poison" (1998) Robert Cohen , Argus


Publishing, Inc., ISBN 0-9659196-0-9.

100. Mabondzo, A., Le Naour, R., Le Grand, R., Vaslin, B.,


Benveniste, O., Cheret, A., Raoul, H., Romet Lemonne, J.L.,
Dormont, D., (1995) Functional consequences of macrophage
infection by human immunodeficiency virus: bispecific antibody
targeting of HIV-1-infected cells to Fc gamma RI expressing
effector cells. J Hematother, 1995 12, 4: 6, 579-585.

101. Grobler, S. R., van Wyk Kotze, T. J., Cleymaet, R., (1991)
Fluoride concentration in drinking water in small villages in the
Cape province, J Dent Assoc S Afr, 1991 12, 46: 12, 571-574.

102. Ibrahim, Y. E., Affan, A. A., Bjorvatn, K., (1995) Prevalence of


dental fluorosis in Sudanese children from two villages with 0.25
and 2.56 ppm fluoride in the drinking water. Int J Paediatr Dent,
1995 12, 5: 4, 223-229.

103. Walvekar, S.V., Qureshi, B. A., (1982) Endemic fluorosis and


partial defluoridation of water supplies - A public health concern in
Kenya. Community Dent Oral Epidemiol, 1982 Jun, 10:3, 156-160.

104. Olsson, B., (1979) Dental findings in high-fluoride areas in


Ethiopia. Community Dent Oral Epidemiol, 1979 Feb, 7:1, 51-56

105. Tobayiwa, C., Musiyambiri, M., Chironga, L., Mazorodze, O.,


Sapahla, S., (1991) Fluoride levels and dental fluorosis in two
districts in Zimbabwe. Cent Afr J Med, 1991 Nov, 37:11, 353-361.

106. Zietsman, S., (1991) Spatial variation of fluorosis and fluoride


content of water in an endemic area in Bophuthatswana. J Dent
Assoc S Afr, 1991 Jan, 46:1, 11-15

107. Altfeld, M., Addo, M. M., Kreuzer, K.A., Rockstroh, J.K.,


Dumoulin, F.L., Schliefer, K., Leifeld, L., Sauerbruch, T., Spengler,
U., (2000) T(H)1 to T(H)2 shift of cytokines in peripheral blood of
HIV-infected patients is detectable by reverse transcriptase
polymerase chain reaction but not by enzyme-linked
immunosorbent assay under nonstimulated conditions. J Acquir
Immune Defic Syndr, 2000 00, 23: 4, 287-294.

108. Beretta, A., Clerici, M., Hasson, H., Fumagalli, L., Trabattoni,
D., Lillo, F., Ferrante, P., Saniabadi, A.R., Adachi, M., Lazzarin, A.,
(2000) Ex-vivo purging of circulating monocytes results in
immunovirologic improvement in partially HAART responder HIV-
infected patients. J Biol Regul Homeost Agents, 2000 00, 14: 1, 27-
31.

109. Bolton, Eric, Mildvan, Albert, Boeke, Jef, (2002) Inhibition of


Reverse Transcription In Vivo by Elevated Manganese Ion
Concentration. Molecular Cell, April 2002, Vol 9, 879-889.

110. Blazevic, V., Heino, M., Lagerstedt, A., Ranki, A., Krohn, K.J.,
(1996) Interleukin-10 gene expression induced by HIV-1 Tat and
Rev in the cells of HIV-1 infected individuals. J Acquir Immune
Defic Syndr Hum Retrovirol, 1996 00, 13: 3, 208-214.

111. Smith, P. D., Chura, K., Masur, H., Lane, H. C., Fauci, A. S.,
Wahl, S. M., (1984) Monocyte function in the acquired immune
deficiency syndrome. Defective Chemotaxis., J Clin Invest, 1984
12, 74: 6, 2121-2128.

112. Srikanth, P., Castillo, R. C., Sridharan, G., John, T. J.,


Zachariah, A., Mathai, D., Schwartz, D. H., (2000) Increase in
plasma IL-10 levels and rapid loss of CD4+ T cells among HIV-
infected individuals in south India, Int J STD AIDS, 2000 01, 11: 1,
49-51.

113. Bialkowska, A., Bialkowski, K., Gerschenson, M., Diwan, B. A.,


Jones, A. B., Olivero, O. A., Poirier, M. C., Anderson, L. M.,
Kasprzak, K. S., Sipowicz, M. A., (2000) Oxidative DNA damage in
fetal tissues after transplacental exposure to 3'-azido-3'-
deoxythymidine (AZT). Carcinogenesis 2000 May;21(5):1059-1062.

114. Lamperth L; Dalakas MC; Dagani F; Anderson J; Ferrari R;


(1991) Abnormal skeletal and cardiac muscle mitochondria
induced by zidovudine (AZT) in human muscle in vitro and in an
animal model. Lab Invest. 1991 Dec;65(6):742-751.
115. Crowley Nowick, P.A., Ellenberg, J.H., Vermund, S.H.,
Douglas, S.D., Holland, C.A., Moscicki, A.B., (2000) Cytokine profile
in genital tract secretions from female adolescents: impact of
human immunodeficiency virus, human papillomavirus, and other
sexually transmitted pathogens. J Infect Dis, 2000 03, 181: 3, 939-
945.

116. Kempf, W., Müller, B., Maurer, R., Adams, V., Campadelli
Fiume, G., (2000) Increased expression of human herpesvirus 7 in
lymphoid organs of AIDS patients. J Clin Virol, 2000 05, 16: 3, 193-
201.

117. Inkielewicz, I., Krechniak, J., (2004) Fluoride effects on


glutathione peroxidase and lipid peroxidation in rats. Fluoride
(2004) Vol. 37; No 1; 7-12.

118. Shanthakumari D, Srinivasalu S, Subramanian S., (2004) Effect


of fluoride intoxication on lipidperoxidation and antioxidant status
in experimental rats. Toxicology. 2004 Nov 15;204(2-3):219-28.

119. Vani, M. L., Reddy, K. P., (2000) Effects of fluoride


accumulation on some enzymes of brain and gastrocnemius
muscle of mice. Fluoride 2000; 33(1): 17-26.

120. Gartner, R., Gasner, B. C. H., Dietrich, J. W., Krebs, B.,


Angstrum, M. W. A., (2002) Selenium Supplementation in Patients
with Autoimmune Thyroiditis Decreases Thyroid Peroxidase
Antibodies Concentrations. The Journal of Clinical Endocrinology
& Metabolism Vol. 87, No. 4 1687-1691.

121. Beckett, G. J., Arthur, J. R., (2005) Selenium and endocrine


systems Journal of Endocrinology (2005) 184, 455-465.

122. Patrick, L., (2003) Toxic metals and antioxidants: Part II. The
role of antioxidants in arsenic and cadmium toxicity. Altern Med
Rev. 2003 May;8(2):106-28.

123. Gregus, Z., Varga, F., (1985) Role of glutathione and hepatic
glutathione S-transferase in the biliary excretion of methyl
mercury, cadmium and zinc: a study with enzyme inducers and
glutathione depletors. Acta Pharmacol Toxicol (Copenh), 56(5):398-
403 1985 May.
124. Gregus, Z., Stein, A. F., Varga, F., Klaassen, C. D., (1992) Effect
of lipoic acid on biliary excretion of glutathione and metals.
Toxicol Appl Pharmacol, 114(1):88-96 1992 May.

125. Ballatori, N., Clarkson, T. W., (1985) Biliary secretion of


glutathione and of glutathione-metal complexes. Fundam Appl
Toxicol, 5(5):816-31 1985 Oct.

Author:

The author formed and directs the Magnum-Opus Project to


correct and expose the wrongs the Manhattan Project and the
abuses of openness in national security. He is former Senior
Development Staff of Oak Ridge National Laboratory and has
direct experience with some of the most toxic materials from the
nuclear industry. He worked on toxic site remediation, radiation
detection, invented the USRADS survey system, and won ORNL
significant event award. He discovered high levels of hydrogen
fluoride emissions from the gas diffusion plants and noticed the
link to CFS like illnesses in the worker and local community
populations. He defined the basic mechanism for cancer, CFS, and
HIV in national security circles in the 1980's. He claims his
inspiration for the discovery came from the icon imagery of
volcanism connected to the story of the Ark and the environmental
imagery associated with Mary controlling the poisons from the
Earth entering the food chain. The ultimate of the inspiration came
from the understanding of the Global Sulfur Cycle and how this
associated to the story of a volcanic mountain near an oil field of
Midian, Saudi Arabia and how this process formed DMS. Author
says enzyme, bone, and lymph immune system mechanism
information was suppressed for more than two decades by
industry control of research, negligence on the part of CDC,
ATSDR, and EPA, and criminal cover up on the part of the DOE. He
purposely chose public publication of his work to express the
need for preventive and alternative medicine to take a more
balanced stance against AMA and pharmaceutical based
dominance and excessive profiteering in medicine.

RETROSPECTIVE: The process of discovery of the principle failure


system in Human Health.

The aftermath for the Manhattan Project is the fitting setting for the
discovery of the principle failure mechanism leading to cancer,
CFS, immune illnesses, and AIDS. The Manhattan Project
discovered early on the acute effects of radiation due to ROS
forming in the marrow death, intestinal death, and nervous system
death effects. The studies in Oak Ridge also found that sub-lethal
radiation exposures lead to the need for antibiotics to protect the
person from the immune system loosing its ability to protect
against viruses, mycoplasma, and other infections.

The 1980s brought on the problems of AIDS and HIV nearly


simultaneously, and the research in this period identified the loss
of glutatione (GSH) and superoxide dimutase (SOD) enzymes
connected with CFS. The glutathione metals clearance mechanism
also pinned down that toxic metals upset the cell mitochondria
processes leading to high rates of ROS from the mitochondria ATP
production. CFS would involve endogenous DNA viruses, HIV
exogenous retrovirus from monkeys, and cancer the radiation
mutation of activated endogenous viruses. The entire process for
CFS, AIDS, and cancer was uniquely defined by three simple
enzymes: Se-GSH, Mn-SOD, and Mn dependent 2-5A RNase L.

In the 1980s, Jim Phelps was the first at Oak Ridge to correctly flag
all the problems of the Ozone Hole or the UV problem in upsetting
both the Global Warming factors and the Global Sulfur Cycle of the
planet. The largest CO-2 sink on the planet is the ocean's plankton
and the UV was impairing and killing the plankton's CO-2
conversion process. The plankton process is also part of the
global Sulfur Cycle that supplies DMS into the atmosphere that
places DMSO and MSM into the human and animal food chain.
These place sulfur into the food, which is in turn used to make the
Se-GSH to clean the body of toxic metals. DMS also supports
cloud seeding that acts as a sunscreen for heat from the sun and
regulates the Earth's temperature. The loss of DMS levels directly
drives global warming and the loss of immunity in humans and
animals.

The higher levels of retained metals in the body due to loss of the
hepatic phase II elimination of toxic metals sets up a slow shift
toward hyperthyroidism like problems due to the AlFx effects and
this process sets up a metabolic acidosis that slows the kidney
clearance of aluminum and other metals. The rise of the toxic
metals within cells causes mitochondria ROS generation to rise
and greater demand on Mn-SOD to compensate, and upsets of the
Mn dependent 2-5A RNase L generation.

With the discovery of the function of the 2-5A RNase L enzyme in


controlling the internal cell viral infections the association of the
metals induced ROS and the radiation induced ROS paths
crossing paths became highly evident. The discovery that these
three enzymes dominated the failings of the immune system from
either radiation or toxic metals was fully discovered in the mid-
1980s at Oak Ridge National Laboratory by Jim Phelps.

Jim Phelps' discovery of this principle mechanism for illnesses


began when his father became sick while working as a uranium
machinist at the Y-12 plant and was highly exposed to PCBs used
as a uranium cutting tool coolant. This lead to gall bladder
problems, which are directly connected with PCB exposures. The
Y-12 managers moved Jim Phelps father from the dirty PCB
uranium cutting operations to the cleaner Y-12 9201-1 buildings
operation.

Jim Phelps' Division at ORNL designed the TSCA incinerator for


the K-25 plant in the 1980s and he discovered the issues behind
the need to ban PCBs and Dioxin were due to cumulative damage
effects to the enzymes GSH and SOD, which eventually leads to
free radical damage to the RNase L enzyme's effectiveness and
viral infection problems within cells. Jim Phelps' dad came down
with Parkinson's and had to take early retirement from Y-12, and
the mechanism of glutathione was the main clearance mechanism
for toxic metals and chemicals from the brain. Jim Phelps quickly
spotted this as associated with his father's progressive illness
pattern from his occupation exposures at Y-12.

Jim Phelps' dad also worked on the K-25 improvement program


which exposed him to aluminum parts run in a fluoride chemical
process, which made an extremely dangerous AlF3 coat on these
parts. This exposed his father to one of the most dangerous of the
Oak Ridge toxic insecticide effects that mimic the TSH pituitary
hormone and upsets the GSH and SOD levels in cells. His dad had
multiple toxic insults [PCBs, then AlFx] to the same enzyme
systems that protect the body and brain from toxic injury. This was
the process that cracked the issue that Harold Hodge spotted in
1944 about the F factor causing health problems in those exposed
to UF-6. The AlFx problems were now exposed, and the process
via which they caused illnesses in the work force.

With that mechanism defined, it was a short time before the


problems of hydrogen fluoride (HF) and other toxins were
identified as upsetting the GSH and SOD levels. HF effects were
quickly connected to the high rates of thyroid illness seen in the
work force due to accumulation of mercury in the thyroid gland
leading to thyroid cancer like problems normally associated with
radiation damage.

These were the natural order of events that lead to the major
discovery for the causes of cancers, CFS, immune disorders, and
even AIDS in the mid-1980s at the Oak Ridge National Laboratory
by Jim Phelps.

Jim Phelps was the first to connect that HF emissions from the
Oak Ridge plants impacted GSH and SOD, and that this effect was
becoming worse on a national scale from coal plant emissions of
HF. The effect was leading to problems of "Mad Cow" and "BSE" in
even grazing animals. Jim Phelps proposed the mediation factor
by spraying titanium dioxide from planes to offset the problem in
grazing animals.

This idea became the start of the so called "Chemtrails" activities


and top secret compartmented research at LANL on the rising
problem in animals. Jim Phelps also discovered an atmospheric
injection vector involving HF and H2SO4 in combination with
hydrocarbons in the air that dominated the global warming effects.

Jim Phelps discovery that all of medicine comes down to damage


factors from environment and industry to these three principle
enzymes proved highly embarrassing to the Govt., Industry, and
AMA; to the point that the AMA styled medicine could be forced
out of business and charged with malpractice on a national scale.
This began the massive cover up for this discovery that could well
change the world, if it became public knowledge. Jim Phelps'
discovery not only showed that the common cold could be made
extinct, but that man could be made to have the Biblical longevity
of Genesis. His discovery even impacted the interpretations for
religion and exposed massive problems there.

The discovery of the toxic metals mechanism has strong links to


religion, as the Egyptians were into metals mining. They were the
first to use copper for water pipes, while the Romans used lead
pipes and poisoned themselves into self-destruction. Also in these
times, Joseph of Aramea held tin mines in the UK, and the so-
called "white lead" made a highly safe metal for use in cookware
and food storage. "Tin lined" copper cookware (Gérard Leclerc,
etc.) is still in use today and is some of the finest and most
expensive of French cookware.

In these old world cultures the use of mercury, which is the worst
of the worst of toxic metals, in the mining for gold via an
amalgamation process made Kings and Rulers rich. It was not in
the interest of the powers of those times to expose that mercury
made these gold miners sick, so that information was suppressed.
Vatican and Jewish religious interpretations of issues like eternal
life were suppressed in those times as they played the game that
kept them and their rulers in gold.

The US plays the same games today in the cover ups on health
connected with processing aluminum, a strategic metal. Aluminum
uses fluoride to process it to metal and the AlFx health effect on
GSH and SOD appears there strongly. Similarly the strategic metal
Uranium production for bombs uses lots of Fluorine and coal
power that released mercury and HF. This too causes serious AlFx
health problems. And the list goes on into the cover-ups on PCBs,
Dioxin, DDT, and all the other chemicals that suppress the GSH
and SOD enzymes needed for health and longevity.

The knowledge of the GSH, SOD, and Mn based viral protection


enzymes is literally the issue of how to attain very long longevity
by avoidance of toxic metals and chemicals. This is the theme of
the eternal life part of religion and elements from the story of
Genesis. Moses was educated in Egypt by what some term the
Egyptian School of Mysteries or what might better be termed the
school of the natural orders of the world. They knew well the
power of metals to heal and to make ill. There was one special
metal that had the ultimate power to heal and produce clarity of
mind, expanded cognitive powers, the realm of divine thought.
Gold Colloids were part of the story of Moses and the Manna.
Later, Jesus and Joseph lived in Egypt and were exposed to these
same teachings.

Jesus was termed a magician and had unusual powers to heal


people. In those times the knowledge of natural processes and the
health problems linked to fluoride and toxic metals effects would
be the ultimate in health knowledge. This knowledge is still the
ultimate in health conservation today. It is this knowledge that
appears connected to the graduated learning needed to attain that
associated with the Holy Grail.

The Masons Organization (Scottish Rite Temple) still practice part


of this ancient Egyptian School of Mysteries type teachings in their
progressing up their orders. They seek to imitate the knowledge
and attainments from Old Egypt that lead to Jesus' divine level of
knowledge.

So, one can now see that the information of how health is affected
by toxic metals can play a strong role in the interpretations and
misinterpretations of the church on the true story of what Jesus
was about. Jesus was also said to be an Essene and this faction
also practices a version of the divine knowledge keeping from the
Egyptian Mystery School knowledge base.

It is for this association that many of these illnesses connected


with this failure mechanism are called "mystery illnesses;" CFS,
GWS, Gas Diffusion Worker Illness, Cancer, ALS, etc. The illnesses
represent no mystery, as the mechanism for them is well known.
To acknowledge the mechanism for these illnesses is to open up
Pandora's Box and to expose the very serious problems in
religion, both in Judaism and Catholicism, as well as the problems
of modern medicine that make their entire profits from this health
failure mechanism.

One of the most prized metals in Egypt was copper and was
associated with eternal life and the symbolism of the Ankh (The
first religious Cross). Later, gold took over as the leading metal for
health, as its colloid form could remove fluoride and mercury from
the body and brain. The ultimate powers of the Ark of Moses were
closely associated with this metal's healing power and how to
make it.

Thus, one can see why the corrupted power of religion and
government in the US attempt to keep these associations a
mystery for the public at large. Keeping the mechanism a mystery
allows industry to pollute and harm health of large populations,
while others make money from treatment of the illnesses induced.
Doing such is a crime against humanity and racketeering beyond
the wildest imagination. Those associated with such deception are
assigned the definition of anti-Christ.

It is these three enzymes that form a sort of Holy Trinity for man's
existence on this planet, and the inner sanctum for why Jesus was
so special in the realm of religion. With the knowledge of the Final
Diagnosis report in hand, the real issues of religion come into
view. It is part of the story of Jesus' Revelations.

The bottom line is that places like Oak Ridge released hydrogen
fluoride, which combines with aluminum in the body to form a
toxic compound like the insect poison called cryolite, sodium
aluminum fluoride. Cryolite's pesticide mechanism works by
upsetting the trace metals metabolisms within cells, and this is
exactly the problem seen in Oak Ridge and elsewhere with the
mysterious illnesses and diseases. It affects every man, woman,
and child on this planet and is directly connected with killing them
in the long term.

This same effect is the trigger mechanism for Gulf War Syndrome,
and all that and much more could have been averted if Oak Ridge
was not a criminal entity seeking to cover ups its many mistakes
and toll on human life.
1

The interface between science and society:


water fluoridation as a case study, Bundaberg
1952-57†
HF Akers and SAT Porter*
Between 1945 and 1954, the concept of adjusting the fluoride content in
reticulated water supplies (henceforth referred to as water fluoridation) for
the partial prevention of dental caries was in its infancy. While Australia’s
peak scientific body, the National Health and Medical Research Council
(NHMRC) had conditionally endorsed this public health measure in
December 1953, two factors hampered prospects for its implementation in
Queensland.1 First was a political legacy arising from the widely publicised
impact of naturally over-fluoridated water on sheep in the western
parts of the State. This caused public confusion and concern when the
biological impact of the continual ingestion of naturally over-fluoridated
water on sheep was extrapolated to the fluoridation of community water

Bundaberg ca 1951.
(Picture Queensland Collection, State Library of Queensland)

†This article has been peer reviewed.


*Mr Harry F Akers is a PhD student at The University of Queensland’s School of Dentistry,
Turbot St, Brisbane. Dr Suzette AT Porter is the Director of Clinical Placements and
the Coordinator of Community Dentistry at The University of Queensland’s School of
Dentistry, Turbot St, Brisbane.
2

Figure 1 Professor SF Lumb to Director General, 2 March 1954.


(Reproduced courtesy of The University of Queensland School of Dentistry)
3
supplies. While Queensland’s
2

agrarian bureaucracy had


perceived natural artesian fluoride
as a post-1945 threat to the
pastoral industry, major veterinary
issues had been largely resolved
by 1953.3 The second factor was
a legitimate scientific hesitancy
due to contemporaneous concerns
about human fluid homeostasis
(compensation mechanism).
Queensland’s tropical and sub-
tropical climates meant fluid
intakes were likely to be higher
than those of the more temperate
climates in the southern States.
In November 1954, the NHMRC
addressed this issue with Professor SF Lumb, Professor of
implementation protocols that Dentistry & Dean of the Dental Faculty,
modified bioavailable (active) 1938-1963
fluoride concentrations to allow (Picture Queensland Collection, State
for potentially higher fluid intake Library of Queensland)
in parts of Queensland.4
In this era, the ravages of the
caries epidemic were obvious
and often traumatic for patients
and dentists. The Dean of the
Faculty of the Department of
Dentistry at The University of
Queensland, Professor SF Lumb
was naturally interested in water
fluoridation (Figure 1). In 1953,
Lumb commissioned a young,
credentialled, post-graduate
research student, Dr Brian Kruger
to investigate suitable locations.5
Kruger was Ipswich ‘born and
bred’, a Rotary Foundation
Fellow who had returned from US Alan Simmonds, Engineer, Department
study commitments. Kruger was of Local Government , Queensland’s first
well acquainted with the North strong fluoride advocate.
American water fluoridation field (Reproduced courtesy of John Bristow)
4
trials and considered a range of provincial municipalities from their
scientific and political perspectives. In consultation with the Department of
Local Government, Bundaberg was recommended as one of Queensland’s
few locations that satisfied the relevant criteria for a Queensland trial.6 The
climate was appropriate in that it was within the extended ranges of the
NHMRC’s revised guidelines on climate and fluid intake. The Bundaberg
City Council’s engineer, C Brewer, was qualified to supervise the
appropriate engineering infrastructure. Moreover, fluoridation equipment
could be easily installed at the partly constructed South Bundaberg
treatment plant.7
Engineering personnel and infrastructure were often understated
but critical factors in water fluoridation proposals.8 Furthermore, the
Bundaberg dentists, led by J Wainwright, had expressed strong support
and would publicly support the proposal. Other important factors were
that the Burnett River divides Bundaberg into two communities with
separate sub-artesian water supplies of similar mineral composition. South
Bundaberg water could have adjusted fluoride concentrations to achieve
the test population while North Bundaberg water remained sub-optimally
and naturally fluoridated as the control.9
Another advantage in selecting Bundaberg was the potential for the
dental research team to maintain cross-disciplinary scientific collaboration
with the Department of Physiology at The University of Queensland

Bundaberg Mayor Fred Buss hosts a public reception for Queen Elizabeth and
Prince Philip at the Bundaberg Showgrounds on 11 March 1954. His daughter
Bettina welcomes the Queen.
(Picture Queensland Collection, State Library of Queensland)
5
(in an adjacent building on the St Lucia campus). In 1953, Professor
WV MacFarlane, from the Department of Physiology was researching
human fluid homeostasis within tropical climates and was a colleague
of Kruger. MacFarlane was an appointee on the NHMRC sub-committee
that investigated climate and protocols for water fluoridation. Bundaberg
cane cutters had a high daily fluid intake due to their long hours of
manual labour and exposure to heat from cane fires. Bundaberg’s flat
terrain predisposed cane cutters to riding bicycles to and from the cane
fields, which further accentuated dehydration. For these reasons, cane
cutters, especially Bundaberg’s cane cutters, held a special place in
MacFarlane’s research.10 Moreover, in the course of his work, MacFarlane
had established a favourable rapport with the powerful Australian Workers’
Union and its Bundaberg secretary, E Barnes, who was supportive of water
fluoridation.11
Although the Bundaberg recommendation was primarily based on
scientific criteria, political stability was also a consideration. The City
Council was stable and its Mayor, Alderman FH Buss (Mayor 1936-58,
excluding three years war service) held a secure tenure on the mayoralty.
The research team had been informed that Buss was interested in
fluoridation.
It would also be important to the success of the project to have the
support of the major local industry (or at least not have opposition from it).
Bundaberg was a “sugar city” and the history of the sugar industry’s attitude
towards water fluoridation indicated it would satisfy these requirements
and support water fluoridation.12 The 1949-53 era was one of escalating
tension between the sugar industry and the dental profession. Dentists’
attempts to restrict dietary sugars as a preventive strategy to reduce dental
caries alienated sections of the sugar industry. This antipathy from sections
of the sugar industry was particularly strong in Queensland, Australia’s
leading sugar producer.13 Tension peaked in 1953 at the Australian Dental
Association’s Congress (an international meeting for dentists held that
year in Brisbane) with a widely publicised American dental expert’s
claim of an association between sugar consumption and caries rates.14
R Muir, General Secretary of the Queensland Sugar Growers’ Council,
retaliated with sharp criticism of the dental profession’s management of
preventive strategies and its attitude to sugar consumption.15 The Colonial
Sugar Refinery Company also responded that ‘fluoridation and general
all-round diet’ were better preventive strategies than ‘the elimination of
carbohydrates from the diet’.16 Furthermore, former Queensland premier,
W Forgan Smith, was the Chairman of the Queensland Sugar Cane Prices
Board, and had formally expressed positive sugar industry interest in water
6

Figure 2 Professor SF Lumb to Alderman FH Buss, Mayor of Bundaberg, 12


October 1954.
(Reproduced courtesy of The University of Queensland School of Dentistry)
7
fluoridation. Though not stated, Lumb and Kruger would have been aware
17

that the sugar industry would either support, or at worst not oppose, the
Bundaberg proposal. Hence this proposal to fluoridate Bundaberg’s water
supply was carefully planned and historically significant. Under Kruger’s
cautious guidance, Bundaberg could have been not only an Australian
mainland pilot for water fluoridation research but also an internationally
acclaimed field trial like that of Grand Rapids (Michigan, USA).
Lumb’s Proposal
In October 1954 Lumb wrote to Buss with a proposal to undertake pilot
research into water fluoridation and sought an expression of interest from
Bundaberg in participating (Figure 2).18 Lumb forwarded enclosures on
American data, costing, engineering assessment and NHMRC protocols to
support the proposal. Lumb also stressed the importance of such a pilot,
the dental benefits, the need for strict control, Kruger’s availability and the
resolution of the NHMRC’s concerns about fluid homeostasis in a climate
like Bundaberg’s. In his letter, Lumb indicated that the City Council had to
desire water fluoridation. Several aspects of Lumb’s proposal are important
in analysing and understanding Bundaberg’s reaction. Lumb disclosed that
there had been a discussion with Wainwright leading Lumb to believe
that Buss was ‘well acquainted with the literature on fluoridation’ and
had ’expressed interest in it as a public health measure.’ The background
surrounding this advice is unclear. However, subsequent events revealed
that Wainwright, and hence Lumb, misjudged both Buss’s and Bundaberg’s
interest in water fluoridation. Secondly, although Lumb and Kruger were
commissioned to select a suitable location, Dr A Fryberg, Director General
of Health and Medical Services within the Department of Health and
Home Affairs (hereafter referred to as the Department of Health), made
the final authorisation. Fryberg stressed that financial assistance would be
available ‘if the Bundaberg City Council indicated in writing their desire
to fluoridate.’19 However, the Department of Health saw its role as advisory
and did not engage either the City Council or the community in any form
of public debate.
Whilst the Bundaberg proposal had administrative and scientific
endorsement, this support was provisional because section (vi) part (b)
of the 1953 NHMRC protocols stated that: ‘A large proportion of the
community should desire that fluorine be added to the water supply, or
alternatively, a substantial proportion of the community does not oppose
the addition of fluorine to the water.’20 The terms ‘desire’ and ‘oppose’ were
not defined and could have implied a range of options from autonomous
Council decision to an opinion poll or to a full or partial referendum. In
this epoch, the dental profession believed that the emotional, biological
8
and financial burden of the caries epidemic would outweigh opposition
to this community health measure. However, all parties forwarding
the proposal agreed that Bundaberg had to express its interest in water
fluoridation before the project could continue. Lumb had provided Buss
with the NHMRC protocol and, for reasons that are not clear, Buss
quickly announced that a referendum was required in Bundaberg. Another
confounding variable emerged when the proposal and the correspondence
between Lumb and Buss became public and the subject of media reports.21
Whether Lumb envisaged that the preliminary discussions would be
confidential is conjectural, but if Buss had quietly rejected the proposal,
it is possible that the research plan may have been quietly withdrawn and
submitted to another local authority. However, between Lumb’s proposal
of 12 October 1954 and the full City Council meeting of 28 October,
there were media releases based on statements by Buss and Wainwright.
Both interpreted the approach as a firm proposal for water fluoridation.22
The Bundaberg News-Mail published three articles on water fluoridation
in this period. Lumb’s approach elicited an official response in the
Council minutes of ‘interest … but would like more details’.23 How that
message was conveyed to Lumb involves some conjecture, but anecdotal
evidence suggests that media statements and hearsay preceded official
communication. The net effect of the publicity was that the researchers
were locked into the Bundaberg proposal without the guarantee of final
Council approval.
The public reaction
The Bundaberg City Council was an open body, the proposal attracted
public interest and councillors’ reservations were published in the
Bundaberg News-Mail on the following day of the full Council meeting.24
Buss publicly endorsed a referendum by saying there would be no
water fluoridation without one. In essence, the Council neither rejected
fluoridation nor endorsed it. The reasons were many: conflicting expert
evidence about fluoridation; fear of an experiment; Bundaberg was a
‘guinea pig’; costing; insufficient data; confusion and lack of confidence.25
The Bundaberg News-Mail published more local anti-fluoride views and
it was inevitable that community reaction to water fluoridation became an
integral part of the campaign for the municipal elections scheduled for
April 1955.26 The Bundaberg Ratepayers’ Association capitalised on the
timing of the announcement of the proposal and pushed water fluoridation
onto the electoral agenda. The Ratepayers’ Association not only opposed
water fluoridation but also a referendum, which it perceived as ‘a waste of
money’.27 Accordingly, it endorsed two members opposed to fluoridation,
J Eriksen and N Spence, as candidates for the imminent elections.
9
The “Bundaberg Tragedy” of 1928 – a communal legacy
Although careful planning had gone into the Bundaberg proposal, one
local factor had been given scant attention. Significant sections of the
Bundaberg community had developed a suspicion of scientific and medical
assurances following a vaccination tragedy in 1928. Twelve children died
following the vaccination of twenty-one children with a staphylococcal-
contaminated multi-dose bottle of diphtheria toxin-antitoxin inoculant.
This tragedy and subsequent evidence from the Royal Commission deeply
permeated the city’s psyche and divided the community over the need for
inoculation.28 In 1992, T Healy, (city council employee 1945-1993 and
Health Inspector 1961-1993) reported ‘the memory of 1928 lingered’.29
The Bundaberg-born B Courtice (ALP MHR Hinkler 1987-1993), in
commenting on Bundaberg’s fluoridation history endorsed Healy’s view:
‘The 1928 vaccination tragedy had a massive effect on the Bundaberg
psyche. It is not obvious now … but previously it was indelible … and
it was handed down.’30 This tragedy deeply eroded the perceived veracity
of communal health assurances and indirectly reappeared during the
Council’s consideration of water fluoridation.
These concerns were heightened in October 1954 by an outbreak of
poliomyelitis in Bundaberg.31 Polio was an emotive communal health
problem with an unknown method of transmission. There was publicity
and communal concern over alleged inadequate Council warnings
involving large local social gatherings like the ‘Railway Picnic’ and
‘Back to Bundaberg Week’. This concern became political and directed at
Buss. The issue was raised at the same Ratepayers’ Association meeting
that discussed water fluoridation. In 1954, the parents of the children in
the polio scare were the generation directly affected by the vaccination
tragedy. Hence this water fluoridation proposal, which some viewed as an
experiment, carried unforseen sociological repercussions.
Influence of the 1955 City Council election
Buss partly defused the water fluoridation opposition by restating the
need for a referendum. He further distanced himself from fluoride related-
issues with pre-election media statements and assured the electorate that
the City Council ‘would move further when it wanted information …
and there was no provision in the budget for it [fluoridation]’.32 By mid-
December 1954, Buss had conceded ‘that the present City Council had no
intention of proceeding with fluoridation’ and, if it was reconsidered, then
a referendum would be warranted in spite of the ratepayers’ association
policy opposing both water fluoridation and a referendum.33
Over a few weeks, the initial Council response of ‘interest’ had evolved
10
into procrastination and thence to an ambiguous refusal.34 This deflected
the fluoride focus from the councillors to a media debate between the
ratepayers on the one hand and Wainwright and the Australian Dental
Association Queensland Branch (hereafter referred to as the ADAQ)
on the other.35 Professor Lumb was alienated by the City Council’s
failure to personally liaise in detail to the dental faculty initiative; by
the politicisation of dental health issues; and by the polarised public
reaction and the apparent rejection of a prestigious research proposal in a
scientifically desirable locality. Moreover, there were few alternative sites
for a similar demonstration in Queensland. In what was a severe blow to
the future prospects of promoting water fluoridation in Queensland, Lumb
informed the ADAQ that fluoride advocacy was not a Dental Faculty
responsibility, but one for the Department of Health or the ADAQ. He
played no part in future Queensland proposals.36 Kruger continued by
participating in several public functions. However, Queensland’s Social
Crediters, some of whom mounted arguments like ‘Fluoridation is Jewish’,
targeted Kruger who was not prepared to engage in a political line of
debate.37 After 1958 he played no further part in public fluoride politics
despite achieving international acclaim for his continuing research into
trace elements, including fluoride.
In the 1955 municipal elections, Buss was unopposed and all incumbent
councillors were returned. Nonetheless, the 1955 return of the status
quo did not dampen the enthusiasm of the Bundaberg ADA sub-branch,
which was frustrated by the fluoride impasse. The ADAQ Vice-President,
Dr FG Christensen, also ‘threw himself into the Bundaberg campaign.’38
Heartened by Christensen’s approach, the Bundaberg ADA Sub-branch
members took every opportunity to educate the public at a personal level.
As a result, the Bundaberg Junior Chamber of Commerce approached the
City Council to reconsider fluoridation.39 The Sub-branch also organised
two visits by fluoride advocates. One lecture was given at a public meeting
at the Austral Hall in central Bundaberg, at which the motion: ‘that
Bundaberg City Council gives such proposals favourable consideration
with a view to the fluoridation of the Bundaberg water supply as soon as
possible’ was strongly supported (90 for and 10 against).40
Ramifications of the Austral Hall meeting
The public Austral Hall meeting reinstated fluoridation on the public
agenda and pressured the City Council to abandon its procrastination. The
City Council wrote to the Department of Health and asked questions that
had been previously answered by Lumb.41 The Department’s responses
reiterated that the City Council had autonomy in any decision regarding
the implementation of water fluoridation.42 When departmental advice and
11
details of Council minutes were published in the Bundaberg News-Mail it
was obvious that water fluoridation did not have Council support.43
Two developments subsequent to the Austral Hall meeting put further
pressure on councillors. To begin with, the Ratepayers’ Association
continued to reject any fluoridation proposal.44 Furthermore, another
civic association, the South Bundaberg Progress Association, called for
a referendum on water fluoridation at the next municipal election.45 In
July 1956, councillors resolved, ‘That this Council take no action towards
fluoridation of the Bundaberg City Water Supply until such time as there is a
demand from the people to do so, backed up by a petition signed by at least
3,000 persons eligible to vote at referendum.’46 This resolution absolved
the Council’s responsibility by decentralising the decision-making process
and placed the initiative on to dentists to support fluoridation.
This constraint on future Council response created problems for the
ADAQ. It was difficult to promote fluoridation in Bundaberg because of
the previously discussed wariness of health assurances. Secondly, anti-
fluoridationists became aware immediately of any petition and had time
to organise. Subsequent controversy empowered their cause, created delay
and enhanced opposition. Thirdly, the public meeting at Austral Hall
triggered the development of a more widespread Queensland anti-fluoride
infrastructure and network, as distinct from an isolated local fluoridation
opposition in Bundaberg. That evening a leading Queensland anti-
fluoridationist and Social Crediter, J Harding, attended Austral Hall and
established the Rockhampton Antifluoridation Group that networked with
M Compton, the secretary of the Ratepayers’ Association.47 Queensland’s
Social Crediters worked through this Rockhampton group, which would
evolve into a dominant force inside the Australian anti-fluoride movement.
By 1956, both sides of the fluoridation debate had external advisors as well
as local support and the anti-fluoridation group had become stronger and
more conspicuous. Bundaberg dentists conducted a domestic campaign
and generated favourable, State-wide publicity but could not mobilise
sufficient local support. In February 1957, Bundaberg dentists informed the
ADAQ that hope of widespread civic support for Bundaberg’s fluoridation
was a doubtful proposition, and ADAQ minutes recorded that Bundaberg
dentists ‘had reached their limit financially and physically … and were
much discouraged.’48 Although the City Council held to the principle of
‘deferral’ not ‘rejection’, opponents of water fluoridation could for all
intents and purposes claim success.
A number of observations and inferences can be drawn from aspects
of the aforementioned experiences and the political responses to them.
When viewed in Bundaberg’s socio-political context, a belief that water
12
fluoridation was a public health issue and not a political issue was naïve.
The activists from both sides of the public debate assumed an adversarial
perspective and observers and commentators saw the debate as bipolar.
The proposal to use Bundaberg as a pilot study assumed that fluoridation
was a legal power vested in a local authority, which allowed the State
Government to distance itself from the debate. This assumption was not
authoritatively questioned until 1963.49 Moreover, while the Bundaberg
proposal was conditional on popular endorsement, no authority established
a protocol to define or quantify the NHMRC’s terms of popular ‘desire’ or
‘oppose’. Because the Bundaberg City Council was the first local authority
to be offered a realistic prospect of water fluoridation in Queensland, the
official response was important. In this sense, the Council’s response was
public and political, and established a significant Queensland precedent.
In simple terms the City Council won its case against The University
of Queensland’s Department of Dentistry, the dental profession and
indirectly the State Government. Moreover, Bundaberg’s City Council
assumed a pseudo-authoritative status on water fluoridation because
other local authorities perceived its response as important. To approach
a local authority on water fluoridation immediately prior to a municipal
election was poor tactics. Councillors perceived fluoridation as technical,
experimental and divisive and were not competent to arbitrate on the
scientific merit of this public health measure. Dental health had never been
a priority within local authority elections. However, councillors knew their
constituents and presumably recognised the paucity of political support
from the State Government. The Queensland Treasurer and Member
for Bundaberg, E Walsh (ALP) and the Secretary for Health and Home
Affairs, W Moore (ALP), were conspicuously silent. Although not obvious
within the body of fluoride literature the Bundaberg proposal extended
into an era where an entrenched, but divided, state ALP government moved
towards the internecine split of 1957. The ensuing coalition years divided
political responsibility for water fluoridation between the health (Liberal)
and local government (Country Party) portfolios, and this fragmentation
permeated Queensland’s fluoride debates for decades.50 Finally, the role and
opinion of any local municipal Mayor has subsequently been established
as a critical factor within any fluoridation campaign.51 In Bundaberg, Buss
was, at best, ambivalent. Elected or bureaucratic advocates (or opponents)
to fluoride played a similar role. There was no persistent, public fluoride
advocate within the Bundaberg City Council. The converse was true in that
some councillors emerged with views opposed to water fluoridation. This
evidence suggests that the problems at Bundaberg were political, tactical
and sociological. They were not related to the contemporaneous science
underwriting water fluoridation.
13
This paper integrates a 1952-57 Bundaberg experience into its
contemporaneous social context and demonstrates how this interface
was projected into the city’s fluoridation politics. The official response
to meticulous scientific planning was rejection, framed as a delay to seek
information and then to elicit public support. These developments were a
significant blow to dental research and damaged prospects for future water
fluoridation proposals in Queensland. The methods and outcomes alienated
clinicians and researchers within the Faculty of Dentistry at The University
of Queensland, demoralised local dentists and demonstrated that political
tactics were integral components within community management of
fluoride-related controversy.
In Bundaberg, water fluoridation passed from a scientific to a political
arena. This experience set a Queensland precedent, crystallised formal
resistance, generated political concern and exposed problems that still
permeate Queensland’s fluoridation debate. The causes were many.
Fluoride advocacy was in its infancy and proponents used tactics that
ignored the beliefs and attitudes of the Bundaberg community. The
Dental Faculty placed too much faith in science over politics. The
socio-political circumstances were misread and insufficient attention
was paid to the impact of the 1928 vaccination tragedy. However,
the contemporaneous NHMRC guidelines, which were reflected in the
Department of Health directives, constrained the proponents’ and the
City Council’s options. Lumb and Kruger faced additional scientific,
geographic and infra-structural restrictions that limited Queensland
locations as water fluoridation research sites. The Dental Faculty offered
Bundaberg’s municipal leaders an authoritative well-planned pilot scheme
and an eminent world-class researcher. However, councillors who were
not scientists had to assume responsibility for a scientific decision. They
were given discreet administrative support but State parliamentarians
failed to publicly endorse water fluoridation. It is not surprising that
councillors, who well understood their local community, perceived water
fluoridation as a political issue. In response to actions from ratepayer
groups, Social Crediters and anti-fluoride groups, councillors forged an
innovative referendum policy, requiring 3,000 signatures before a poll
would be conducted. This milieu was the partial genesis of an anti-fluoride
movement, which in Queensland became self-propagating, institutionalised
and still carries consequences for oral health in this state.
Endnotes
The authors acknowledge the co-operation of the Bundaberg City Council and Enid
Cullen.
1 Commonwealth Department of Health, Fluoridation of water a collection of reports
14
and statements, Canberra, Australian Government Publishing Service, 1985, pp. 34-6.
2 HF Akers and SAT Porter, ‘A historical perspective on early progress of water
fluoridation in Queensland 1945-54: Sheep, climate and sugar’, Australian Dental
Journal, vol. 49, no. 2, 2004, pp. 61-6 and MA Simmonds, ‘The medication of water
supplies’, Queensland Dental Journal, vol. 4, no. 11, 1952, pp. 388-93.
3 HF Akers and SAT Porter, ‘The 1945 – 1955 Queensland artesian fluoride experience:
a unique phenomenon within the Australian wool industry’, Historical Records of
Australian Science, vol. 18, no. 2, 2007, pp. 177-89.
4 National Health and Medical Research Council, National Health and Medical Research
Council measures for the partial prevention of dental caries, Canberra, NHMRC, 1954,
pp. 1-3.
5 SF Lumb and BJ Kruger, Report on fluoridation, Brisbane, University of Queensland
Faculty of Dentistry, 1953, pp. 1-11.
6 SF Lumb to F Buss, 12 October 1954 and SF Lumb to JE Jordan, 31 August 1955,
Personal collection in author’s possession.
7 ‘Council to consider water fluoridation’, Bundaberg News-Mail, 20 October 1954, p.
4.
8 HF Akers and SAT Porter, ‘Water fluoridation: the engineers’ perspective’, Water, vol.
31, no. 6, 2004, pp. 44-9.
9 Lumb and Kruger, Report on fluoridation, p. 4.
10 ‘Fluoridation move backed “in interest of dental health”’, Bundaberg News-Mail, 9
May 1956, p. 3.
11 ibid., and J Francis to Bundaberg City Council, 29 May 1956, Personal collection in
author’s possession.
12 P Trundle, ‘Is the dentist’s drill on the way out?’, Courier-Mail, 5 June 1953, p. 2
and SF Lumb to W Forgan Smith, 2 March 1953, Personal collection in author’s
possession.
13 G Simmonds, ‘Preventive dentistry’, Queensland Dental Journal, vol. 4, no. 5, 1952,
pp. 178-80 and J Sagar, ‘Editorial – the role of sugar in dental caries’, Queensland
Dental Journal, vol. 4, no. 10, 1952, p. 366.
14 ‘Sugar answers its critics on diet and good health’, Australian Sugar Journal, vol. 46,
no. 6, 1954, pp. 361-5.
15 ‘Mr Muir replies to “attack” on sugar’, Bundaberg News-Mail, 9 June 1953, p. 3.
16 P Trundle, ‘Is the dentist’s drill on the way out?’, p.2.
17 Lumb to Forgan Smith, 2 March 1953.
18 Lumb to Buss, 12 October 1954.
19 SF Lumb to Jordan, 31 August 1955.
20 Commonwealth Department of Health, Fluoridation of water a collection of reports
and statements, Canberra, Australian Government Publishing Service 1985, p. 35.
21 ‘Council to consider water fluoridation’, Bundaberg News-Mail, 20 October 1954, p.
4.
22 F Martens, ‘Fluorine and caries’, Bundaberg News-Mail, 22 October 1954, p. 3; ‘No
danger in water fluoridation’, Bundaberg News-Mail, 26 October 1954, p. 4 and
‘Council to consider water fluoridation’, Bundaberg News-Mail, 20 October 1954, p.
4.
23 Bundaberg City Council Public Utilities Committee, Minutes submitted to Bundaberg
City Council on 28 October 1954, pp. 1-2.
24 ‘Decision deferred on water fluoridation’, Bundaberg News-Mail, 29 October 1954, p. 2.
15
25 ibid.
26 F Martens, ‘Fluorine and caries’, Bundaberg News-Mail, 22 October 1954, p. 3; L
Guth, ‘Water supply’, Bundaberg News-Mail, 30 October 1954; ‘Not “guinea pigs”
on fluoridation’, Bundaberg News-Mail, 5 November 1954, p. 2 and ‘Strong attack on
mayor over polio’, Bundaberg News-Mail, 4 November 1954, p. 2.
27 ‘Strong attack on mayor over polio’, Bundaberg News-Mail, 4 November 1954, p. 2 and
‘Not “guinea pigs” on fluoridation’, Bundaberg News-Mail, 5 November 1954, p. 2.
28 ‘City in mourning – Bundaberg grief stricken’, Brisbane Courier, 30 January 1928, pp.
13-15.
29 T Healy, ‘The memory lingers’, Queensland Environmental Health, September 1992,
pp. 10-13.
30 B Courtice, Interview by H Akers, 25 May 2003 and M Derry, ‘Vaccination tragedy
revisited – researching tragic deaths’, Bundaberg News-Mail, 23 November 2002,
p. 4.
31 ‘North boy polio victim’, Bundaberg News-Mail, 22 October 1954, p. 2 and ‘Strong
attack on mayor over polio’, Bundaberg News-Mail, 4 November 1954, p. 2.
32 ‘Decision deferred on water fluoridation’, Bundaberg News-Mail, 29 October 1954,
p. 2; ‘No fluoridation without vote’, Bundaberg News-Mail, 8 December 1954;
Bundaberg City Council, Minutes of council meeting, 23 December 1954, p. 2 and
‘Would supply data on fluoridation’, Bundaberg News-Mail, 17 November 1954, p. 5.
33 ‘No fluoridation without vote’, Bundaberg News-Mail, 8 December 1954.
34 Bundaberg City Council, Minute of a council meeting, 23 December 1954. p. 2.
35 ‘Claims argument for water fluoridation “grossly misleading”’, Bundaberg News-Mail,
26 January 1955.
36 Lumb to Jordan, 31 August 1955.
37 DW de Louth, ‘Fluoridation’, Fluoridation and Conspiracy, vol. 5, August, 1956,
p. 4 and FT Griffiths, Poison in your water supply, Brisbane, Queensland Anti-Fluoride
Association, 1956, p. 2.
38 HG Jones, JA Sagar and W Morrison, A history of the Australian Dental Association
(Qld Branch) 1906-1992, Brisbane, ADA (Qld Branch), 1995, p. 123.
39 A Saranin to LJ Lucas, 7 March 1956, Personal collection in author’s possession.
40 ‘Fluoridation move backed “in interest of dental health”’, Bundaberg News-Mail,
9 May 1956, p. 3.
41 L Lucas to A Fryberg, 11 June 1956, Personal collection in author’s possession.
42 A Fryberg to LJ Lucas, 18 June 1956, Personal collection in author’s possession.
43 ‘To seek opinion on water fluoridation’, Bundaberg News-Mail, 8 June 1956, p. 4.
44 ‘Strongly oppose fluoridation in Bundaberg’, Bundaberg News-Mail, 7 June 1956,
p. 4.
45 W Smyth to Bundaberg City Council, 25 June 1956, Personal collection in author’s
possession.
46 Bundaberg City Council, Minutes of council meeting, 5 July 1956, p. 1.
47 Rockhampton Anti-Fluoridation Association, Minute Book 1956-1968, 4 October
1956 and J Harding, ‘The fluoridation battle in Australia’, 1961, pp. 1-3. Fryer Library,
University of Queensland Library, Jack Harding collection, UQFL 265, box 22 and
10.
48 Jones, Sagar and Morrison, A history of the Australian Dental Association (Qld
Branch), p. 126.
49 HF Akers, SAT Porter and R Wear, ‘Water fluoridation in Queensland, why not?
16
Timing, circumstance, and the nature of the Fluoridation of Public Water Supplies Act
(1963)’, Health and History, vol. 7, no. 2, 2005, pp. 30-55.
50 ibid., and HF Akers and MP Jackman, ‘A paralysis in public health policy: water
fluoridation in Queensland (1996-2006)’, ADAQ News, April 2007, pp. 10-14.
51 RL Crain, E Katz and DB Rosenthal, The politics of community conflict the fluoridation
decision, Indianapolis, Bobbs-Merrill Company Inc, 1969, pp. 132-3.
IS OUR WATER SAFE TO DRINK?
by J. Gordon Millichap, MD, Pediatric Neurologist, Northwestern University
Medical School and the Attention Deficit Disorder Clinic, Division of
Neurology, Children’s Memorial Hospital, Chicago, Illinois,

and Kathleen Haviland, JD, Managed Care Specialist, On Lok, Inc., San
Francisco, California, and former aide to United States Congressman John
D. Dingell.

Material for this article was adapted from Dr. Millichap’s new book, IS OUR
WATER SAFE TO DRINK? A guide to Drinking Water Hazards and Health
Risks, (ISBN 0-9629115-5-0, PNB Publishers, P.O. Box 11391, Chicago,
Illinois 60611)

The safety of our drinking water is often taken for granted. In recent years,
however, environmentalists and the media have drawn attention to the
dangers of ground water pollution and the health risks from lead, chlorine,
pesticides, organic chemicals, and various microorganisms that have been
found to contaminate our public water supplies. Outbreaks of waterborne
diseases are a common occurrence and have involved entire city
populations, sometimes leading to serious complications and even
fatalities. The potential carcinogenic effects of long-term exposure to
certain organic chemicals in our water supplies are of increasing concern
in this industrialized society.

What is the United States Government doing to safeguard our water?

The controlling law governing our drinking water is the Safe Drinking Water
Act (SDWA) of 1974, as amended. The SDWA provides the Environmental
Protection Agency (EPA) the authority to safeguard public drinking water
through regulatory programs that protect groundwater aquifers and to
establish standards for the purification, treatment, and testing of municipal
water supplies.

Both the House of Representatives and the Senate passed their own
versions of the reauthorization of the SDWA in the 103rd Congress, but
they adjourned before differences could be reconciled and a law passed. In
the new 104th Congress, as of press time, contentious issues are delaying
debate over the reauthorization of the Act. The Chairman of the Senate
Committee on Environment and Public Works, John Chafee (R-R.I.) is
favoring the reauthorization vehicle that he co-sponsored in the 103rd
Congress, S.2019, which passed the Senate in May of 1994. S.2019 would
have given the EPA greater flexibility to consider the relationship between
costs and health benefits when setting future drinking water standards.

However, the Chairman of the Subcommittee on Drinking Water, Fisheries,


and Wildlife, Richard Kempthorne (R-ID), is in conflict with his full
committee chairman in that he supports much weaker regulatory language.
He favors language that would base standards on what is technologically
achievable, as opposed to feasible; he also favors language that would
require proposed standards to be subjected to explicit cost-benefit
analyses and to be justifiable in terms of the risk reduction produced. The
proposals in Congress favor a weakening of Federal standards and
controls and the transfer of some responsibility for water quality from the
EPA to the States and local governments, which are often ill equipped and
under funded.

The carcinogenic properties of organic chemicals as well as radionuclides


are a main cause for concern. Public health authorities have in the past
relied more on filtration and disinfection treatment processes rather than
water monitoring to ensure the safety of drinking water, because of the
complexity of laboratory analyses. In recent years, more communities are
using treatment processes other than disinfection to remove inorganic and
organic contaminants. The cost of meeting stricter water quality standards
is particularly high for smaller communities.
The proposals in Congress favor a weakening of Federal standards and
controls and the transfer of some responsibility for water quality from the
EPA to the States and local governments, which are often ill equipped and
under funded.

In the State of Illinois, beginning January 1993, all municipal suppliers are
required to monitor for 29 synthetic organic chemicals (SOCs), mostly
pesticides. All surface water suppliers must test quarterly until no SOCs
are detected or the level of each contaminant is below its maximum
contaminant level (MCL). Ground water suppliers will test for most of the
SOCs before December 31, 1995 unless the present Congress votes to
change these regulations and a less restrictive bill is passed into law.

Do we need to spend more on improved water purification technologies


and a tightening of EPA standards for potential cancer-causing chemicals,
or should we cut costs and limit regulation of contaminants to those known
to cause the greatest immediate health risks, for instance, lead? The former
solution would result in criticism by state and local governments who find
the present regulations to be costly and sometimes impractical, particularly
for smaller municipalities, while the latter would probably lead to an even
greater incidence of cancer (and other diseases) among our citizens and
will certainly cause an outcry from environmentalists who are pressing for
more stringent controls.

Is the consumer sufficiently informed of risks?

There is a need for education of consumers regarding the sources and


types of water contamination, the recognition of symptoms of waterborne
diseases, and home methods for prevention and control of drinking water
hazards. Some waterborne health hazards, such as lead, nitrate, arsenic,
and mercury, can be avoided by having municipal or well water checked
and by taking certain precautions. For example, to avoid lead from old
plumbing, flush the faucet until the water is cold before drinking.

Bacterial contamination should be suspected at times of flooding or


earthquake. The water should be boiled or chlorinated, or bottled water
substituted. A sudden change in water appearance from clear to turbid
might suggest contamination with the parasite, Cryptosporidium, the
organism that caused serious diarrheal illness in one half million of the
population of the city of Milwaukee in the spring of 1993, with 100 fatalities.
Avoidance of water that loses its clarity or develops an unpleasant odor or
taste could protect the consumer from potential health risks caused by a
faulty public water filtration system.

There is a need for education of consumers regarding the sources and


types of water contamination, the recognition of symptoms of waterborne
diseases, and home methods for prevention and control of drinking water
hazards.

While these simple consumer tips and precautions may help in avoidance
of acute illness caused by waterborne microorganisms and certain
inorganic pollutants, for example, nitrate and arsenic, the far more serious
danger of the chronic and lifetime exposure to potentially carcinogenic
organic chemicals will persist and remain unanswered. Only our
government and a more environmentally responsible corporate industrial
society can lower the carcinogenic hazards lurking in our water and food
supplies, since only they have the resources to prevent or remove these
contaminants.

Is the medical profession sufficiently aware of the problem?

The massive outbreak of Cryptosporidium parasitic infection in Milwaukee


in 1993 was a reflection not only of the inadequate filtration system and
inefficient water quality monitoring but also resulted from the slow
response of physicians to recognize and diagnose the cause of the
waterborne illness in patients who sought medical help. Cases were
misdiagnosed as viral gastroenteritis or "intestinal flu" without further
investigation, and the special testing procedures required for the detection
of Cryptosporidium in stools examined for ova and parasites were not
requested. The delay in diagnosis resulted in an outbreak involving nearly
one half a million individuals. If the medical community had been more
alert to possible contamination of water supplies with parasites, the
outbreak would have been contained and the deaths of 100 patients may
have been prevented.

. . . a federal lawyer for the AMA stated that "clean water is an


environmental and political issue and not strictly a health matter." This
apparent disinterest or ignorance of the hazards and health risks of
contaminated water by representatives of our medical profession is
alarming.
In the treatment and prevention of various cancers, the influence of
environmental factors, especially chemical and viral contamination of
drinking water and foods, has received little attention in medical oncology
research. The American Medical Association is not actively involved in
lobbying for cleaner water and the passage of legislation to maintain strict
governmental controls of water resources. In answer to a question
regarding the role of the AMA in the present overhaul of the Clean Water
Act, a federal lawyer for the AMA stated that "clean water is an
environmental and political issue and not strictly a health matter." This
apparent disinterest or ignorance of the hazards and health risks of
contaminated water by representatives of our medical profession is
alarming.

Contamination of Public Water Supplies and Microbial Disease Outbreaks

The safety and quality of drinking water in the United States are dependent
on the efficiency and maintenance of the water treatment processes
commonly used in most public water systems. The removal of
microorganisms by disinfection and filtration has dramatically reduced the
incidence of waterborne diseases such as typhoid fever, cholera, and
hepatitis, and the banning of lead in pipes and solder has reduced the
exposure of millions of Americans to lead and the risks of lead poisoning.

The Safe Drinking Water Act of 1974 and the Amendments of 1986 set
standards of drinking water quality to protect our health, but deficiencies in
filtration technology and regulatory programs enforcing these goads have
led to numerous outbreaks of disease. Tests employed to check for certain
parasitic organisms and viruses are sometimes inadequate and the disease
causing or pathogenic nature of parasites such as Blastocystis hominis,
especially in immuno-compromised individuals with cancer or AIDS, is
often not recognized.

The Safe Drinking Water Act of 1974 and the Amendments of 1986 set
standards of drinking water quality to protect our health, but deficiencies in
filtration technology and regulatory programs enforcing these goads have
led to numerous outbreaks of disease.

A total of 96 outbreaks of waterborne disease reported to the Center for


Disease Control and the Environmental Protection Agency, 1986-1992,
accounted for 46,712 confirmed cases of gastrointestinal illness. The
majority of cases were either of unknown cause, presumed viral in origin,
or traced to Crybtosporidium. Other common organisms were Salmonella,
E. coli, Campylobacter, and hepatitis A. Since the 1993 outbreak in
Milwaukee, Cryptosporidium has outnumbered all other organisms in
terms of numbers of individuals affected by waterborne illness.

Drinking water suspected of bacterial contamination should either be


boiled, chlorinated, or bottled water substituted. Chlorination will not
remove Cryptosporidium and the water must be boiled or filtered by
reverse osmosis.

Lead in Our Drinking Water

Lead in drinking water contributes between 10 and 20 percent of the total


environmental exposure to lead. Young children are particularly
susceptible to lead poisoning, and even low dose exposure can cause
intellectual deficits and behavior disorders. Water as a source of lead
poisoning may increase in relative importance since leaded gas has been
abolished and abatement programs have reduced exposure from lead-
based paint and urban soil and dust.

Chlorination will not remove Cryptosporidium

The EPA estimated in 1986 that some 40 million Americans were drinking
water that contained potentially hazardous levels of lead. Until 1993 the
EPA limit for lead levels in drinking water was 50 parts per billion (ppb).
The new limit for lead has now been set at 15 ppb. Approximately half a
million children with hazardous lead levels in their blood will be benefited,
and lead exposure will be minimized for millions of Americans.

Simple consumer steps to reduce lead exposure from drinking water

These include the following:

• Flush the faucet until the water is cold before drinking. Water
obtained after flushing will not have been in extended contact
with pipes or solder that may contain lead.
• Never cook with or drink and do not mix the baby formula with
water from the hot tap. Hot water dissolves greater quantities of
lead more quickly than cold water. Formula preparation with
lead contaminated water accounted for 9 of 50 cases of lead
poisoning reported in infants in the year 1992.
• Have your water tested for lead and purchase bottled water for
home and office consumption, if public supplies are suspect.
• In a newly built home, remove all strainers from faucets and
flush the water for at least 15 minutes to remove loose solder
or flush debris from the plumbing. Plumbers should use only
lead-free materials, but monitoring is sometimes deficient. The
newer the plumbing installation, the greater the risk of lead
leaching from pipes, especially when the water is soft, acidic
and corrosive. Older pipes develop a protective coating of
mineral deposits on the inside, insulating the water from the
solder and decreasing the danger of leaching lead.
• Water softeners should be avoided in homes where lead is a
problem. They may contribute to corrosiveness of the water
and increase the potential for lead contamination.
• Well water may contain lead from a submersible pump
containing brass and bronze alloys. The pump may need to be
replaced or a reverse osmosis or cartridge filtering unit
installed. The Water Quality Association will advise on water
filters for specific purposes (Website: www.wqa.org ).

Contaminants Peculiar to Well Water

Coliform bacteria, nitrates, and arsenic contaminate well water more


commonly than municipal water supplies. The presence of nitrates
suggests that animal or human wastes or fertilizers used in agriculture or
on lawns are entering the well from land runoff, seepage, or migration into
ground water aquifers. Nitrates are of special concern to the health of
young children, and in women of child-bearing age. Nitrates converted to
nitrites in the stomach cause methemoglobinemia in infants. The
hemoglobin in the blood is oxidized to methemoglobin, a form of
hemoglobin that cannot bind and carry oxygen from the lungs to the
tissues. The blood turns a chocolate brown color and the patient’s skin
becomes gray blue or cyanotic. Water containing nitrate in amounts greater
than the permitted maximum contaminant level (MCL, 10 mg/L) should be
avoided and bottled water substituted. Nitrate-containing water should not
be boiled, since evaporation will result in increased concentrations of
nitrate.

Nitrates are of special concern to the health of young children, and in


women of child-bearing age.
An outbreak of methemoglobinemia in New Jersey in 1992 involved more
than 40 elementary school children in first through fourth grades. They
visited the school nurse within a 45-minute interval following the school
lunch period. They all suffered from an acute onset of blue lips and hands,
vomiting, and headache. Fourteen were hospitalized, and all recovered in
36 hours. The outbreak, due to nitrite poisoning, was traced to soup
contaminated by nitrites in a boiler additive. The authors of this reported
incident aptly named the soup "Boilerbaisse."

Nitrites are also potentially carcinogenic. They act on amines in the diet to
form nitrosamines, which have been shown to cause cancer in animals.
High levels of nitrate have been found in well waters of regions of China,
Columbia, and in two towns in England where the incidence of stomach
cancer is unusually high. A link between nitrate in well water and cancer of
the stomach needs further investigation.

EPA National Survey of well water

The EPA has completed a five-year national survey of nitrate and


pesticides (NPS) in drinking water wells. Of 10 million rural domestic wells
that were studied, nitrate was detected in 57 percent, pesticides in 4
percent, and both in 3 percent. The pesticides detected most frequently in
the survey were DCPA (Dacthal) acid metabolites and atrazine. DCPA is a
herbicide used primarily as a weedkiller on lawns, turf, and golf courses,
and on some fruits and vegetables. Atrazine is used to control annual
broadleaf weeds and grasses in corn and soybean farms.

Pesticides had been used at about 80 percent of homes and farm


properties where domestic wells were located. These pesticides migrate
through soil and some had concentrated in rural domestic wells at levels
above their maximum contaminant levels (MCLs) and health advisory levels
(HALs).

Pesticides had been used at about 80 percent of homes and farm


properties where domestic wells were located. These pesticides migrate
through soil and some had concentrated in rural domestic wells at levels
above their maximum contaminant levels (MCLs) and health advisory levels
(HALs).

A variety of potentially carcinogenic chemicals used in industry, business,


or households may endanger the safety of drinking water obtained from
wells. The evidence of widespread migration of chemicals into wells
demonstrates the need for improved ground water protection.

Well owner safety tips include the following:

• Avoid sources of contamination, such as use of synthetic


fertilizers and herbicides and careless disposal of cleaning
fluids and other household wastes;
• Test well water periodically for nitrate, coliform organisms, and
also arsenic in some areas;
• Consult a health department official if a sudden change in the
appearance, taste, or smell of the water is noted and
contamination is suspected. Call the EPAs Safe Drinking Water
Hotline (800-426-4791) for names and telephone numbers of
state certification officers.

Cancer Related Water Pollutants

Cancer related hazards in drinking water are man-made and are derived
from industrial, domestic, and agricultural wastes, the polluted
atmosphere, leaching from soil, land runoff, motorboat engines, and spilled
chemicals. There are four main groups of potential carcinogenic chemicals:

1) synthetic organic chemicals (SOCs)—pesticides including lindane,


chlordane, 2,4-D, endrin, and toxaphene;

2)volatile organic chemicals (VOCs)—industrial chemicals and solvents,


degreasing agents, varnishes, and paint thinners, including carbon
tetrachloride, vinyl chloride, and benzene;

3) polychlorinated biphenyls PCBs)—waste products from electrical


transformer, capacitor, and plasticizer factories, banned in the 1970s but
persisting in the water of rivers and the Great Lakes, where they were
dumped years ago; and

4) trihalomethanes (THMs)—by-products of chlorine disinfection of


drinking water, especially chloroform.

The disinfection of water with chlorine is the source of cancer risk


receiving most attention from the EPA. The Food and Drug Administration
in 1976 restricted the use of chloroform that previously had been employed
in cough syrups, mouthwashes, toothpastes, and other common consumer
products. The cancer risk of exposure to chloroform may have decreased
over the past 20 years, but chloroform in drinking water is a significant
cancer-related hazard.
The disinfection of water with chlorine is the source of cancer risk
receiving most attention from the EPA.

The EPA regulates and monitors the maximum contaminant levels (MCLs)
of organic pollutants, and the World Health Organization (WHO) issues
guideline values, the concentration of a chemical in drinking water
associated with an estimated risk of one additional case of cancer per
100,000 population over a lifetime of 70 years exposure. None of these
guidelines take into account the additive and synergistic effects of the vast
number of chemicals to which we are exposed.

Cancer Risk: Incidence and Assessment

Cancer may be caused by a combination of factors, both environmental


toxins and internal susceptibility. Environmental causes include chemicals,
infection with viruses, and ionizing radiation. Internal factors are hormonal,
changes in the immune system, and inherited mutations. An interval of ten
or more years may pass between exposure to chemicals or radiation and
the clinical signs of cancer. A steady rise in cancer mortality rate in the
United States has been recorded by American Cancer Society statistics in
the last 50 years. One out of every five deaths is from cancer and more
than one half million deaths from cancer are expected this year.

Although lung cancer is the major reason for this increased incidence,
other forms of cancer are also responsible for the increased cancer
mortality. For example, breast cancer incidence rates for women have
increased about 2 percent a year since 1980, and they now number 110 per
100,000. Breast cancer is the second major cause of cancer death in
women and, unlike many other cancers, a five year survival does not
necessarily mean a cure of breast cancer. The number of deaths from
breast cancer per 200,000 population in 1961 was 24,311 and in 1991, it had
risen to 43,583, an increase explained partly by the aging of the population
but also by a greater profusion of industrial and agricultural organic
chemicals in our environment.

Risk assessments are therefore very rough estimates.


The determination of potential cancer risk from chemicals in water and
food is usually based on long-term animal studies. Data are also available
on the incidence of cancer in humans, mostly from occupational exposure.
Risk assessment is in two stages: 1) identification of the toxic properties of
potential carcinogens, and 2) measurement of the degree of human
exposure to the chemical.

Chemical hazards are tested for oncogenicity in laboratory animals or cell


systems and in clinical and epidemiological studies. Levels of exposure
through air, water, and food are measured and the degree of contact with
the hazard is estimated. Risk assessment is usually based on high-dose
exposure for a short time in animals. In setting human safety standards,
scientists must extrapolate from animals to humans and from high-dose
acute exposures to low-dose long-term conditions. Risk assessments are
therefore very rough estimates. The EPA tends to rely on data showing the
highest incidence of cancer for setting regulatory controls, but some
authorities question the value of present estimates from laboratory animals
and call for improved methods more relevant to humans.

Water source and risk

Epidemiological studies of populations exposed to surface, upland,


chlorinated, and reused waters have demonstrated an increased incidence
of cancer of the gastrointestinal and urinary tracts. As one example of a
population-based approach, United States case-controlled studies in New
York counties compared mortality from gastrointestinal and urinary tract
cancer with noncancer death controls. There was an excess of male deaths
in chlorinated surface water areas from cancer of the esophagus, stomach,
large intestine, rectum, liver, kidney, pancreas, and bladder, and an excess
of female deaths from cancer of the stomach.

Upland surface water and polluted river sources that have been chlorinated
carry the highest risk of cancer. Unchlorinated ground water has the lowest
cancer risk.

In England, the relative risks of river Thames reused water and upland
water compared to ground water showed a statistically significant
increased risk of stomach cancer mortality in persons supplied by upland
and river water for drinking purposes.

Upland surface water and polluted river sources that have been chlorinated
carry the highest risk of cancer. Unchlorinated ground water has the lowest
cancer risk. Studies have shown sufficient evidence of a cancer risk
associated with organic micropollutants in certain drinking waters that a
causal relationship has been accepted. The high prevalence of polluted and
chlorinated waters in public supplies demand the enforcement of EPA
regulations to monitor the MCLs of organic pollutants.

Consumer risk assessment factor

Consumers vary in the way they view these hazards and their respective
risks. Some will accept a small risk without concern for health effects
whereas others will view any risk as unacceptable and cause for alarm.

"Is the Water Safe to Drink?" not "How Safe is Our Drinking Water?" is the
question asked by many consumers at a personal level. Unfortunately, a
simple "yes" or "no" answer is not possible, given the many variables in
water sources, environmental factors, and water treatment processes.
Clearly, there is a risk involved by ingesting low levels of organic chemical
contaminants every day of our lives. That one additional case of cancer per
100,000 population might be someone close!

The following guidelines relate to possible carcinogens in our drinking


water:

• Use activated carbon filtration in the home to remove chlorine


and reduce levels of organic materials, including
trihalomethanes, the by-products of chlorination, some volatile
organic contaminants, and certain pesticides, including
fungicides. The level of contaminant removal will vary with the
size and type of filter, the degree of pollution, and the
frequency of carbon renewal. All carbon filters require periodic
replacement of cartridges to maintain efficiency and to lessen
the risk of bacterial overgrowth.
• Substitute bottled water in areas of landfills where risk of
organic chemical pollution is high or where cancer clusters
have been observed.
• Alternate consumption of municipal water with various brands
of bottled water, to avoid longterm exposure to one possible
source of cancer-related drinking water pollutants.

Bottled Water Usage and Safeguards

Public concern with both the quality and safety of drinking water has
become so compelling that many consumers now rely almost exclusively
on bottled water for drinking purposes. Bottled water is now preferred by
millions of Americans and the cost is enormous. To learn that regulations
governing the purity and safety of bottled water are often less stringent
than those for municipal water supplies may come as a surprise to some
consumers.

Bottled water is a luxury to many and a necessity to others. Company


advertising has promoted bottled water as "purer," "safer,<!70> "chlorine-
free," and an essential component of a healthy lifestyle. It is not generally
recognized that one-third of all bottled water in the United States comes
from public water supplies and is no safer than the water obtained from the
faucet.

An Environmental Policy Institute Report (1989) refers to the frequency of


contamination of bottled water with low levels of heavy metals, solvents,
and bacteria. The carcinogenic chemical migrants (for example, methylene
chloride and vinyl chloride) from plastic bottle containers are also a
concern. Despite the value of bottled water as an alternative source of
drinking water at times of emergency, consumers should not presume that
bottled water is invariably preferable to tap water.

Buy bottled water

• If your drinking water suddenly becomes turbid, changes in


color or taste, or an unpleasant odor develops.
• If you learn that the public water system has become
contaminated and you are instructed to boil the water. Bottled
water is a simpler alternative.
• At times of floods or earthquakes when water contamination is
a common hazard.
• If your home has lead pipes or lead solder. Drink bottled water
until your water has been tested.
• If you have a private well and you suspect contamination with
coliform bacteria or nitrates. Drink bottled water until the well
water is tested.
• If your neighborhood has a cluster of cancer patients and water
contamination from a landfill is suspected. Bottled water may
be safer than community water supplies or private wells.
• If you need to limit your intake of sodium for medical reasons.
Bottled waters of low sodium content or distilled water may be
preferred to public supplies.
• If you are traveling and suspect contamination of local water
supplies. Drink only brand named bottled waters from sealed
containers.
• If your water tastes strongly of chlorine. Bottled water is
preferable for cooking as well as drinking. Bottled water does
not contain chlorine and does not taint food.
• Buy well known and respected brands of water from approved,
protected sources and bottled at the source. Alternate the
brands and check the expiration dates in order to limit the
dangers of bacterial growth and the concentration of plastic
chemical contaminants after prolonged storage.

Consumer Concerns and Home Water Treatments

The most frequent questions asked by consumers are about the level of
lead in their drinking water and about taste and odor problems. "Is our
water safe to drink?" "Do we need to substitute bottled water?" "Should we
install a home water treatment unit and, if so, which type of unit would be
most satisfactory for our particular needs?"

The EPA provides information in response to inquiries about the necessity


for home treatment units. It does not regulate the manufacture, distribution,
or use of these units. The EPA stresses that the units should not be relied
upon for the removal of organisms and chemicals injurious to our health.
Nonetheless, certain filtration units, especially reverse osmosis, will lower
the concentration of several contaminants, including lead, copper, nitrates,
pesticides, and parasites. No system is warranted for complete elimination
of all contaminants.

The government and the medical profession appear to be failing in their


duties.

Controversies concerning the sale and use of home treatment units have
arisen because of unsubstantiated claims of benefits and scare tactics.
Consumers should beware of "free" water testing by a salesperson to
determine the drinking water quality. An independent analysis is usually
more accurate and meaningful.

Conclusion

The government and the medical profession appear to be failing in their


duties. The former should ensure the safety of our drinking water and the
latter should recognize of health risks associated with contaminants. The
more we understand about our own local water supplies and the nature of
the health risks, the more we as consumers and citizens can do to protect
ourselves from these hazardous environmental pollutants and their
sources.
_____________

Selected Bibliography

American Academy of Pediatrics, 1994 Red Book: Report of the Committee


on Infectious Diseases, 23rd edition, Elk Grove Village, Illinois.

Askew, G.L. et al., "Boilerbaisse: an outbreak of methemoglobinemia in


New Jersey in 1992," Pediatrics 94:381-4, September 1994.

Baghurst, P.A., et al, "Environmental exposure to lead and children’s


intelligence at the age of seven years," New England Journal of Medicine
327:1279-84, October 29, 1992.

Baron, E.J., L.R. Peterson, S.M. Finegold, Bailey and Scott’s Diagnostic
Microbiology, 9th edition, Mosby, St. Louis, 1994.

Mackenzie, W.R., N.J. Hoxie, M.E. Proctor et al., <169.A massive outbreak in
Milwaukee of Cryptosporidium infection transmitted through the public
water supply," New England Journal of Medicine 331:61-7, July 21, 1994.

Millichap, J.G., Environmental Poisons in Our Food, PNB Publishers,


Chicago, 1993.

Millichap, J.G., Is Our Water Safe to Drink? A Guide to Drinking Water


Hazards and Health Risks, PNB Publishers, Chicago, 1995.

Ram, N.M., E.J. Calabrese, R.F. Christman, Organic Carcinogens in


Drinking Water: Detection, Treatment, and Risk Assessment, John Wiley &
Sons, New York, 1986.

U.S. Center for Disease Control and EPA, "Waterborne disease outbreaks,
1986-1992," Morbidity and Mortality Weekly Reports, 1990, 1991, & 1993.

U.S. Congress House Floor Brief, "Safe Drinking Water Act of 1994,"
October 7, 1994.

U.S. Environmental Protection Agency, National Survey of Pesticides in


Drinking Water Wells, Phase1 Report, Washington , D.C., Office of Water,
Office of Pesticides and Toxic Substances, EPA, November 1990.

Idem., "Home water treatment units: Filtering fact from fiction," EPA,
Washington, D. C. 1992.

Idem., "Drinking Water Protection: A general overview of Safe Drinking


Water Act Reauthorization," Office of Water, February 1994.
Article from NOHA NEWS, Vol. XX, No. 4, Fall 1995, pages 3-8.
Isis Announces Award of Up to $8.4 Million in New Government
Grants and Contracts to Its Ibis Biosciences Subsidiary for
Pathogen Detection and Human Forensics

http://ir.isispharm.com/releasedetail.cfm?ReleaseID=338306

CARLSBAD, Calif., Oct 03, 2008 /PRNewswire-FirstCall via COMTEX News


Network/ -- Isis Pharmaceuticals, Inc. (Nasdaq: ISIS) announced today that
its majority-owned subsidiary, Ibis Biosciences, Inc. (Ibis), was awarded
government grants and contracts from the United States Department of
Agriculture (USDA), National Institute of Justice (NIJ) and other government
agencies totaling up to $8.4 million. These awards will fund the utilization of
several Ibis assays through Ibis' service laboratory to characterize samples
provided by the government sponsor and will provide support for further
development of assays to support government-sponsored projects. The focus
of these projects ranges from human forensics, to detection and identification
of influenza viruses and other pathogens, that could have a profound effect
on animal and human health.

The USDA Animal and Plant Health Inspection Service (APHIS) agency
awarded Ibis up to $4.2 million to fund the utilization of Ibis' commercial
influenza assay to identify and differentiate avian influenza strains, to
distinguish high pathogenicity from low pathogenicity strains, and to aid in
the tracking of avian influenza transmissions. The contract also provides
funding for the development of assays to detect a broad range of additional
agricultural pathogens that are considered important to animal health and
that could have a significant impact on the U.S.'s agricultural economy.

"We are pleased with the continuing support from our government partners
and the opportunity to expand our commercial applications, especially in
areas that are vital to our health and economy such as agriculture. As we
work closely with the USDA to develop additional products that can aid in the
monitoring and surveillance of avian flu, we will expand our detection assays
to meet the needs of the agricultural community," said Michael Treble,
President of Ibis and Vice President of Isis.

The NIJ also awarded Ibis a new two-year project that will fund the
development and implementation of next-generation human forensics
markers, which are measured on the Ibis T5000(TM) Biosensor System. In
addition to the new USDA and NIJ contracts, Ibis also received new contracts
from other government agencies that will fund expansion of pathogen
detection and identification assays and use Ibis' assay services laboratory.

Additionally, with Lovelace Respiratory Research Institute (LRRI), Ibis has


successfully completed the first year of a National Institutes of Health grant
in which the Ibis influenza assay characterized over 2,000 tissue extracts to
study animal models of influenza transmission. Through LRRI, Ibis has been
awarded the next year of funding to continue these efforts.

"The utilization of the Ibis platform by our existing partners and the
cultivation of new projects with new government agencies is a testament to
the broad applicability of our technology. The enthusiasm of our government
partners to invest in our technology to meet their objectives in homeland
security, animal and human health, and human forensics illustrates the
breadth and depth of the Ibis platform," said Steven A. Hofstadler, Ph.D.,
Vice President of Ibis Research.

"To date, we have earned approximately $73 million in revenue to fund


development of our biosensor system and our diverse commercial assays in
many different areas including biodefense and infectious disease surveillance.
We are now in the position to continue to fulfill our government contracts
while focusing on clinical applications with Abbott and quickly moving into
larger commercial markets," concluded Mr. Treble.

ABOUT IBIS T5000 BIOSENSOR SYSTEM AND IBIS BIOSCIENCES, INC.

Ibis Biosciences, Inc., a majority-owned subsidiary of Isis Pharmaceuticals,


has developed and is commercializing the Ibis T5000(TM) Biosensor System
for rapid identification and characterization of infectious agents. The Ibis
T5000 is currently intended for research use only and not for use in
diagnostic procedures. It is capable of identifying virtually all bacteria,
viruses and fungi, and can provide information about drug resistance,
virulence and strain type of these pathogens. Commercial applications for the
Ibis T5000 Biosensor System include epidemiologic surveillance, monitoring
of pandemic diseases, identification of emerging or previously unknown
pathogens, forensic characterization of human samples, identification of
sources of hospital-associated infections, and, in the future, human infectious
disease diagnostics. Ibis develops, manufactures and markets Ibis T5000
instruments and assay kits. Additional information about Ibis can be found by
selecting the Ibis link from Isis' homepage at http://www.isispharm.com.

ABOUT ISIS PHARMACEUTICALS, INC.

Isis is exploiting its expertise in RNA to discover and develop novel drugs for
its product pipeline and for its partners. The Company has successfully
commercialized the world's first antisense drug and has 19 drugs in
development. Isis' drug development programs are focused on treating
cardiovascular and metabolic diseases. Isis' partners are developing
antisense drugs invented by Isis to treat a wide variety of diseases. Ibis
Biosciences, Inc., Isis' majority-owned subsidiary, is developing and
commercializing the Ibis T5000(TM) Biosensor System, a revolutionary
system to identify infectious organisms. Isis is a joint owner of Regulus
Therapeutics LLC, a joint venture focused on the discovery, development and
commercialization of microRNA therapeutics. As an innovator in RNA-based
drug discovery and development, Isis is the owner or exclusive licensee of
over 1,500 issued patents worldwide. Additional information about Isis is
available at http://www.isispharm.com.

This press release includes forward-looking statements regarding the


development and commercialization of the T5000 Biosensor System, Ibis'
technology, and the revenue potential of certain government contracts and
grants. Any statement describing Isis' goals, expectations, financial or other
projections, intentions or beliefs is a forward-looking statement and should
be considered an at-risk statement, including those statements that are
described as Isis' goals or projections. Such statements are subject to certain
risks and uncertainties, particularly those inherent in the process of
discovering, developing and commercializing drugs that are safe and
effective for use as human therapeutics, in developing and commercializing
systems to identify infectious organisms that are effective and commercially
attractive, and in the endeavor of building a business around such products.
Isis' forward-looking statements also involve assumptions that, if they never
materialize or prove correct, could cause its results to differ materially from
those expressed or implied by such forward-looking statements. Although
Isis' forward-looking statements reflect the good faith judgment of its
management, these statements are based only on facts and factors currently
known by Isis. As a result, you are cautioned not to rely on these forward-
looking statements. These and other risks concerning Isis' programs are
described in additional detail in Isis' annual report on Form 10-K for the year
ended December 31, 2007, and its most recent quarterly report on Form 10-
Q, which are on file with the SEC. Copies of these and other documents are
available from the Company.

In this press release, unless the context requires otherwise, "Isis,"


"Company," "we," "our," and "us" refers to Isis Pharmaceuticals and its
subsidiaries.

Isis Pharmaceuticals is a registered trademark of Isis Pharmaceuticals, Inc.


Ibis Biosciences and Ibis T5000 are trademarks of Ibis Biosciences, Inc.
Regulus Therapeutics is a trademark of Regulus Therapeutics LLC.

SOURCE Isis Pharmaceuticals, Inc.

http://www.isispharm.com

Copyright (C) 2008 PR Newswire. All rights reserved

News Provided by COMTEX


National Pure Water Association
Draft Toxicological Profile for Fluorides
http://www.npwa.org.uk/index.php?option=com_content&view=article&id=103:draft-
toxicological-profile-for-fluorides&catid=37:to-be-categorised&Itemid=92

The Draft Toxicological Profile for Fluorides (2001), produced by the US Agency for
Toxic Substances and Disease Control (ATSDR), was presented for Public Comment
prior to publication.

The Toxicological Profile for Fluorides, which is updated from time to time, is
supposed, by most toxicologists, to be the quintessential work on fluoride toxicity.
However, whilst the Draft Profile deals with some salient aspects of F toxicity, the
credibility of the work is compromised throughout by the use of inappropriate dental
dogma and the promotion of water fluoridation as a prophylactic for dental caries.

After reading the following Comment to the ATSDR, Professor Albert Burgstahler, co-
author of "Fluoride, the Great Dilemma", wrote to George Glasser:

"Your letter to the ATSDR is a model of clarity and forensic skill."

Here is that letter

February 13, 2002

Agency for Toxic Substances and Disease Registry


Division of Toxicology
1600 Clifton Road
Atlanta, Georgia 30333

Dear Sirs,

"The mission of the Agency for Toxic Substances and Disease Registry (ATSDR),
as an agency of the U.S. Department of Health and Human Services,
is to serve the public by using the best science,
taking responsive public health actions, and providing trusted health information
to prevent harmful exposures and disease related to toxic substances."
- ASTDR WEBSITE

After reviewing the 2001 Draft Toxicological Profile for Fluorides, errors, omissions and
misrepresentations of research work were noted in the first and subsequent chapters.

Since publication of the 1993 Toxicological Profile on Hydrogen Fluoride, Fluorides, and
Fluorine, very substantive findings on the adverse health effects of a variety of fluorides
and fluorinated substances have been published. These have been excluded from the new
Draft, while disproportionate attention is given to the prophylactic effects of fluorides on
teeth.

On page 2, the authors refer to "sodium fluoride" as being "often" used to fluoridate
drinking water. On page 15, we read: "One of the principal uses for sodium fluoride is the
fluoridation of public water for the prevention of dental caries." There are many similar
statements throughout the Draft which mislead readers into believing that this chemical is
the most common fluoridating agent. Not until page 60, paragraph 2, do the authors
acknowledge (in passing?) ". . . hydrofluosilicic acid, so exposure to this chemical is
included in some epidemiological studies".

Hydrofluosilicic acid (H2SiF6) is used to fluoridate about 90% of the fluoridation


schemes in the US where populations exceed 10,000. The American Water Works
Association states very clearly that sodium fluoride (NaF) is used in a very small number
of water fluoridation schemes.

The only health-related epidemiological studies which directly address H2SiF6 were
done by Masters, et al. These were primarily concerned with the effects that
silicofluorides in drinking water have on the availability of lead.(1)(2)(3). Why were
these references not cited?

In his own 1931 review, McClure noted that previous experiments conducted in the
1920s by Taylor, et al showed that calcium fluorosilicate is more toxic to animals than
sodium fluoride.(4) Definitive experimental work on fluorosilicates was published by
Kick, et al, in 1935(5) (see Table). However, a later paper by McClure, et al in 1950,
selectively used Kick's findings to promote the use of fluorosilicates for drinking water
fluoridation.(6)

None of the early published experimental work on fluorosilicates is discussed or


cited in the Draft Profile. Moreover, the McClure review, "Availability of Fluorine
in Sodium Fluoride vs, Sodium Fluosilicate"; Public Health Reports Vol 65 No 37;
1175-86; 1950 has been omitted from the Draft.

The omission of such a vital body of science provokes the notion that the ASTDR
might have sought to avoid addressing the adverse health effects created by
exposures to fluorosilicates from any source.
Kick, et al 1935, pg. 61

Fluorine Supplement Time Fluorine Fluorine Fluorine Fluorine Fluorine Fluorine


in ingested in feces absorbed in urine balance retained
Days Mg. Mg. Mg. Mg. Mg. %
Rock Phosphate 10 213.6 131.5 82.1 20.5 +61.6 28.8
Sodium Fluorsilicate 23 269.9 94.3 175.6 93.6 +82.0 30.4
Sodium Fluorsilicate 22 269.9 94.4 175.5 90.2 +85.3 31.6
Sodium Fluoride 18 211.2 116.5 94.7 25.8 +68.9 32.6
Calcium Fluoride 11 229.6 225.5 4.1 4.2 -00.1 0.0

Kick was an eminent early pioneer in animal nutrition. Although McClure referred to the
above table in promoting the use of fluorosilicates for drinking water fluoridation, neither
he, nor any subsequent scientists took proper account of the data presented.

The Table shows significant differences in absorption from ingestion of sodium


fluorosilicates than from sodium and calcium fluorides.

In their extensive experiments, Kick et al demonstrated the bioavailability of F from the


different fluoride salts. They found that:

• The retention of sodium fluoride was similar to that of sodium fluorosilicate.


• The amount of F absorbed from fluorosilicates was about twice the level as that
from sodium fluoride.
• Urine levels of F in the sodium fluorosilicate groups were three times higher
than those found in the sodium fluoride groups.

The initial Kick, et al, experiments were undertaken using pigs as test animals to
determine the effects of fluorine in mineral supplements, primarily raw phosphate rock.
When the phosphate rock was digested in stomach acid (a process similar to creating
phosphoric acid), one of the products was H2SiF6. On autopsy, the scientists found that
chronic, parenchymatous nephritis (kidney failure) had occurred in the pigs. They wrote:

• They were pale in color, contracted, and firm in texture, and their surfaces
roughened by numerous nodules and depressions. The capsules were slightly
thickened, and in some instances, firmly adherent to the surface.
Occasionally, small cysts containing a clear or amber colored fluid protrudes
above the surface, or were more deeply situated in, the kidney. One section of
the cortex appeared reduced in width, and frequently the medulla contained
a considerable amount of fat.

Microscopically the kidneys showed a nephritis with a varying degree of


degeneration of the tubular epithelium and, as a terminal result, the replacement of
many tubules and glomeruli with fibrous tissue. None of the animals in the sodium
fluoride-fed lot exhibited this condition.(7)
Taylor GE, 1929 noted that calcium fluorosilicate caused more adverse health effects in
dairy cows than sodium fluoride.(8)

These fundamental experimental findings by Kick, Taylor and their peers, were
either missed - or concealed - by McClure. Later scientists, including the authors of
the Draft Toxicological Profile for Fluorides, who referenced McClure in their own
work also appear to have accepted McClure's own citations on trust alone.

These long-standing errors and omissions must be rectified in the new Toxicological
Profile for Fluorides.

Aluminum fluoride:

Speciation of fluoroaluminum complexes in soil and water was briefly discussed in the
Draft. However, a large body of science dealing with the effects of fluoroaluminum
complexes on G-proteins, neurological effects, etc, (which can be located on Pubmed via
the internet), were not addressed.

Fluoridation agents added to the drinking water can enhance leaching of aluminum from
cookware (Literature review for the NIEHS, 2000).(9)

On Page 91, the Draft authors note Varner, et al, 1998. However, extremely important
results regarding aluminum fluoride toxicity were omitted by the authors of the Draft
Profile, who briefly addressed only the sodium fluoride aspect of the work. (10)

The Varner team observed that the animals who drank the aluminum-fluoride-laced water
developed sparse hair and abnormal, copper-colored underlying skin which is related to
premature aging. Further autopsy results showed serious kidney abnormalities in animals
that drank water containing both sodium fluoride and aluminum fluoride.

The Varner team wrote: "Striking parallels were seen between aluminum-induced
alterations" in cerebral blood vessels that are associated with Alzheimer's disease and
other forms of presenile dementia." They concluded that the alterations of the blood
vessels may be a primary event, triggering neuro-degenerative diseases.

Describing themselves as "astounded," the researchers further stated: "Not only did the
rats in the lowest dose groups die more often during the experiment, they looked poorly
well before their deaths. Even the rats in the lowest dose group that managed to survive
the 45 weeks looked to be in poor health."

The Draft authors did not acknowledge that these results were a replication of two earlier
Varner, et al experiments addressing aluminum-fluoride toxicity.(11), (12)

Following the three Varner, et al, aluminium fluoride studies conducted between 1991
and 1998 80% of the experimental rats died before the end of each of the
experiments.
The Draft authors should have mentioned that the NIEHS joined with the EPA to request
the National Toxicology Program to commission studies on aluminum complexes - and
specifically fluoroaluminum complexes - in drinking water. (Federal Register:
December 4, 2000 (Vol. 65, No. 233)] [Notices] [Pages 75727 - 75730].).

Other notable omissions

1. The Roholm 1937 data which is cited in all basic fluorine toxicology papers.(13)

2. The toxicology of fluorinated pesticides.

While the Draft briefly mentions the use of fluorinated pesticides, no reference is made of
the toxicity/neurotoxicity of pesticides and other organic fluorides to which much of the
population is daily exposed.

The authors failed to provide a list or source of information for fluorinated pesticides,
fungicides and herbicides.

3. Fluorinated medicaments

Fluorinated medicaments are briefly mentioned, but there is no substantive discussion,


nor a comprehensive list.

Conclusion

The authors of the Draft included some new data, but omitted very troubling findings
contained in the early and more recent research.

Is the ASTDR prepared to honor its Mission Statement to the American public in the new
Toxicological Profile on Fluorides "to serve the public by using the best science, taking
responsive public health actions and providing trusted health information to prevent
harmful exposures and disease related to toxic substances"?

Yours truly,

George C. Glasser,

Formerly of St Petersburg, Florida.

REFERENCES

1. Masters RD, Coplan MJ, Hone BT, Dykes JE, Association of silicofluoride treated
water with elevated blood lead, Neurotoxicology. 2000 Dec;21(6):1091-100.
2. Masters RD, Coplan MJ, Water Treatment with Silicofluorides and Lead Toxicity,
Intern. J. Environmental Studies 56, 435-449 (1999).

3. Masters, RD and Coplan, M. Brain Biochemistry and the Violence Epidemic, Nova
Science Publishers, Inc, New York (1999).

4. McClure FJ, Mitchell HH (1931) The effect of calcium fluoride and phosphate rock on
the calcium retention of young growing pigs, J Agric Res 42: 363-373.

5. Kick CH, et al, Fluorine in Animal Nutrition, Ohio Agricultural Experiment Station,
Bulletin 558, Nov. 1935.

6. McClure FJ:, Availability of Fluorine in Sodium Fluoride vs, Sodium Fluosilicate,


Public Health Reports, vol 65 No 37; 1175-86; 1950.

7. Kick CH, Bethke RM, Edgington BH, Effect of Fluorine on the Nutrition of Swine,
with Special Reference to Bone and Tooth Composition, The Journal of Agricultural
Research, Vol. 46 No. 11, January 1- June 15, 1933

8. Taylor GE, Effect of fluorine ration in cattle ration: Experimental evidence indicated
fluorine content of raw rock phosphate is the detrimental factor, Mich. Agr. Expt. Station
Qrt. Bulletin 11, 101 - 104, 1929.

9. Aluminum Compounds - Review of Toxicological Literature, Abridged Final Report


Prepared for Scott Masten, Ph.D., National Institute of Environmental Health Sciences,
Contract No. N01-ES-65402, Submitted by Bonnie L. Carson, M.S. Integrated
Laboratory Systems, October 2000.

10. Varner JA, Jensen KF, Horvath W, Isaacson RL, Chronic administration of
aluminum-fluoride or sodium-fluoride to rats in drinking water: alterations in neuronal
and cerebrovascular integrity, Brain Res. 1998 Feb 16;784(1-2):284-98

11. Isaacson RL, Varner JA, Jensen KF, Toxin-induced blood vessel inclusions caused by
the chronic administration of aluminum and sodium fluoride and their implications for
dementia, Ann N Y Acad Sci. 1997 Oct 15;825:152-66.

12. Varner JA, Horvath WJ, Huie CW, Naslund HR, Isaacson RL, Chronic aluminum
fluoride administration, I. Behavioral observations, Behav Neural Biol. 1994
May;61(3):233-41.

13. Roholm K [1937]. Fluorine intoxication: A clinical hygiene study with a review of the
literature and some experimental investigations, London, England: H.K. Lewis & Co.

Professor of Chemistry, Paul Connett, and Ellen Connett, also wrote a tour de force.
It can be read on the FluorideAlert website at
http://www.fluoridealert.org/pesticides/Fluorides.Comments.ATSDR.02.htm
National Research Council of Canada
NRC Associate Committee on Scientific Criteria for
Environmental Quality

Environmental Fluoride 1977

by Dyson Rose & John R. Marier


National Research Council of Canada

NRCC NO. 16081


ISSN 0316-0114
http://www.fluoridealert.org/NRC-Fluoride.htm

The Associate Committee on Scientific Criteria for Environmental Quality was


established by the National Research Council of Canada in response to a mandate
provided by the Federal Government to develop scientific guidelines for defining the
quality of the environment. The concern of the NRC Associate Committee is strictly with
scientific criteria. Pollution standards and objectives are the responsibility of the
regulatory authorities and are set for the purpose of pollution control. These may be
based on scientific criteria starting point but they also take into account the optimal
socioeconomic impact of proposed measures as well as the state of existing technology.

The Associate Committee's program includes the evaluation of available information on


the probability of effects of contaminants on receptors together with the related
fundamental principles and scientific knowledge. In this work particular attention is
directed to receptors and contaminants (and their interactions) important to Canada. This
Canadian approach is necessary because evaluations made in other countries or regions
will not always be applicable to the particular circumstances prevailing in Canada.

Members of the Associate Committee, its Subcommittees and Expert Panels, serve
voluntarily and are selected for their individual competence and relevant experience with
due consideration for a balance among all sectors in Canada. Responsibility for the
quality of study documents rests with the Associate Committee. Each report is carefully
reviewed according to a multi-stage procedure established and monitored by the National
Research Council of Canada in order to preserve objectivity in presentation of the
scientific knowledge. Publication and distribution of the report are undertaken only after
completion of this review process.
Comments on Associate Committee documents are welcome and will be carefully
reviewed by the Expert Panels. It is foreseen that these scientific criteria may be revised
from time to time, as new knowledge becomes available.

All documents published by the Associate Committee are published in both French and
English.

FOREWORD

This report was requested by the Management Subcommittee of NRC's Associate


Committee on Scientific Criteria for Environmental Quality. Dr. Dyson Rose (retired),
formerly of the National Research Council's Division of Biological Sciences, undertook
the task of preparing this report, with assistance from J.R. Marier of NRC's
Environmental Secretariat

The report emphasizes Cause/Effect interrelations of environmental fluoride, and also


attempts to identify deficiencies in the current scientific knowledge. The compilation
covers the scientific literature that came to the authors' attention prior to June 30, 1977.

The report has been reviewed by the members of the Management Subcommittee of
NRC's ACSCEQ, and by the following individuals:

Dr. J. Franke, Orthopedics Clinic, Martin Luther University, Halle, Wittenburg, DDR;

Drs. C.C. Gordon and P.C. Tourangeau, Environmental Studies Laboratory, University of
Montana, Missoula, U.S.A.;

Dr. E. Groth, Environmental Studies Board, National Research Council, Washington,


D.C., U.S.A.;

Dr. R.J. Hall, Analytical Chemistry Department, U.K. Ministry of Agriculture, Fisheries,
and Foods, Newcastle-upon-Tyne, England;

Dr. S.S. Sidhu, Newfoundland Forest Research Centre, Canadian Forestry Service,
Environment Canada, St. John's, Newfoundland, Canada.

The authors wish to express their thanks to the members of the Management
Subcommittee, and to the other reviewers, for the valuable comments received. However,
we must emphasize that the viewpoints expressed in this report represent our own
assessment of the environmental fluoride situation.

The authors also wish to express their gratitude to Miss Lynda Boucher and Miss Pat
Moss, for their sustained cooperation in typing this report.
Dyson Rose and J.R. Marier
October 4, 1977

TABLE OF CONTENTS

LIST OF TABLES
LIST OF FIGURES

INTRODUCTION

1.0 SOURCES AND DISTRIBUTION OF FLUORIDE POLLUTION

1.1 SOURCES

1.1.1 Atmospheric Emissions


1.1.2 Aqueous Discharges
1.1.3 Solid Wastes

1.2 DISTRIBUTION OF FLUORIDE

1.2.1 Airborne Fluoride


1.2.2 Water-borne Fluoride

2.0 EFFECTS OF FLUORIDE POLLUTION ON THE ENVIRONMENT, AND ON


AGRICULTURE AND FORESTRY

2.1 EFFECTS ON VEGETATION

2.1.1 Aquatic Vegetation


2.1.2 Terrestrial Vegetation
2.1.2.1 Ecological Effects
2.1.2.2 Fluoride-Induced Effects on Agricultural and Forest Crops
2.1.3 Criteria for Crop Injury

2.2 EFFECTS ON ANIMALS

2.2.1 Aquatic Species


2.2.2 Insects
2.2.3 Wildlife
2.2.4 Livestock

3.0 PHYSIOLOGICAL EFFECTS OF FLUORIDE ON ANIMALS AND MAN

3.1 BLOOD
3.1.1 Fluoride Content of Blood
3.1.2 Effect of Fluoride on Blood Components

3.2 URINE

3.2.1 Fluoride Content of Urine


3.2.2 Effect of Fluoride on Urine Components

3.3 FLUORIDE-INDUCED CHANGES IN ENZYMES AND METABOLITES IN


SOFT TISSUES

3.4 BONE

3.4.1 Fluoride Content of Bone


3.4.2 Fluoride Induced Changes in Bone

3.5 MUTAGENIC AND RELATED EFFECTS OF FLUORIDE

4.0 ORGANIC FLUORIINE COMPOUNDS

4.1 METHOXYFLURANE
4.2 OTHER ORGANOHALIDE ANASTHETICS
4.3 MISCELLANEOUS ORGANIC FLUORINE COMPOUNDS

5.0 FLUORIDE AND HUMAN ILLNESS

5.1 FLUORIDE INTAKE BY HUMANS

5.1.1 Intake From Foods and Beverages


5.1.2 Intake From Air

5.2 CARCINOGENIC IMPLICATIONS


5.3 OCCUPATIONAL FLUOROSIS
5.4 NEIGHBORHOOD FLUOROSIS
5.5 ENDEMIC FLUOROSIS (HYDROFLUOROSIS)
5.6 DIETARY-NUTRITIONAL DEFICIENCIES OR IMBALANCES AND
FLUOROSIS
5.7 THYROID FUNCTION
5.8 KIDNEY RELATED PROBLEMS
5.9 ATTEMPTS TO ESTIMATE CRITERIA FOR HUMAN INTAKE OF FLUORIDE

5.9.1 Criteria Based on Bone Fluoride and Plasma F-


5.9.2 Assessment of Fluoride Intake From Air

6.0 OVERVIEW AND RECOMMENDED RESEARCH


REFERENCES

LIST OF TABLES (back to top)

1 - Total Fluoride Emissions to the Atmosphere by Canadian Industrial Sources in 1972


2 - Estimated Soluble Fluoride Emission Rates and Total Emissions for U.S. Industries,
1968 or 1970 Data
3 - Fluoride Emission Rates Collected from Various Reports on the Aluminum Industry
4 - Comparison of Fluoride Emission Rates in the Primary Aluminum Industry in Canada
and the U.S.
5 - Fluoride Emissions from Phosphate Fertilizer Plants
6 - Volumes and Fluoride Contents of Some Industrial Waste Waters
7 - Fluoride Content of Water from the East Gallatin River, Montana
8 - Influence of Domestic and Industrial Sewage on the Fluoride Content of Rhine and
Ham River Water
9 - Regression Equations Relating Airborne Fluoride Concentration to Plant Response
10 - Fluoride Content of Insects from Polluted and NonPolluted Areas of Montana
11 - Fluoride Content of Bones of Animals Collected in Non-polluted Areas of Montana
12 - Fluoride Levels in the Bones of Wild Birds from Non-polluted Areas
13 - Regression Equations Relating Plasma Ionic Fluoride Levels to Age in Adult
Humans
14 - Mean Plasma Ionic Fluoride Levels for Humans Residing in Non-fluoridated and
Fluoridated Communities
15 - Effect of Fluoride on the Levels of Various Blood Components in Experimental
Animals
16 - Effect of Fluoride on the Levels of Various Blood Components in Humans
17 - Effect of Fluoride on Levels of Metabolites in, and Physiological Activities of,
Animal Soft-Tissue Organs
18 - Effect of Fluoride on Some Physical Parameters of Animal Bones
19 - Recent Data Illustrating the Effects of Environmental Factors on the Range of
Fluoride in Some Foods
20 - Recent Data on the Daily Intake of Fluoride by Children
21 - Recent Data on the Daily Intake of Fluoride by Adults
22 - The Percentage Contribution of Water and of Various Foods to the Fluoride Ingested
by Humans
23 - Health Problems Among Residents Near Fluoride-Emitting Sources
24 - Symptoms Common to Both Fluoride Intoxication and Magnesium Deficiency
25 - Fluorosis in Persons Who Have the Diabetes Insipidus Syndrome

LIST OF FIGURES (back to top)


1 - An illustration of the atmospheric distribution of gaseous fluoride, in relation to
elevation and distance from an industrial point source. (see figure)
2 - Influence of airborne gaseous fluoride on the yield of beans, strawberries, and
oranges, as plotted from the data of several authors. (see figure)
3 - Influence of dietary fluoride on the weight-gain of young swine. (see figure)
4 - Interrelation between rib bone fluoride content, blood plasma F-, and fluoride intake
from three daily meals. Data are for 55-year-old lifetime residents. (see figure)

INTRODUCTION (back to top)

"Environmental Fluoride" (Marier and Rose 1971) was largely completed before the
National Research Council, Canada, Associate Committee on Scientific Criteria for
Environmental Quality had become operational. The document thus differs somewhat in
format from later Associate Committees' documents. The relevant Subcommittee
therefore requested another document on this topic.

Comprehensive reviews on fluoride were published by the World Health Organization


(WHO 1970), by the U.S. National Academy of Sciences (NAS 1971), and as "a non-
experimental dissertation on a topic dealing with political aspects of public policy-
making on scientific issues" (Groth 1973). These three documents differ from one
another in intent, but all agree on the need for further research on the effect of
environmental fluoride. Thus the WHO (1970) report states:

"Little is known about the in vivo effects of fluoride at the low levels occurring naturally
in body-fluids and soft tissues on enzymes and the various facets of general metabolism
in the living organism..."

"However, the indices of early intoxication are poorly defined and this has resulted in an
element of speculation and confusion about the toxic potentialities of the fluoride ion".

Similar statements emphasizing the lack of precise knowledge are found elsewhere in the
document.

Similarily, the National Academy of Sciences document (NAS 1971) states:

"The available information is insufficient in depth and scope to allow unequivocal


statements to be made about the effects on plants of fluoride at low atmospheric
concentrations. One reason for the lack of information is the paucity of experiments
designed to relate air quality to effects on plants. A second is the lack of sufficient
ambient-air monitoring in connection with field studies and surveys, due in part to the
lack of accurate and precise methods for the separation and collection of particulate and
gaseous fluorine compounds. A third reason is the inadequacy of present experimental
techniques for long-term studies in which field conditions can be simulated".
"Unfortunately, many studies for a better evaluation of the effects of airborne fluoride on
human health remain to be done. Not many authors have investigated the incidence and
magnitude of effects on the thyroid gland, the hematopoietic system, the cardiovascular
system, and the central nervous system. However, these systems respond readily to a
number of stresses, not only to fluoride, and a causal relation to airborne fluoride has
been established only poorly or not at all. More careful studies are required, with better
attention being paid to the nature of the responses, the presence or absence of other
medical or physical conditions that might contribute to the occurrence of the responses,
and the proper control groups".

"The airborne fluorides to which subjects are exposed must be better evaluated with
respect to amounts of fluoride-containing material, proportions of gaseous and particulate
fractions, chemical and physical properties (including particle size) of the particulate
fraction, and meteorologic conditions in the surrounding community when resident
populations are being studied".

The third document (Groth 1973) presents the need for further research even more
emphatically. Thus

"...there have been very few studies of potential non-lethal effects of chronic
accumulation of fluoride on populations exposed to lifetime ingestion".

"Amounts of fluoride ingested by average adults are sufficient to produce chemical and
structural changes in the mineral of the bones, and the long-term health significance of
these changes is not known".

"In short, there are a great many unanswered questions in regard to long-term potential
adverse effects of fluoridation, and a number of indications of potential harm which have
not been shown yet to be unfounded. In view of the seriousness of some of the possible
consequences if fluoridated water is in fact harmful to a fraction of the population,
extensive, continuing research would seem imperative. However, there are no ongoing
large-scale efforts being made to carry out such research".

During the seven year period (1970 to 1977) covered in the present document, there has
been a voluminous output of literature related to fluoride pollution and fluoride toxicity
to plants, animals and man. This has increased our general knowledge of the multiple
effects of chronic exposure to fluoride, and has confirmed and possibly augmented the
difficulties attending attempts to relate quantitatively exposure and time factors to effect.
Nevertheless, a prime purpose of the present review is to identify criteria (dose-response
relations) that may assist in establishing limits of exposure. A second purpose is to
identify areas where additional research is urgent.

In environmental studies, it is often necessary or convenient to investigate individual


sources of fluoride and to focus on the level of fluoride acting through a particular
pathway. For example, the pathway involving airborne fluoride, forages, and domestic
cattle has been studied extensively. However, it is essential to remember that living
organisms respond to the total fluoride impact from all sources: plants are affected by
fluorides in soil, water, and air; animals by fluorides in their forages, feed supplements
and water; and man by fluorides in his foods, beverages, drugs and prophylactic agents,
cigarettes, and air. Therefore a comprehensive assessment of the cumulative impact of
fluorides on man's environment requires consideration of the total fluoride contributed by
multiple sources.

A serious effort has been made to consider all papers published since 1970 that are
relevant to environmental fluoride. Because of the voluminous literature on the dental
aspects of fluoride and on the freon-ozone argument, these two areas have been
intentionally left for others to summarize and develop criteria. Papers on fluoride therapy
in humans have been included only because data on high-dose, short-term effects appear
relevant to chronic exposure (low-dose, long-term) situations. Reports on pollution
control technology are considered to be outside the scope of this review. Sampling and
analytical methodology are discussed only in relation to the interpretation of
environmental effects.

Undoubtedly we have overlooked valuable research papers particularly among those


published in languages other than English and French; for this we apologize to the
authors concerned. For conciseness and brevity, we have omitted specific reference to
about half the papers we examined.

1.0 SOURCES AND DISTRIBUTION OF FLUORIDE POLLUTION (back to top)

1.1 SOURCES (back to top)

The sources of fluoride in man's environment have been discussed by numerous authors
(e.g. Marier and Rose 1971; NAS 1971; Bittel and Vaubert 1971; Prival and Fisher 1974;
Bojic et al.1975). Sources of fluoride include natural sources such as volcanic gases, and
soluble fluorides in the earth's crust. However, the pre- ponderance of pollution problems
have been caused by modern-day man-made sources which singly, or in combination,
occasionally lead to the presence of harmful levels of fluoride compounds in air, water,
food or forage. In this section, we present data on the amounts of fluoride discharged
from major man-made sources, and attempt to indicate the extent of the geographical
areas affected by the fluoride discharges.

Fluoride emission data from industrial sources are often circumscribed by industrial
secrecy and by industries' ability to have environmentally-relevant data classified as
proprietary to the industry. Also, governments have sometimes been loath to release data
gathered at public expense as well as those submitted by industry. The rationale often
given for this secrecy is that it allows decisions to be made in the absence of public
clamor and emotionalism. Less rationally, it also denies the public's right to take part in
decisions involving a balance of economic and environmental objectives. The secrecy
situation in Great Britain has been discussed by Tinker (1972).

Industrial and governmental secrecy has been detrimental to Canadian efforts to develop
criteria relating the concentration of pollutants to their effects. Thus the studies of
LeBlanc and his students (1971, 1972) on the effects of air-borne fluorides on epiphytes
and bryophytes could not be related to existing but secret data on fluoride concentrations
in the air. Similarly, the author of a report on pollution in the Shawinigan and other areas
of Quebec (Pellissier 1973) repeatedly comments on the non-availability of results from
related air-monitoring programs. Sidhu and Roberts (1976) encountered a parallel
situation in Newfoundland.

1.1.1 Atmospheric Emissions (back to top)

In spite of the secrecy discussed above, some information on atmospheric fluoride


emissions by industry has become available during recent years. Environment Canada
(1976) published data on fluoride emissions to the atmosphere in Canada during 1972. A
portion of the data is reproduced in Table 1 and shows that, with the exception of
aluminum production, the fluoride emissions are preponderantly in gaseous form. The
U.S. Environmental Protection Agency (EPA 1972) reported the corresponding U.S. data
in considerable detail, and we present summarized data in Table 2.

Unfortunately, the data in Table 1 and 2 are not directly comparable. Fluoride emissions
into the atmosphere occur in gaseous and particulate forms, and the particulates vary in
solubility. The solubility of the particulate matter has a marked influence on its toxicity to
plants and animals (NAS 1971). Thus, the "Total soluble fluoride emissions" as recorded
in Table 2 are more directly relevant to environmental-impact criteria than are either the
"total" or "percent gaseous" data of Table 1.

The primary aluminum reduction industry, which is the largest single-industry source of
atmospheric fluoride pollution in Canada (Table 1), and the third largest in U.S., has been
the subject of several studies. Data on the rates of fluoride emission (i.e. the amount of
fluoride released to the atmosphere per unit of aluminum produced) are presented in
Table 3. The low emission rates for recently constructed smelters are indicative of the
progress being made in controlling atmospheric emissions by this industry.

An interesting comparison can be made between the emissions from U.S. primary
smelters in 1970 and those of Canadian smelters in 1972 (Table 4). Effluent fluorides,
(i.e. total fluoride at source, before passage through emission control units) per unit of
aluminum produced, are similar for Canadian and U.S. reduction lines. However, the
average amount of fluoride emitted to the atmosphere, per ton of aluminum produced, is
markedly higher for Canadian than for U.S. smelters.

The steel industry, which is the major source of atmospheric fluorides in U.S. and third
largest in Canada (Tables 1 and 2), does not appear to have been studied as intensively,
regarding fluoride emissions, as the aluminum industry. In part, this is probably related to
the presence of other pollutants besides fluoride in emissions from steel mills, and to the
fact that attention has been primarily focussed on pollution by sulfur dioxide and
particulate matter.
In relation to the phosphate industry, which is also a major source of fluoride emissions,
Osag et al. (1976) have presented a comparison of "industry wide" and "best controlled"
atmospheric emissions (Table 5). It is difficult to relate these data to the rate of emission
(3.1 to 4.1 lb/ton of P205 equivalent) in Table 2, but it would appear that the data of Osag
et al. refer only to specific steps in the process and not to overall emissions. They
probably do not include emissions from the surface of gypsum ponds (King and Ferrell
1975).

Table 1. Total fluoride emissions to the atmosphere by Canadian industrial sources in 1972
(Environment Canada 1976) (back to top)

Sector Total fluorides % of % of gaseous


released (US tons) Canadian fluoride in
total effluent
INDUSTRY
Primary aluminum production 8,852 56.6% 55
Phosphate fertilizer and elemental 2,668 17.1% >96
phosphorous plants
Primary iron and steel production 2,418 15.5% 80-85
Miscellaneous sources 534 3.4% 70-75
FUEL COMBUSTION/STATIONARY
SOURCES
Power generation 1,006 6.4% >90
Industrial and commercial 162 1.0% >90
SOLID WASTE INCINERATION 4 <0.1 >90
TOTAL EMISSIONS 15,644 100.0

Table 2. Estimated soluble fluoride emission rates and totals for United States industries,
1968 or 1970 data (EPA 1972). (back to top)

Industry Rate Total US tons Reference page


or table
Steel 0.99 lb/ton ore 64,600 p. 3-64, Table
3-23
Coal combustion 0.16 lb/ton coal 26,600 p. 3-131, p. 3-
for power 132
Phosphate rock 3.1 to 4.1 21,200 Table 3-46
processing lb/ton P205 equiv
Primary aluminum 8.1 lb/ton prod. 16,230 p. 3-21, Table
3-6
Heavy clay 0.81 lb/ton prod 9,700 Table 3-87, p.
products 3-249
Hydrofluoric acid 4.1 lb/ton HF 8,840 Table 3-104
prod
HF alkylation 0.15 lb/bbl alkylate 7,000 Table 3-101
process
Expanded clay 1.14 lb/ton aggreg. 5,300 Table 3-93
aggreg.
Glass manufacture up to 17 lb/ton glass 3,330 p. 3-220, calc.
from Tables 3-
73 and 3-75
Frit smelting 180 lb/ton CaF2 700-840 Table 3-81, p.
3-235
Cement 0.008 lb/ton cement 270 Table 3-97
manufacture
Non-ferrous metals, 634 p. 3-307
Copper 246 p. 3-314
Zinc 210 p. 3-311
Lead
Uranium 55 + 18 p. 3-321
Aluminum anoding up to 668 p. 3-322

Table 3. Fluoride emission rates, in kg/metric ton, collected from various reports on the
aluminum industry (back to top)

Notes Reported emissions rate, Reference


kg/metric tons
Sweden, newest installations 1.0 total F Linberg 1971
U.S. new control technology 0.25 gaseous F Rosano and Pilet
1971
0.64 solid F
OECD countries, actual emission 6.1 total F OECD 1972
OECD, obtainable emissions 2.3 total F
U.S. 4.1 soluble F EPA 1972
U.S. best primary system 1.2-4.7 total F Rush et al. 1973
Best primary & secondary system 0.8-2.0 total F
U.S., weighted average 5.1 total F
U.S., weighted average 2.1 gaseous F Singmaster and
Breyer 1973,
Table 7-1d
U.S. new construction 1.0 total F EPA 1976
Table 4. Comparison of fluoride emission rates in the primary aluminum industry in
Canada and the U.S. (back to top)

Canada United States


1972 1970
Aluminum production, metric tons 904,491 (1) 3,614,545 (2)
Effluent fluoride, pre-abatement, kg/metric ton
Gaseous 14.1 (3) 13.1 (4)
Particulate 6.6 8.8
Total 20.7 22.5
Fluoride atmospheric emissions, kg/metric ton
Gaseous 4.9 (5) 2.7 (6)
Particulate 4.0 3.2
Total 8.9 5.8

(1) Personal communication, Statistic Canada.


(2) Singmaster and Breyer 1973, Table 7.3.
(3) Environment Canada 1976, p. 4.
(4) Singmaster and Breyer 1973, Table 7. 1d, weighted average.
(5) Calculated from data of Table 1 (this document), and total production.
(6) Calculated from Singmaster and Breyer 1973, p. 7-12 totals.

Table 5. Fluoride emissions from phosphate fertilizer plants (Osag et al. 1976). (back to top)

lb.F/U.S. ton of P2O5 Input


Fluoride Source Industry-wide Best Controlled
Wet Process Phosphoric Acid 0.02-0.60 0.002-0.019
Superphosphoric Acid 0.12 N/A
Diammonium Phosphate 0.06-0.5 0.025-0.06
Triple Superphosphate 0.20-0.60 0.03-0.31
Granular Triple 0.20-0.60 0.04-0.27
Superphosphate

In discussing the lesser sources of fluoride emissions shown in Table 1, the Environment
Canada (1976) report notes that "It is not possible to rationalize" differences in the
fluoride effluent data reported by the Canadian "clay products" industry and by the U.S.
Environmental Protection Agency. Environment Canada's estimates of possible fluoride
emissions by this source therefore vary from 274 to 2463 tons (249 to 2239 metric tons)
in 1972 (Environment Canada 1976, their Table 7). The lower figure was used to
calculate the "misc. sources" total shown in Table I .
Glass manufacturing firms in Canada are reported to have "almost totally phased out by
1972" the use of fluorspar as a flux. Fluoride emissions by this industry are therefore
thought to be low, i.e. 5 tons (Environment Canada 1976, p. 14, 15).

The Environment Canada (1976) report on fluoride emissions by the petroleum industry
(hydrofluoric acid alkylation process) indicates an "HF consumption" of 0.3 to 0.8 lb
HF/barrel of alkylate. Available information does not enable us to relate "consumption"
to emission. However, if we assume that emissions occur at the same rate as in U.S.
plants (Table 2), the estimated total 1972 emissions in Canada of "less than one ton"
(Environment Canada 1976, D. 19) indicates a Canadian production of alkylate of less
than 37 barrels per day. Data published by Energy, Mines and Resources of Canada
(EMR 1973) indicate that Canadian HF-alkylation capacity was 13,470 barrels per day in
1972, and had increased to 24,620 barrels per day in 1975 (EMR 1976).

Data on fluoride added to the atmosphere by domestic burning of coal in Canada are not
available, but the amounts are probably small because of the extensive use of other fuels
for domestic heating in Canada. The potential impact of domestic fuel burning on
fluoride pollution should be considered if changes in fuel consumption patterns occur.
Baum et al. (1972) report that 34 to 72% of the fluoride in coal, which varied from
0.0025 to 0.039% in the coals tested, was contained in the flue gases of an industrial type
furnace. We have been unable to locate similar data for domestic-type furnaces.

1.1.2 Aqueous Discharges (back to top)

Data on the volumes and concentrations of fluoride wastes being discharged to rivers,
lakes and oceans are not plentiful. All wet-scrubbing systems for control of atmospheric
emissions probably contribute some fluoride to the aqueous discharge, but economic
factors often favor recovery of fluoride from the scrubbers (e.g. as precipitated calcium
fluoride) and re-use of the water. Effluents and overflows from limed settling-ponds
contribute fluoride to the aqueous environment. General discussions of problems related
to pollution of waterways have been published by McCaull (1972) and Cheremisinoff and
Habib (1973).

Recent data on the volumes and fluoride contents of industrial waste waters (Table 6)
make it evident that large quantities of fluoride are being discharged to waterways. For
example, it can be calculated that if all North American plants discharge fluoride at the
rate (14 kg/metric ton) reported by Teworte (1972), the total discharge by the aluminum
industry would exceed 63,000 metric tons, or about 4-fold the amount discharged into the
atmosphere.

The production of uranium tetra- and hexa-fluorides involves the discharge of significant
quantities (625 to 1134 tons per year in U.S.) of hydrofluoric acid by way of aqueous
sewage (EPA 1972).

Rak (1969) presented data on the discharge of fluoride in waste waters during production
of some inorganic fluoride compounds. The reported discharges ranged from 5.7 kg per
metric ton of product for aluminum fluoride, to 55 kg/metric ton of product for cryolite.

Pettyjohn (1975) has reported environmental damage caused by an unsuitable aqueous


disposal method applied to steel industry "pickling wastes".

Table 6. Volumes and fluoride contents of some industrial waste waters. (back to top)

Waste water
Industry and location Volume F-content ppm Reference
Aluminum, 200,000 litres per metric 70 Teworte 1972
Germany ton A1
Phosphate fertilizer, 400 gpm (=90,800 1/hr) 35 Cheremisinoff and Habib
U.S. 1973
Phosphate fertilizer, 13,240 1/hr 14-29 Arora and Chattopadhya
India 1974
Stainless steel, U.K. ? 8 Jenkins 1972
Steek, U.S. ? 0.17 kg/metric ton of McCaull 1972
product

1.1.3 Solid Wastes (back to top)

Information on the disposal of solid wastes containing fluoride has not been found in any
of the papers reviewed in the preparation of this document. Presumably, large quantities
are used as landfill or buried (Williams 1975) and, since this practice is considered to be
nonpolluting, the quantities involved are rarely reported. However, Stepanek et al. (1972)
have reported contamination of surface and groundwaters by fluoride from solid wastes.

Williams (1975) has given a brief report on solid wastes from the aluminum industry;
individual smelters are reported to produce from 15 to 30 kg of calcium fluoride sludge
per metric ton of aluminum produced (30 to 60 lb/ton).

The disposal of high-fluoride solid wastes from the reprocessing of nuclear fuels has been
studied by Emma et al. (1968) and by Fitzgerald et al. (1969). Combined chemical
treatments to reduce fluoride volatility, along with sintering or canning, appear to be
prerequisites to safe longterm disposal of these wastes.

Polluted soil can also be considered as a form of solid waste. For land-locked factories,
all of the air-borne emissions discussed above can be considered as eventual soil
pollutants, except for the portion that is carried to rivers and lakes by run-off. This
amounts to about 18,000 tons per year in North America (Tables 1 and 2).

Soils can also become contaminated with fluoride when fertilizers containing fluoride are
used. The fluoride content of fertilizers varies widely (Ammerman 1974) depending on
the method of processing and on the fluoride content of the phosphate raw material used
(Forster 1969). Ammerman (1974) reported the following fluoride concentrations:

Dicalcium phosphate 0.14%


Triple superphosphate 1.87%
Diammonium phosphate 2.00%

Gordon (1970b) lists fluoride contents ranging from 0.58 to 2.34% for fertilizers sold in
Montana.

1.2 DISTRIBUTION OF FLUORIDE (back to top)

Reviews on fluoride and fluoride effects (WHO 1970; NAS 1971) usually stress that
"fluoride is well-nigh ubiquitous: detectable traces occur in almost all substances"
(Hodge and Smith 1977). This can be said about a great number of pollutants;
nevertheless, this fact is relevant to a discussion of fluoride for two reasons: (1) it
emphasizes the need to consider total fluoride from all sources when investigating
fluoride injury to plants, animals and man; and (2) it often makes estimation of the role
played by industrial fluoride pollution more difficult. Manmade fluoride pollution nearly
always arises from a small geographic area or point-source and is detectable above the
natural or background fluoride over a definable area. Assessment of the distribution and
extent of these man-made fluoride anomalies is considered in this section. Attention will,
of course, be focussed on soluble fluoride as this is the most environmentally-relevant
form (cf. p. 10).

1.2.1 Airborne Fluoride (back to top)

The presence of fluoride in rainwater collected in areas remote from human settlements
(Carpenter 1969) suggests that air which has not been contaminated by human activity
does contain some fluoride. However, ambient-air fluoride is usually below the level of
detection, which can be roughly defined as less than 0.05 ug F/m3 air (Thompson et al.
1971). Natural phenomena such as dust storms and forest fires can contribute small
amounts of soluble fluoride to the atmosphere. Volcanic activity can contribute larger
amounts. However, except for unusual circumstances (e.g. volcanic activity), all soluble
fluoride found in the atmosphere in excess of 0.05 ug/m3 can be assumed to have
originated from man-made sources.

From the above discussion, it miqht be concluded that the distribution and extent of
abnormal fluoride concentrations arising from point-sources would be relatively easy to
monitor. Unfortunately, however, man's activities are so widespread that background
levels exceeding 0.05 ug/m3 are not rare, even in rural areas of industrialized countries.
The spread of pollution from a major source often must be determined against a
somewhat variable background level arising from multiple minor sources (e.g. domestic
coal burning) and from distant major sources (Fischer and Brantner 1972). Thompson et
al. (1971) reported data on 9,175 air samples collected in various non-industrial urban
sites and 2,164 samples from non-urban sites. The distributions, as percentages found
within the limits (ug/m3) shown, were: urban = 88% < 0.05; 12% between 0.05 and 1.0;
0.2% > 1.0; non-urban 98.5% < 0.05; 1.5% between 0.05 and 1.0; 0.14% > 1.0. Davison
et al. (1973) reported that only a small percentage of urban air samples from
Northumberland contained < 0.05 ug F/m3, and that the average fluoride level was 0.28
pg/m3. On the other hand, "most" air samples from rural sites contained < 0.05 ug F/m3
even though 19% of the samples exceeded the 0.1 ug/m3 level.

Data which have become available since 1970 confirm the presence of abnormally high
airborne fluoride concentrations in association with many of the industries for which
fluoride emissions are shown in Table 2. Peak fluoride concentrations within these high-
fluoride zones are rarely available, because they occur over company-owned land. In a
study of the effectiveness of potroom ventilization, Sutter (1973) recorded mean daily
atmospheric concentrations (aluminum industry) of 540 to 3700 ug F/m3. In a study of
fluoride emissions from an openhearth (steel smelter) furnace with an electrostatic
precipitator, Brown et al. (1971) presented the data shown in Fig. 1. These data are no
longer representative of this particular smelter, because the operating procedure has been
changed (Schuldt 1977). They do, however, indicate the high concentrations and the
atmospheric stratification that can occur within a few hundred feet of a point-source of
fluoride emissions. The stratification was still apparent 12,000 feet (3.6 km) from the
source (Fig. 1).

Data for airborne fluoride concentrations in areas surrounding fluoride-emitting factories


have been presented in numerous reports. These include data gathered by static and
dynamic air sampling devices (IJC 1971; Linzon 1971; Bourbon et al. 1971) and by
analysis of vegetation (Linzon 1971; Gilbert 1971; Carlson 1972; Gordon 1970a, 1976;
Keller 1975; Jacobson and Weinstein 1977; Sidhu 1977a).

The studies of C.C. Gordon and his co-workers at the University of Montana (Gordon
and Tourangeau 1977; Tourangeau et al. 1977) are particularly important because of their
contribution to our knowledge of "shielding" effects. These studies clearly demonstrate
that vegetation tends to impede or intercept fluoride in air that is moving through the
foliage, thus creating an adjacent down-wind area of lower airborne fluoride
concentration. (Little or no effect of this sort was observed with sulfur dioxide). The
effect is so marked with airborne fluoride that samples of needles taken from the upper,
windward side of a pine tree exposed to atmospheric fluoride will consistently contain 2-
to 4-fold more fluoride than found in equal-age needles from the lower, lee side of the
same tree. The effect becomes even more marked when windward and leeward sides of a
small grove are compared; also, groundcover vegetation under a stand of pines may
contain little fluoride, even in areas that are obviously polluted. Terrain elevations that
allow unimpeded impact by airborne fluoride result in an increased amount of fluoride in
exposed vegetation (Note also the stratification effect illustrated in Fig. 1).

Sidhu (1977b) has similarly observed the effects of terrain elevation and shielding in a
fluoride-polluted Canadian coniferous forest. However, to ensure consistency of
sampling, he recommends collection of foliage samples from the windward side of the
mid-crown, "because defoliation occurred in the upper crown". In a study of the fluoride
content of lichens, Gilbert (1971) observed that even a boulder provided some shielding
from fluoride carried by prevailing winds.

These observations make the siting of air-sampling devices and the collecting-points for
vegetation extremely critical. Gordon and Tourangeau (1977) recommend that the sites
for air-sampling devices for Maryland farmlands be "in the middle of open fields, ... one
to two feet (0.3 to 0.6 m) above the height of corn crops and away from stands of hard
woods which impede or intercept the fluoride-polluted winds". Samples of agricultural
crops should be taken from parts of the field that are 50 ft (15 m) or more from
hedgerows or other vegetation that is taller than the crops. In non-agricultural areas,
sampling should be from near the top of windward slopes, at a height sufficient to be
clear of any screening by vegetation.

The fluoride content of vegetation varies with the plant species and variety, and with the
stage of development (Chang 1975; Weinstein 1977). It is also influenced by the plant
tissue sampled (leaf, fruit, etc.), the age of individual leaves or needles (Chang 1975;
Gordon 1976), the location of sampled foliage on the plant (Gordon 1976), and the
season (Harris 1974). All these factors must be considered when sampling vegetation as a
means of monitoring fluoride in air. [See Guderian and Schoenbeck (1971), Teulon
(1971), and Sidhu (1977a) for a discussion of other aspects of the methodology.] Uptake
from the soil must also be considered (Weinstein 1977).

When the above factors are taken into consideration in the planning of a study, reliable
data on the extent, concentration and distribution of a man-made atmospheric fluoride
anomaly can be determined with reasonable accuracy, even against an urban fluoride
background. These factors are influenced by pollution loading, wind velocity and
constancy, other meteorological conditions, and geographic factors. Some examples of
airborne fluoride discharges are given herein. Preference has been given to Canadian
data.

Gilbert (1971) studied fluoride levels around a small (20,000 tons per year) aluminum
smelter in Scotland. On the basis of an average rate of emission for smelters in O.E.C.D.
countries of 6.1 kg F per metric ton of aluminum (OECD 1972), the total discharge
would have been only 123 metric tons (135 short tons) per year of total fluoride. The
smelter was surrounded by a "bryophyte desert" about 0.5 mile (0.8 km) wide and
extending about 1 mile (1.6 km) downwind and 0.7 mile (1.1 km) upwind. This, in turn,
was surrounded by a further area of damage, and elevated fluoride levels in vegetation
were observed 4.3 miles (6.9 km) downwind.

LeBlanc and co-workers (1971, 1972, 1975) studied epiphytes in the proximity of a
Canadian aluminum smelter with an unspecified (proprietary company data) amount of
atmospheric fluoride discharge. The area of vegetative disturbance, as indicated by an
"Index of Atmospheric Purity" based on species frequencies, extended 10 km (6.2 miles)
downwind.
Carlson and Dewey (1971), Carlson (1972), and Harris (1974) have reported extensively
on the distribution of atmospheric fluoride discharged by an Anaconda aluminum smelter
in Flathead County, Montana. In spite of assurances by the company that vegetation
damage would not occur (Burk 1972), this smelter had a 10-year history of causing
foliage injury in the surrounding territory. Nevertheless, the smelter capacity was greatly
expanded between 1965 and 1970. By 1970, foliar material from various species
contained fluoride levels in excess of background values (i.e. greater than 10 ppm, dry
weight basis) over a 213,760 acre (86,570 hectare) area. Extensive injury, and foliar
fluoride concentrations above 30 ppm, were observed over a 69,120 acre (27,994 ha)
area. During 1970, this Anaconda plant installed fluoride emission control equipment that
reportedly reduced emissions from 7,500 to 2,500 lb (3,410 to 1,136 kg) per day. A
subsequent survey showed above-normal (> 10 ppm) fluoride in 1971 foliage over an
area of 179,200 acres (72,575 ha) along with serious injury and > 30 ppm fluoride in
foliage over 15,200 acres (6,156 ha).

Sidhu and Roberts (1976) reported damage and high foliar fluoride concentrations in the
vicinity of a Canadian phosphorus plant. The total area affected was 11,434 ha (28,242
acres), but fluoride emission data were "confidential to the industry". However, in a
subsequent paper, Sidhu (1977a) reported airborne fluoride concentrations ranging from
0.8 to 20.8 ug/m3 at a 3 0.7 km distance from this factory, and concentrations of 0.06 to
0.34 ug/m at 18.7 km.

Preliminary data have also become available concerning fluoride distribution around an
aluminum reduction site at Kitimat B.C. (Gordon 1976). At a production rate of 250,000
tons aluminum per year, and a reported emission rate of 5 to 7 lb F/ton Al, total fluoride
emissions are estimated at 625 to 875 tons (568 to 795 metric tons) per year or 3,425 to
4,795 lb/day (1,556 to 2,180 kg/day). The data available are insufficient to define the
totality of the area affected by these emissions, but "a twenty-plus square mile 'death
band' of dead timber trees" (5,180 ha) is reported. Foliage collected from coniferous trees
5, 10, 11, and 20 miles north of the smelter contained higher fluoride levels than Gordon
had observed at these distances around other aluminum plants.

Fischer and Brantner (1972) studied the fluoride content of beech (Fagus silvatica) leaves
in Austrian urban areas of heavy and moderate air pollution, and in open country.
Fluoride levels of less than 10 ppm were common in leaves from unpolluted areas.
Fluoride levels in leaves from urban areas were up to 47 ppm. Even in wooded areas
outside the city limits, fluoride levels well above 10 ppm were encountered at "fronts of
collision which were caused by the particular meterological conditions" in the area.

1.2.2 Water-borne Fluoride (back to top)

The "average dissolved fluoride content of the major rivers of the world is fairly well
defined at 0.01 to 0.02 ppm" (Carpenter 1969). Atmospheric dusts are thought to be the
major sources of this "background" fluoride, although the source of a large portion of the
fluoride-containing atmospheric dust is a subject of some dispute (Carpenter 1969,
Bressan et al. 1974). Leaching of fluoride from rocks increases the fluoride content of
ground waters, but under the conditions observed by Jacks (1973), this source contributed
little fluoride to surface waters.

The contribution of domestic sewage from cities to the fluoride content of rivers was
studied by Masudo (1964). The amount of fluoride found in effluent sewage, in excess of
the amounts present in the cities' water supplies, were as follows:

Raw sewage ( 4 cities) 1.30 mg/l


After primary treatment (23 cities) 1.28 mg/l
After secondary treatment (29 cities) 0.39 mg/l

Fluoride is considered to be a "difficult to treat" industrial waste (Environment Canada


1975).

Soltero (1969) and Bahls (1973) reported fluoride concentrations in the East Gallatin
river (Table 7). These data show that elevated fluoride caused by sewage discharge from
the city of Bozeman was detectable for a distance of 4 km below the sewage outlet.

Table 7. Fluoride content of water from East Gallatin River, Montana. (back to top)

Fluoride content, mg/l


Sampling Soltero 1969 Bahls 1973 Bahls 1973
Location Average Average Range

Above sewer outlet 3.8 * 0.33 0.14-0.57


Sewage 16.5
0.3 km below outlet 0.62 0.27-2.00
1.8 km below outlet 6.1
2.2 km below outlet 0.58 0.27-2.00
4.2 km below outlet 4.6
5.3 km below outlet 0.37 0.20-0.55
8.2 km below outlet 3.6

* Soltero (1969) reported the data in meq/l; it appears probable that his data are too high by a
factor of 10.

A study of fluoride input into Narragansett Bay, Rhode Island (reviewed by Groth 1975b)
indicated that "36% of the fluoride entering the Bay was due to fluoridation of water
supplies in five communities on rivers feeding into the estuary".

Data on the fluoride content of the Rhine (Teworte 1972) and Ham (Lee and Whang
1972) rivers (Table 8) also indicate that both domestic and industrial sewage contribute
significantly to the total fluoride content. Seepage and leaching from solid and liquid
waste disposal sites can also cause serious pollution of run-off and ground waters
(Stepanek et al. 1972; Pettyjohn 1975).

Table 8. Influence of domestic and industrial sewage on the fluoride content of Rhine and
Ham River water. (back to top)

F-content, mg/l
Sampling sites Average Range Reference

HAM RIVER 0.12 Lee and Whang 1972


Main Stream .12 .10-.14
City water reservoirs .20 .09-.18
Tributary water, residential areas .26 .19-.27
Tributary water, industrial areas .21-.38

RHINE RIVER Teworte 1970


at Rheinfeld 0.20
below Al smelter 0.22
at Dutch border 0.30 to 0.35

The distribution of fluoride released into flowing bodies of water such as rivers is usually
detectable on the basis of differentials between the fluoride content of samples taken
above and below the known or suspected source of pollution. However, lakes, bays, and
inlets can present a more difficult problem, although comparative analyses (i.e. in relation
to input-sources) can provide meaningful information on the degree and extent of a
contaminated zone. Ocean water has a nearly constant fluoride content of 1.35 to 1.4 mg
total fluoride/litre, (Carpenter 1969; Bewers 1971), and a fluoride-to-chloride ratio of
6.71 0.07 x 10 5:1 (Warner and Jones 1975). Theoretically, inflow of fluoride-
contaminated river water should be detectable as a change in the F:Cl ratio. However, if
an ion-specific electrode is used to determine fluoride in brackish or ocean water, it is
necessary to correct the observed fluoride ion activities for the complexing effect of
magnesium (Thompson 1967; Brewer et al. 1970).

Use of the F:Cl ratio has provided considerable information showing fluoride pollution of
estuaries and ocean-bays. For example, Kitano and Furukawa (1972) determined the
fluoride-to-chloride ratio, to estimate fluoride pollution in Tokyo Bay. Fluoride
concentrations in contaminated inflowing waters ranged from 0.15 to 1.07 mg/l, with
F:Cl ratios of 1.4 x 10-4 to 3.6 X 10-2:1. Surface samples from the bay contained from
0.63 to 1.28 mg F/kg water, and the F:Cl ratio varied from normal (i.e. 6.71 X 10-5) up to
9.05 x 10-5:1. Values above 7.1 x 10-5 were encountered at 11 sampling points (mostly
surface) in the western half of the Bay, but not at sampling points in the eastern half
which is influenced by incoming seawater.
The distribution of waterborne fluoride discharged from the aluminum reduction plant at
Kitimat, B.C., has led to abnormally-high F:Cl ratios throughout the surface waters of
Kitimat Harbour (Harbo e,t al. 1974). Observed F.-Cl ratios ranged from 13 to 1,500 x
10-5 (av. 158 X 10-5) and fluoride concentrations ranged from 0.10 to 11.0 mg/l (av.
1.17). Occasional high F:Cl ratios were also encountered in subsurface waters at depths
from 10 to 100 m (av. 7.61 x 10-5; range 6.64 to 15.0 X 10-5). Comparable samples
taken from Howe Sound "where input of non-natural fluoride is not known to occur" had
F:Cl ratios ranging from 7.8 to 66 X 10-5, av. 14.5 x 10-5 for surface samples; and from
6.55 to 7.42 x 10-5, av. 6.83 x 10-5 for subsurface samples. No investigation of the
factors causing high F:Cl ratios in surface waters of Howe Sound was reported.

An interesting but incomplete study of water-borne fluoride has been reported for Tampa
Bay, Fla. (Taft and Martin 1974). In July 1973, a phosphate plant was discharging an
estimated 24,000 lbs (10,900 kg) of fluorine daily, along with quantities of phosphate and
nitrate, into Tampa Bay. This resulted in deposition of solid calcium fluoride at the point
of discharge and for about 1,000 ft. (300 m) into the bay. The precipitate accounted for
only a small portion of the total fluoride in the discharge. Fluoride concentrations in
samples of surface water above the fluorite deposit varied between 16.3 and 36.5 ppm.
No data were presented for a more extended area of the Bay. Nevertheless, a severe
thermal effect was generated at the fluorite:water interface, and this caused a significant
increase in the temperature of the surface water. The authors also reported the absence of
all living organisms in the afflicted area.

The effect of fluoride on aquatic life is discussed in Sections 2.1.1 and 2.2.1.

2.0 EFFECTS OF FLUORIDE POLLUTION ON THE ENVIRONMENT, AND ON


AGRICULTURE AND FORESTRY (back to top)

The sources of man-made fluoride pollution discussed in Section I result in above-normal


concentrations which impinge on terrestrial and aquatic flora and fauna, and on man. The
exposure of living organisms to above-normal concentrations of fluoride, which induces
fluoride accumulation by the organism, may result in an alteration of the organism's
biochemistry and morphology. Directly or indirectly, such changes may restrict the
organism's ability to maintain its ecological position. In the plant kingdom, an example of
this has been provided by McLaughlin and Barnes (1975) who observed that fluoride
accumulation in the foliage of some pines and hardwoods reduced photosynthesis and
stimulated dark respiration, thus undoubtedly reducing the amount of carbohydrate
available for growth and seed production. In the animal kingdom, Gerdes et al. (1971b)
report that exposure of fruit flies to low levels of atmospheric fluoride significantly
reduced the fecundity and egg hatchability of the descendants who were not themselves
exposed to fluoride.

Some published data suggest that exposure to low levels of airborne fluoride can
stimulate the growth of some plants (cf. Weinstein 1977). Bennett et al. (1974) suggest
that a low level of fluoride and of ozone was the norm under which plants evolved, and
that in tests on the effects of exposure to fluoride the "control" plants should not be
grown in fluoride-free air. However, growth that occurs as a result of fluoride stimulation
is often abnormal (Weinstein 1977). Even the growth stimulation that resulted in an
increased fresh weight in bean plants (Pack 1971a) did not result in an increased yield of
beans, and the ripened beans produced by exposed plants developed less vigorous
seedlings than did beans from control plants (Pack 1971b). It is thus doubtful that the
apparent growth stimulation occasionally observed on exposure of plants to low levels of
atmospheric fluoride is of any evolutionary, ecological, or economic advantage.

2.1 EFFECTS ON VEGETATION (back to top)

2.1.1 Aquatic Vegetation (back to top)

Available data on the responses of aquatic vegetation to fluoride pollution have been
briefly reviewed by Groth (1975a, b). The data are insufficient to allow firm conclusions
to be drawn, but do indicate that levels as low as 2 ppm in water can decrease the growth
of one species of Chlorella. The data also show that many aquatic plants accumulate
fluoride to concentrations that may be many-fold higher than the external concentration.

Ishio and Makagawa (1971) report that Potphyxix tenaa, an alga, was killed by a 4-hour
laboratory fumigation with fluoride (1.8 ppm in head space of growth chamber) and that
the critical concentration appeared to be 0.9 ppm.

Kilham and Hecky (1973) have discussed possible ecological effects of relatively high
natural fluoride levels in African lakes.

The accumulation of fluoride by aquatic plants and plankton is of interest because of its
potential impact on animals that consume these organisms. In an unpolluted area of New
Zealand, Stewart et al. (1974) observed fluoride levels from 31 to 209 ppm in the shells
of species feeding on plankton, and from 1,425 to 1,882 in the skeleton of Blue cod that
feed on crabs, shrimp, shell-fish, etc. The data suggest that, for the stages mentioned
above, the food-chain concentration factor is at least 10:1. As noted by Groth (1975b),
"we have very little knowledge of the sublethal effects of fluoride on behaviour or
reproductive processes, or of the potential accumulation of the pollutant in aquatic
foodchains. Yet such effects, should they occur, would probably be more important
ecologically than the mortality which might result from very high, but short lived,
pollution episodes".

2.1.2 Terrestrial Vegetation (back to top)

Dochinger (1971) dates the awareness of fluoride-induced damage caused in terrestrial


vegetation back to German reports of the 1880's and states that "For the last 30 years, the
injury to agriculture by fluorine compounds has intensified because of the expansion of
industries ...." Bossavy (1971) has summarized estimates of the damage occurring
primarily to forests, in European countries.
Literature on the biochemical and morphological changes caused by exposure of
terrestrial vegetation to fluoride has been reviewed by McCune and Weinstein (1971),
Chang (1975) and Weinstein (1977). For consideration of some other aspects of the
effects of fluoride on plants, such as the uptake of fluoride from soils, the influence of
environmental factors on the uptake of airborne fluoride, etc., the reader is referred to
Marier and Rose (1971), NAS (1971), Treshow (1971), Miller and McBride (1975) and
Weinstein (1977).

Terrestrial plants exposed to airborne fluoride frequently display foliar damage,


sometimes grow less vigorously, and almost invariably accumulate significant amounts
of fluoride in their foliage. These effects are all of aesthetic, economic or environmental
significance. The interrelations among, and criteria for, each of these factors will
therefore be considered with regard to airborne fluoride concentrations.

2.1.2.1 Ecological Effects (back to top)

As noted above, it can be assumed that many of the fluoride-induced changes occurring
in vegetation will decrease the plant's ability to maintain its ecological position.
However, studies of the actual ecological effects have rarely been undertaken. Coniferous
trees seem to be the most seriously affected forest species in many situations (Gordon
1976; Tourangeau et al. 1977; Carlson and Dewey 1971). Moreover, fluoride-induced
changes in relative species dominance have been confirmed by Sidhu (1977b), who also
commented that:

"Preliminary results of a recent long-term study of the effects of fluoride on forest


vegetation in Newfoundland showed that the softwood tree canopy (balsam fir, black
spruce, larch) was being replaced by undergrowth of hardwoods (white birch, American
ash). As the mortality of the original tree cover (softwoods) continued, the shrub layer
showed a significant increase in raspberry, skunkcurrant, calamagrostis, and fireweed,
underneath the hardwood tree species. Hardwood species (which defoliate every year)
tend to accumulate fluorides at higher concentrations and at a faster rate than the
softwoods. Therefore, it is suspected that the change from soft- to hardwood tree cover
will result in the addition of higher amounts of fluoride to the soil. Also, the wildlife of
the area feeding on the hardwoods will experience fluoride toxicity within a shorter
period and over larger affected areas."

Although epiphytes and bryophytes are considered more tolerant to fluoride than conifer
species (Sidhu 1977b), alterations in species frequency among these organisms have been
observed (LeBlanc et al. 1971, 1972; Gilbert 1971). LeBlanc et al. (1972) report that a
few species such as Frullania ebotrancensis, Lecanora impudens, and Physcia ciliata
could not be found within a 12 km (7.5 miles) distance from a fluoride source, although
they were prevalent in the surrounding territory. Even the species that were able to
maintain themselves close to the source were up to five times more plentiful beyond the
pollution zone. Gilbert (1971 also reported complete absence of a Lecanora species in a
fluoride-polluted area.
It should also be noted that if fluoride is injurious to pollinating insects (see Section
2.2.2), this could result in an indirect, but potentially extensive, effect on some ecological
communities.

2.1.2.2 Fluoride-induced Effects on Agricultural and Forest Crops (back to top)

Information on fluoride-induced injury to vegetation, which is often not directly


applicable to the development of criteria, has appeared in numerous reports. This
information is nevertheless important for an overall concept of fluoride phytotoxicity, and
is therefore briefly reviewed.

Bennett and Hill (1973) exposed 4- to 8-week-old barley and alfalfa plants to hydrogen
fluoride in fumigation chambers for a single 2-hour period, and measured carbon dioxide
uptake as an index of photosynthesis. With this short exposure period, 50 ppb HF were
required "before clearly measurable inhibition of the net carbon dioxide rates occurred".
The percentage inhibition of apparent photosynthesis was linearly related to HF
concentration throughout the range from 0 to 250 ppb, with no evidence of a no-effect
threshold within the accuracy of the measurements. Poovaiah and Wiebe (1973) noted
that fumigation of soybean plants with low (15 to 20 ppb) concentrations of HF for 1 to 4
hours caused stomatal closing, reduced transpiration, and increased leaf temperature.
McLaughlin and Barnes (1975) report that trees which had accumulated 10 to 60 ug
fluoride per g dry weight of leaf tissue (from sodium fluoride in an aqueous spray) had a
reduced rate of photosynthesis and an increased rate of dark respiration.

Bale and Hart (1973a, b) exposed seedling roots of barley (Hordeum vulgare) to solutions
containing 1 x 10-2, 1 x 10-4 and 1 x 10-6 M (190, 1.9 and 0.019 ppm) fluoride (as NaF
or HF) for 12 to 72 hours and examined dividing cells for chromosomal aberrations. They
concluded that "it is clear that each of the concentrations of sodium fluoride and
hydrofluoric acid used in these experiments is capable of inducing chromosomal
abnormalities and of producing mitotic inhibition in the meristematic region of roots".

Pack (1971a, b) grew beans from seedling to maturity in the presence of 0.58 to 10.5 ug
fluoride/m3 air, then grew a second generation, without exposure to fluoride, from the
seeds of these plants. Exposure of the first generation to as little as 2.1 ug F/m3 caused
the development of less vigorous second-generation seedlings. Vins and Mrkva (1973)
report a decrease of 30 to 70% in the diameter growth of pine trees at pollution levels that
caused no otherwise-visible injury. These authors relate the decreased growth primarily
to sulfur dioxide pollution, but there is an interesting relation between increasing fluoride
emissions between 1960 and 1967 (their Fig. 1) and the rapid decline in annual diameter
increments (their Fig. 5) during this same period. (NOTE: See also Carlson, C.E., and
Hammar, W.P. 1976. Impact of fluorides and insects on radial growth of lodgepole pine.
Proc. Montana Acad. Sci. 35: 39.)

Facteau et al. (1973) reported that the growth of pollen tubes in the styles of cherry
blossoms was decreased by fumigation with hydrogen fluoride either before or after
pollination. Pollen tube length, expressed as a percent of style length 72 hours after
fumigation, decreased linearly as a function of the product of exposure-time and
atmospheric fluoride level. A somewhat similar result was obtained in studies with
apricot flowers (Facteau and Rowe 1977). Fluoride-induced reduction in pollen
germination and tube growth has also been observed in tomato and cucumber plants
(Sulzbach and Pack 1972) while inhibited seed production or fruiting has been reported,
with soybean, bell-pepper, sweet corn, and cucumber being more susceptible than pea,
grain sorghum, or wheat (Pack and Sulzbach 1976).

Conover and Poole (1971) found that cuttings of Cordyline terminalis var "Baby Doll", a
horticultural foliage plant, suffered serious (approaching 50%) leaf necrosis when set for
rooting in water containing 0.5 ppm fluoride.

"Soft-suture" of peaches is the "best known example of fluoride injury to fruit" (NAS
1971). Facteau and Rowe (1976) were able to induce this injury in Elberta peaches by
spraying the trees at weekly intervals with 0.025% ammonium fluoride solution.

Maclean et ae. (1976) conclude that hydrogen fluoride (0, 5.0 and 9.7 ug F/m3 for 7 days)
was more phytotoxic to tomato plants grown in magnesium-deficient media than to those
grown in complete media. Similarly, Pack and Sulzback (1976) have demonstrated how
calcium nutrition can influence the response of plants to airborne gaseous fluoride. Pilet
and Bejaoui (1975) report that fluoride added to the culture medium for Rubus hispidus
tissues markedly reduced oxygen absorption by the tissues, particularly in media deficient
in calcium and magnesium. Increased levels of calcium and magnesium had a protective
action, in that they lessened the degree of fluoride inhibition of oxygen absorption.

The concept that vegetation may be stressed by pollutants present at levels that induce
relatively minor injury, or even at levels that do not induce detectable injury in normal
healthy plants, requires further study. The importance of this concept relates to the
possible summing of stresses from various sources, with the total stress inducing an
injury that cannot be easily related to any one cause. Evidence of such stress-induced
injuries resulting from multiple causes is difficult to establish experimentally, but the
effect of magnesium deficiency discussed above (MacLean et al. 1976) is probably a
dual-stress phenomenon. However, in foliage, there can also be an in situ effect of
fluoride on magnesium. In a study of air pollution, Garrec et al. (1977) observed that
fluoride accumulation led to a depletion in the magnesium content of pine needles; in
addition, there was a similar depletion in foliar manganese content.

Probably the most striking example of multi-stress effects is to be found in studies of the
relation between atmospheric pollution and insect infestations of forest species. The host-
parasite relation is complex, and as noted by Heagle (1973), the presence of an
atmospheric pollutant may act to either the advantage or disadvantage of the insect.

However, studies of forest species under field conditions have demonstrated that the
stress placed on trees by pollutants can increase the degree of infestation by insects.
Heagle (1973) states that "A common finding is that trees injured and weakened by
pollutants are more likely to be attacked by insects that normally require weakened trees
for successful reproduction". Jensen (1975) notes that "Some evidence has been provided
that air-pollution stress can initiate and/or aggravate insect infestation and microbial
infection of woody plants". Hay (1975) states that "Insects and mites have been
implicated as a stress factor on trees being influenced by pollutant emissions".

Most of the above statements have been made relative to pollutants in general, but the
work of Carlson et al. (1971, 1974) and of Carlson and Hammer (1974) shows that
atmospheric fluoride induces an insect-favouring stress in forest trees. Failure to
recognize this stress-factor led prior investigators to incorrectly diagnose a combined
fluoride injury and insect attack in the "death-band area" near Kitimat, B.C. (Gordon
1976).

When pollutants act in combination, each exerts its own stress, and each can influence a
different metabolic function. Thus, the effects of exposure to sulfur dioxide and gaseous
fluoride mixtures induced additive effects on citrus species, but may have induced
greater-than-additive effects on Zea mays and Hordium vutgare (Reinert et al. 1975).

In apricot orchards, trees that were stressed by competition from weeds showed more leaf
damage from airborne fluoride than did trees from well-tended plots (Oelschlager and
Moser 1969).

Fluoride-induced stresses undoubtedly affect vegetation in diverse ways, depending on


the species and conditions. One possible mode of action in coniferous trees has been
noted by Bligny et al. (1973) who report that exposure to fluoride delayed the formation
of epicuticular waxes on the lower surfaces of Abus alba needles. This could increase
water loss from the needles, and also increase their susceptibility to invasion by parasitic
organisms. Keller and Schwager (1971) have attempted to relate fluoride-induced stress
to an increased activity of an enzyme (peroxidase). Yee-Meiler (1974) has shown an
increased phenolic content of Norway spruce subjected to "physiologischen
Schadigungen" by fluoride (0.257 mg F/dm2 per 30 days).

Fluoride concentrations expressed in ug/dm2 per day or month refer to data collected by
exposing lime-filter papers to ambient air for the started time. Marier and Rose (1971),
using the greenhouse data of Adams (1961), suggested conversion by the equation:

Airborne F(ug/m3) = 0.006 x lime-paper (ug F/dm2 per month).

Israel (1974a) has compared results based on field trials, and suggested the equation:

Airborne F(ug/m3) = 0.003 x lime-paper (ug F/dm2 per month).

Israel's estimate of the accuracy of the conversion is + 50%.

The difference in conversion factors (0.006 vs 0.003) may relate to differences in air
velocity across the lime-paper (Israel 1974a).
More recent, Sidhu (1977a) has also conducted a field-study intercomparison, and has
proposed an equation that can be expressed as follows:

Airborne F(ug/m3) = 0.0076 x lime-paper (ug F/dm2 per month),

which yields values 2 1/2 times higher than Israel's, but only about 25% higher than the
Adams equation proposed by Marier and Rose (1971). Furthermore, Sidhu (1977a)
concludes that "In the absence of a more reliable and accurate regression equation,
Adams' equation can be used to convert the fluoridation plate data to the ug F/m3."

2.1.3 Criteria for Crop Injury (back to top)

Regression equations calculated from data presented in recent papers and which indicate
mathematical relations between yield and airborne fluoride; or yield and foliar fluoride;
or foliar fluoride, airborne fluoride and exposure time, are presented in Table 9. The yield
vs airborne fluoride data are also presented in Fig. 2. Because of the small number of
data-points available, some of these regressions do not achieve statistical significance.
However, taken as a group, they reveal a consistent pattern of increasingly harmful
effects with increasing exposure of vegetation to fluoride.

Significant correlations between airborne fluoride levels and foliar fluoride


concentrations ("C" and 'T' in Table 9) are difficult to attain under field conditions.
However, if close attention is paid to the location of sampling sites and to the selection of
foliage of uniform age from specific species and varieties, such correlations can be
achieved. The correlation coefficient for Linzon's (1971) data (Table 9) is 0.48. In
controlled greenhouse studies, the concentration of fluoride and the age of foliage are
usually controllable factors; under these conditions, the time of exposure can be included
as a component of the regression equation [data of McCune and Hitchcock (1971) and
MacLean and Schneider (1973) in Table 9].

The data on the yield of oranqes (Leonard and Graves 1970, 1972) shown in Table 9 and
Fig. 2, were for trees exposed for 28 months in field shelters with low ambient levels of
fluoride pollution (i.e. 0.1 to 0.4 ug/m3). Data for beans (Pack 1971a) were from a 70-day
greenhouse study at high levels of airborne fluoride. Both indicate a severe loss of yield
with increasing fluoride levels, i.e. approximately 19% per 0.1 ug/m3 for oranges, and
3% per ug/m 3 (approximately 1.2 ppb) for beans. The data on strawberries (Pack 1972)
are from a 5-month greenhouse study, and indicate about a 5% loss in weight of
individual fruits per ug/m3 increase in airborne fluoride. This loss in yield (fruit set does
not appear to have been affected) was accompanied by a statistically significant decline
in fruit quality, as indicated by the "development rating" assigned by the original author.

Yield of oranges in field shelters was also related to the fluoride content of the foliage
(Leonard and Graves 1972), declining by about 5% for each 100 ppm increase in fluoride
in 10-month-old leaves.

In field tests, Israel (1974b) observed a highly significant multiple regression between the
fluoride content of forage and of air-plus-soil. This was expressed as:

F(foliage) = 11.4 F(air) + 0.0085 F(soil),

where fluoride content of foliage and soil is expressed in ppm and of air in ug/dm2 per
day absorbed by lime-paper.

In a recent survey of a Newfoundland region in Canada, Sidhu (1977a) concluded that


"The safe levels of fluoride in air for forest species appear to be between 0.17 to 0.23
ug/m3." This is very close to the lower limit given by the estimates of Marier and Rose
(1971), i.e. "The average gaseous fluoride level in ambient air should be below 0.4 ug/m3
and might have to be as low as 0.2 ug/m3."

Table 9. Regression equations relating fluoride concentrations to plant response. (back to


top)

Plant studied Range of fluoride Regression equation (1) Note Reference


concentrations
Citrus 0.14 - 0.45 ppb Y (%) = 99.7 - 176 F (2) Leonard
and
Graves
1970
Citrus Not stated Y = 381.91 - 1.3132 C (3) Leonard
Y = 417.25 - 0.8797 C (4) and
Graves
1972
Pine Not stated BI = 0.06 + 0.1607 F (5) Hortvedt
BI = 0.93 + 0.0027 F (6) 1971
Bean 2.2 - 13.9 ug/m3 C = 14 + 102 F (7) Pack
Y (%) = 102.2 - 3.45 F (8) 1971a
Orchard up to 11 ug/m3 C = 1.13 FT - 1.17 (9) McCune
grass up to 11 ug/m3 C = 1.89 FT + 0.74 (9) and
Alfalfa Hitchcock
1971
Vegetation 20 - 128 ug/m3 C = 8.50 + 0.314 F (10) Linzon
1971
Strawberry 0.55 - 10.4 ug/m3 Y (%) = 99.5 - 5.1 F (11) Pack 1972
Timothy and 2.3 ug/m3 C = 2.555 + 4.120 FT (12) MacLean
red clover 5.0 ug/m3 C = 30.288 + 3.820 FT (13) and
mix Schneider
1973

(1) Y = yield, BI = Tip burn index, F = airborne fluoride concentration, C = concentration of


fluoride in foliage, T = time; all expressed in units used by the original authors except where (%)
indicates our calculations as a percentage of the control value.
(2) Data of author's Table 4, average value for 6 varieties, converted to % of control (Pot 6); "F"
values from Table 1, "Mean".
(3) Author's Figure 1, p. 158, 10-month old leaves.
(4) Author's text, p. 158, "old" leaves.
(5) Author's Figure 5, p. 300, 1-year old needles.
(6) Author's Figure 5, p. 300, 2-year old needles.
(7) Data from author's Table 1, 70-day exposure. We calculated a single average "control" value
of "F" for each variety.
(8) Data from author's Table 3, yields calculated as a percent of the individual controls.
(9) Author's equations from p. 291.
(10) Regression equation calculated by us from all complete data, except for three with foliage
levels above 200 ppm fluoride, dry weight basis, in author's Tables 1, 3, 5 and 6.
(11) Data on "Weight per fruit" from author's Table 3, calculated as a percentage of the weight
of fruit from control plants. Calculations based on the author's data suggest that the number of
fruit set ranged from 399 to 558 for the control plants and from 348 to 576 for the treated plants
and was not significantly affected by fluoride concentration.
(12) Author's Table 1, "F" = 2.3 ug/m3.
(13) Author's Table 1, "F" = 5.0 ug/m3.

2.2 EFFECTS ON ANIMALS (back to top)

2.2.1 Aquatic Species (back to top)

The ecological significance of the exposure of aquatic animals to fluoride has been
studied to a limited extent, but much more research is required before broad conclusions
can be drawn. The following paragraphs summarize the available recent information.

A large number of species have been shown to suffer injury from exposure to fluoride
(Groth 1975a). The response of fish to fluoride is influenced by a number of factors such
as species and strain, concentration of calcium and chloride in the water, temperature, and
the size or age of fish used in the study (Sigler and Neuhold 1972). The response of other
species to fluoride is probably influenced by at least some of these factors, but few data
are available.

Fish and other aquatic species tend to accumulate fluoride from the environment,
primarily in the skeleton (including the gills) and exoskeleton. Groth (1975a) has
tabulated the accumulation of fluoride by a number of species. Stewart et al. (1974)
analyzed specimens from an uncontaminated estuarine-coastal area of New Zealand.
They report fluoride levels from 509 to 2885 ppm (ash basis) in the skeleton, and from 31
to 209 ppm in the exoskeletons, of different species. Wright and Davison (1975) also
report "background" fluoride levels for a number of species, but give the data only as
ug/g fresh weight. These authors also report data from controlled experiments that clearly
demonstrate accumulation of fluoride in the exoskeleton of shore crab (Carcinus maenas
). Blue crab (Callinectus sapiduz), exposed to 20 ppm fluoride in water, accumulated
fluoride in the exoskeleton and suffered a 4.5% reduction in growth increment per molt
(Moore 1971). Moore estimates that this would result in a 52% reduction in the final size
of an average crab.

Wright (1977) reported a whole-body fluoride concentration of 10 ppm, wet weight basis,
in fry of Brown trout exposed to 5 ppm fluoride in tap water for 200 hours. These fry
suffered increased mortality, as compared to fry in a control tank, but mortality appeared
to occur only in a susceptible portion of the total population.

Hemens and Warwick (1972) and Hemens, et al. (1975) studied the potential
environmental effects of the "scrub water" from an aluminum smelter in South Africa.
Brown mussels (Perma perma) were the most sensitive of the organisms tested. In this
species, mortality occurred at fluoride levels from 1.4 to 7.2 mg/l in sea water after
exposure for 15 days, but lack of food during the test-period may have enhanced toxicity.
All species tested had accumulated fluoride extensively (wholebody fluoride to water-
borne external fluoride ratios varied from 25:1 to 149:1) after exposure for 72 days at 52
ppm fluoride. The authors interpret some of their data as being indicative of a greater
fluoride accumulation during deposition of new skeletal material.

Lubinski and Sparks (1975) attempted to assess the total toxicity to Bluegills of several
pollutants present in the Illinois river by expressing the contribution of each pollutant as
"Bluegill toxicity units". They found that fluoride was one of six major contributors to
the total toxicity of the river water. Taft and Martin (1974) have reported the absence of
all living organisms in a fluoride-polluted zone of Tampa Bay.

2.2.2 Insects (back to top)

Data on the effects of exposure of insects to fluoride are limited. Lillie (1970) has
reviewed the literature on the toxicity of fluoride to honeybees and concluded that 4 to 5
ug of accumulated fluoride per bee may be the lethal level. Assuming an average dry
weight per bee of 30 m , this corresponds to 130 to 170 ppm (dry weight). Trautwein et
al. (1972) reported that the average total-body fluoride content of winter-killed bees
ranged from 0.63 to 4.81 ug per bee (21 to 160 ppm dry weight basis). The highest levels
were found in bees from hives located near sources of fluoride pollution.

Carlson and Dewey (1971) report data from the analysis of a number of insect species
captured in non-polluted and polluted areas of Montana (Table 10). All insects were
presumably collected live, but the honeybees with an average fluoride content of 221
ppm probably would not overwinter successfully. Other insects, such as bumblebees at
406 ppm and sphinx moth at 394 ppm fluoride, must be considered endangered, even in
the absence of further evidence.

Mohamed (1971) reported evidence that exposure to fluoride caused chromosome


damage and mutagenesis in fruit flies (Drosophila metanogaster). In a continuation of
these studies, Gerdes et al. (1971a, exposed four strains of fruit flies at airborne gaseous
HF levels of 0, 1.3, 2.9, 4.2 and 5.5 ppm for periods of up to 6 weeks. All flies were
killed within 3 days at 5.5 ppm. All strains suffered at least 25% mortality in 6 weeks,
even at the lowest level (1.3 ppm) of exposure, but the relation between mortality and
fluoride concentration was non-linear, especially for the two "wild type" strains. In these
two strains, about 65% of the population appeared to be resistant to fluoride, even at the
4.2 ppm level.

The offspring of the surviving flies from the 0, 1.3, and 2.9 ppm fluoride levels of the
above experiment were also studied (Gerdes et 1971b). Statistically significant declines
in fecundity and egg hatchability with increasing parental exposures were observed.
Gerdes et al. concluded that the exposure to fluoride caused genetic damage. The dose-
response plots for vegetation (Section 2.l.3) and swine (see Section 2.2.4) do not appear
to indicate the existence of a no-effect threshold for fluoride. If the genetic effects in
insects respond to dose in a similar manner, the cumulative genetic, evolutionary, and
ecological effects of exposure to low levels of environmental fluoride could become
manifest with continued exposure of successive generations.

Table 10. Fluoride content of insects from polluted and non-polluted areas of Montana
(Carlsson and Dewey 1971). (back to top)

Type of insect Range of fluoride contents, ppm, dry weight basis


Non-polluted area
8 species, all types 3.5 - 16.5
Polluted area
Pollinators 58 - 406
Foliage feeders 21.3 - 48.6
Cambium feeders 8.5 - 52.5
Predators 6.1 - 170

2.2.3 Wildlife (back to top)

Considerable data on the accumulation of fluoride in the skeleton of wild animals have
become-available recently (Kay 1975; Kay et al. 1975a, b; 1976; Stewart et al. 1974), but
data on actual injury to wild species remain sparse. Wild animals accumulate some
fluoride from natural sources, and early field studies were handicapped by a lack of data
on this "background" level. This lacuna has now been partially filled.

The fluoride concentration of femurs from over 30 species collected in non-polluted areas
of Montana have been reported (Kay et al. 1975a). Data for species from which bones of
5 or more individuals were analyzed are summarized in Table 11. This tabulation
indicates that the bones of carnivorous species contained more fluoride (dry fat-free
basis) than did those of herbivorous species, but the data are insufficient to permit firm
conclusions regarding food-chain build-up of fluoride.

In general, data on the accumulation and distribution of fluoride in the bones of wild
species confirm the observations made on laboratory and domestic animals. Fluoride
concentrations were lower in "the less metabolically active diaphyseal portion of the long
bones" than in the distal portions which are "composed largely of cancellous bone" (Kay
1975). Bone fluoride content appeared to increase linearly with the age of the animal for
6 years or longer (Kay et al. 1976). Geographic variations were observed (e.g. means of
72.5 and 248.4 ppm fluoride in bones from different populations of deer mice), but these
were small relative to changes known to result from environmental contaminations (Kay
et al. 1975a).

Table 11. Fluoride content of bones of animals collected in non-polluted areas of Montana
(Kay et al. 1975a). (back to top)

Species No. of animals F content of femur ppm, dry fat-free


HERBIVOROUS
Chipmunk 19 103.1 + 16.2*
Columbian ground squirrel 23 112.5 + 10.2
Deer mouse 70 143.8 + 7.8
Muskrat 11 266.4 + 59.8
Northern flying squirrel 6 141.8 + 30.7
Porcupine 6 161.0 + 37.1
Red squirrel 9 151.9 + 29.5
Redback vole 5 258.0 + 25.3
Whitetail jackrabbit 4 258.6 + 27.7
CARNIVOROUS
Shortail weasel 5 363.6 + 97.1
Vagrant shrew 5 474.8 + 98.1

* Mean and standard error of mean.

Stewart et al. (1974) have provided data on the "background" fluoride levels in bones of
various species in New Zealand, Tibia or entire skeletons were analyzed; data are
reported as ppm in bone ash. (NOTE: Bones contain 50 to 70% ash. Thus a rough
conversion of "ppm, ash" to "ppm, dry fat-free" can be made by multiplying the former
by 0.6.) The mean value for two opossums was 247 ppm, and that for a single rabbit was
184 ppm fluoride. These values thus agree with those reported for Montana.

When compared with these background levels, bone fluoride concentrations ranging up to
and above 5000 ppm dry fat-free basis, (Kay et al. 1975b; Newman and Yu 1976; Harris
1974) are clearly indicative of environmental contamination by fluoride and its ingestion
by wild animals. Gordon (1970a) recorded extreme values of 12,700 ppm fluoride (ash
basis) in the femur of Mus musculus, and of 16,000 ppm in a rabbit femur. A relation
between bone fluoride levels in small rodents and the distance from a fluoride source has
been demonstrated (Gordon 1970a).

The data currently available are not sufficient to indicate the environmental significance
of fluoride pollution for wildlife, but there are indications of serious effects. Lameness
induced by fluorosis has been observed in wild ungulates by Kay et al. (1975b), who note
that it appeared to be more severe than the lameness observed in cattle at similar bone
fluoride levels. In a predator-prey situation, even a minor loss of mobility can lead to
rapid elimination of the individual affected. An apparent population age-shift was also
observed (Kay et al. 1975b), and this "suggests that fluorosis was so severe that older,
most susceptible, deer had been removed from that (the Teakettle mountain) herd".

In view of the data discussed above, we feel obligated to disagree with the statement
made by Suttie (1977), to the effect that "There seems to be no real basis for assuming
that these animals (wildlife) are any more susceptible to the adverse effects of fluoride
ingestion than other herbivores, and it is generally felt that if the most sensitive domestic
species, cattle, are protected the area will be safe for wildlife". In Section 2.2.4 on
"Livestock", we discuss a number of factors that influence the severity of skeletal
fluorosis. In a comparison of domestic to wild animals, nearly all of these factors [e.g.
nutritional status (particularly in winter), physical exertion, variability of fluoride
exposure-level, age when exposure begins, degree of individual variability, etc.] can be
unfavorable to the wild animal. Suttie's statement ignores all of these factors, and also
ignores the increased vulnerability that even mild fluorosis can create in a predator-prey
situation. Kay et al. (1975b) observed that, for a given level of fluoride in the bones, deer
appear to suffer more severe lameness than cattle. This confirms that the factors listed
above do influence the severity of fluorosis, and also increase the wild animals'
susceptibility to fluoride toxicity.

Data on wild birds are very limited. Stewart et al. (1974) and Kay et al. (1975a) have
reported some background data (Table 12). In general, short-lived, seed-eating birds had
lower bone fluoride levels than the longer-lived omnivorous species.

The mobility of birds largely precludes sampling of individuals who have remained in a
fluoride contaminated area for long periods. However, the high "background" fluoride
levels observed in some members of the omnivorous species suggests that there may be
some danger of developing skeletal fluorosis. [Note: Fluoride levels exceeding 4,500 to
5,500 ppm, dry fat-free basis in the long bones, are considered indicative of marginal
fluorosis in cattle (NAS 1971)].

House martins (Dilichon virbica) may be sensitive to fluoride, as few nests were found in
heavily polluted areas (Newman 1977).

Table 12. Fluoride levels in the bones of wild birds from non-polluted areas. (back to top)

Reference and bird species Number of species F content of bones


ppm, ash basis
Stewart et al. 1974 Mean Range
Carnivorous or omnivorous
Red-billed gull 16 4003 1058-8050
White-faced heron 3 2208 1006-3264
Mallard duck 11 1902 430-5440
Black-backed gull 16 1907 754-3140
Harrier hawk 14 1445 379-4775
Herbivorous
Hedge sparrow 1 1021
Starling 14 703 157-1390
Pukeko 16 489 143-1400
Kay et al. 1975a (ppm, dry fat-free)
Mean Standard Error
Blackbilled magpie 4 535 155.5
Blue grouse 3 321 40.4
Ruffed grouse 5 128 16.3
Sage grouse 1 216
Sharptail grouse 1 97
Spruce grouse 2 176 5.5

2.2.4 Livestock

Aschbacher (1973) has stated that "Of all airborne pollutants which may affect farm
animals, fluorine has caused the most serious and widespread damage". Research on
fluorosis in livestock has been extensive and a number of reviews have been published
(Shupe 1970; Obel 1971; Shupe et al. 1972; Trautwein et al. 1972; NAS 1974; Fleischer
et al 1974; Suttie 1977).

In brief, studies on skeletal fluorosis in livestock have led to the following conclusions:

(1) Fluorosis results from chronic ingestion of fluoride at levels above those usually
arising from natural sources over a prolonged period; thus, it is more commonly observed
in older animals.

(2) If exposure occurs during the period of tooth formation, tooth damage may occur.
This can increase tooth wear and contribute to a decline in the nutritional status and well-
being of the animal.

(3) In severe cases, animals become intermittently or permanently lame, and bone
exostoses become radiologically or even visually apparent, especially near the leg joints.

(4) The severity of the fluorosis is influenced by a number of factors in addition to total
fluoride intake and duration of exposure. Absorption of ingested fluoride is influenced by
the chemical form and solubility of the fluoride and by other components of the diet (e.g.
calcium, aluminum, etc., NAS 1974). Fluoride toxicity is enhanced by a low nutritional
status of the animal (Suttie and Faltin 1973). The schedule of exposure also influences
fluoride toxicity, with alternating periods of high and low exposure being more harmful
than uniform exposures (Suttie et at. 1972). Physical activity also tends to increase the
severity of bone lesions caused by excessive fluoride (Shupe and Olson 1971; Shupe et
at. 1972).

The age of the animal when exposure begins also affects the development of fluorosis.
This is especially important as regards dental effects caused by exposure during the
period of tooth formation, although age also influences the receptivity (i.e. affinity) of
bone for fluoride. Evidence for a declining rate of fluoride accumulation with age does
not seem to have been presented for large domestic species, but has been shown with rats,
rabbits, and dogs (WHO 1970; NAS 1971). Because bone lesions appear to be related to
bone fluoride levels (NAS 1971), exposure to fluoride from weaning onward may be
more harmful than exposures later in life.

(5) There are distinct differences among domestic species in their tolerance to fluoride.
Cattle seem to be the most sensitive of the common North American domestic species,
whereas swine are less sensitive and poultry are comparatively resistant.

Although there is general agreement on the above points throughout the industrialized
countries, there is a diversity of opinion as to the levels of fluoride that can be permitted
in animal forages and feeds. There are a number of reasons for this diversity, not the least
of which has been the emphasis placed on osteosclerosis by many researchers in the field,
and the difficulty of quantitatively expressing the degree of osteofluorotic injury.
Particular attention should be given to the more insidious forms of osteofluorosis, such as
the marked arthritic changes observed in dairy cattle fed fluoride-contaminated phosphate
supplements (Griffith-Jones 1977).

Three indices of fluoride exposure have been proposed for use with livestock. The most
widely accepted index in the U.S. is the fluoride content of fodder (and of feed
supplements); however the fluoride content of bone is a more useful diagnostic index,
and the fluoride content of urine may also have some diagnostic value.

Suttie (1969a) has proposed that standards for the fluoride content of forage should be set
at:

not over 40 ppm, dry weight basis, as a yearly average;


not over 60 ppm, for more than 2 consecutive months;
not over 80 ppm, for more than one month.

Various U.S. State regulations make it unlawful for an industry to emit fluoride at a level
that will cause the fluoride content of locally-grown forage to exceed 30 (Kay 1971) or
40 (Gordon and Tourangeau 1977) ppm, dry weight basis. These levels have been
selected largely on the basis of data obtained in controlled animal studies (Suttie 1969a)
which are not always relevant to actual farm conditions.

In controlled tests, conditions are selected to minimize the effects of many of the factors,
discussed on p. 46, that are known to influence the severity of fluorosis. For example, the
exposure level is kept constant or varied on a simple controlled schedule; animals of
uniform age are selected; adequate nutrition is provided; physical exertion is restricted;
and individual responses are largely eliminated by randomization and averaging.
Obviously, the severity of fluorosis observed in such tests will be less than those to be
expected in some individual animals in a range herd. In general, it can be concluded that
the toxicity of a substance having a crippling effect will be underestimated by studies
done on penned animals (i.e., those having restricted mobility) rather than on grazing
animals whose nutritional needs cannot be met without mobility.

Bourbon et al. (1971) and Gordon and Tourangeau (1977) have suggested a single
standard of 20 ppm fluoride, air-dried basis, for all fodder. However, it must be noted that
soils and fertilizers also contribute to the fluoride content of fodders. Suttie (1969b)
reported that "some rather high fluoride forages (112 ppm) can be found in areas with no
known source of industrial fluorides ..." Thus, regulations that attempt to control the level
of fluoride in fodders by restricting airborne industrial emissions may prove inadequate.

Standards controlling the fluoride content of fodders also fail to provide protection
against high fluoride levels in mineral supplements and other types of feed (Suttie 1969b;
Marier 1971; Obel 197 Griffith-Jones 1977; Hillman 1977).

The fluoride content of bone has also been suggested as a quantitative index of exposure
to fluoride (NAS 1971). For monitoring of live animals, this would require an
inconvenient biopsy; but, in the case of farm herds, post-mortem samples from
slaughtered animals are often available. Results of feeding trials at the University of
Wisconsin (summarized in NAS 1971) indicated that bone fluoride levels in "the range of
4,500 to 5,500 ppm (dry fat-free basis in long bones such as metacarpal or metatarsal)
might be considered as the marginal zone of toxicosis, and that lower concentrations were
not indicative of damage". This conclusion, however, appears to be specific to the
experimental conditions used. Another NAS (1974) report has stated:

"Cancellous bone such as the frontal ribs, vertebrae, and those of the pelvis, have a higher
fluoride content than the more compact metatarsal and metacarpal bones ... There is also
a marked variation in the fluoride content of such different anatomical areas (within)
bone (such) as the metatarsal or metacarpal; the diaphyseal portion has a lower fluoride
content than the metaphyseal portion"

Obel and Erne (1971) observed serious fluorosis in calves with 500 to 2,400 ppm, and in
cows with 900 to 2,800 ppm fluoride in metacarpal bone ash (assuming 60% ash, these
figures correspond to 300, 1,440, 540 and 1,680 ppm, dry fat-free basis, respectively).
Obel and Erne suggest that a phosphate deficiency may have contributed to the severity
of fluorosis in some of the cattle examined. Zumpt (1975) observed fluorosis in sheep at
femur bone fluoride levels of 2,400 to 3,200 ppm dry fat-free basis.

The fluoride content of urine has also been suggested (Burns 1970) as an index of
fluoride ingestion by cattle. This index might be advantageous because of the ease of
sample collection, but the relation between fluoride intake and urinary fluoride is not well
established.
Although Burns (1970) reports a reasonably close relation between urinary fluoride and
the fluoride concentration in samples from the pasture vegetation, Huber and Schurch
(1970) report much less agreement. Israel (1974b) reports a correlation coefficient of 0.87
between annual average urinary fluoride levels from cattle and annual average feed and
forage samples. Annual averages of urinary fluoride were based on 3 samples per year
from each of 10 to 13 animals per herd. Thus, under practical conditions, it appears that
extensive sampling is required for urine analyses to provide a reliable indication of
fluoride ingestion. Burns (1970) suggests that 10 ppm would be "a suitable figure to use
as a threshold level" for urinary fluoride. Based on the equation given by Israel (1974b),
this would correspond to a fluoride content in the fodder of less than 20 ppm.

There are continuing difficulties in answering the question of whether or not fluorine is
an essential element of diet (NAS 1974). The criteria for essentiality and the difficulties
of proving it by animal experimentation have been discussed (Underwood 1962; NAS
1971). One of the greatest difficulties is that practically every natural water supply and
foodstuff contains traces of fluoride and it is almost impossible to prepare fluorine-free
(e.g. < 0.005 ppm) control diets adequate in other respects (NAS 1974). In view of the
conflicting results and conclusions from experiments with mice (Underwood 1977) it is
not yet possible to assign an essential role to traces of dietary fluoride.

We have found only one set of research data from which a mathematical relation between
fluoride intake and the response of a livestock species can be calculated. Forsyth et al.
(1972c) fed diets containing 0, 30, 150 and 450 ppm fluoride, as sodium fluoride, to
young swine, and recorded average daily weight gains for up to 18 weeks. No data are
given on the fluoride content of the basal diet. The data (reproduced in Fig. 3) indicate a
linear decline in growth rate with increasing dietary fluoride. In the 18-week experiment,
the values at 150 and 450 ppm fluoride are significantly (p < 0.01) different from the
control values. The regression equations (our calculations) indicate a loss of about 4% in
the average daily weight gain, over the 18-week period, for each 100 ppm increment in
dietary fluoride. Said et al. (1974) have reported that "retarded liveweight gain was the
first significant sign of fluorosis" in a 25-month study of Wether sheep fed from 53 to 70
ppm fluoride in the total ration.

In the absence of additional quantitative criteria, and in view of the fact that the indices of
fluorosis discussed above (i.e. bone and urine fluoride concentrations) do not appear to be
satisfactory relative to actual farm experience, and do not appear to give adequate
protection to wild species, the present authors cannot suggest criteria that would be of use
in setting or revising Canadian standards for exposure of animals to fluoride. However,
two suggestions can be made.

1. It should be emphasized that total fluoride intake is the only reliable index of chronic
exposure for fluoride. The use of maximum "safe-levels" of fluoride in fodders is based
on the assumption that intake of fluoride from all other sources, including water, will be
low and relatively constant. Reported instances in which fluoride from sources other than
fodder detrimentally affected the health of animals (Obel 1971; Griffith-Jones 1972,
1977; Parsonson et al. 1975; Hillman 1977) testify to the need to assess the contribution
from all sources. Oelschlager (1974) has stated that "there appears to be a lack of full
appreciation of the extraordinary amounts of fluoride which reach the feed rations
through mineral supplement mixtures..."

2. Further research aimed at developing criteria relating fluoride intake, preferably in


mg/kg body weight per day, to tissue fluoride contents and injury should be stressed. This
research should include studies on animals at less-than-optimum nutritional status.
Attention should be paid to the less obvious effects of fluoride, such as the reduced
growth of swine (and sheep) discussed above, rather than to osteofluorosis. Blood plasma
F- should be assessed, as a possible indicator of fluoride exposure and the likelihood of
fluoride intoxication. Nutritional factors are of extreme importance in chronic fluoride
intake (see Section 5.6). Chronic dietary deficiencies can aggravate the effects of a given
fluoride dosage, and such factors should be considered in the assessment of
dose:response interrelations.

3.0 PHYSIOLOGICAL EFFECTS OF FLUORIDE ON ANIMALS AND MAN


(back to top)

Terrestrial species have evolved in contact with small but variable amounts of fluoride,
and can be assumed to have a degree of tolerance for trace amounts of ingested fluoride.
Nevertheless, ingestion of even small amounts seems to induce physiological responses,
and many of these responses are dose-dependent. At some level of intake and duration of
exposure, therefore, the effects will cease to be "tolerable" and will begin to exert a stress
on the organism. The level of bioaccumulation of fluoride that will exceed the animal's
tolerance is not necessarily constant but may vary with the efficiency of various bodily
functions and with the stresses being imposed concurrently by environmental, nutritional,
pathological, and other factors. The various physiological responses of animals to
fluoride are thus of interest. In the following section, we attempt to review and
summarize recent information relative to these responses.

3.1 BLOOD (back to top)

3.1.1 Fluoride Content of Blood (back to top)

The presence of fluoride in animal and human blood has been recognized for many years
(WHO 1970). About three-fourths of the fluoride in blood is contained in the plasma; the
remainder is in the erythrocytes, which make up 40 to 50% of the blood volume. For
various reasons, analysis of serum provides the most satisfactory information for the
assessment of interrelations between fluoride and other factors (WHO 1970). Cowell
(1975) noted that some anticoagulants used in the preparation of serum may contain
fluoride as a contaminant; caution is therefore necessary in their use.

The forms in which the fluoride in blood exists are still the subject of research. Taves
(1968) presented evidence for the existence of two forms of fluoride in human blood, i.e.
organically-bound (4.6 umol/1) and free or ionic fluoride (0.7 umol/l; data for people in a
non-fluoridated community). The ionic fluoride (F-) moiety was shown to be the one that
responded to changes in fluoride ingestion; total serum fluoride is a less sensitive
indicator of such changes (Taves 1968, 1970). Some doubt as to the significance of the
organically-bound fluoride fraction was raised when Taves (1971) reported that it was not
present in the blood of dogs and rats. Taves had suggested that the bound fluoride was
associated with serum albumin, but neither Jardillier and Desmet (1973) nor Ekstrand et
al. (1977) could find any evidence for protein-bound fluoride in human blood. Jardillier
and Desmet (1973) suggested that the bound fluoride reported by Taves was "en fait du
fluor lie par covalence a des petites molecules organiques". This suggestion has now been
partially confirmed (Taves et al. 1976) by the isolation of a major component of the
bound fluoride, showing "an nmr pattern consistent with a derivative of perfluorinated
octanoic acid". Taves et al. suggest that the presence of this compound in plasma is "at
least partially the result of contamination from industrial sources".

Final identification of the bound fluoride in human plasma, and clarification of its source
and physiological significance, must await further research. Its absence from the plasma
of dogs and rats (Taves 1971) and from bovine plasma (Taves et al. 1976) may indicate a
specificity of human metabolism or a peculiarity of the human environment.

As recently as 1970 (WHO 1970), it could be stated that "regulatory mechanisms operate
within the body to maintain the plasma fluoride content... within narrow limits".
However, improved analytical procedures, greater attention to the ionic fluoride fraction
in blood, and more critical studies have now shown that the plasma inorganic fluoride ion
concentration responds rapidly and systematically to varying fluoride ingestion and to
various physiological factors. Thus, Taves (1970) observed that "serum ion
concentrations (of fluoride) were 0.6 and 0.7 umol/l in two individuals after an overnight
fasting and increased to nearly twice this level in about 50 minutes after drinking 500 ml
of water" containing 52 umoles fluoride per litre (i.e. 1 ppm).

Intraperitoneal injection of 0.1 mg F/kg body weight into rats caused a rapid rise in
plasma F- values, which reached a peak of about 10 umol/l in less than 10 minutes
(Angmar-Manson et al. 1970). Plasma F- levels then declined progressively to levels of
less than 2 umol/l 45 minutes after injection.

When rats were provided with drinking water containing 50 ppm fluoride, the plasma F-
level increased from 0.17 ± .007 mg/kg to 0.26 ± 0.013 mg/kg in 4 weeks (Singer et al.
1976). After replacement of the fluoridated water with distilled water, plasma F- dropped
to the original level in 3 days. Suketa et al. (1976) found that a single oral dose of 50 mg
F/kg body weight given to rats raised plasma F- levels to above 2.0 ppm (105 pmol/1) in
one hour. This peak was followed by a somewhat irregular decline, and the plasma F-
concentration approached the original level 10 hours after fluoride administration.

The plasma F- level of 4- to 5-month-old humans also varied with fluoride intake
(Hellstrom 1976). Fourteen infants on breast feeding (low fluoride ingestion) had a mean
plasma F- level of 0.027 ppm, while 16 infants on formulae prepared with fluoridated
water (1.2 ppm) had a mean plasma F- level of 0.045 ppm (1.42 and 2.37 umol/l,
respectively). Kuznetso (1969) reported that total fluoride in the "biological media" of
human fetuses during the 5th to 12th week of pregnancy was 1.56 ppm in unexposed
mothers, and 2.72 ppm in mothers working in a superphosphate factory.

Posen et al. (1971) reported that plasma F increased with increasing bone fluoride (iliac
crest, dry fat-free basis) in human patients undergoing hemodialysis treatment with
fluoridated water l ppm. Ericsson et al. (1973) examined humans in a community with 10
ppm fluoride in the drinking water, and reported a positive correlation between bone
fluoride (iliac crest biopsy) and plasma F-. Urine fluoride, on the other hand, showed
little relation to either bone or plasma fluoride. An interrelation between bone fluoride
and plasma F- is also suggested by the data of Parkins et al. (1974), which indicate that
both bone fluoride (iliac crest biopsy) and plasma F- increased with increasing age in
humans.

Equations relating plasma F- level to age in humans have been presented by several
authors (Table 13). Some of the researchers found no significant correlation for some of
the sub-groups studied [e.g. men under 45 (Husdan et al. 1976)], but the trend towards
increasing plasma F- with increasing age is clear. In non-fluoridated communities, young
adults tend to have plasma F- levels below 0.7 umol/l, and this increases by about 0.01 to
0.02 pmol/l per year (Table 13).

As illustrated by Hanhijarvi's data (Table 13), plasma F levels vary with the amount of
fluoride in the drinking water. However, the range of values reported by various workers
(Table 14) suggests that interlaboratory standardization of the methodology might be
advantageous.

Table 13. Regression equations relating plasma ionic fluoride levels to age in adult
humans. (back to top)

Community water Subjects Regression equation (1) Reference


Fluoridated Both sexes F = 0.631 + 0.0368A Parkins et al. 1974
Non-fluoridated Both sexes F = 0.761 + 0.00259A Hanhijarvi 1975
Fluoridated Both sexes F = 0.975 + 0.00929A
Fluoridated Women F = 0.375 + 0.022A Husdan et al. 1976
Fluoridated Men over 45 (2) F = 0.906 + 0.0101A
Non-fluoridated Men F = 0.683 + 0.016A Kuo and Stamm 1975
Non-fluoridated Women No correlation

(1) F = plasma F-, umol/l; A = age in years.


(2) Husdan et al. (1976) report a constant plasma F- level of 0.906 + 0.306 umol/l for men under
45 years of age.

Table 14. Mean plasma ionic fluoride levels for humans residing in non-fluoridated and
fluoridated communities. (back to top)

No. of individuals Community Plasma F- umol/l Reference


501 Non-fluoridated 0.88 + 0.009 Hanhijarvi 1975
1083 Fluoridated 1.3 + 0.0005
14 Non-fluoridated 3.3 + 0.6 Jardillier and Desmets 1973
28 Fluoridated, 3.8 ppm 6.7 + 1.2
41 Non-fluoridated 0.46 + 0.1 Bierenbaum et al. 1974
41 Fluoridated 0.41 + 0.02
76 Non-fluoridated 1.1 Desmet et al. 1975
0.15 ppm

Administration of 27.15 mg fluoride (as 60 mg NaF) to patients suffering from


osteoporosis or Paget's disease gave rise to plasma Flevels of 3.26 to as high as 14.41
umol/l in the individual patients (Cowell 1975). Cowell states that the plasma F- levels
"appear to be directly proportional to the dose", but examination of his Figures 8 and 9
suggests that the relation was non-linear. The range of plasma F levels reported by
Cowell (1975) for normal adults was 0.31 to 2.21 umol/l.

Posen et al. (1971) reported arterial blood plasma F- levels ranging from 8.9 to 23 umol/l
in 10 patients receiving hemodialysis treatment with fluoridated (1 ppm) water. The
plasma F- tended to increase with increasing time on the hemodialysis program, and the
mean F- value increased during dialysis (pre-dialysis mean, 16 ± 4 umol/l; postdialysis
mean, 28 ± 3). Cordy et al. (1974) reported a mean plasma F value of 3.35 ± 0.28 umol/l
for 34 patients using a non-fluoridated water for hemodialysis, and of 12.30 ± 1.98 umol/l
for 7 patients using fluoridated water.

Renal insufficiency in humans can result in high plasma F levels. Seidenberg et al. (1976)
reported a mean value of 2.40 umol/l in 10 patients suffering from a renal insufficiency in
a non-fluoridated area, whereas thirteen "controls" from the same area had a mean plasma
F concentration of 0.67 umol/l. Hosking and Chamberlain (1972) observed a slower
decline in the plasma F level in anuric than in normal patients following single-dose
intravenous injection of 18F; however, in anuric patients with secondary
hyperparathyroidism, the uptake of fluoride by bone offset the lack of renal excretion,
and plasma F- declined even more rapidly than in control patients. Kuo and Stamm
(1975) report that an impaired ability to excrete creatinine was apparently not related to
plasma F- levels. Hanhijarvi (1975) has shown that some of the persons with renal
insufficiency show no change in plasma F- level, while others have a level 312 to 5 times
higher than seen in the similarly-exposed general population. In the same survey,
Hanhijarvi has also shown that diabetics have abnormally high plasma F- levels.

3.1.2 Effect of Fluoride on Blood Components (back to top)

In addition to increasing the plasma F- levels, ingestion of fluoride influences several


blood constituents. Recent reports on such changes are summarized in Table 15 for
experimental animals, and in Table 16 for humans. Because of the multiplicity of
experimental procedures used and the various blood components studied, comparisons
are difficult. The most obvious onsistent observation in animals (Table 15) has been a
decrease in red blood cells; this was observed in both the rabbit and rat, and by various
methods of measurement (blood iron, blood hemoglobin, erythrocyte count). This
observation is of interest because of the reports of anemia in humans residing near
sources of fluoride emissions (see Section 5.4).

The relations between some of the changes reported in Table 16 and fluorosis in humans
will be discussed in Sections 5.4 to 5.9. For the present, we conclude, in agreement with
Manocha et al. (1975), that "More elaborate studies on non-human primates .... are
needed to clarify the effects of different doses of fluoride on the biological system".

When a single intraperitoneal dose of 20 mg fluoride/kg body weight was given to rats
(Baker 1974), total serum fluoride increased by over 100-fold in 5 minutes, serum
calcium declined 20% in 30 minutes, and serum phosphorus increased 40% in 1 hour. For
all three components, there was a gradual reversal from these peak values, and
concentrations were approaching normal 4 hours after injection.

For more discussion of this aspect of fluoride interactions, the reader is referred to the
reports by Guminska and Sterkowicz (1975) and Manocha et al. (1975), who also discuss
various enzymatic processes.

Table 15. Effect of fluoride on the levels of various blood components in experimental animals.
(back to top)

Species Fluoride source Duration of Blood component Response Reference


study studied
Rat Diet, 450 or 600 3 days Citrate Increased Shearer et al. 1971.
ppm 2 weeks Citrate Returned to
normal
Rabbit Oral, 1 mg/kg 30 days Total blood iron Decreased Soldatovic and
Nadeljkovic-Tomic
1971
" Oral, 20 mg/kg 30 days Erythrocytes Decreased
body weight daily Leucocytes "
Hemoglobin "
Blood iron "
Rat Water, 150 ppm 75 days Red cell count Decreased Kahl et al. 1973
Rat Air, 0.05, 0.47 and - Blood hemoglobin Decreased Danilov and
4.98 mg/m3 Leucocyte count " Kas'yanova 1975
Erythrocyte count "
Cholinesterase activity "
Rabbit Water, 10 ppm 12 weeks Serum glutamate- Decreased, total Ferguson 1976
oxalate transaminase period
Serum alkaline Decreased, 2nd
phosphatase 6-week period
Serum malate Decreased, 1st 6-
dehydrogenase week period
Serum lactate Decreased, total
dehydrogenase period
Serum isocitrate Decreased, 2nd
dehydrogenase 6-week period
Rat Single oral dose, 3 hours Erythrocyte fluid Increased Suketa et al. 1976
50 mg/kg body potassium Decreased
weight " " calcium Decreased
Plasma acid No change
phosphatase Increased
Plasma alkaline Decreased
phosphatase
Mg-activated ATPase Returning to
12 hours Na + K-activated normal
ATPase """

Mg-activated ATPase
Na + K-activated
ATPase
Rat Water 57 ppm 70 days Whole body Decreased Kahl and Ewy-Dura
hematocrit Slightly 1976
Erythrocyte volume decreased
Plasma volume Increased
True blood volume "
Plasma vol./unit body "
weight "
True blood vol./unit
body weight
Guinea Water; 5, 25 ppm 20 weeks Townsend and Singer
pig High-fat diet Serum triglycerides Decreased 1977
Low-fat diet "" Increased
High-fat diet Serum phospholipids Decreased
Low-fat diet "" No change

Table 16. Effect of fluoride on the levels of various blood components in humans. (back to top)

Fluoride source Duration of Blood component Response Reference


study studied
Industrial exp. Not stated Manganese Nikolaev and
Kas'Yanova 1971
Oral, 5 mg/day 6 weeks Alkaline phosphatase Ferguson 1971
Water 1 ppm 3,4 weeks ""
22 weeks ""
Industrial exp. Long-term Manganese Decreased Nikolaev and Sidorkin
Aluminum Decreased 1972
Cobalt Increased
Zinc Increased
Iron Increased
Industrial exp. 18 years Erythrocyte pyruvate Increased Guminska and
kinase Increased Sterkowicz 1975
Serum pyruv. kinase Increased
Serum lactate Decreased
dehydrogenase
Erythrocyte ATP
Infants on formula, 1.2 ppm 4-5 months Serum alkaline Increased Hellstrom 1976
in water phosphatase

3.2 URINE (back to top)

3.2.1 Fluoride Content of Urine (back to top)

The fluoride content of urine has been suggested as an index of animal exposure (cf.
Section 2), and as a diagnostic test for humans during chronic exposure to fluoride (e.g.
Pantucek 1975). A number of reports dealing with the fluoride content of urine under
various conditions have been published during the last seven years, and these are
reviewed below.

Toth and Sugar (1975) reported data from a survey of individuals in an area of Hungary
in which the water was low in fluoride and there was no industrial source of fluoride
emissions. The average fluoride content of 24-hour urine samples was 0.26 ± 0.01 mg/l;
the highest value recorded was 0.57 mg/l. Variations between days, and with time of day,
were apparent but rarely exceeded 0.2 mg/l.

Mose et a. (1969) reported a relation between average urinary fluoride levels, population
density, and degree of industrialization, indicating that urinary fluoride was increased by
domestic and industrial pollution. Archer et al. (1975) were unable to detect an increase
in urinary fluoride among grade 5 students residing at various distances from an
aluminum smelter. However, Archer et al. did not take 24-hour urine samples, and their
study was conducted against a background intake from fluoridated (0.8 ppm) water and a
mean excretion of 0.97 ± 0.42 mg fluoride per litre urine. This is in contrast with the
Mose et al. (1969), study, where the average urinary fluoride level for the "control" rural
population was only 0.27 ± 0.03 mg/l (our estimate from authors' bar-gravph).

Balazova et al. (1970), and Tsunoda et al. (1973) also report increased urinary excretion
of fluoride by individuals residing near sources of airborne fluoride emissions. Mean
values from Tsunoda et ai. are (i.e., as mg F excreted in 24 hr):
Non-polluted area Polluted Area
Men 0.79 + 0.07 2.05 + 0.30
Women 0.73 + 0.07 1.77 + 0.43

Tsunoda et al. (1973) emphasize the inadequacy of spot-testing of urines as a means of


detecting exposure to fluoride. Hodge and Smith (1977) also note that it is "impossible to
assess general working conditions from a single spot urine sample from a single
individual". The limited usefulness of spot-urine samples is also indicated by the data of
Ericsson et al. (1973), who reported that the fluoride concentration of "night urine" from
individuals in a community with 10 ppm fluoride in the drinking water was not related to
either plasma F- or iliac crest fluoride concentrations. Plasma F- itself was positively
related to iliac crest fluoride.

Relative to the absorption and excretion of fluoride by workers and by residents in areas
subjected to fluoride emissions. it appears that particulate fluoride is excreted in the urine
"as promptly and quantitatively" as gaseous fluoride (Hodge and Smith 1977).

Polakoff et ae. (1974) observed small but statistically significant increases in urinary
inorganic fluoride by some workers in a polytetrafluoroethylene factory.

Pantucek (1975) studied the excretion of fluoride in urine by welders over a one month
period. The average urinary fluoride level in groups of unexposed workers was 0.70 ±
0.03 mg1l or less. Exposed workers excreted from 1.4 to 1.8 mg fluoride/l urine before
work on Monday, and the level rose progressively to attain 2.0 to 2.3 mg/l on Friday
morning. Afternoon samples (between 1300 and 1400 hours) ranged from 2.5 to 3.3 mg/l
on Mondays, and from 3.6 to 4.4 mg/l on Fridays.

Urinary fluoride excretion in 24-hour samples taken at least 6 days after any period of
exposure was markedly higher in long-term aluminum smelter workers (average of 27
years' exposure) than in a control group (Boillat et al. 1976). Values estimated from the
authors' graphs are:

Controls, av., 0.7 mg/24 hrs; range, 0.2 to 1.1 mg


Exposed, av., 2.4 mg/24 hrs; range, 1.2 to 5.3 mg.

Dinman et al. (1976a) report a linear relation between 24-hour fluoride excretion in urine
and the atmospheric fluoride level to which potline workers in an aluminum smelter were
exposed (11 workers over a single 24-hour period). Dinman et al. (1976b) also present
curves showing a relation between the concentration of fluoride in post-shift urine and
the number of days worked after a 2- or 3-day break, but these curves must be accepted
with caution. No probability limits are shown, and the curves are not carried beyond the
third working day, because "the variation after the third day was so great between and
within job categories, that it was impossible to fit a statistically significant regression
line". Calculations from the tabular data (Dinman et a. 1976b, Table 2) give coefficients
of variation between 5.8 and 22.9 for days 0 to 3, and between 6.7 and 10.6 for days 4 to
7. Also, the 2.5- to 3.4-fold increases represented by these curves are excessive even in
terms of the assumptions made by Dinman et al., that workers in a "non-steady state"
excrete 50% of the ingested fluorine, while for workers in a "steady-state" at the end of
the week, excretion "approaches 100%" of the dose.

Fluoride that has accumulated in the skeleton of humans is not readily excreted in urine,
following a reduction in fluoride intake. Thus, when Spencer, Osis and Wiatrowski
(1974) administered 10 mg fluoride daily for 32 days to hospitalized patients, a total
retention of 114 mg (36%) occurred. Retention was relatively constant throughout the 32-
day period, with no evidence that the proportion excreted increased with exposure-time.
Of the 114 mg retained, only 9.8 mg was excreted in 12 days following cessation of
treatment. In a later paper, Spencer et al. (1975) note that a negative fluoride balance
occurred only during the first six-day period following cessation of fluoride
administration. The fluoride ingestion subsequent to treatment was 4.36 mg/day from
foods and beverages.

Jolly (1976) conducted fluoride-balance studies on control and fluorotic patients (10 in
each group) having fluoride intakes from dietary sources of 3.74 ± 0.30, and 3.44 ± 0.25
mg/day, respectively, during the test period. Fluoride excretion, over three consecutive
24-hour periods, was 3.34 ± 0:23 mg/day (urine plus feces; feces contributed 8 to 12% of
the total) in control patients and was not related to age. In the fluorotic group, excretion
averaged 6.55 + 1.52 mg/day, and tended to decline with increasing age. The length of
the hospitalization period before the tests is not reported. Presumably, the excess fluoride
excretion over intake involves loss of non-lattice bound (i.e. surface) skeleton fluoride
from these fluorotic patients (WHO 1970).

Hanhijarvi (1975) also reported a variation in renal fluoride excretion with age. Fluoride
clearance increased with age "Until about age 50, whereafter a slight decline was found"
in communities with either low (0.02 ppm) or high (1 ppm) fluoride in the water.
Hanhijarvi interprets the increase before age 50 to "a possible slow saturation of the
bones with fluoride", and the subsequent decrease to "diminishing renal function which is
characteristic for older people".

Urinary excretion of fluoride is affected by a number of factors besides age. Kuo and
Stamm (1975) studied groups of men and women classified on the basis of creatinine
clearance tests, and recorded the following 24-hour urinary fluoride outputs:

Creatinine clearance: Normal Impaired


Men 0.87 + 0.70 mg 0.30 + 0.35 mg
Women 0.70 + 0.58 mg 0.24 + 0.12 mg

Hanhijarvi (1975) reported the following renal fluoride clearances for patients with
various conditions:

Controls (28 patients) 1.10 + 0.10 mg/day


Pregnancy (11 patients) 0.84 + 0.08 mg/day
Diabetes mellitus (2 patients) 0.59 + 0.19 mg/day
Renal insufficiency (5 patients) 0.59 + 0.12 mg/day

Buttner and Karle (1974) observed greater fluoride retention, which implies lower urinary
excretion, in unilaterally nephrectomized rats given 25 to 100 ppm fluoride in drinking
water.

3.2.2 Effect of Fluoride on Urine Components (back to top)

Fluoride ingestion also influences the concentration of some other urine components.
Polyuria occurred in rats following addition of 0.1% sodium fluoride to the diet (Hamuro
1972b). Urinary excretion of calcium and magnesium by rats increased significantly with
increasing fluoride in the diet (Benetato et al. 1970); for the final three months of the test
period, the recorded values were:

Fluoride levels: 0 2.26 4.25 mg/day


Calcium excretion 0.16 + 0.010 0.19 + 0.003 0.26 + 0.017 mg/day
Magnesium excretion 0.24 + 0.010 0.24 + 0.25 0.41 + 0.025 mg/day

Marier (1968) reviewed the importance of dietary magnesium and its interrelations with
fluoride. In a more recent study, Hamuro (1972a) observed that, in a strain of mice which
are prone to kidney calcification induced by magnesium deficiency, the normally-
observed increase in urinary phosphorus, in response to magnesium deficiency, was
largely prevented by increased dietary fluoride. Added dietary fluoride had no effect on
urinary phosphorus in normal mice. In a study of kidney calcification, Ophaug and Singer
(1976) found that fluoride "exerted an initial protective effect", but that the longer term
effect was "to promote calcification of kidneys". They also noted that fluoride
significantly retarded the mobilization of skeletal magnesium.

Speirs and Adams (1971) reported that ingestion of 2 or 4 mg fluoride per day by healthy
men increased the 24-hour urinary excretion of hydroxyproline and of citrate (3-week
control period vs 3-week exposure period). These authors conclude that "low doses of
fluoride seem to have some (additional) systemic effects, but relatively large daily
variations in the urinary composition .... mask the significance of these small effects".
Additional observations on the urinary excretion of hydroxyproline (and other
metabolites) are referred to in our discussion of fluorosis in humans (see Sections 5.3 to
5.8).

3.3 FLUORIDE-INDUCED CHANGES IN ENZYMES AND METABOLITES IN


SOFT TISSUES (back to top)

Recent reports in which data on fluoride-induced changes in liver, kidney, bone-marrow,


spleen, and some neural tissues of experimental animals have been presented, are
summarized in Table 17. Only one corresponding study on humans has been noted:
Franke et al. (1973) discussed structural changes in anterior brain cells and muscle cells
of fluorotic patients.

The involvement of neural and muscle cells in the pathology of fluorosis, as discussed by
Franke et al. (1973), accords with observations of Czechowicz et at, (1974) on brain cells,
and of Benetato et al. (1970) on neuro-muscular excitability (Table 17). The loss of
auditory response in Guinea pigs (Kowalewska 1974) may also be indicative of neural
injury.

Although a single high dose of fluoride caused an increase in the calcium and magnesium
content of rat kidneys, (Suketa et al. 1976), the longer-term response to low doses was a
decrease in calcium and magnesium in kidneys (Benetato et al. 1970). Somewhat
contrasting changes in enzyme activities have been reported for high (Zhavaronkov and
Dubynin 1971) and low (Manocha et al. 1975) doses of fluoride in squirrel monkeys
(Table 17).

The changes in liver enzymes related to carbohydrate metabolism observed by Shearer et


al. (1970, 1971, 1972) appear to have been transient in normal rats, but observations were
not carried beyond 17 days. Related non-transient changes have been reported in guinea
pigs (Czechowicz et al. 1974) and squirrel monkeys (Manocha et al. 1975

The changes in iron incorporation by spleen and whole blood (Kahl et al. 1972) are
probably related to the erythrocyte changes noted in Table 16.

Table 17. Effect of fluoride on levels of metabolites in, and physiological activities of, animal soft-
tissue organs. (back to top)

Species Fluoride Duration Organ or tissue studied Response Reference


source of study
Rat Sub-cut. inject. 206 days Liver Marked impairment of Zharvoronkov et
.3, 1.0 mg/kg " ATPase act. al. 1969
body weight " Decreased ability to
daily " absorb 02 and discharge
" CO2
Decreased respiratory
coefficient
Decreased alk.
phosphatase act.
Cytological changes in
cell nuclei
Rat Oral in milk, 4 months Cerveau, kidney, muscles Decreased calcium Benetato et al.
2.26, 4.52 ,g Kidney, liver Decreased magnesium 1970
F/l Neuro-muscular Excitability, changes
characteristic of latent
tetany
Rat Inter-perit. 15 min. Liver Apparent inhibition of Shearer and
inject. " pyruvate kinase Suttie 1970
2 mg/kg body Possible inhibition of
weight enolase
Diet, 450, 600 3 day Liver Increased citrate
ppm 17 day " Little effect on citric acid
Controlled cycle intermediates
feed
Rat Diet, 450, 600 3 day Liver Citrate increased Shearer et al.
ppm 14 day " Citrate returned to normal 1971
Controlled
feed
Rat Sub-cut. inject. 12 weeks Kidney Morphological alterations Zhavoronkov
12 mg/kg body Increased enzyme and Dubynin
weight daily activities 1971
Decreased alk. and acid
phosphatase activity
Rat Diet, 600 ppm 3 day Liver, normal animal Citrate decreased Shearer 1972
14 day """ Citrate returned to normal
3 day Liver, parathyroidect. rat Citrate increased
14 day """ Citrate remained high
Rat Water, 150 75 day Liver Increased incorporation Kahl et al. 1973
ppm Bone marrow of iron
Spleen """
Whole blood Decreased " " "
Decreased " " "

Guinea Sub-cut. inject. 90 day Corte organ Microphonic potential Kowalewska


pig 4 mg/kg Auditory nerve decreased 1974
Nerve potential decreased
Guinea Inter. musc. 3 months Purkinje's cells, Intensified reaction for Czechowicz et
pig inject. (Cerebral cortex) succinic dehydrogenase, al. 1974
4 mg/kg b.w. glucose-6-phosphatase,
daily ATPase, alk.
phosphatase, and non-
specific esterase.
Squirrel Water, 1, 5 18 Kidneys Cytological changes, Manocha et al.
monkey ppm months increased acid 1975
phosphatase activity
Increased activity of
enzymes of citric acid
pentose shunt
Rat Int. perit. 6 to 96 Kidney medulla Increased calcium, Suketa et al.
16 mg/kg b.w. hours Kidney cortex increased magnesium 1977
Increased calcium,
increased magnesium,
increased Ca++-ATPase

3.4 BONE (back to top)

3.4.1 Fluoride Content of Bone (back to top)

We have already discussed some aspects of bone fluoride in Section 2.2.4. In the
following paragraphs, we attempt to summarize recent studies dealing with the
physicochemical effects of fluoride on bones. The health aspects of this subject, and the
hormonal etc. interrelations, will be considered in Sections 5.1 to 5.8. For additional
information on the skeletal effects of fluoride, the reader is referred to recent discussion
papers (Spencer et al. 1971; FCT 1973; Franke et al. 1975; Rao and Friedman 1975), as
well as to the WHO (1970) monograph, Marier and Rose (1971), Groth (1973), and
Section 5 of the present review.

Accumulation of fluoride in the mammalian skeleton begins during gestation. Female


mice given water containing 50 ppm fluoride gave birth to offspring with a skeletal
fluoride content of 900 ppm, as compared to 4300 ppm in the dam's skeleton (Messer et
at 1974 . The fluoride level in the newborn mice decreased slightly during breastfeeding,
because the fluoride content of milk is low. In swine (Forsyth et al. 1972b), the fluoride
content of the bones of newborn piglets appeared to be a linear function of the fluoride
fed to the dams, which were given fluoride supplements ranging from 0 to 450 ppm in the
diet. Increasing the calcium and phosphorus content of the dam's diet decreased the
fluoride concentration in the piglets' bones. Inorganic fluoride that has been metabolically
released from methoxyflurane (a fluorinated anesthetic also used as an analgesic during
human childbirth) is "preferentially deposited in the fetal skeleton" in rats after 15 days of
gestation (Fiserova-Bergerova 1976).

Shen and Taves (1974) showed that, in humans, blood from the fetal cord contained
about 75% as much fluoride ion as found in the mothers' blood, indicating that the fetal
bones are exposed to fluoride during development. Hanhijarvi (1975) reported a decrease
in plasma F- concentration in the mothers' blood during human pregnancy; this decrease
presumably resulted from a rapid transfer of fluoride to the developing fetal skeleton.
Hellstrom (1976) observed that the fluoride content of the bones of newborn humans
were higher, by 50% or more, when the mothers drank water containing 1.1 ppm F, than
when the mothers drank low-fluoride (about 0.25 ppm) water.

Although a number of ancillary factors have been identified, the accumulation of fluoride
in the skeleton of animals during growth and maturity is primarily controlled by three
factors: the amount of fluoride absorbed via the digestive system and lungs; the reactivity
or receptivity of the skeletal surfaces; and the efficiency of fluoride excretion by the
kidneys. Receptivity of the skeletal surfaces is a function of bone age and type, with
young bone and cancellous bone being more receptive than old bone or cortical bone
(WHO 1970). The efficiency of renal excretion is a function of kidney health, and may
decline with increasing age (cf. discussion by Husdan et al. 1976).

If no large variations in fluoride ingestion have occurred, analyses of a selected bone


sample such as the iliac crest (cf. Franke and Auermann 1972) usually show a
progressive increase in bone fluoride with age in humans. Theoretically, fluoride
accumulation in bone might occur less rapidly as the fluoride content of bone increases,
and a "plateau" effect after about age 50 has been discussed (cf. Jackson and Weidmann
1958; WHO 1970). However, this effect, if it occurs, may be offset by declining kidney
efficiency with age, and the net effect in humans seems to approximate a linear relation
between bone fluoride content and age. For a population (100 individuals) using a low-
fluoride water (0.2 ppm), the regression equation for bone fluoride (iliac crest) and age
found by Schellmann and Zober (1975) was:

Bone F(ug/g ash) = 136.5 + 6.1 x Age (years) or,


Bone F(ug/g fresh weight) = 37.5 + 1.38 x Age (years).

For 20 individuals currently using fluoridated water (1 ppm, residence time not reported),
Parkins et al. (1974) also analyzed iliac crest bone, and found the equation to be:

Bone F(ug/g fresh weight) = 441.9 + 48.3 x Age (years).

Comparison of this equation with that of Schellman and Zober (1975) clearly
demonstrates the cumulative effect of even 1 ppm fluoride in water on skeletal fluoride of
the aging human. Persons with renal failure can have a skeletal fluoride content 4-fold
greater than that of similarly exposed persons who have healthy kidneys (Mernagh et al.
1977; Marier 1977; see also Section 5.8).

3.4.2 Fluoride-Induced Changes in Bone (back to top)

The changes induced in bone as a result of fluoride accumulation can include both direct
and indirect (e.g. hormonal, as discussed in Section 5) effects. Most studies on the direct
effects of fluoride on bone, such as those on bone density, attempt to relate the bone
properties directly to dietary or drinking-water fluoride (cf. Section 2.2 . 4). However, it
appears probable that analysis of blood plasma F- concentrations in exposed individuals
and populations would provide a more meaningful index of the chronic exposed and
saturation-status of bones to fluoride (cf. Section 3.1.1).

Recent reports on some effects of fluoride on physical properties of animal bone are
summarized in Table 18. The data in this Table adequately present the complexity of the
interrelations involving fluoride, calcium, age, and species. They clearly show, however,
that exposure to fluoride, at dose-levels and durations that induce no recognizable
symptoms of bone-fluorosis, is nevertheless a potent cumulative agent affecting structure
of bone and its response to other stress factors. For more extensive discussion, see
Spencer et al. (1971), Cohn et al. (1971), Franke et al. (1976), and Inkovaara et al.
(1975).

Recent papers have also confirmed that ingested fluoride influences the chemical
composition of bones. Wolinsky et al. (1972) analyzed pooled samples of femurs and
tibias from control rats and rats given 200 ppm fluoride in drinking water for 2 weeks.
Fluoride ingestion decreased the concentration of citrate and of lipids in the bone, and
decreased the in vitro formation of lipid from 14C-acetate or citrate.

Chan et al. (1973) reported that, in quail, fluoride (750 ppm in diet for 35 days) increased
bone ash and the magnesium content of the ash. Rosenquist (1974) observed a higher
magnesium level in fluorotic bone from rabbits given 10 mg fluoride/kg body weight per
day for 14 weeks. Fluoride ingestion also increased the magnesium content of bone ash
of rats, roosters, and quail which had been made osteopenic by control of the calcium and
phosphorus content of the diets (Riggins et al. 1976).

Miller et al. (1977) report a higher calcium and somewhat lower phosphorus content in
bones of cows suffering from osteoporosis as a result of environmental exposure to
fluoride. They also observed an increased bone alkaline phosphatase activity, but no
change in the citrate content of these bones.

Henrikson et al. (1970) found that, in osteoporotic bones of dogs, fluoride caused a slight
decrease in calcium content, and an increase in phosphorus content of bone ash. The
mineral mass also increased with increasing dietary fluoride, but there was no fluoride-
related improvement (i.e. radiographic etc.) in the degree of osteoporosis. The effects of
fluoride on human bone are discussed in Sections 5.3 to 5.6.
Table 18. Effects of fluoride on some physical properties of animal bones. (back to top)

Species Fluoride source and Observations Reference


duration
Rat Diet, 3.4, 10, 45 With adequate calcium, increase in Beary 1969
ppm, flexability, no decrease in strength
15 weeks
With deficient calcium, increase in
flexibility, decrease in strength
Dog Diet, 1, 3, 9, 27 With low calcium - high Henrikson et al. 1970
ppm, 287 days phosphorous, no radiologic effects,
decreased mineral mass in
mandibles, no effect on bending and
tension tests
Mice Water, 10 ppm Slight reduction in age-related Rao et al. 1972
from birth decline in breaking strength
Rat, young 45, then 135 ppm in Increased radiographic density if Reddy et al. 1972c
water during growth calcium adequate

Decreased radiographic density if


calcium deficient
Rat, adult Same as above Slightly increased radiographic
density
Quail Diet, 750 ppm, 35 Increased radiographic density if Chan et al. 1973
days calcium deficient

Reduced breaking strength of femurs


Rat Increased radiographic density Erickson and Ekberg 1975
Rat Water, 50, 150 ppm Reduced breaking strength Guggenheim et al. 1976
Reduced cross-sectional area
Reduced modulus of elasticity

Calcium, phosphorous deficiency


aggravated these effects
Rat Water, 100 ppm, 3 Reduced breaking strength in Riggins et al. 1976
Rooster months osteogenic bone
Quail Diet, 600 ppm, 4 Reduced breaking strength in
months osteogenic bone
Diet, 750 ppm, 35 Reduced breaking strength in
days osteogenic bone

3.5 MUTAGENIC AND RELATED EFFECTS OF FLUORIDE (back to top)

During the past seven years, a number of research papers presented evidence that some
inorganic fluorides are mutagenic to plant and animal cells. These papers, exclusive of
those dealing with humans, are discussed in the following paragraphs.
Reference has been made in Section 2 to the studies of Bale and Hart (1973a, b) on
fluoride mutagenicity in Hordium vulgare (barley), and to the studies of Gerdes et al.
(1971b) on mutagenicity in Drosophila melanogaster (fruit fly). As little as 10-6 M
sodium fluoride (0.019 ppm F) caused chromosomal-bridges, fragments, and gaps to
develop during mitosis of cells in the root tips of barley seedlings (Bale and Hart 1973a).
In fruit flies (Gerdes et al. 1971b), 1.3 and 2.6 ppm of airborne fluoride, as hydrofluoric
acid, caused genetic damage during a six-week exposure.

Mohamed and Kemner (1970) and Mohamed (1971) have also demonstrated
chromosomal damage in D. melanogaster after exposing males of a specific genotype to
an unspecified concentration of hydrogen fluoride. The degree of chromosomal damage
increased with increasing exposure times from 6 to 12 hours. Mitchell and Gerdes (1973)
exposed adult D. melatogaster flies to fluoride by allowing them to feed on filter paper
strips saturated with a 7% sucrose solution containing up to 6% sodium fluoride. Gene
changes in chromosome X were then detected by a cross-breeding technique. The
percentage of sex-linked recessive lethals observed was linearly related to the
concentration of fluoride in the food (our plot), and was significantly different from the
control value at the two highest fluoride concentrations (original authors' calculations).
Tests with stannous fluoride gave similar results, except that the stannous salt was about
one-third as mutagenic (on a fluoride-equivalent basis) in comparison to the sodium salt.

Jagiello and Lin (1974) examined meiotic division stages in mammalian oocytes that
were exposed to fluoride, as NaF, in vitro. Chromosomal aberrations were observed at the
following concentrations of fluoride in the medium:

Mouse oocytes: 91 and 181 ppm


Ewe oocytes: 11, 23 and 91 ppm
Cow oocytes: 4.5, 11, 23 and 9 1ppm

The percentage of ewe oocytes undergoing division was sharply reduced by fluoride
concentrations above 23 ppm, and the percentage divisions of cow oocytes was reduced
at 4.5 ppm fluoride and above.

Mohamed and Chandler (1976) examined cells from the bone marrow and testes of mice
after exposure of the animals to fluoride in drinking water at levels of 0, 1, 5, 50, 100,
and 200 ppm for up to six weeks. The number of chromosomal breaks and abnormalities
increased with the fluoride content of the drinking water and with duration of exposure.
The authors concluded that, with mice, even 1 ppm fluoride in the drinking water (the
diet contained 0.263 ppm) caused genetic damage.

Russian researchers (Voroshilin et al. 1973, 1975; Gileva e,t al. 1972, 1975) have
presented data on the mutagenic effects of inorganic fluoride on bone marrow cells of
white rats. Inhalation of cryolite or of a cryolite + HF mixture (e.g. 271, 543 and 1628 ug
F/m3 as cryolite, 6 hours/day, 6 days/week for up to 5 months) induced chromosomal
aberrations and hyperploidy. The extent of damage increased with increasing fluoride
concentration. Damage was greater in 17-months old than in one- to two-months-old rats.
Voroshilin et al. (1975) observed no increase in dominant lethals (total embryonic deaths)
when male mice were exposed to 1.0 mg HF/m3 for 2 or 4 weeks before mating. On the
other hand, Danilov and Kasyanova (1975) reported increases in embryonic deaths
resulting from exposure of female rats to 0.05, 0.5 and 5.0 mg HF/m3 (conditions of
exposure are poorly specified).

4.0 ORGANIC FLUORINE COMPOUNDS (back to top)

The WHO monograph (1970) on "Fluorides and Human Health" repeatedly states that the
fluorine-carbon bond is not cleaved by biological processes. However, evidence for
biological cleavage of the C-F bond had been presented in 1956 and confirmed in 1961
(cf. Ward and Huskisson 1972). Between 1965 and 1968, Goldman and his colleagues
presented a series of papers on the bacterial cleavage of C-F bonds, including that in 2-
fluorobenzoic acid (cf. Harper and Blakley 1971). During recent years, a considerable
volume of additional data on the biological cleavage of C-F bonds has accumulated. It is
now apparent that few, if any, organo-fluorine compounds are biologically stable.

Much of the recent interest in the biological breakdown of organic fluorine compounds
has arisen because there has been widespread use of some organohalides as anesthetics.
Under operating-room conditions, anesthetics must be considered as atmospheric
environmental pollutants. It has been shown that operating-room pollution with fluorine-
containing organohalides can give rise to an increased urinary output of inorganic
fluoride by operating-room personnel (Spierdijk 1972). Spierdijk (1972) also reviewed
data indicating an increased "incidence of abortion occurring amongst the wives of male
anaesthetists, female anaesthetists and nurse-anaesthetists" during employment.
Exacerbation of subclinical myasthenia gravis has been attributed to occupational
exposure to methoxyflurane (Elder et al. 1971).

4.1 METHOXYFLURANE (back to top)

Methoxyflurane (Penthrane), CH3-0-CF2-CC12H, appears to be one of the most


biologically unstable of the organohalide anesthetics. Research on methoxyflurane and
related anesthetics has been reviewed by Holaday (1972), Schuh (1974), Conn (1974),
and Gottlieb and Tray (1974). Biochemical pathways for the breakdown of several of the
organofluoride anesthetics have been reviewed by Loew et al. (1974).

Kidney damage can appear within a few days following methoxyflurane anesthesia. This
phenomenon was studied by Cousins and Mazze (1973), who reported that peak (i.e.
transient) post-anesthesia plasma F- levels in afflicted humans exceeded 90 umol/l. The
nephrotoxicity was accompanied by an increased urine volume of low osmolarity, and
increased thirst, with the syndrome tending to obey a short-term dose-response pattern in
man. Mazze et al. (1972) and Cousins et al. (1974) have shown that kidney damage in
rats exposed to methoxyflurane was caused by high inorganic fluoride concentrations and
not by oxalic acid, which is also a metabolic breakdown product of methoxyflurane.
Taves et al. (1972) also related the nephrotoxicity and polyuria to the
metabolicallyreleased inorganic fluoride. Mazze et al. (1972) showed that the degree of
kidney damage was related to methoxyflurane dose in rats.

Mazze and Cousins (1974) state that

"The predominant factor in the production of nephrotoxicity following methoxyflurane


administration appears to be the dosage; however, additional important factors are the
rate of metabolism of the drug, renal sensitivity to inorganic fluoride, presence of enzyme
induction, and interaction with other nephrotoxins. A high rate of methoxyflurane
biotransformation to inorganic fluoride in a patient overly susceptible to fluoride's renal
toxic effects could result in the occurrence of marked nephrotoxicity from a relatively
low dose of methoxyflurane".

A high degree of individual variability has also been noted, relative to other
organofluorine anesthetics (see later) such as halothane (Cascorbi et al. 1970). Also,
Eichhorn et al. (1976) have postulated that "the threshold for fluoride-induced
nephrotoxicity (following enflurane anesthesia) may be lower in diseased kidney".

Hagood et al. (1973) reported that nephrotoxicity induced by methoxyflurane anesthesia


in clinical practice gave a calculated mortality rate of 50%.

The fluoride-mediated toxicity of methoxyflurane is influenced by the presence of other


drugs (Churchill et al. 1976; Cousins et al. 1974). Also, metabolic breakdown of
methoxyflurane is enhanced in obese patients (Young et al. 1975; Samuelson et al. 1976)
and is probably related to the retention of organofluorine compounds in fatty tissue, as
noted in studies with halothane (Bhoopathi et al. 1974) as well as methoxyflurane (Bell et
al. 1975).

In rats, low dose levels of methoxyflurane over long periods were more injurious than
were equivalent high-dose short-term treatments (Arthaud and Loomis 1975). In rats
treated with either methoxyflurane or inorganic fluoride, nephrotoxicity was associated
with plasma F levels of 20 umol/l (Roman et at,1977).

Creaser et al. (1974) and Clark et al. (1976) determined the plasma F- levels of mothers
and their newborn children when methoxyflurane was used as an analgesic during labor.
Measured values in the mother's blood were somewhat higher than in the neonate's blood
at birth (e.g. 23.1 ± 1.6 and 16.3 ± 1.4 umol/l, respectively (Clark et al. 1976)). The
plasma F level of the mothers' blood declined progressively after delivery, but was still
markedly above normal 48 hours postpartum. The infants' blood lost fluoride less rapidly
than the mothers' blood, and the plasma F level in infants was not significantly different
from that of the mother's blood either 24 or 48 hours postpartum. Fiserova-Bergerova
(1976) observed deposition of fluoride in the bones of fetal rats after exposure of
pregnant female rats to enflurane or methoxyflurane.

4.2 OTHER ORGANOHALIDE ANESTHETICS (back to top)


Enflurane (Ethrane), CFzH-0-CF2-CFCIH, and sevoflurane, CFH2-0-CH(CH3)-CF3, are
also metabolized with consequent release of inorganic fluoride in the human, but the
extent of fluoride release is less than with methoxyflurane (Schuh 1974; Loew et al.
1974; Cook et al. 1975; Carter et al. 1976). However, nephrotoxicity was observed within
5 days following administration of enflurane in humans (Mazze et al. 1.977). In these
patients, the average (24 hr) plasma F- level was 15 umol/l, and there was no evidence of
a no-effect threshold.

Other organohalides used to induce anesthesia,'such as fluoroxene (CF3-CH2-0-


CH=CH2), isoflurane (CF3-0-CClH-CF3) and halothane (CF3-CBrClH), release little
inorganic fluoride during oxidative metabolism (Loew et al. 1974; Gion et al. 1974.)
(NOTE: Metabolites other than inorganic fluoride compounds may, however, be toxic,
e.g. trifluoroethanol (Gion et al. 1974; Tucker et al. 1973; Fiserova-Bergerova 1977).) It
appears that this relatively greater stability is attributable to the bonding position of
fluorine in these compounds (i.e. entirely on CF3 groups). However, Hitt et al. (1974)
noted that isoflurane is approximately one-tenth as soluble as methoxyflurane, and
suggested that the substrate concentration in vivo may limit its metabolic degradation to
inorganic fluoride. Hitt et al. (1974) observed a release of inorganic fluoride from
isoflurane by preparations of rat-liver mitochondria in vitro, especially if the live rats had
been preconditioned (enzyme induction) by exposure to phenobarbital.

The fluoride of the CF3 groups in these compounds is released during metabolism under
hypoxic conditions in vitro (van Dyke and Gandolfi 1976) and in vivo in rats (Widger et
al.1976).

4.3 MISCELLANEOUS ORGANIC FLUORINE COMPOUNDS (back to top)

As mentioned above, inorganic fluoride is released from 2-fluorobenzoic acid by


bacterial metabolism. Inorganic fluoride is also released by bacteria from p-fluorobenzoic
acid (Harper and Blakley 1971). However, release of inorganic fluoride from
fenfluramine, which has a CF group in the ortho-position on the benzene ring, has not
been detected (Arvela et al. 1973; Macrae 1975).

Gerhards et al. (1971) reported that fluorine in the 6a-position of fluocortolone (a


corticoid drug) is released during metabolism of this compound in the human body.
Schellman and Zober (1975) observed an "abnormally-high" iliac crest bone fluoride
level (2,640 pg/g ash) in a patient following prolonged treatment with fluorine-containing
corticosteroids (see Sections 3.4.1 and 5.3).

Excretion of inorganic fluoride by rats after inhalation of various fluorinated ethylene


compounds has also been reported (Dilley et al. 1973).

Another class of organo-fluorine compounds that has aroused considerable environmental


interest involves conversion of inorganic to organic fluoride (i.e. formation of C-F
bonds). This conversion leads to the formation of monofluoro-organic acids (e.g.
fluroacetate) in some species of vegetation (NAS 1971; Ward and Huskisson 1972).
Studies published since our previous review (Marier and Rose 1971) have shown that
both fluoroacetate and fluorocitrate are formed by cultured soybean (Glycine max) cells
(Peters and Shorthouse 1972b), and fluorocitrate by cultured tea (Thea sinensis) cells
(Peters and Shorthouse 1972a) when 10-3 M sodium fluoride is added to the medium.

No correlation between soil fluoride and organic fluoride in plant leaves has been
observed (Hall and Cain 1972); however, studies on vegetation subjected to airborne
fluoride still appear to be lacking for follow-up assessment of biotransformation
phenomena (cf. Marier and Rose 1971). Analysis for organo-fluoride compounds should
include plant tissues other than foliage, because Hall (1972) detected high levels of
organic fluorides in the seeds of some plant species. Also, Vickery and Vickery (1972,
1975) studied the locale of synthesis and translocation of fluoroacetate in Dichapetalum
species. Conversion to long-chain fluoro-fatty acids appeared to occur in the developing
seeds.

It has been reported that the toxicity of fluorocitrate to rats is much lower when it is
administered orally than when injected intraperitoneally (Peters et al. 1972). When 14C-
labelled fluorocitrate was administered orally to rats, most of the citrate moiety (73% of
the 14C-label) was excreted in the urine within 24 hours, along with considerable
quantities of inorganic fluoride. The toxicity of fluoroacetate, which is subject to in situ
conversion to fluorocitrate, was essentially unchanged whether it was administered orally
or by interperitoneal injection (Peters and Shorthouse 1971). One of the features of this
poisoning is the inhibition of aconitase, which results in an elevated blood citrate level
(Peters 1957).

In recent toxicological studies on the industrial use of BF3 catalysis, Bedford et al. (1977)
have isolated "two fluoroacetate precursors" (i.e. 2-fluoroethanol and 2-fluoroethoxy-
ethanol) which are apparently found as by-products, subsequent to fluoride-ion release
during catalysis.

5.0 FLUORIDE AND HUMAN ILLNESS (back to top)

There has been an increasing utilization of fluorine compounds by our technologically-


oriented society (EST 1972; Farkas and Parsons 1974). There has also been evidence of
an increased fluoride content in the human food-chain of several North American
localities (Prival and Fisher 1974; Kramer et al. 1974).

Studies of the interrelation between human illness and fluoride exposure are largely
dependent on uncontrolled exposure of industrial workers to variable concentrations of
fluoride, or on epidemiological studies in polluted neighborhoods. Total fluoride
exposure from all sources is usually not known. Accurate definition of the dose-response
relation is thus rarely possible, even under the specific conditions of a particular study.
Because factors that influence the nutritional and health status of some individuals also
affect their response to fluoride, meaningful dose-response criteria having broad
applicability to all humans are presently unattainable.
Nevertheless, in the following discussion, we attempt to assemble and review recent
reports relating to fluoride-induced illness in humans. This includes data on total
exposure from all identifiable sources, and information on the clinical and subclinical
aspects of fluoride-induced injuries and on their detection. Also, where possible,
emphasis is put on the identification and fluoride-response of segments of the total
population who, for one reason or another, may be more "at risk" than other segments of
the population. In the absence of criteria from which "safe levels" having a defined
margin of safety can be determined, observed injuries in such "at risk" groups may
provide an indication that exposure levels are approaching those that might adversely
affect an "average" individual exposed to various co-existing sources of fluoride in man's
everyday environment.

5.1 FLUORIDE INTAKE BY HUMANS (back to top)

5.1.1 Intake From Foods and Beverages (back to top)

The amount of fluoride ingested daily from foods and beverages by humans has been a
subject of controversy during the period under review. The history of one widely-quoted
Table, which appears in the National Academy of Sciences (NAS 1971) and WHO
(1970) monographs, has been reviewed by Farkas (1975a). Farkas concludes that
composite tables on fluoride intakes published prior to and during the early 1970s were
based on insufficient data and included misquoted data. Having examined the original
sources, we conclude that these Tables require major revision.

Recent reviews on the intake of fluoride by humans include those by Jerard and Patrick
(1973), Prival and Fisher (1974), and Marier (1977). Two quotations from these reviews
illustrate the concern being caused by increased human exposure to fluoride:

"Considering the paucity of recent data available on total fluoride intake, there is a clear
need for more accurate, detailed information concerning the distribution of fluoride
intake levels in the population" (Prival and Fisher 1974).

"Careful study is needed of the upward shift in environmental fluoride and an effort
should be made to appraise total exposure from all sources in order to protect the
environment and people of varying vulnerability" (Jerard and Patrick 1973).

One of the major factors thought to be contributing to the increase in human exposure to
fluoride is the increasing fluoride content of foods. Such an increase can arise from three
main sources, namely, the use of fluoridated water in food and beverage processing, the
exposure of crops to airborne fluoride [and to water-borne fluoride in areas irrigated with
fluoridated water (Auermann 1973)], and the use of fluoride-containing fertilizers.
Literature on the contributions of fluoride from air, irrigation waters, and fertilizers, to
man's total intake has been reviewed by Jerard and Patrick (1973). Bittel and Vaubert
(1971) state that:

"Il faut noter qu'en general la teneur en fluor des aliments vegetaux de l'homme ne cesse
de croitre: il y a a ce fait plusieurs raisons, d'abord l'utilisation, de plus en plus grande,
d'engrais et amendements calciques ou phosphocalciques de moins en moins purifies en
vue de contenir suffisamment d'oligoelements (bore en particulier) et, d'autre part,
l'influence de plus en plus etendue de la pollution industrielle".

Not enough work has been done on food-chain infiltration of fluoride, to assess the extent
to which this contributes to total intake from all sources. The data in Table 19 are
presented to illustrate the influence of the various environmental factors discussed above.
The data are restricted to those that have appeared since 1970, and are representative of
the effects of these environmental factors. The effect of fluoridated water used for food
processing is apparent from the data on Gouda cheese (Elgersma and Klomp 1975) and
beer (Tamacas et al. 1974) and is probably also a factor in the data on baby formula
(Farkas and Farkas 1974). The influence of airborne fluoride is obvious in the high values
for leafy vegetables reported by Gordon (1970a), Jones et ciL (1971) and Vouilloz. The
influence of fertilizer-borne fluoride is less obvious, but the high values for "control"
lettuce samples reported by Gordon (1970b) are thought to have resulted from this
source. The high fluoride content of wheat, spinach, cabbage, carrots, and other Indian
foods (Lakdawala and Puneka1973) presumably results from uptake of soil- or fertilizer-
borne fluoride. The high value for Cola soft-drink in Bombay was not caused by a high
fluoride level in the city's own water (Lakdawala and Punekar 1973).

Table 19. Recent data illustrating the effects of environmental factors on the range of fluoride
content in some foods. (back to top)

Food Explanation Fluoride content * Reference


(ppm, or mg/kg, or
mg/l)
Gouda cheese Normal 0.27 Elgersma and Klomp 1975
"" Fluoridated, 1 ppm in processing up to 2.16
water
Beers Fluoridated areas up to 1.0 Tamacas et al. 1974
Wines "" up to 0.7
Pablum Ready to use 4 to 12 Farkas and Farkas 1974
Baby formula """ 0.9 to 1.0
Orange juice """ 0.9
Cabbage Exposed, washed (1) 2.8 to 3.24 (2) Jones et al. 1971
Lettuce "" 12.0 to 19.6 (2)
Fruits and Exposed up to 100 Vouilloz 1975
vegetables
Lettuce Control samples 24 to 80 Gordon 1970b
" Exposed 39 to 226
Whole wheat As used 2.6 to 3.3 Lakdawala and Punekar
Wheat flour "" 4.8 to 6.4 1973 (3)
Spinach "" 0.8 to 4.1
Cabbage "" 1.3 to 2.3
Carrots "" 1.9 to 4.9
Cola drinks "" 1.3 to 1.4 (4)
Cow's milk Normal 0.087 to 0.132 Dirks et al. 1974
"" Exposed pastures 0.287
Pork Mechanically deboned 8.8 to 13.5 (5) Field et al. 1976
Cow beef "" 30.4 to 41.7 (5)
Choice beef "" 13.6 to 23.3 (5)
Beef Mechanically deboned 9.8 to 16.2 Kruggel and Field 1977
Pork "" 7.6

* As reported by the various authors.


Notes: (1) "Exposed" signifies exposed to airborne fluoride pollution.
(2) Mean values for various locations and times.
(3) Selected items from an extensive table of foods from Bombay, India.
(4) Bombay city water contained only 0.08 ppm fluoride.
(5) Values for hand deboned products; pork - 1.7 to 3.2; cow beef - 3.1 to 3.5; choice beef - 1.6 to 3.2

ADDENDUM: For a comprehensive review, see Kumpulainen, J., and Koivistoinen, P. 1977. Fluorine in
foods. Residue Rev. 68: 37-57.

The data on mechanically-deboned meat (Table 19) indicate how a change in processing
procedure can alter the trace element composition of a food. The high fluoride content of
the mechanically-deboned meats results from the inclusion of bone chips, and hence is
related to the fluoride intake of the animals (Kruggel and Field 1977). Contamination of
forages by fluoride increased the fluoride content of milk by 0.15 to 0.19 ppm (Dirks et
al. 1974); however, it must be remembered that reconstitution of powdered milk with
fluoridated water will cause a much larger increase in the fluoride content of the milk
beverage. The same applies to reconstitution of frozen concentrated fruit juice and other
such products.

A survey conducted by Farkas and Parsons (1974) indicated that the use of fluoridated
water for food and beverage processing in Canada is extensive. Specific production data
are not available, but 50% of the cities in which breweries were located, and 43% of the
cities where carbonated beverages were processed in cans, had fluoridated water.
Similarly, 51% of the factories processing vegetables, and of those processing pasta
products and soups, were located in cities with fluoridated water. Thus, it is probable that
about 50% of the beverages, pasta products, and canned foods consumed by Canadians,
contain about 0.5 ppm more fluoride (Marier and Rose 1966; SanFillipo and Battistone
1971) than the same products contained before the cities' waters were fluoridated.

Cigarettes may be another significant source of fluoride intake by humans. Okamura and
Matsuhisa (1965) reported the following results for fluoride content of cigarettes:

Type of No. of Brands ppm F in Cigarettes ug F per


Cigarette Analyzed Cigarette
Range Average (Average)
42 to
Japanese 16 163 157
640
35 to
American 19 236 244
420
This is the only published report we have seen on the fluoride content of cigarettes.
Although Cecilioni (1974) mentions cigarettes as a source of fluoride, we are not aware
of any published North American study in which the contribution of cigarette smoking
has been seriously considered relative to total fluoride intake.

A study by Full and Parkins (1975) raises the possibility that Teflon-lined cookware may
contribute to the fluoride ingested by humans. Full and Parkins boiled fluoridated (1
ppm) water at a moderate rate until a one-third or one-half reduction in volume was
attained, then determined the fluoride content of the residual water by ion specific
electrode. In aluminum ware, waterborne fluoride concentration was decreased. In
stainless steel and Pyrex ware, fluoride ion concentration increased, but to a lesser degree
than expected on the basis of volume reduction. In Teflon-coated ware, the concentration
of fluoride ion increased to nearly 3 ppm. This result requires confirmation; but, if it is
correct, then the release of fluoride into foods during cooking in plastic-coated wares
requires investigation.

In their study of English teenagers, Hardwick and Ramsey (1976) estimated that the mean
daily intake of fluoride from dentrifice was 0.32 mg, with an extreme high of 5.0 mg.
Three children out of 274 "usually swallowed all of the dentifrice used". Fluoride tablets
(1 mgF/ tablet) are also available in the U.K., and Hamilton (1974) notes that, in spite of
a cautionary statement on the package, "the sale of fluoride tablets does not appear to be
related to the fluorine content of the drinking water".

Recent data on the amount of fluoride ingested by children and adults are summarized in
Tables 20 and 21, respectively. However, few, if any, of these data are all-inclusive
estimates of total fluoride intake. None of the data include fluoride intake from dentifrice,
or from cigarettes. Kramer et al. (1974) state that their data are "exclusive of drinking
water". The "market basket" approach would appear to underestimate the effect of
fluoridated water used for domestic and commercial food preparation. In describing this
approach, Cummings (1966) listed only five canned foods (fish, corn, pork-and-beans,
tomatoes, and peaches). SanFillipo and Battistone (1971) list only one canned food (pork-
and-beans). Neither author lists any canned soups. This does not appear to be realistic;
Kramer et al. (1974) state that, in their survey the hospital diets studied "in great part
consist of processed, canned foods ..." Cummings (1966) indicates a "market basket"
allowance of only 1800 g (about 63 oz) of soft drinks for a two-week period, which
probably does not allow for between-meal consumption of such beverages. Lakdawala
and Punekar (1973) discuss the fluoride content of carbonated beverages, but it is not
clear whether between-meal beverages were included in their calculated fluoride intakes,
as quoted in Table 20.

The intakes for adults reported by Jenkins (1973) may be somewhat atypical, because
they are estimated on the basis of urinary excretions of 4 to 5 mg/day by people who
drink large amounts of tea.

Probably the most all-inclusive data in Table 21 are those of Spencer et al. (1970), which
were obtained under hospital conditions. There is no reason to assume that the hospitals
diets were selectively high in fluoride.

In Table 22, data on the percentage contribution of low-fluoride water and various foods
to the fluoride intake are compared for India and North America. The marked differences
shown by these data reflect the low estimates of fluoride intake from food that were
commonly accepted in North America during the 1960s, especially relating to "baseline"
estimates in unfluoridated areas.

Until further data become available we recommend that statements relating to fluoride
intakes by adults in North America should assume a "from foods" fluoride intake of 1.5
to 2.75 mg/day, and an intake from "foods and beverages" (in areas with water
fluoridated at 1 ppm) of 3.5 to 5.5 mg/day. Such estimates should include the caution that
these intakes may be exceeded by persons exposed to hot environments, by copious tea
drinkers, and by individuals with polydipsia (excessive thirst).

Table 20. Recent data on the daily intake of fluoride by children. (back to top)
Fluoride intake, mg/day
Age Locality with Locality with Reference
1 ppm F in water low F in water
School 1.0 to 2.15 (1) Balazova et al. 1970
Infants 1.48 to 1.90 Ericsson et al. 1972
0-1 year 0.37 to 1.29 0.11 to 0.45 Auermann 1973
9-11 year 1.60 0.89
15-18 year 2.25 1.07
2-8 year 2.7 1.6 Jenkins 1973
under 12 0.74 to 2.0 Lakdawala and Punekar
over 12 1.21 to 2.71 1973
5-6 year 0.85 to 1.1 Lee 1975
14 year 1.06 to 2.10
1-4 week 0.32 Wiatrowski et al. 1975
6-8 week 0.57
3-4 month 1.02
4-6 month 1.23

(1) The high value refers to children living in an area exposed to airborne fluoride. "Food" contributed 1.4
mg in this area as compared to 0.8 mg in a "control" area.

Table 21. Recent data on the daily intake of fluoride by adults. (back to top)

Fluoride intake, mg/day


1 ppm F Low F
Reference
in water in water
Spencer et al.
3.57 to 5.37 1.45 to 2.74
1970
San-Fillippo and
2.1 to 2.4 0.8 to 0.9 ("food stuff" only) Battistone 1971
(1)
1.34 0.81 (without exercise)
2.45 1.20 (moderate exercise) Auermann 1973
4.75 1.98 (strenuous excercise)
7 to 10 (heavy tea drinkers) Jenkins 1973
1.73 to 3.44 0.78 to 1.03 (exclusive of beverages) Kramer et al. 1974
1.23 to 2.41 0.73 to 0.94 (three meals only) Osis et al. 1974.

(1) A second report by San-Fillippo et alo. (1972) has been omitted from this table as it refers exclusively
to military meals.

Table 22. The percentage contribution of water and various foods to the fluoride ingested by humans.
(back to top)
% contribution of F
Source Range Average
India (Lakdawala and Punekar 1973)
Water (0.083 ppm) 2.0 - 10.8 5.0
Tea 0.7 - 21.0 5.3
Cereals 16.0 - 52.0 33
Vegetables 9.0 - 45.0 21
Pulses 6.0 - 22.0 11
Other 0.3 - 15.0 -

U.S. (NAS 1971, Table 9-4) - 60


Water (< 0.1 ppm) - 40
All foods

5.1.2 Intake From Air (back to top)

It is generally assumed that an "average" man doing moderately strenuous work inhales
approximately 20 m3 of air in a 24-hour period (NAS 1971). In view of the known
relations between fluoride ingestion and urinary excretion (NAS 1971), the rapid
response of urinary fluoride to inhaled gaseous or particulate fluoride (Hodge and Smith
1977) is indicative of efficient and probably essentially-complete absorption of inhaled
fluoride into the body. Inhalation of air containing 0.1 ug fluoride/m3 [a level that is
rarely encountered in non-industrial urban areas (Thompson et al. 1971)] would thus
result in an intake of only 2.0 ug fluoride per day. The contribution of airborne fluoride to
the daily intake is therefore considered to be negligible (however, see below) by most
authorities (e.g. NAS 1971).

However, at the other end of the scale, Hodge and Smith (1977) appear to consider it
acceptable to expose workmen, during an 8-hour shift, to a fluoride concentration of 2.5
Mg/m3. Assuming the respiration of 10 m3 of air during a working shift (Dinman et al.
1976a), fluoride absorption from the air by workers exposed to this concentration could
approach 25 mg. In summer, potroom workers perspire an average of 6 kg sweat per day
and may thus excrete 25 to 50% of the ingested fluoride in sweat (Dinman et al. 1976a).
Nevertheless, post-shift urinary fluoride concentrations of 7.01 ± 0.47 to 8.65 ± 0.69 mg/l
(daily averages for 25 "anode-men" exposed to an average airborne fluoride
concentration of 2.19 ± 0.16 Mg/M3) have been reported (Dinman et al. 1976b). These
data clearly indicate that, under some circumstances, humans can receive a considerable
amount of fluoride from airborne sources (see Section 5.9.2).

5.2 CARCINOGENIC IMPLICATIONS (back to top)

Fluorides are known to cause chromosome damage and mutations in plant and animal
cells (Section 3.5) and might therefore be considered as possible carcinogens. The
majority of studies on correlations between fluoride exposure and deaths from various
causes, including cancer, have focussed on fluoride exposure via drinking water. Studies
of differences in the "crude cancer death-rate" between cities with nonfluoridated and
fluoridated water supplies have led to conflicting results (Nixon and Carpenter 1974;
Bierenbaum et al. 1974; Kinlen 1974, 1975; Burk 1975; Yiamouyiannis and Burk 1976,
1977; Hoover et al. 1976).

An excess of respiratory-tract cancers was reported in fluorspar miners in Newfoundland


and attributed to airborne radon and radon daughters (deVilliers and Windish 1964;
deVilliers et al. 1971). Since the rate of incidence in these miners was five times greater
(per-unit of radiation exposure) than in Colorado uranium miners, Little et al, (1965)
postulated a co-carcinogenic role for fluorspar.

Cecilioni (1972a, b) has drawn attention to a three-fold increase in the death rate from
respiratory cancer in the steel city of Hamilton, Ontario, in comparison with the Canadian
average.

Studies of steelworkers (Lloyd et al. 1970) and aluminum workers (Discher et al. 1976;
Discher and Breitenstein 1976; Milham 1976) have led to inconclusive results concerning
the effect of the work environment on respiratory health. In all the studies involving
industrial exposures, no distinction can be discerned among various toxic and possibly
carcinogenic factors in the work environment. Such factors can act independently or
synergistically. Until definitive studies involving specific exposures to fluorides have
been made, we can draw no conclusions about the carcinogenic or co-carcinogenic
activity of fluoride.

5.3 OCCUPATIONAL FLUOROSIS (back to top)

Hodge and Smith (1977) have recently reviewed occupational exposure to fluoride, as it
relates to aluminum or phosphate fertilizer production, with emphasis on clinical
osteosclerosis. Other metabolic irregularities (e.g. those affecting respiratory function,
arthritis, kidney, blood, etc.) are considered, but Hodge and Smith (1971) state that, in
general, "their relation to fluoride exposure is doubtful, unless the exposure conditions
exceed those typical of U.S. operations" However, it is important to recognize that there
is usually a preemployment selection of workmen on a health basis. Thus Franke et al.
(1975) have reported that
"At the examination for employment, persons with the following diseases are considered
totally unsuitable: liver and kidney changes, blood and thyroid gland diseases, post-
traumatic or congenital skeletal damage, infections and para-infectious diseases of the
apparatus of locomotion (rheumatism; Bechterev's disease); also, workers with distinct
degenerative changes of the spine and of the large joints are unsuitable".

In all probability, there is also a continuing selection for health among exposed workers
(cf. Lloyd et al. 1970). Thus, at least some smelters exercise a "selection of the fittest"
policy, thereby ensuring that the workmen are in good health and, as such, more likely to
tolerate exposure to fluoride. In spite of this, Guminska and Sterkowicz (1975) and
Schellmann and Zober (1975) have recently emphasized that fluoride intoxication is a
problem of increasing importance in technological countries.

Although emphasis in North America has been on the osteosclerotic manifestations of


occupational fluorosis, earlier stages of fluoride-induced changes in bone are now being
utilized as diagnostic aids by some researchers. Franke and Auermann (1972) have
described this procedure, and Horn and Franke (1976) have demonstrated how
microscopic scanning techniques can be used to recognize graduated bone changes
associated with mild to severe fluorosis. Franke and Auermann (1972), and Schlegel
(1974) emphasized that muscular-skeletal complaints can be related to the histological
bone changes of mild fluorosis. Moreover, Popov et cit. (1974) observed neurological
symptoms in 63 of 80 workmen examined, and noted that the incidence of neurological
symptoms was not related to the skeletal stage (whether pre-osteal or definite osteal) of
fluorosis. Hiszek et al. (1971) emphasized that the high incidence of locomotor ailments
caused by fluoride occur in the absence of obvious radiological evidence of fluorosis.

Other recent observations indicate that fluoride-induced bone changes are not necessarily
symmetrical or bilateral. Thus, Herbert and Francon (1971) describe the case of a
Potroom worker who had left-hip sciatica and nephritis, with diffuse lumbar arthralgias.
The fluoride content of the iliac crest bone was between 5,100 and 5,800 ppm, ash basis.
Harbo (1973) describes the case of a workman with sensory loss in the upper left
extremity, with muscular wasting and pain. The highest fluoride content found in
vertebral bone samples was 2,700 ppm, ash basis.

In a discussion of bone fluoride levels, Riggins et al. (1974) report that some researchers
feel that 2,000 ppm fluoride in dry fat-free bone "should be considered toxic" and that
"skeletal fluorosis in humans can be seen when the concentration of fluoride in bone ash
exceeds 3,000 ppm". These two values for bone fluoride are compatible with each other,
assuming that bone contains about 60% ash. Franke and Auermann (1972) have
concluded that "In cases of genuine violent complaints, clear histological changes, and
fluorine values above 4,000 ppm in the bone ash of the iliac crest cylinder, the disease
should be classified as an occupational one, even with few clinical or radiological
findings". Boillat et al. (1976) advocated bone-biopsy fluoride analysis as a diagnostic
aid in the case of workmen with "articular pain and limitation of motion"; these cases had
concomitant hypocalcaemia, hypocalciuria, and hyper-hydroxyprolinuria, and Boillat et
al. concluded that nutritional factors play an important role in such afflictions.

These various observations indicate that the diagnosis of fluoride-related ailments is in a


state of evolution, and is approaching a hitherto unknown degree of thoroughness and
sensitivity.

Respiratory ailments may also be related to occupational exposure to fluoride. Mangold


and Beckett (1971) observed an "immediate upper respiratory irritation" by fluorides, as
contrasted to a "delayed pulmonary response to cadmium oxide fumes and nitrogen
dioxide" among silver brazers exposed to the mixed fumes. This suggests that respiratory
ailments may not reflect the total body-burden of fluoride, but might accrue from
repeated localized contacts of fluoride (especially HF) with respiratory tissues. It is
interesting to note that, after intravenous infusion of Na 18F into rats, the "lungs
contained the greatest amount of fluoride" of any of the soft tissues (Knaus et al. 1976).

Golusinski et al. (1973) reported that, of 130 potroom workers in an aluminum smelter,
30% had the characteristic changes of rhinitis, with hypertrophic and atrophic lesions.
Similarly, Fesenko et al. (1972) found that, of 1,141 workmen examined, 36% had
skeletal fluorosis, and 10% of these also had rhinopharyngolarynqltis. The
rhinopharyngolaryngitis topic is one that Hodge and Smith (1977) consider worthy of
consideration for future research on fluoride effects. As for atrophic rhinitis, Brown et al.
(1966) have studied its etiology, pathogenesis, and prophylaxis in swine; among their
conclusions, the authors emphasized that an inadequate calcium ingestion (or a low
dietary Ca/P ratio) leads to nutritionally-induced secondary hyperparathyroidism and
consequent generalized osteitis fibrosa. Thus, we again note the contribution of
nutritional inadequacies (or imbalances) in such syndromes.

The diagnostic value of plasma inorganic fluoride determinations has been discussed
elsewhere in this report (Section 3) and by Marier and Rose (1971), Ericsson and Ekberg
(1975), and Inkovaara et al. (1975). Guminska and Sterkowicz (1975) have reported a
significant decrease in blood erythrocyte ATP in workmen exposed to fluorides. Nikolaev
et al. (1971, 1973) have drawn attention to a 16-to-30% reduction in blood manganese
among workers exposed to fluorides. Although Furlanetto et al. (1973) concluded that
"manganese seemed not to affect the proportional fixation of fluoride" in bones and teeth,
researchers must not lose sight of the fact that a dietary lack of manganese can induce
skeletal abnormalities, including generalized rarefaction of bone (Tal and Guggenheim
1965), thickened leg joints with stunted growth, and impaired reproductive function
(NAS 1973). Rao and Friedman (1975) have reported that "A further toxic effect of
fluoride on bone formation may relate to the fluoride bonding with manganese, a cation
necessary for glycosylation, an intermediary step in the formation of collagen".

The foregoing examples, along with the blood and tissue changes noted in Tables 15, 16,
and 17, attest to the need for consideration of a multiplicity of factors in the assessment
of injuries accruing from long-term exposure to fluorides. The metabolic changes
discussed cannot be assumed to be of no biological significance, as regards chronic
fluoride intoxication.

Hodge and Smith (1977) concluded that a workplace airborne fluoride concentration
below 2.5 mg/m3 "will be tolerated without injuring human health during a working
lifetime". In contrast, Vishnevski (1969) questioned the U.S.S.R. airborne limit of 0.5
mg/m3 because workmen were found to exhibit increased sensitivity to light, increased
toxic symptoms and increased skeletal incorporation of fluoride. Vishnevski concluded
that the occupational fluoride level in ambient air should not exceed 0.1 mg/m3.
Guminska and Sterkowicz (1975) expressed concern that occupational airborne fluoride
concentrations of 0.22 mg/M3 would be deleterious to workers' health (see Section
5.9.2).

5.4 NEIGHBORHOOD FLUOROSIS (back to top)

As discussed in Section 5.3 on occupational fluorosis, screening of workmen to assure a


reasonable health status (Franke et al. 1975) undoubtedly reduces the incidence of overt
fluoride-related complaints. No such protection is provided for people residing in areas
adjacent to fluoride-emitting industries. Hodge and Smith (1977) considered this aspect
of fluoride pollution, but additional discussion is warranted. It is indisputable that persons
exposed to fluorides in the workplace constitute an "at risk" group because of the high
concentrations of fluoride to which they are exposed during their working shift. It is less
widely recognized that persons residing in polluted areas also constitute an "at risk"
segment of the population because of their more continuous exposure to moderate
concentrations (cf. Hunter 1969). It must not be forgotten that children, the elderly, and
the chronically ill and infirm, all form part of populations residing adjacent to sources of
fluoride emissions. Table 23 summarizes some of the metabolic abnormalities that have
been observed in such persons.

In Table 23, note that the "joint pains" alluded to by Murray and Wilson (1946) and the
"neuromuscular arthritis" described by Waldbott and Cecilioni (1969) are similar to
symptoms that were discussed in our preceding comments about occupational fluorosis
(Hiszek et az. 1971; Franke and Auermann 1972; Harbo 1973; Popov et al. 1974;
Schlegel 1974; Boillat et al. 1976). Riggs and Jowsey (1972), in their studies of fluoride
therapy for osteoporosis in humans, observed that some patients developed "transient
arthralgias and stiffness of the joints. These symptoms are dose-dependent and promptly
disappear on discontinuation of the drug (i.e. fluoride)". The occurrence of anemia in
"neighborhood fluorosis" accords with earlier observations (cf. Marier and Rose 1971)
and with the related data in Table 16, as discussed in Section 3.1.2.

In a preceding Section of this report, Tables 15, 16 and 17 presented summaries of


biochemical changes induced by fluoride in blood and in soft tissues. It remains to be
determined whether some of these changes are consistent features of subclinical or mild
forms of neighborhood fluorosis in humans.
Table 23. Health problems among residents near fluoride-emitting sources. (back to top)

Place Source Population Symptoms Reference


England Iron 5 adults Murray and Wilson 1946.
4 children
Czechoslovakia Aluminum 78 children Low hemoglobin with Rippel et al. 1967
surveyed high erythrocyte Balazova et al. 1970
Canada-U.S. Phosphate 31 adults Neuromuscular arthritis Waldbott and Cecilioni
Fert. etc. 1969.
U.S. Iron 1 adult Neuromuscular arthritis """
etc.
Hungary Aluminum 227 children Low hemoglobin Leloczky 1971
surveyed
E. Germany HF plant 27 adults Early skeletal fluorosis Schmidt 1976a
E. Germany Aluminum 16 adults Bone changes Schmidt 1976b

5.5 ENDEMIC FLUOROSIS (HYDROFLUOROSIS) (back to top)

This form of fluorosis has been linked to chronic ingestion of naturally-fluoridated waters
(WHO 1970). In a recent Algerian study of hydrofluorosis, Poey et al. (1976) have
reported that the early stages of chronic fluoride intoxication are associated with changes
in blood and urine components, and that these precede radiologically-detectable bone
abnormalities. In the early phase, there was an increase in blood urea and acid
phosphatase, with a concomitant increase in urinary output of phosphorus and urea. As
the fluoride intoxication progressed, there was a gradual impairment of urinary creatinine
clearance, leading to renal insufficiency (see Sections 3.2.1, 3.2.2, and 5.8).

Much of the information relating to endemic fluorosis has originated from India, where
skeletal fluorosis has been associated with water-borne fluoride concentrations of 2 to 3
ppm or lower (Jolly et al. 1968; Krishnamachari 1976). Although osteosclerosis seems to
be the only fluoride-related bone abnormality recognized in North America (see Hodge
and Smith 1977), the skeletal abnormalities observed in India are not confined to the
osteosclerotic form (Teotia et al. 1976).

Even at comparable degrees of fluoride exposure, the epidemiological studies in India


have provided some striking contrasts. In the Punjab area, Jolly et al, (1968, 1974) have
invariably observed the osteosclerotic type of bone disease in fluorotic patients. In
contrast, Teotia et al. (1974, 1976) have encountered osteoporosis, rachitis, and the
osteomalacia type of bone disease associated with a fluoride-induced compensating
secondary hyperparathyroidism. The bone rarefaction phenomena observed by Teotia et
al. were not confined to adults, but were common in children 11 to 14 years of age
(Teotia et a. 1971). Faccini and Teotia (1974) described the histopathological features of
the osteomalacia-like fluorotic bone. This abnormality can resemble the osteitis fibrosa
cystica of the "wine fluorosis" described by Soriano (1966). It also resembles the
condition reported in fluoridated hemodialysis patients by several researchers (Posen et
al. 1971; Jowsey et al. 1972a; Johnson and Taves 1974; Riggs et al. 1976).

In Teotia's surveys, the serum immuno-reactive parathyroid hormone levels correlated


positively with serum alkaline phosphatase and with urinary excretion of total
hydroxyproline (Teotia et al. 1974; Faccini and Teotia 1974). In studies of hydrofluorosis
in Italy, Frada et al. (1974) observed increases in bone alkaline phosphatase and urinary
hydroxyproline in fluorotic patients. These observations are in accord with those of
Boillat et al. (1976) who reported hydroxyprolinuria in patients with occupational
fluorosis. Boillat et al. concluded that nutritional factors play an important role relative to
fluorosis-related hydroxyprolinuria.

Jolly et al. (1974) discussed nutritional factors relative to the different clinical patterns
seen in different regions of India. They state that "In Punjab, where the (daily) dietary
intake of calcium averages 1 gram, osteomalacia and rickets are not encountered in cases
of fluorosis. However, in Andhra Pradesh and Rajasthan, a low calcium intake coupled
with intake of fluoride produces changes of rickets and osteomalacia". This conclusion is
supported by other reports. Thus, in the Rai Bareli district, where osteomalacia is the
commonly-seen form of bone fluorosis, Teotia et al. (1974) reported a daily calcium
intake averaging 645 mg, and a phosphorus intake averaging 1738 mg/day (Ca/P ratio =
0.37). Krishnamachari and Krishnaswamy (1974) reported that the adult male in the
Nalgonda district, where Genu VaIgum (see next paragraph) is the prevalent form of
fluorosis, has an average daily intake of 297 mg calcium and 2096 mg phosphorus (Ca/P
ratio = 0.14).

An extremely severe form of fluorosis observed in India is termed "genu valgum", and is
characterized by a crippling "knock knees" syndrome with osteosclerosis of the spine and
concomitant osteoporosis of the limb bones, and by very high serum parathyroid
hormone levels suggestive of hyperparathyroidism (Krishnamachari and Krishnaswamy
1973). Dietary studies indicated no vitamin D deficiency, but low dietary calcium, a low
Ca/P ratio, and a high molybdenum content in some locally-grown foods; a high urinary
excretion of copper was also noted (Krishnamachari and Krishnaswamy 1974;
Agarwal,1975; Krishnamachari 1976). The crucial role of copper was recognized by
Krishnamachari (1976) who states that "None of the villagers whose water contained
more than 0.1 ppm of copper had Genu Valqum, although their water contained high
levels of fluoride".

These studies on Genu Valqum indicate that water-borne elements other than fluoride can
influence the skeletal abnormalities encountered in endemic fluorosis. Several reports
have shown a relation between the development of fluorosis and the calcium and
magnesium content of the drinking water. Jolly et al. (1968) reported on the situation in
two villages whose water contained an average of 3.3 ppm fluoride, but where the two
populations had a markedly different (10% as compared to 45.6%) incidence of skeletal
fluorosis. The lower incidence of fluorosis was associated with a higher total hardness of
the water. Because the nutritional status, climate, duration of fluoride exposure etc., did
not differ between the two villages, Jolly et al. (1968) concluded that the calcium and
magnesium components of hard water had a "protective influence". Such a protective
effect has been discussed by Marier, Rose and Boulet (1963).

Similar results have been reported from the Rajasthan area of southern India, where
Thergaonkar and Bhargava (1974) compared fluoride intoxication in 16 villages with
waters of different degrees of hardness and fluoride contents ranging from 0.3 to 2.7
ppm. They concluded that "incidence of fluorosis is probably reduced by (waterborne)
calcium ... ard the severity ... is (directly) related to bicarbonates in the water, apart from
the fluoride concentration". These conclusions are supported by the data of Kathuria et al.
(1974). Teotia and Teotia (1975), in a study in the Uttar Pradesh area of India, did not
find a reduced incidence of fluoride intoxication in hard-water areas, and suggested that
"the simultaneous intake of excessive amounts of (waterborne) magnesium ... interferes
with calcium's (protective) action".

No clear relation between waterborne magnesium and fluorosis was observed in the
studies conducted by Thergaonkar and Bhargava (1974) or by Kathuria et al. (1974), but
the assessment may have been complicated by "low nutritional levels and lack of a
balanced diet" (Thergaonkar and Bhargava 1974). A similar survey of human population
groups in Czechoslovakia (Vejrosta et al. 1975) attributed a beneficial effect to
waterborne magnesium, in terms of ensuring the integrity of mineralized tissues. In
Rumania, Benetato et al. (1970) studied calcium and magnesium metabolism in
hospitalized patients who had neurological symptoms of early (i.e. pre-skeletal) chronic
fluorosis, associated with ingestion of drinking-waters containing 2.85 to 3.6 ppm
fluoride. The study included parallel observations in rats, and led the authors to conclude
that chronic fluoride intake can induce latent calcium and magnesium deficiency in which
the electrolyte changes (especially of magnesium) contribute to the serious metabolic
derangements. A report of the Royal College of Physicians of London (1976) concluded
that "There is no evidence that the consumption of water containing approximately 1
mg/litre of fluoride in a temperate climate is associated with any harmful effect
irrespective of the hardness of the water."

The role of drinking water components should not be underestimated. Hankin et al.
(1970) found that hard waters can contribute significantly to the total dietary intake, i.e.
from 3.5 to 15.9% of the daily intake of calcium, and from 8.9 to 27.3%0 of the daily
magnesium. During recent years, the World Health Organization has been emphasizing
this area of research (Masironi 1975). Sundstrom (1972) observed bone-resorption
cavities indicative of "mild fluorosis" in some rats given 1 ppm fluoride in distilled
drinking-water during a 2-year period, and therefore recommend "A special long-term
study, in which the effects of (fluoride in) distilled and artificially-fluoridated waters are
compared with those of naturally fluoride-containing waters".

5.6 DIETARY-NUTRITIONAL DEFICIENCIES OR IMBALANCES AND


FLUOROSIS (back to top)

In the preceding discussion, we have considered the influence of waterborne calcium and
magnesium, and how this factor may help to protect against the onset and severity of
fluorosis.
The beneficial effects of calcium and magnesium in alleviating fluorosis has been
confirmed in animal studies. Low-calcium diets increased bone fluoride in rats
(Guggenheim et al. 1976), increased the severity of bone fluorosis, with "exostosis"
lumps, in rabbits (Reddy and Rao 1972b), and increased bone fluoride and the severity of
its effects in monkeys (Reddy and Srikantia 1971). Conversely, high dietary calcium and
phosphorus lowered bone fluoride in swine (Forsyth et al. 1972), and calcium
supplementation decreased the lesions of fluorosis in cows, horses, and swine (Spencer,
Cohen and Garner 1974).

Marier (1968) reviewed the metabolic interrelation of magnesium and fluoride; Table 24
represents his summary comparison. Marier notes that, in magnesium-deficient dogs,
fluoride supplements prevented soft-tissue calcification, but not the muscle weakness or
convulsions; in magnesium-deficient rats, fluoride aggravated the hypomagnesaemia,
thereby intensifying the convulsive seizures.

Rapidly growing chicks appear to present a particular problem, because they develop a
"leg weakness" syndrome when fed diets that contain high levels of both magnesium and
fluoride (cf. Marier 1968). Also, Rogler and Parker (1972) have observed that a diet high
in calcium could partially prevent the onset of toxicity with the high-magnesium high
fluoride diet. An underlying imbalance among the various mineral nutrients is thereby
suggested. Hakansson and Svensson (1977) have reported that rapidly growing chicks,
especially when given highly concentrated feed, seem to have difficulties in utilizing
dietary magnesium, and retaining it in their leg bones. It appears probable that this
magnesium-related problem is aggravated by concomitant high-fluoride supplementation,
even though the toxic symptoms can be partially alleviated by prior increases in dietary
calcium.

Hamuro (1972a, b) studied the effects of fluoride on magnesium-deficient mice and


concluded, on the basis of 6-day studies, that fluoride supplements prevented renal
calcinosis. However, a longer-term study with magnesium-deficient rats indicated
(Ophaug and Singer 1976) that fluoride exerted only an initial protective effect on kidney
calcinosis, and that the long-term effect was to promote kidney calcification. Suketa et al.
(1977) observed that, in rats, a single large dose of fluoride increased kidney calcium 10
times more than it increased kidney magnesium; this would favor in situ calcification
(Marier 1968).

Pita et al. (1972) have shown that fluoride supplements increased the magnesium content
of mineralized tissues in rats. Ophaug and Singer (1976) reported that fluoride exerted a
significant effect in retarding the mobilization of skeletal magnesium in rats. O'Dell et al.
(1973) observed that fluoride had a "magnesium-sparing" effect in Guinea pigs, but
found that high fluoride supplements were toxic when magnesium was severely limiting.
O'Dell et al. concluded that "a high intake of magnesium should be highly beneficial in
areas where fluorosis prevails".

Thus, there is evidence that fluoride intake can increase the long-term metabolic
requirement for magnesium. The same may be true for manganese. Note that we have
previously discussed depletion of manganese in fluoride-polluted pine needles (Garrec et
al. 1977), and the reduction in blood manganese among workers exposed to fluorides
(Mikolaev et al. 1971, 1973). These nutritional interrelations have not yet been
adequately quantified.

The same considerations apply to vitamin C. Unlike most species, primates cannot
synthesize their own vitamin C, and are entirely dependent on their food-chain to supply
an adequate intake. In a study of fluoride supplementation in monkeys, Reddy and
Srikanti (1971) showed that a diet low in vitamin C enhanced the onset of skeletal
fluorosis, and that a low protein intake accelerated rarefaction of bones. Earlier,
Gabovich and Maistruk (1963) had shown that vitamin C supplementation reduced the
toxic effects of fluoride in industrial workers and in Guinea pigs. Marier and Rose (1971)
discussed Russian studies in which fluorosis was found to be most severe in children who
had a vitamin C deficiency. Marier and Rose also discussed Australian work, which
showed that vitamin C supplementation alleviated fluorosis in Guinea pigs.

It appears possible that chronic exposure to fluoride increases the metabolic requirement
for vitamin C; but again, such nutritional interrelations have not yet been quantified.

There is, however, definite evidence that fluoride supplementation creates a greater
metabolic requirement for calcium in humans. Much of this evidence has accrued from
attempts to treat human osteoporosis by means of high doses of fluoride.

Some researchers (e.g. Franke et al. 1974) have reported success in the treatment of
human osteoporosis, using 20 to 60 mg NaF per day (i.e. 9 to 27 mg F/day). However,
experiments with several species of animals have shown that administration of fluoride
alone does not reverse or improve osteoporosis (Henrikson et al. 1970; Spencer et al.
1971; Reddy and Rao 1972a; Kuo and Wuthier 1975; Griffiths et al. 1975, 1976).
Similarly, several researchers have concluded that administration of fluoride alone does
not improve human bone rarefaction (Albright and Grunt 1971; Cohn et al. 1971;
Inkovaara et al. 1975). Jowsey et al.(1972b) have emphasized that administration of less
than 20.5 mg F/day did not consistently increase bone formation, whereas 27 or more mg
F/day produced abnormal bone. This form of high-fluoride therapy has been termed "an
experimental drug for osteoporosis" (Gordan 1976).

Using 25 and 20.5 mg F/day, respectively, Inkovaara et al. (1975) and Zanzi et al. (1975)
observed spontaneous bone fractures during the course of treatment. Merz et al. (1970),
using dosages usually ranging between 22 and 34 mg F/day, discontinued fluoride
administration to their patients, to avoid the eventual development of osteomalacia.
(Note: Osteomalacia and spontaneous bone fractures have also been encountered in
patients on hemodialysis with fluoridated water; see Section 5.8).

Studies with rats, swine, dogs, and monkeys, have shown that, in the absence of fluoride
supplementations, a calcium deficiency (or too low a dietary Ca/P ratio) is likely to lead
to "nutritional osteoporosis" (Henrikson 1968; Reddy and Rao 1972a; Rantanen et al.
1972; Kuo and Wuthier 1975; Griffiths et al.. 1975 and 1976). The osteoporotic condition
will not be reversed or improved by supplementation with fluoride alone (Henrikson et al.
1970; Reddy and Rao 1972a; Spencer et al. 1971 and 1974; Kuo and Wuthier 1975). If
the calcium insufficiency is not corrected, fluoride supplementation can induce
osteomalacia (Rantanen et al. 1972; Kuo and Wuthier 1975; Griffiths et al. 1975 and
1976).

The most positive results in the treatment of human osteoporosis with fluoride have been
obtained by use of concomitant calcium supplements. In the studies by Cohn et al.
(1971), high calcium supplements reduced bone pain in osteoporotic patients, whereas
fluoride administration did not achieve this effect.

Jowsey et al. (1972b) have stated that "osteomalacia and secondary hyperparathyroidism
observed in previous studies were caused by fluoride and a calcium intake insufficient to
mineralize the new bone ... Fluoride might be expected to aggravate any tendency toward
increased parathyroid hormone secretion in osteoporosis". Kyle et al. (1975) commented
that "in the absence of additional calcium, the bone is incompletely mineralized. If
fluoride administration continues ... the net result will be osteomalacia and increased
bone resorption".

To prevent osteomalacia, the calcium supplement must be "administered concurrently"


with fluoride (Riggs and Jowsey 1972). Jowsey et al. (1972b) and Kyle et al. (1975)
recommend that, in high-fluoride therapy, the calcium supplements, given concomitantly,
should be 35 to 40 times the fluoride supplement, by weight. Marier (1977) noted that the
calcium supplement is given in addition to the "adequate" calcium levels ingested in a
normal diet, and this is thus indicative of a fluoride-induced increase in the metabolic
requirement for calcium. If this same fluoride-to-calcium proportionality applies to
chronic daily intake of fluoride, then the ingestion of 5 mg of fluoride per day would
require a supplemental intake of 200 mg calcium per day. This extrapolation may not be
justified, but it serves to emphasize the need for an adequate intake of dietary calcium
during long-term exposure to fluoride.

A vitamin D supplement of 50,000 units twice weekly has been recommended during
high-fluoride treatment of osteoporosis (Jowsey et ae. 1972b; Riggs and Jowsey 1972;
Kyle et al. 1975). However, Takizawa et al. (1975) did not obtain improvement in
geriatric patients with this high vitamin D dosage. Riggs et al. (1976) recently compared
two dosages of vitamin D (50,000 units, twice weekly, vs 400 units daily) given in
conjunction with the calcium and fluoride. They concluded that "we do not recommend
the large doses of vitamin D". (The vitamin D topic is also discussed in connection with
fluoridated hemodialysis; see Section 5.8).

In relating the significance of the various nutrient-versus fluoride interrelations discussed


above to low-dose long-term daily exposure of humans to fluoride, it is pertinent to note
that ingestion of fluoride has increased over the past few decades and is probably still
escalating (Marier 1977; also Section 5.1). When one considers that nutritional surveys
have shown that sizeable proportions of the North American population have an
inadequate dietary intake of calcium and of vitamin C (see "U.S. 1969"; "Canada 1973"),
the need for vigilance is apparent.

Table 24. Symptoms common to both fluoride intoxication and magnesium deficiency (Marier 1968).
(back to top)

Symptom Fluoride intoxication Magnesium deficiency


Leg cramps, or "pins and needles" Sauerbrunn et al. 1965 Fourman and Morgan 1962
(human) (human)
Muscular twitching Kretchner et al. 1963; Hanna et al. 1960;
Taves et al. 1965 Suter and Klingmann 1955
(human) (human)
Tetaniform convulsions Ibid. Fourman and Morgan 1962
(with normal serum Ca) (human)
2 to 3-fold increase in serum P Ibid. Martindale and Heaton 1964
(at time of convulsion) (rats)
Cataracts (optical neuritis) Geall and Beilin 1964 Fourman and Morgan 1962
(human) (human)
Bone exostoses and/or Weatherall and Weidmann 1959 O-Dell et al. 1960
soft tissue calcification (rabbits, cats, and rats) (rats)

5.7 THYROID FUNCTION (back to top)

Day and Powell-Jackson (1972) reported that water-borne fluoride appeared to increase
the prevalence of goitre in an area where goitre was already endemic. Teotia and Teotia
(1975) observed a high incidence of goitre (up to 18% in the total population) in areas of
endemic hydrofluorosis. Crawford (1972) has commented on such interactions as
follows:
"A Medical Research Council (U.K.) memorandum reported that, in some areas, even
moderate concentrations of fluoride in drinking-waters could block iodine absorption. It
is known that the iodine concentrations are lower in soft than in hard waters .... If fluoride
is added to soft waters .... a proportion of the population may come to have suboptimal
iodine intake. The effects might be subtle and slow to develop, and would certainly not
be picked up by the crude screening used at present".

In studies with rats, Back (1970) found that the thyroid preferentially retained increased
amounts of fluoride for two weeks following fluoride administration. Zucas and Lajolo
(1975) reported that removal of the pituitary gland caused increased deposition of skeletal
fluoride, an effect that seemed to be "related to thyroid hypofunction". Bobek et al.
(1976) observed that fluoride supplementation for a two-month period caused a slight
decrease in blood thyroxine, a phenomenon thought to be caused by a fluoride-mediated
alteration in the functioning of thyroxine-binding proteins.

Day and Powell-Jackson (1972) recommended further research on the amino-acid


precursors of thyroxine, particularly tyrosine and its metabolites, because increased
urinary loss of tyrosine has been reported in fluorosis; also, because tyrosine deficiency is
a known cause of thyroid hypofunction.

5.8 KIDNEY-RELATED PROBLEMS (back to top)

In the human body, the kidneys are probably the most crucial organ during the course of
low-dose lonq-term exposure to fluoride. Healthy kidneys excrete 50 to 60% of the
ingested dose (Marier and Rose 1971). Kidney malfunction can impede this excretion,
thereby causing an increased deposition of fluoride into bone. Marier (1977) has
reviewed data showing that, in persons with advanced bilateral pyelonephritis, the
skeletal fluoride content can be 4-fold that of similarly-exposed persons with normal
kidneys. Similarly, Mernagh et al. (1977) have reported a 4-fold higher skeletal fluoride
content in persons with the renal failure of osteodystrophy. It has also been shown
(Seidenberg et al. 1976; Hanhijarvi 1975) that plasma F- levels can be 3 1/2 to 5 times
higher than normal in persons with renal insufficiency. It is thus apparent that persons
afflicted with some types of kidney malfunction constitute another group that is more "at
risk" than is the general population. (Note: Some kidney-related problems have already
been discussed in Sections 4.1 and 4.2).

Understandably, people who have little, or no, kidney function constitute a particular "at
risk" group. This includes persons exposed to long-term hemodialysis with fluoridated (1
ppm) water, which aggravates the bone lesions of uremic renal osteodystrophy, by
increasing the severity of bone osteomalacia and the incidence of spontaneous bone
fractures (Posen et al. 1971; Johnson and Taves 1974). These effects parallel those
observed in high-dose fluoride therapy of osteoporotic patients, i.e. osteomalacia (Merz et
al. 1970; Jowsey et al. 1972b; Kyle et al. 1975) and spontaneous fractures (Inkovaara et
al. 1975; Zanzi et al. 1975).

Inkovaara et al. (1975) recommended that the plasma inorganic fluoride ion (plasma F-)
concentration should not exceed 3 umol/l if spontaneous fractures are to be avoided. As a
basis for comparison, Nielsen et al. (1973) report predialysis plasma F- levels of 9 umol/l,
and Posen et al. (1971) extrapolate their observations to an initial (i.e. before the first
dialysis treatment) level of 7 umol/l. Still higher plasma F- levels have been observed
during the course of fluoridated dialysis (Posen et al. 1971; Jowsey et al. 1972a; Nielsen
et al. 1973; Cordy et al. 1974). The plasma F- can attain a concentration of 36 pmol/l
during long-term fluoridated hemodialysis treatment (Fournier et a. 1971), and this level
is about 50 times higher than normally found in residents of unfluoridated communities
(Taves 1968; Hanhijarvi 1975).

During maintenance of patients on fluoridated hemodialysis, the increased body-burden


of fluoride is reflected by high levels of fluoride in bone (Posen et al. 1971), and a high
molar F/Ca ratio in bone (Jowsey et al. 1972a; Cordy et al. 1974). Posen et al. (1971)
administered high doses (as high as 200,000 units per day) of vitamin D concurrently,
and it was felt that this contributed to the severity of the bone changes. The patients
studied by Cordy et al. (1974) had a daily vitamin D intake of only 460 units (Note:
Riggs et al. (1976) now recommend 400 units daily during high fluoride therapy). Cordy
et al. (1974) observed lower plasma F- levels and less severe bone disease than
previously reportedly Posen et al. (1971).

In a study of fluoridated-hemodialysis patients, Nielsen et al. (1973) observed that 86%


of their patients showed evidence of secondary hyperparathyroidism, along with a
significant increase in serum alkaline phosphatase. These manifestations have also been
seen in endemic fluorosis patients (Krishnamachari and Krishnaswami 1973; Teotia et al.
1974; Faccini and Teotia 1974; Sivakumar and Krishnamachari 1976).

As discussed by Rao and Friedman (1973), some dialysis clinics have not encountered
problems with fluoridated hemodialysis. Nevertheless, several researchers consider it
prudent to use non-fluoridated water, so as to reduce the risk of osteomalacia (Stewart
1969; Posen et al. 1971; Jowsey et al. 1972a; Cordy et al. 1974; Lough et al. 1975; Rao
and Friedman 1975).

Persons suffering from nephropathic Diabetes Insinidus make up another subgroup that is
more "at risk" than the general Population. Table 25 summarizes the observations on 10
such cases about whom we have found reports. A striking feature of this tabulation is the
young age at which skeletal fluorosis has become evident in some of these patients. Thus,
Juncos and Donadio (1972) diagnosed skeletal fluorosis in an 18-year-old boy and a 17-
year-old girl. The only other report of skeletal fluorosis in children appears to be that of
Teotia et al. (1971), which dealt with endemic hydrofluorosis in India.

Table 25. Fluorosis in persons who have the Diabetes Insipidus syndrome. (back to top)

Patient Drinking-water F intake Diagnosis Authors' Comments Reference


Age Sex F, Intake, from
mg/l l/day Drinking-
water
mg/day
64 M 2.56 4 to 10 10.24 to Skeletal "Drinking-water seems to have been his Sauerbrunn
25.6 fluorosis only source of fluoride et al. 1965
polydipsia intake...Prolonged polydipsia may be
polyuria hazardous to persons who live in areas
pyelonephritis where the levels of fluoride in drinking-
Diabetes water are not those usually associated
Insipidus with significant fluorosis."
18 M 2.6 "about 2 approx. 20 Skeletal "It is postulated that the renal Juncos and
gal." fluorosis insufficiency, which resulted in the Donadio
17 F 1.7 ? polydipsia large intake of fluoride-containing 1972
"large polyuria water and reduced excretion of fluoride,
amounts" renal combinedto produce systemic
insufficiency fluorosis."
10 M 1.0 1.25 to 1.25 to 3.0 Dental "We are reporting two children with Greenberg
3.0 fluorosis nephrogenic diabetes insipidus and et al. 1974
11 M 1.0 1.25 to 3.0 polydipsia fluorosis, and suggest looking for
1.25 to polyuria evidence of fluoride toxicity in
3.0 nephropathy individuals with polydipsia.
Diabetes Substituting non-fluoridated water as
Insipidus part of the fluid intake is
recommended."
35 F 0.5 10 to 15 5 to 7.5 Dental "Drinking of large amounts of water, Klein 1975
14 F 0.5 10 to 15 5 to 7.5 fluorosis even with lower-than accepted fluoride
13 F 0.5 10 to 15 5 to 7.5 polydipsia content, can produce fluorosis of the
10 F 0.5 4 to 5 2 to 2.5 polyuria teeth."
8 M 0.5 4 to 5 2 to 2.5 Diabetes
Insipidus

Comparison of the "Diagnosis", "F intake", and "Age" columns in Table 25 suggests that
there is a progression from nephropathy, to renal insufficiency, to pyelonephritis,with
increasing age and/or sustained fluoride intake. This is corroborated in the Algerian
studies of various stages of human hydrofluorosis, as conducted by Poey et al. (1976).
Gradual impairment of urinary creatinine clearance was indicative of progressive
inhibition of kidney glomerular filtration, affecting tubular reabsorption of water. In the
final stage, urinary excretion of fluoride accounted for only 10 to 20% of the intake (i.e.
about 1/6 to 1/3 of normal), and was thus indicative of high fluoride retention. Based on
histologically-detectable glomerular degeneration, Poey et al. concluded that fluoride can
complicate, or can actually induce, nephropathy. The WHO (1970) report had recognized
that "the remote possibility that fluoride may aggravate renal disease has not been
conclusively ruled out".

In all the cases tabulated in Table 25, the patients had the excessive thirst of polydipsia.
As noted by Klein (1975), even if the beverages consumed to satisfy this thirst have a
"lower-than-accepted" fluoride content, this can result in an excessive intake of fluoride.
Experinmental confirmation of fluoride-induced polydipsia is found in the 18-month
study by Manocha et al. (1975), who observed-that fluoride caused a considerable
increase in the water intake of monkeys.

Another aspect of the Diabetes Insipidus syndrome is the abnormally-high output of urine
(polyuria). In a report of a study with rats, Hamuro (1972b) has stated:

"The Polyuria induced by fluoride was accompanied by an enhanced sodium excretion


and a decrease in osmolality. These results were consistent with previous findings that the
administration of fluoride caused polyuria in laboratory animals".

In a study with humans, Taves et al. (1972) remarked that "The data .... is consistent with
the hypothesis that F (i.e. fluoride) is the cause of the polyuria"

Singer and Forrest (1976), writing about drug-induced states of nephrogenic Diabetes
Insipidus in humans, state that

"these studies (with sodium fluoride) have been interpreted to suggest that sodium
fluoride does not grossly impair (kidney) ascending-limb sodium chloride transport, but
may cause nephrogenic Diabetes Insipidus, either by washing-out the medullary solute
(since fluoride is a vasodilator in many vascular beds), or by reducing the collecting-duct
permeability".

Manocha et ai. (1975) reported "significant cytochemical changes" in the kidneys of


monkeys which had consumed water containing 1 or 5 ppm fluoride for an 18-month
period. Thus, there is suggestive evidence that fluoride may cause nephrogenic Diabetes
Insipidus.

Corroborative evidence for the above statementsis found in the results of studies on the
effect of the metabolically-unstable anesthetic, methoxyflurane, which releases inorganic
fluoride to body fluids. Thus, Gottlieb and Trey (1974) have stated:

"This (methoxyflurane) syndrome is .... similar to that of nephrogenic Diabetes Insipidus


.... these patients were unable to concentrate urine, despite fluid deprivation or
administration of vasopressin .... the (kidney) changes indicated that the lesion was of the
distal nephron .... None of the control patients developed nephrogenic Diabetes Insipidus,
while methoxyflurane patients developed this syndrome. (There was) a relationship
among the dose of methoxyflurane .... serum peak inorganic fluoride levels, and renal
effects".

Cousins and Mazze (1973) also commented on the methoxyflurane syndrome as follows:

"Serum hyperosmolality occurring simultaneously with polyuria, and decreased urine


osmolality is evidence of water-losing nephropathy, although primary antidiuretic
hormone deficiency (Diabetes Insipidus) could produce similar abnormalities. However,
unlike Diabetes Insipidus, polyuria following methoxyflurane administration was
vasopressin-resistant, indicating a renal lesion .... (Also, excessive) thirst and polyuria
added difficulty to post-operative management".

With reference to the foregoing quotation, it is pertinent to note (see Table 25) that the
patient treated by Sauerbrunn et al. (1965), and the two treated by Greenberg et at, (1974)
were vasopressin-resistant; this suggests that they were suffering from fluoride-mediated
renal lesions. Conversely, the two youngest patients in Klein's (1975) study responded to
vasopressin treatment, i.e. indicative of hereditary Diabetes Insipidus (Cousins and
Mazze 1973; Klein 1975).

Thus, as noted by Marier (1977), there are identifiable individuals among the general
population who are more "at risk" relative to fluoride intoxication, because they are
afflicted with the polyuria-polydipsia syndrome of Diabetes Insipidus. Such people ingest
abnormal amounts of fluoride in beverages, and retain an abnormally high proportion of
the total ingested fluoride, as reflected in Hanhijarvi's (1975) observation that they have a
low urinary fluoride clearance and a high plasma F- level. It is therefore appropriate to
note that, recently (see JAMA 1976), diabetes (including cases with nephropathy) has
been ranked third as a cause-of-death factor, accounting for an estimated 300,000 deaths
per year; also, the incidence of diabetes increased by 6% per year during the period 1965-
1975. If an escalation in the incidence of nephropathic diabetes has occurred, it should be
carefully considered in relation to the evidence discussed in the present report.
5.9 ATTEMPTS TO ESTIMATE CRITERIA FOR HUMAN INTAKE OF
FLUORIDE (back to top)

Precise data on the total daily intake of fluoride by humans are scarce. Most studies of
fluoride as a possible hazard to human health have reported only the fluoride exposure
from a single source (e.g. water, or polluted air in the workplace). This preoccupation
with fluoride from one source, coupled with the difficulty of quantifying or even
identifying, with certainty, the early stages of a fluoride-induced injury, has inhibited
attempts to establish criteria that would define an acceptable level of intake. However,
the need for such criteria is apparent, and two recent publications have reported attempts
to set a value for an acceptable daily intake.

Farkas (1975) attempted to estimate a "safe" level of fluoride intake by means of a


questionnaire directed to "authorities" in the fields of dentistry, medicine, nutrition, and
biological research. The questionnaire requested a definite estimate in absolute terms
(mg/kg body weight per day), but no consensus developed. Many respondents merely
indicated that various levels of ingested fluoride, expressed in parts-per-million (ppm),
were acceptable or recommended. However, five of the respondents agreed that 0.05 to
0.07 mg/kg body weight per day was a reasonable estimate of the acceptable daily intake
of fluoride.

Toth (1975) contended that the amount of fluoride "which is ingested with drinking-
water" should be considered optimal. Toth estimated that this amount is 0.045 mg/kg
body weight per day for infants, and declines to 0.023 mg/kg for adults. By considering
various factors, Toth also estimated a "tolerable dose" (which presumably approximates
an acceptable daily intake) of 0.073 mg/kg body weight per day for infants, and 0.033
mg/kg for adults. Reference Man has a body mass of 70 kg (ICRP 1975). Man's total
water intake has been estimated to be 2400 ml/day (Spencer et al. 1970). Therefore,
ingestion of 2400 ml of water with a fluoride concentration of 1 mg/l would provide a
daily fluoride intake of 0.034 mq/kg from water.

A more direct, criteria-based, approach to the estimation of an acceptable daily intake is


urgently required, and the present authors therefore reluctantly present the following
calculations, in spite of the obvious limits to their accuracy.

5.9.1 Criteria Based on Bone Fluoride and Plasma F- (back to top)

Kramer et al. (1974) presented data on the fluoride content of drinking water, in relation
to the total fluoride intake from three daily meals by adults residing in 16 locations in the
U.S. The regression equation calculated (by us) from these data is:

Daily fluoride intake, mg = (0.98 ± 0.41) + (ppm waterborne F x 1.63 ± 0.50)

This equation (hereafter referred to as "Equation A") has an r2 value of 0.44. Although
the error factors are large, this equation enables us to convert waterborne fluoride levels
to daily dietary intakes. It must be emphasized that the Kramer et al. (1974) data do not
include between-meal ingestion of drinking-water or other fluoridated beverages, and
therefore underestimate the total daily fluoride intake.

Hodge (1952) and Jackson and Weidmann (1958) reported the fluoride content of
drinking-water as it relates to the fluoride content of dry fat-free rib bone of lifetime
residents in four communities whose drinking-waters differ in fluoride content (i.e. 0.06,
0.5, 0.8, and 1.9 ppm). In Fig. 4, we have plotted dietary fluoride intake (calculated from
waterborne fluoride by Equation A, above) in relation to the fluoride content of rib bone
from 55-year-old individuals, as reported by Hodge (1952) and by Jackson and
Weidmann (1958).

If a fluoride content of 2500 to 4000 ppm in dry fat-free rib (a cancellous-type bone) can
be taken as an upper range of tolerable limits (cf Section 5.3; also Jackson and Weidmann
1958), this would reflect an intake of 2.5 to 4.1 mg fluoride from the three daily meals.
For a 70 kg adult, this calculation leads to an estimated acceptable intake, from the three
daily meals, of 0.036 to 0.059 mg/kg body weight.

Another approach to criteria is based on blood plasma ionic fluoride. Hanhijarvi (1975)
has determined the equations relating blood plasma F- levels to age of humans residing in
areas with non-fluoridated (0.2 ppm) or fluoridated (1.0 ppm) water. The conversion of
waterborne fluoride content to dietary fluoride intake was again calculated (by us) from
Equation A, above. Blood plasma F- levels for 55-year-old humans were calculated by
using Hanhijarvi's equations. The results are plotted in Fig. 4, where they are extrapolated
linearly to allow an interpretive assessment.

Inkovaara et al. (1975) have provided the best available estimate of a tolerable maximum
level for plasma F-; during a 10-month study of geriatric patients, they observed
spontaneous bone fractures at blood plasma F- levels as low as 2.1 umol/l, and
recommended that it should not rise in excess of 3.0 pmol/l. In terms of Fig. 4, these
levels reflect a range of fluoride intakes of 3.7 to 5.3 mg fluoride from the three daily
meals, i.e. equivalent to a range of 0.053 to 0.076 mg/kg for a 70 kg human.

In summary (and including the estimates by Farkas and by Toth, cited in Section 5.9), the
available estimates of an acceptable daily intake of fluoride for humans are:

0.05 to 0.07 mg/kg (Farkas; questionnaire)


0.033 to 0.073 mg/kg (Toth; "tolerable" level)
0.036 to 0.059 mg/kg (our calculation based on rib bone)
0.053 to 0.076 mg/kg (our calculation based on plasma F-)

The agreement among these values is sufficiently close to suggest that the various
approaches are meaningful. Serious attempts to increase the data-base for such
calculations should be encouraged. However, it must not be overlooked that the
acceptable intake derived from such calculations applies only to an "average" individual,
and that some "safety factor" must be applied to ensure protection of the less resistant
individuals in the general population.
In Sections 3.1.1 and 5.8, we discussed the fact that, in persons with renal insufficiency,
the bone and plasma F levels can be 4 times higher than in similarly-exposed persons
with normal kidneys. Until there is evidence to the contrary, we must therefore conclude
that some persons with renal insufficiency have only one-quarter the fluoride tolerance
reported in the above tabulation.

In Section 5.1.1, we stated that the current total fluoride intake from foods and beverages,
in areas with fluoridated (1 ppm) water, probably ranges from 3.5 to 5.5 mg/day, i.e.
equivalent to 0.05 to 0.08 mg/kg/day for a 70 kg "average" human. This range is almost
within the ranges for long-term "acceptable daily intake" tabulated above.

5.9.2 Assessment of Fluoride Intake From Air (back to top)

The information discussed in Sections 5.9 and 5.9.1 allows an evaluation of human intake
of fluoride from air, especially in the workplace where there has been disagreement about
what constitutes an acceptable concentration of airborne fluoride. Inhaled fluorides,
whether in gaseous or in particulate form, are almost completely absorbed into the
bloodstream (WHO 1970; Hodge and Smith 1977). Therefore, assuming an inhalation of
10 m3 of air during an 8-hour working shift (Dinman et al. 1976a), the various airborne
fluoride levels discussed for workplace exposure can be converted into daily uptakes of
fluoride by a 70 kg human.

Because workplace exposure is on a 5 day/week basis, a correction factor of 5/7 was used
to express intake on an equalized "per day" basis. [In summary, the airborne fluoride
concentration is multiplied by 10 (M3), divided by 70 (kq), then multiplied by 5/7; the
overall conversion factor is thus 0.102]. This calculation leads to the following
tabulation:

Airborne Fluoride Uptake From


Fluoride Workplace Air
mg/m3 Discussed by mg/kg/day
2.5 Hodge and Smith (1977) 0.255
0.5 Vishnevski (1969) 0.051
0.22 Guminska and Sterkowicz (1975) 0.022
0.1 Vishnevski (1969) 0.010

These calculated intakes are from air only and must be considered additional to those
discussed in Section 5.9.1. it is apparent that the long-term implications of the
occupational exposures require careful study, taking into consideration both the non-
occupational exposures to fluoride and the period (i.e. portion of lifetime) of additional
exposure to workplace airborne fluorides.

6.0 OVERVIEW AND RECOMMENDED RESEARCH (back to top)

1. Despite improvements in, and more extensive use of, emission control equipment,
large quantities of fluoride continue to be discharged into the atmosphere from industrial
sources. In 1972, at least 14,236 metric tons of fluoride (calculated as fluorine) were
discharged into the air in Canada, and some 150,000 metric tons were discharged in all of
North America.

2. Large quantities of fluoride are also discharged into streams, rivers, lakes and oceans,
as a component of industrial waste-waters. It appears probable that the amounts thus
discharged are several-fold larger than the amounts discharged into the atmosphere.
Many systems utilized for airborne emission-control contribute extensively to the amount
of fluoride discharged in wastewaters.

3. Much of the fluoride discharged into the atmosphere arises from "point sources" such
as smelters. Dispersion of the pollutant in the surrounding area is not uniform; therefore,
the siting of monitoring devices, and the selection of sites for sampling of vegetation,
must consider:

a) Stratification of the pollutant, with the higher levels of atmospheric fluoride found at
the greater heights. This has significance to ecological damage to vegetation on exposed
hilltops or mountainsides, even at considerable distances from the emitting source;

b) The "shielding" effects of vegetation and other obstacles, which results in lower
fluoride exposure (and uptake by) vegetation growing on the downwind side of such
obstacles.

4. The ecological impact of airborne fluoride emissions is known to be serious with


regard to coniferous forests and to epiphytes and bryophytes. However, lichens and
mosses are less susceptible to fluoride injury than coniferous trees. Relatively little is
known about the effects of fluoride on aquatic life, even though large amounts of fluoride
are known to be released into some waterways. More attention should be paid to fluoride
effects on pollinating insects and on plankton.

5. Airborne fluoride has had a serious impact on agricultural and silvicultural species.
With airborne gaseous fluoride there is no evidence for a no-effect threshold level below
which no reduction in crop yield occurs, especially over the long term. For exposure of
Canadian forest species, the average (30-day) airborne gaseous fluoride concentration
should not exceed 0.2 ug/M3. There is an urgent need for long-term Cause/Effect studies
of species known to be sensitive to fluoride injury.

6. There have been episodes where the impact of fluoride pollution on livestock and on
wild ungulates has been severe. To date, regulations limiting the fluoride content of
fodders have provided neither adequate protection against economic loss to the farmer
nor adequate control of airborne fluoride. For young growing swine, an 18-week
exposure to dietary fluoride (whether in forages, feeds, or mineral supplements) can be
expected to decrease daily weight-gain by about 4% for each 100 ppm increment of
dietary fluoride. The need for further data on which Cause/Effect equations can be based
is apparent. Loss of weight-gain may be a suitable measure of sub-clinical (pre-skeletal)
intoxication.
7. There is clear evidence that wildlife species are more vulnerable to fluoride toxicosis
than are livestock species. The impact seems to be most severe on predator species,
because they must capture their prey and because they are more susceptible to the
bioaccumulation of fluoride through their food chain. Cause/Effect studies of these
species should include consideration of the multiple stresses imposed by the ecosystem
(e.g. malnutrition).

8. Researchers in various regions of the world have reported that human hydrofluorosis is
less severe when the waterborne fluoride is ingested from hard waters, than from soft
waters. There is evidence that chronic intake of fluoride increases the long-term
metabolic requirement for both calcium and magnesium. Other studies have indicated
that fluoride may increase the metabolic requirement for vitamin C and manganese. The
Cause/Effect aspects of these dietary/nutritional factors require urgent attention, with
regard to chronic intake of fluoride. There is no doubt that inadequate nutrition increases
the severity of fluoride toxicosis.

9. Fluoride has displayed mutagenic activity in studies of vegetation, insects, and


mammalian oocytes. There is a high correlation between carcinogenicity and
mutagenicity of pollutants, and fluoride has been one of the major pollutants in several
situations where a high incidence of respiratory cancer has been observed. For these
reasons, the relation between airborne fluoride and incidence of lung cancer needs to be
investigated.

10. Long-term ingestion, with accumulation of fluoride in animals and man, induces
metabolic and biochemical changes, the significance of which has not yet been fully
assessed. It cannot be assumed that such changes are of no significance to human health.
There is evidence that neurological complaints are related to the early histological
changes that precede overt skeletal fluorosis. There is also evidence that the early bone
changes can reflect an entire gamut of abnormalities, depending on factors such as
nutritional and metabolic status. Further studies on the early subtle changes of fluoride
toxicosis in humans, in terms of both diagnostic aids and Cause/Effect interrelations,
should have a high priority.

11. Fluoride is a persistent bioaccumulator, and is entering into human food-and-


beverage chains in increasing amounts. Careful consideration of all available data
indicates that the amount of fluoride ingested daily in foods and beverages by adult
humans living in fluoridated communities currently ranges between 3.5 and 5.5 mg. For
a 70 kg human adult, this range is close to the 0.03 to 0.07 mg/kg/day estimated for "an
acceptable daily intake". In addition to the food-chain, dentifrices and pharmaceuticals
can contribute siqnificantly to the fluoride intake of some individuals.

12. Inhalation of airborne fluoride may contribute several milligrams to the total daily
intake of industrial workers, and may be significant for persons residing near sources of
fluoride emissions. However, the effect of airborne fluoride on human respiratory tissue
is not necessarily related to total bodyburden, but may relate to the direct impact of
fluoride on respiratory tissues. The contribution of cigarette-smoking to fluoride intake
also requires study.

13. In the assessment of the impact of fluoride on animals and man, more attention
should be focussed on the concentration of inorganic fluoride in blood plasma. Available
evidence indicates that accurate assessment of the plasma F concentration can provide
valuable information about the body-burden during chronic fluoride intake.

14. In addition to industrial workers, there are several sub-groups of the population who
may be more affected by environmental fluoride than the population at large. These are
persons who:

a) Have a sub-optimal nutritional status, especially with regard to calcium, magnesium,


vitamin C, manganese, or a low dietary Ca/P ratio (Note: This also applies to animals);
b) Live in the proximity of fluoride-emitting industries;
c) Live in regions where goitre is endemic, because there is suggestive evidence that
fluoride may increase the incidence of goitre in such regions;
d) Have kidney impairments, particularly those with bilateral pyelonephritis or
nephropathic Diabetes Insipidus;
e) Have the excessive-thirst polydipsia associated with diabetes, because they consume
large quantities of fluids.

These may be called "critical groups" (ICRP 1977) either because they accumulate more
fluoride or suffer toxic effects more readily.

15. Standards limiting emissions or environmental concentrations of fluoride should be


based on criteria which include those derived from studies of these "critical groups".

16. In addition to the research recommendations we have made, we would like to


acknowledge those presented in a recent U.S. National Academy of Sciences report (see
Fleischer et al. 1974):

a) Additional detailed studies are needed of the health of human and animal populations
exposed to high concentrations of airborne fluorides;

b) The gross effects of fluoride on plants and animals have been studied, but much needs
to be done on the basic biochemical lesions induced by fluoride, and on dietary factors
affecting fluoride uptake by man;

c) The very large emission of fluorocarbons (freons), and their rapidly increasing use,
require study of their distribution, rate of degradation, and possible effects on plants,
animals and humans;

d) Waste waters of high fluoride content have been released from phosphate processing
and from the aluminum industry, with detrimental effects to such marine organisms as
oysters and crabs. Possible chronic effects from exposure of such organisms to lower
levels of fluoride need study;
e) In view of the high fluoride content reported to exist in some fish-protein concentrates
used as food supplements, the possible impact of this added source of fluoride in the diet
should be further investigated;

f) Methods of sampling and separating gaseous and particulate forms of airborne fluoride
need study and standardization;

g) Further work is needed on the relation of the uptake of fluorine by plants to its
concentration in the air;

h) Study of the form of fluorine in plants is highly desirable, especially the nature of
fluorine bonding in plant tissue and its solubility in aqueous solutions;

i) More data are needed on the relation of the fluoride content of groundwaters to the
mineralogical and chemical composition of the source rocks.

These NAS recommendations are fully compatible with the information that we have
presented in this report or in our previous review (Marier and Rose 1971).

REFERENCES (back to top)

Adams, D.F. 1961. A quantitative study of the limed filter paper technique for fluorine air
pollution studies. Internal. J. Air Water Pollution 4: 247-255.

Agarwal, A.K. 1975. Crippling cost of India's big dam. New Scientist, Jan. 30; 260-261.

Albright, J.A. and Grunt, J.A. 1971. Studies on patients with osteogenesis imperfecta. J.
Bone and Joint Surgery 53A: 1415-1425.

Amerman, C.B. 1974. Phosphorus supplementation during periods of short supply. Amer.
Feed Manuf. Assoc., Proc. Nutr. Counc. 34: 33-35.

Angmar-Mansson, B., Ericsson, Y. and Ekberg, 0. 1976. Plasma fluoride and enamel
fluorosis. Calcif. Tiss. Res. 22: 77-84.

Archer, D.P., Gurekas, V.L. And White, F.M.N. 1975. Urinary fluoride excretion in
school children exposed to fluoride airpollution: a pilot study. Can. J. Public Health 66:
407-410.

Arora, H.C. and Chattopadhya, S.N. 1974. A study on the effluent disposal of
superphosphate fertilizer factory. Indian J. Environ. Health 16: 140-150.

Arthaud, L.E. and Loomis, T.A. 1975. The relationship of the total dose and duration of
methoxyflurane anesthesia to renal toxicity in Fischer 344 rats. Toxic. Applied
Pharmacol. 33: 176.

Arvela, P., Karki, N.T., Niemenin, L., Bjondahl, K.B. and Mottonen, M. 1973. Effect of
long-term fenfluramine treatment on drug metabolism in rat-. Experimentia 29: 454-455.

Aschbacher, P.W. 1973. Air pollution research needs: livestock produ systems. J. Air
Pollution Control Assoc. 23: 267-272.

Auermann, E. 1973. Fluoride intake in humans. Fluoride 6(2): 78-83.

Back, K.C. 1970. Aerospace technology. I. Propellant technology. Fed. Proc. 29: 2000-
2005.

Bahls, L.L. 1973. Diatom community response to primary wastewater effluent. J. Water
Pollut. Control Fed. 45: 134-144.

Baker, K.L. 1974. Fluoride and tetracycline-induced changes in rat serum calcium and
phosphorus level. Arch. Oral Biol. 19: 717-723.

Balazova, C., Rippel, A. and Hluchan, E. 1970. Effect of atmospheric fluoride pollution
on the living organism. Nutr. Proc. 8th Internal. Congr. Prague, Sept. 1969: 709-711.

Bale, S.S. and Hart, G.E. 1973a. Studies on cytogenetic and genetic effects of fluoride on
barley. I. A comparative study of the effects of sodium fluoride and hydrofluoric acid on
seedling root tips. Can. J. Genet. Cytol. 15: 695-702.

Bale, S.S. and Hart, G.E. 1973b. Studies on cytogenetic and genetic effects of fluoride on
barley. II. The effects of treatment of seedling coleoptiles with sodium fluoride. Can. J.
Genet. Cytol . 15: 703-712.

Baum, von F., Giebel, J. and Brell, H. 1972. Uber die Erfassung gasformiger Schadstoffe
bei steinkohlegefeuerten Einzelofen. Gesundh. Ing. 93: 102-108.

Beary, D.F. 1969. physical 305-316. The effects of fluoride and low calcium on the
properties of the rat femur. Anal. Rec. 164:

Bedford, C.T., Blair, D. and Stevenson, D.E. 1977. Toxic fluorinated compounds as by-
products of certain BF3-catalyzed industrial processes. Nature 267: 335.

Bell, L.E., Hitt, B.A. and Mazze, R.I. 1975. The influence of age on the distribution,
metabolism and excretion of methoxyflurane in Fischer 344 rats: a possible relationship
to nephrotoxicity. J. Pharmacol. Exper. Therapeut. 195: 34-40.

Benetato, G., Giuran, A.M., Cirje, M., Cirmaciu, R., Petrescu, A. and Vacariu, A. 1970.
Effet du fluor de Veau potable sur le metabolisme du calcium and du magnesium et sur
1'excitabilite neuro-musculaire (recherches experimentales et observations cliniques).
Rev. Roum. Physiol. 7: 335-352.

Bennett, J.H. and Hill, A.C. 1973. Inhibition of apparent photosynthesis by air pollutants.
J. Environ. Qual. 2: 526-530.

Bennett, J.P., Resh, H.M. and Runeckles, V.C. 1974. Apparent stimulation of plant
growth by air pollutants. Can. J. Bot. 52: 35-41.

Bewers, J.M. 1971. North Atlantic fluoride profiles. Deep-sea Res. 18: 237-241.

Bhoopathi, B., Ostapowicz, F. and Rosaria, L.D. 1974. Fluothane (Halothane) anesthesia
and acute hepatic toxicity. Missouri Med. 71:581-583.
Bierenbaum, M.L., Fleischman, A.I., Stein, R. and Haydon, T. 1974. Effect of fluoridated
water upon serum lipids, ions, and cardiovascular disease mortality rates. J. Med. Soc.
New Jersey, 71: 663-666.

Bittel, R. and Vaubert, B. 1971. Analyse des problemes de protection poses par le fluor et
les composes fluords. Commissariat a l'energie atomique, Fontenay-aux-Roses, France.
CEA-BIB-200, EUR. 4669 f. 54 pp.

Bligny, R., Bisch, A-M., Garrec, J.P. and Fourcy, A. 1973. Observations morphologique
et structurales des effets du fluor sur les cires epicuticulaires et sur les chloroplastes des
aiguilles de sapin (Abies Alba Mill.). J. Microscopie 17: 207-214.

Bobek, S., Kahl, S. and Ewy, Z. 1976. Effect of long-term fluoride administration on
thyroid hormones level blood in rats. Endocrin. Experimentalis 10: 289-295.

Boillat, M.A., Baud, C.A., Lagier, R., Donath, A., Dettweiler, W. and Courvoisier, B.
1976. Fluorose industrielle. Schweiz. Med. Wschr. 106: 1842-1844.

Bojic, M., Jecko, G., Klein, F. and Raquin, J. 1975. Etude bibliographique sur les
emissions de fluor en siderurgie. Circ. d'Information Tech. Centre de Documentation
Siderurgique. 32: 439-454.

Bossavy, J. 1971. Les polluants atmospheriques, leurs effets sur la vegetation. Ann. de
Gembloux 77: 163-173.

Bourbon, P., Tournut, J., Alary, J., Rouzaud, J.F. and Alengrin, F. 1971. Consequences
d'une pollution fluorde de faible importance dans une vallee de montagne. La Tribune du
Cebedeau 24: 62-66.

Bressan, D.J., Carr, R.A., Hannan, P.J. and Wilkniss, P.E. 1974. The determination of
trace metals and fluoride in mineralogical and biological samples from the marine
environment. J. Radioanalytical Chem. 19: 373-381.
Brewer, P.G., Spencer, D.W. and Wilkniss, P.E. 1970. Anomalous fluoride
concentrations in the North Atlantic. Deep-Sea Res. 17: 1-7.

Brown, C.K., Taylor, J.C. and Skov, T.V. 1971. Fluoride levels in and out of #35 open
hearth electrostatic precipitator. Ontario Res. Found. report to The Steel Co. of Canada
Ltd., Hilton Works, Hamilton, Ont. 22 pp.

Brown, W.R., Krook, L. and Pond, W.G. 1966. Atrophic Rhinitis in Swine. Etiology,
Pathogenesis and Prophylaxis. The Cornell Veterinarian 56, Supp. 1. 108 pp.

Burk, D.A. 1972. The wind of death. Amer. Forests 78: 12-15.

Burk, D. 1975. Letter to Hon. J.J. Delaney. U.S. Congr. Record House, Dec. 16, 1975.
H12732.

Burns, K.N. 1970. Methods of assessing the fluorosis hazard to foragefed livestock. In
"Trace Element Metabolism in Animals". Proc. WAAP/IBP Internal. Symp., July 1969,
Scotland. Ed. C.F. Mills. Publ.by E. and S. Livingstone, London. pp. 490-492.

Buttner, W. and Karle, E. 1974. Chronic toxicity and retention of fluoride in the
unilaterally nephrectomized ral. Caries Res. 8: 359-367

Canada 1973. Nutrition--a national priority. Publ. by Dept. National Health & Welfare,
Ottawa. (136 pp.).

Carlson, C.E. and Dewey, J.E. 1971. Environmental pollution by fluorides in Flathead
National Forest and Glacier National Park. U.S. Dept. Agric., Forest Service, Div. of
State and Private Forest., Missoula, Montana. 57 pp.

Carlsson, C.E. 1972. Monitoring fluoride pollution in Flathead National Forest and
Glacier National Park. Insect and Disease Branch, Division of State and Private Forestry,
Missoula, Montana. 25 pp.

Carlson, C.E., Bousfield, W.E. and McGregor, M.D. 1974. The relationship of an insect
infestation on lodgepole pine to fluorides emitted from a nearby aluminum plant in
Montana. U.S. Forest Service, Division of State and Private Forestry, Missoula, Montana.
Report 74-14. 21 pp.

Carlson, C.E. and Hammer, W.P. 1974. The impact of fluorides and insects on radial
growth of lodgepole pine near an aluminum smelter in northwestern Montana. A
preliminary enquiry. U.S. Forest Service, Division of State and Private Forests, Missoula,
Montana. Report 74-25.

Carpenter, R. 1969. Factors controlling the marine geochemistry of fluoride. Geochimica


et Cosmochimica Acta. 33: 1153-1167.
Carter, R., Heerdt, M. and Acchiardo, S. 1976. Fluoride kinetics after enflurane
anesthesia in healthy and anephric patients and in patients with poor renal function. Clin.
Pharmacol. Therap. 20: 565-570.

Cascorbi, H.F., Vesell, E.S., Blake, D.A. and Helrich, M. 1970. Genetic and
environmental influence of halothane metabolism in twins. Clin. Pharmacol. Therapeut.
12: 50-55.

Cecilioni, V.A. 1972a. High lung cancer rates linked to heartland of steel industry. Water
and Pollut. Control. August. pp. 48-49.

Cecilioni, V.A. 1972b. Lung cancer in a steel city: its possible relation to fluoride
emissions. Fluoride 5(4): 172-181.

Cecilioni, V.A. 1974. Further observations on cancer in a steel city. Fluoride 7(3): 153-
165.

Chan, M.M., Rucker, R.B., Zeman, F. and Riggins, R.S. 1973. Effect of fluoride on bone
formation and strength-in Japanese quail. J. Nutr. 103: 1431-1440.

Chang, C.W. 1975. Fluorides. In:"Responses of plants to air pollution" Ed. J.B. Mudd
and T.T. Kozlowski. Academic Press, N.Y. pp.57-95.

Cheremisinoff, P.N. and Habib, Y.H. 1973. Air clean-up can start water pollution
problems. Water and Wastes Eng. WPCF Conference Issue, Sept. pp. E12-08.

Churchill, D., Yacoub, J.M., Siu, K.P., Symes, A. and Gault, M.H. 1976. Toxic
nephropathy after low-dose methoxyflurane anesthesia: drug interaction with
secobarbitol? Canad. Med. Assoc. J. 114: 326-332.

Clark, R.B., Beard, A.G., Thompson, D.S. and Barclay, D.L. 1976. Maternal and
neonatal plasma inorganic fluoride levels after methoxyflurane analgesia for labor and
delivery. Anesthesiology 45: 88-91.

Cohn, S.H., Dombrowski, C.S., Hauser, W. and Atkins, H.L. 1971. Effects of fluoride on
calcium metabolism in osteoporosis. Amer. J. Clin. Nutr. 24: 20-26.

Conn, H.O. 1974. Halothane - associated hepatitis. Israel J. Med. Sci . 10: 404-415.

Conover, C.A. and Poole, R.T. 1971. Influence of fluoride on foliar necrosis. Proc. Fla.
State Hort. Soc. 84:380-383.

Cook, T.L., Beppu, W.J., Hitt, B.A., Kosek, J.C. and Mazze, R.I. 1975. Renal effects of
metabolism of sevoflurane in Fischer 344 rats. Anesthesiology 43: 70-77.

Cordy, P.E., Gagnon, R., Taves, D.R. and Kaye, M. 1974. Bone disease in hemodialysis
patients with particular reference to the effect of fluoride. Canad. Med. Assoc. J. 22:
1349-1353.

Cousins, M.J. and Mazze, R.I. 1973. Methoxyflurane nephrotoxicity - a study of dose
response in man. J. Amer. Med. Assoc. 225: 1611-1616.

Cousins, M.J., Mazze, R.I., Kosek, J.C., Hitt, B.A. and Love, F.V. 1974. The etiology of
methoxyflurane nephrotoxocity. J. Pharmacol. Exper. Therapeut. 190: 530-541.

Cowell, D.C. 1975. The determination of fluoride ion concentration in biological fluids
and in the serum and urine of fluoridetreated patients with Paget's disease and
osteoporosis. Med. Lab. Technol. 32: 73-89.

Crawford, M.D. 1972. Fluoride, water hardness, and endemic goitre. The Lancet, June
10. p. 1293.

Creasser, C.W.,Stoelting, R.K., Krishna, G. and Peterson, C. 1974. Methoxyflurane


metabolism and renal function after methoxyflurane analgesia during labor and delivery.
Anesthesiology 11: 62-66.

Cummings, J.C. 1966. Pesticides in the total diet. Residue Rev. 16: 30-45.

Czechowicz, K., Osada, A. and Slesak, B. 1974. Histochemical studies on the effect of
sodium fluoride on metabolism in Purkinje's cells. Folia Histochem. Cytochem. 12: 37-
44.

Danilov, V.B. and Kas'yanova, V.V. 1975. Experimental data on the effect of
hydrofluoric acid on embryogenesis of white rats. Gig. Tr. Prof. Zabol. 1(3): 57-58.

Davison, A.W., Rand, A.W. and Betts, W.E. 1973. Measurement of atmospheric fluoride
concentrations in urban areas. Environ. Pollut. 5: 23-33.

Day, T.K. and Powell-Jackson, P.R. 1972. Fluoride,water hardness and endemic goitre.
The Lancet, May 27.pp. 1135-1138.

Desmet, G., Leroux, D., Boitieux, J.-L. and Jardillier, J.-C. 1975. Utilisation d'une
dlectrode specifique pour le dosage du fluor dans le serum et diverses parties de la dent.
Organisation des Laboratoires - Biologie prospective; IIIe Colloque de Pont-A-Mousson.
L'expansion scientifique frangaise, editeur. pp. 697-699.

deVilliers, A.J. and Windish, J.P. 1964. Lung cancer in a fluorspar mining community. I.
Radiation, dust and mortality experience. Brit. J. Indust. Med. 21: 94-109.

deVilliers, A.J., Windish, J.P., Brent, F. deN., Hollywood, B., Walsh, C., Fisher, J.W. and
Parsons, W.D. 1971. Mortality experience of the community and of the fluorspar mining
employees at St. Lawrence, Newfoundland. Occup. Health Rev. 21: 1-15.
Dilley, J.V., Carter, V.L. and Harris, E.S. 1973. Fluoride ion excretion after inhalation of
several fluoroethylene derivatives. Toxicol. Applied Pharmacol. 25: 470.

Dinman, B.D., Bovard, W.J., Bonney, T.B., Cohen, J.M. and Colwell, M.O. 1976a.
Absorption and excretion of fluoride immediately after exposure. Part I. J. Occup. Med.
18: 7-13.

Dinman, B.D., Bovard, W.J., Bonney, T.B., Cohen, J.M. and Colwell, M.O. 1976b.
Excretion of fluoride during a seven-day workweek. Part II. J. Occup. Med. 18: 14-16.

Dirks, O.B., Jongeling-Eijndhoven, J.M.P.A., Flissebaalje, T.D. and Gedalia, 1. 1974.


Total and free ionic fluoride in human and cow's milk as determined by gas-liquid
chromatography and the fluoride electrode. Caries Res. 8: 181-186.

Discher, D.P. and Breitenstein, B.D. 1976. Prevalence of chronic pulmonary disease in
aluminum potroom workers. J. Occup. Med. 18: 379-386.

Discher, D.P., Breitenstein, B.D. and Schweid, A.I. 1976. Sputum cytology among
aluminum potroom workers. Ann. N.Y. Acad. Sci. 271: 239-242.

Dochinger, L.S. 1971. The symptoms of air pollution injuries to broadleaved forest trees.
Mitteilungen der forstlichen BundesVersuchsanstalt. Wien. 92: 7-32.

Eichhorn, J.H., Hedley-White, J., Steinman, T.I., Kaufmann, J.M. and Laasberg, L.H.
1976. Renal failure following enflurane anesthesia. Anesthesiology 45: 557-560.

Ekstrand, J., Ericsson, Y., and Rosell, S. 1977. Absence of proteinbound fluoride from
human blood plasma. Arch. Oral Biol. 22: 229-232.

Elder, B.F., Beal, H., DeWald, W. and Cobb, S. 1971. Exacerbation of subclinical
myasthenia gravis by occupational exposure to an anesthetic. Anesthesia Analgesia 50:
383-387.

Elgersma, R.H.C. and Klomp, H. 1975. The effect of fluoridated tapwater, used in the
Qheesemakina process, on the fluoride content of Gouda cheese. Neth. Milk Dairy J. 29:
3-15.

Emma, L.C., Johnson, R., Bartlett, C. and Hatch, L.P. 1968. Disposal of solid wastes
generated in fluidized-bed fluoride volatility fuel reprocessing. Report, Brookhaven
National Lab. Oct. pp. 1-9.

EMR 1973. Energy, Mines and Resources, Canada. Petroleum Refineries in Canada.
Operators List 5. pp. 1-33.

EMR 1976. Energy, Mines and Resources, Canada. Petroleum Refineries in Canada.
Operators List 5. pp. 1-33.

Environment Canada 1975. Canada Water Year Book. pp. 179-183.

Environment Canada 1976. National Inventory of Sources and Emissions of Fluoride


(1972). Report APCD 75-7. Air Pollution Control Directorate. 31 pp.

EPA 1972. U.S. Environmental Protection Agency. Office of Air Programs. Engineering
and cost effectiveness study of fluoride emissions control. SN16893.000. January/72.
Contract EHSD 71-14. Vol. 1. 404 pp.

EPA 1976. U.S. Environmental Protection Agency. Office of Air Programs. Performance
standards for new stationary sources. Primary aluminum industry. U.S. Federal Register
41: 3826-3830.

Ericsson, Y., Hellstrom, I. and Hofvander, Y. 1972. Pilot studies on the fluoride
metabolism in infants on different feedings. Acta. Pedial. Scand. 61: 459-464.

Ericsson, Y., Gydell, K. and Hammarskiold, T. 1973. Skeletal fluoride saturation and
body fluid fluoride levels. J. Dent. Res. 52: 273.

Ericsson, Y. and Ekberg, 0. 1975. Dietetically provoked general and alveolar osteopenia
in rats and its prevention or cure by calcium and fluoride. J. Periodontal Res. 10: 256-
269.

EST 1972. "Cleanup pays off for fertilizer plant". May, 1972. Environmental Sci.
Technol. 6: 400-401.

Faccini, J.M. and Teotia, S.P.S. 1974. Histopathological assessment of endemic skeletal
fluorosis. Calc. Tissue Res. 16: 45-57.

Facteau, T.J., Wang, S.Y. and Rowe, K.E. 1973. The effect of hydrogen fluoride on
pollen germination and pollen tube growth in Prunus avium L. cv. "Royal Ann." J. Amer.
Hort. Soc. 98: 234-236.

Facteau, T.J. and Rowe, R.E. 1976. The effects of aqueous sprays of ammonium fluoride
on oxygen consumption and firmness of suture and dorsal tissues of "Early Improved
Elberta" peaches. Hort. Sci. 11: 253-254.

Facteau, T.J. and Rowe, R.E. 1977. Effect of hydrogen fluoride and hydrogen chloride on
pollen tube growth and sodium fluoride on pollen germination in "Tilton" apricot. J.
Amer. Hort. Soc. 102: 95-96.

Farkas, C.S. and Farkas, E.J. 1974. Potential effect of food processing on the fluoride
content of infant foods. The Sci. of the Total Environ. 2: 399-405.
Farkas, C.S. and Parsons, C. 1974. The extent of usage of fluoridated water in
commercial food and beverage processing. J. Canad. Dietetic Assoc. January. pp. 51-55.

Farkas, C.S. 1975a. Total fluoride intake and fluoride content of common foods: A
Review. Fluoride 8(2): 98-105.

Farkas, C.S. 1975b. The safe maximum daily intake of fluoride. Fluoride 8: 105-110.

FCT 1973. "Another fluoride chapter". Food Cosmet. Toxicol. 11: 1131-1134.

Ferguson, D.B. 1971. Effects of low doses of fluoride on serum proteins and a serum
enzyme in man. Nature, New Biol. 231: 159-160.

Ferguson, D.B. 1976. The effects of low doses of fluoride on enzyme activity in rabbit
serum. Archs. Oral Biol. 21: 449-450.

Fesenko, N.P., Brodsky, O.B. and Volkova, V.M. 1972. Some clinicalmorphological
manifestations of fluorine intoxication. Vrachebnoe Delo, Nauchnyi 8: 129-131.

Field, R.A., Kruggel, W.G. and Riley, M.L. 1976. Characteristics of mechanically
deboned meat, hand separated meat and bone residue from bones destined for rendering.
J. Animal Sci. 43: 755-762.

Fischer, G. and Brantner, H. 1972. Studies on air pollution in the Graz region. Part 5. The
effects of fluoride emissions on the green areas of a large city. Experimental
investigations of Fagus silvatica L. Arch. Hyg. Bakteriol. (Zbl. Bakt. Hyg.) B-155: 425-
434.

Fiserova-Bergerov-a, V. 1976. Fluoride in bone of rats anesthetized during gestation with


enflurane or methoxyflurane. Anesthesiology 45: 483-486.

Fiserova-Bergerova, V. 1977. Species differences in metabolism and toxicity of


fluoroxene. Xenobiotica 7: 113-114.

Fitzgerald, C.L., Godbee, H.W., Shockley, W.E. and Davis, N.M. 1969. Disposal of solid
waste from the reprocessing of nuclear fuels by the fluidized-bed fluoride-volatility
process: evaluation of canning of waste powders. Report Oak Ridge National Lab.
December. pp. 1-31.

Fleischer, M., Forbes, R.M., Krook, L. and Kubota, J. 1974. "Fluorine". In"Geochemistry
and the Environment" Vol.l. The Relation of Selected Trace Elements to Health and
Disease. Part II, U.S. Nal. Acad. Sci. Publ. No. 2223. pp. 22-25.

Forster, J.H. 1969. Some problems of industrial waste disposal from a fertilizer plant.
Proc. 16th Ontario Industrial Waste Conf., June 1969. Spons. by Ont. Water Resources
Com. pp. 6-17.
Forsyth, D.M., Pond, W.G., Wasserman, R.H. and Krook, L. 1972a. Dietary calcium and
fluoride interactions in swine: Effects on physical and chemical bone characteristics,
calcium binding protein and histology of adults. J. Nutr. 102:1623-1638.

Forsyth, D.M., Pond, W.G. and Krook, L. 1972b. Dietary calcium and fluoride
interactions in swine: In utero and neonatal effects. J. Nutr. 102: 1639-1646.

Forsyth, D.M., Pond, W.G. and Krook, L. 1972c. Effect of dietary calcium and fluoride
levels on growth and reproduction of swine. Nutr. Reports Internal. 5: 313-320.

Fourman, P. and Morgan, D.B. 1962. Chronic magnesium deficiency. Proc. Nutr. Soc.
21: 34-41.

Fournier, A.E., Johnson, W.J., Taves, D.R., Beabout, J.W., Arnaud, C.D. and Goldsmith,
R.S. 1971. Etiology of hyperparathyroidism and bone disease during chronic
hemodialysis. I. Association of bone disease with potentially etiologic factors. J. Clin.
Invest. 50: 592-598.

Frada, G., DiBlasi, S. and Pintacuda, S. 1974. Comportamento della fosfatasi alcalina
ossea nella fluorosi umana. Boll. Soc. It. Biol. Sper. 50: 1952-1962.

Franke, J. and Auermann, E. 1972. Die Bedeutung der Beckenkammpunktion mit


histologischer und microanalytischer untersuchung des gewonnen Knochenmaterials bei
der Diagnostik der Fluorose. Internal. Arch. Arbeitsmed. 29: 85-94.

Franke, J., Lahl, R., Fengler, F. and Hempel, H-D. 1973. Contribution to the neurological
symptoms of fluorosis. Deutsche Gesundheitswesen 28: 120-124.

Franke, J., Rempel, H., and Franke, M. 1974. Three years of experience with sodium
fluoride therapy of osteoporosis. Acta Orthop. Scand. 45: 1-20.

Franke, J., Rath, F., Runge, H., Fengler, F., Auermann, E. and Lenart, G. 1975. Industrial
fluorosis. Fluoride 8(2): 61-83.

Franke, J., Runge, H., Grau, P., Fengler, F., Wanka, C. and Rempel, H. 1976. Physical
properties of fluorosis bone. Acta Orthop. Scand. 47: 20-27.

Full, C.A. and Parkins, F.M. 1975. Effect of cooking vessel composition on fluoride. J.
Dent. Res. 54: 192.

Furlanetto, S.M.P., Zucas, S.M. and Penteado, M. deV. C. 1973. Contribuicao ao estudo
da interrelacao fluor-manganes. Rev. Farm. Bioquim. Univ. S. Paulo. 11:179-196.

Gabovitch, R.D. and Maistruk, P.N. 1963. Dietotherapy and dietoprophylaxis in the
fluorine industry. Voprosy Pitaniya 22: T450- T452.
Garrec, J.P., Plebin, R. and Lhoste, A.M. 1977. Influence du fluor sur la composition
minerale d'aiguilles poluees de sapin. Environ, Pollut. 13: 159-167.

Geall, M.G. and Beilin, L.J. 1964. Sodium fluoride and optic neuritis. Brit. Med. J. 8
Aug. pp. 355-356.

Gerdes, R.A., Smith, J.D. and Applegate, H.G. 1971a. The effects of atmospheric
hydrogen fluoride upon Drosophila melanogaster. I. Differential genotype responses.
Atmos. Environ. 5: 113-116.

Gerdes, R.A., Smith, J.D. and Applegate, H.G. 1971b. The effects of atmospheric
hydrogen fluoride upon Drosophila melanogaster. II. Fecundity, hatchability and fertility.
Atmos. Environ. 5: 117-122.

Gerhards, E., Nieuweboer, B., Schultz, G. and Gibian, H. 1971. Stoffwechsel von 6a-
fluor-16amethyl-pregna-1,4-dien-11B,21-diol-3,20dion (fluocortolon) beim menschen.
Acta. Endocrin. 68: 98-126.

Gilbert, O.L. 1971. The effect of airborne fluorides on lichens. The Lichenologist 5: 26-
32.

Gileva, E.A., Plotko, E.G. and Gatiyatullina, E.Z. 1972. The mutagenicity of inorganic
fluorine compounds. Gig. Sanit. 37(l): 9-12.

Gileva, E.A., Plotko, E.G. and Gatiyatullina, E.E. 1975. The mutagenic activity of
inorganic fluorine compounds. Fluoride 8(l): 47-51.

Gion, H., Yoshimura, N., Holaday, D.A., Fiserova-Bergerova, V. and Chase, R.E. 1974.
Biotransformation of fluroxene in man. Anesthesiology 40: 553-562.

Golusinski, J., Szmeja, Z. and Sowinski, H. 1973. Clinical and histochemical


examinations of the nasal mucosa in aluminum workers. Fluoride 6(3): 138-142.

Gordan, G.S. 1976. Fluoride -- an experimental drug for osteoporosis. Drug Therapy
6(3): 61.

Gordon, C.C. 1970a. Garrison Report III. Fluoride accumulation in plants and animals in
Garrison, Montana. Dept. Botany, Univ. of Montana. Feb. 13 pp.

Gordon, C.C. 1970b. Report to Benjamin Wake on effects of smelter emissions at


Columbia Falls, Montana. Dept. Botany, Univ. of Montana. Jan. 20 pp.

Gordon, C.C. 1976. A preliminary study of fluoride concentrations in vegetation samples


collected Sept. 8 and 9, 1976, in and around the town of Kitimat, B.C., Canada. Dept.
Botany, Univ. of Montana. pp. 1-27.
Gordon, C.C. and Tourangeau, P.E. 1977. The impact of fluoride on farmlands of
Buckeystown, Maryland, caused by the Eastalco aluminum smelter, Section 11: A study
of fluoride accumulation in vegetation collected in the vicinity of the Eastalco Aluminum
plant, October 1976. pp. 42-73. Dept. Botany, Univ. of Montana. Feb./77.

Gottlieb, L.S. and Trey, C. 1974. The effects of fluorinated anesthetics on the liver and
kidneys. Ann. Rev. Med. 25: 411-429.

Greenberg, L.W., Nelson, C.E. and Kramer, N. 1974. Nephrogenic. Diabetes Insipidus
with fluorosis. Pediatrics 54: 320-322.

Griffith-Jones, W. 1972. Fluorosis in a dairy herd. Veterinary Record 90: 503-507.

Griffith-Jones, W. 1977. Fluorosis in dairy cattle. Veterinary Record 100: 84-89.

Griffiths, H.J., Hunt, R.D., Zimmerman, R.E., Finberg, H. and Cuttino, J. 1975. The role
of calcium and fluoride in osteoporosis in Rhesus monkeys. Investigative Urology 10:
263-268.

Griffiths, H., Zimmerman, R.E., Hunt, R.D. and Wolfe, H.H. 1976. Experimental use of
photon absorptiometry in animal research models. Amer. J. Roentgenol. 126: 1309.

Groth, E. 1973. Two issues of science policy: Air pollution control in the San Francisco
Bay area and Fluoridation of community-water supplies. Ph.D. Thesis, Stanford Univ.
(University Microfilms, Ann Arbor, Mich.). 534 pp.

Groth, E. 1975a. An evaluation of the potential for ecological damage by chronic low-
level environmental pollution by fluoride. Fluoride 8(4): 224-240.

Groth, E. 1975b. Fluoride pollution. Environment 17: 29-38.

Guderian, R. and Schoenbeck, H. 1971. Recent results for recognition and monitoring of
air pollutants with the aid of plants. Proc. 2nd Internal. Clean Air Congress, Ed. H.M.
Englund and W.T. Berry. Academic Press, London. pp. 266-273.

Guggenheim, K., Simkin, A. and Wolinsky, 1. 1976. The effect of fluoride on bone of
rats fed diets deficient in calcium or phosphorus. Calcif. Tissue Res. 22: 9-17.

Guminska, M. and Sterkowicz, J. 1975. Biochemical changes in the blood of humans


chronically exposed to fluoride. Acta. Med. Pol. 16: 215-223.

Hagood, C.O., Kemmerer, W.T. and Jackson, B. 1973. Nephrotoxicity associated with
methoxyflurane (Penthrane) anesthesia. Amer. J. Surgery 125: 786-788.

Hakansson, J. and Svensson, S.A. 1977. Feed effects on leg bone size and composition in
chicks. Swed. J. Agr. Res. 7: 43-56.

Hall, R.J. 1972. The distribution of inorganic fluorine in some toxic tropical plants. New
Phytol. 71: 855-871.

Hall, R.J. and Cain, R.B. 1972. Organic fluorine in tropical soils. New Phytol. 71: 839-
853.

Hamilton, E.L. 1974. The chemical elements and human morbidity - water, air and places
- a study of natural variability. Sci. Total Environ. 3: 3-85.

Hamuro, Y. 1972a. Prevention by fluoride of magnesium deficiency defects such as


growth inhibition, renal abnormalities hyperuremia, and hyperphosphatemia in KK mice.
J. Nut 102: 419-425.

Hamuro, Y. 1972b. Relationship between prevention of renal calcification by fluoride


and fluoride-induced diuresis and reduction of urinary phosphorus excretion in
magnesiumdeficient KK mice. J. Nutr. 102: 893-900.

Hanhijarvi, H. 1975. Inorganic plasma fluoride concentrations and its renal excretion in
certain physiological and pathological conditions in man. Fluoride 8(4): 198-207.

Hankin, J.H., Margen, S. and Goldsmith, N.F. 1970. Contribution of hard water to
calcium and magnesium intakes of adults. J. Amer. Diet. Assoc. 56: 212-224.

Hanna, S., Harrison, M., MacIntyre, 1. and Fraser, R. 1960. The syndrome of magnesium
deficiency in man. The Lancet, July 23: 172-175.

Harbo, K. 1973. Fluorosis with neurological complications. Acta. Orthop. Scand. 44: 87-
88.

Harbo, R.M., Comas, F.T. and Thompson, J.A.J. 1974. Fluoride concentration in two
Pacific coast inlets - an indication of industrial contamination. J. Fisheries Res. Bd.
Canada 31: 1151-1154.

Hardwick, J.L. and Ramsey, A.C. 1976. Fluoride intake in young English teenagers from
beverages and fluoridated dentrifices. Caries Res. 10: 134-135.

Harper, D.B. and Blakley, E.R. 1971. The metabolism of p-fluorobenzoic acid by
Pseudomonas sp. Can. J. Microbiol. 17: 1015-1023.

Harris, R.L. 1974. Fluoride pollution in Flathead county, Montana, U.S. Environ.
Protection Agency, Region VIII, Air and Water Programs Div., Denver, Col. 159 pp.

Hay, C.J. 1975. Anthropod Stress. In:"Air Pollution and Metropolitan Woody
Vegetation". Ed. W.H. Smith and L.S. Dochinger. Yale Univ., Printing Service. pp. 33-
34.

Heagle, A.S. 1973. Interactions between air pollutants and plant parasites. Ann. Rev.
Phytopath. 11: 365-389.

Hellstrom, 1. 1976. Studies on fluoride distribution in infants and small children. Scand.
J. Dent. Res. 84: 119-136.

Hemens, J. and Warwick, R.J. 1972. The effects of fluoride on estuarine organisms.
Water Res. 6: 1301-1308.

Hemens, J., Warwick, R.J. and Oleff, W.D. 1975. Effect of extended' exposure to low
fluoride concentration on estuarine fish and crustacea. Progr. Water Technol. 7: 579-585.

Henrikson, P.A. 1968. Periodontal disease and calcium deficiency. Acta. Odontologica
Scand. Vol. 26, Suppl. 50. 132 pp.

Henrikson, P.A., Lutwak, L., Krook, L., Skogerboe, R., Kallfelz, F., Belanger, L.F.,
Marier, J.R., Sheffy, B.E., Romanus, B. and Hirsch, C. 1970. Fluoride and nutritional
osteoporosis: Physicochemical data on bones from an experimental study in dogs. J. Nutr.
100: 631-642.

Herbert, J.J. and Francon, J.J. 1971. Reversibilit6 radioclinique dans un cas
d'ost6opdtrose fluor6e. Acad. nationale de Med. (Paris) Bull. 155: 679-686.

Hillman, D. 1977. Fluorosis from mineral supplements in Michigan dairy herds. J. Dairy
Sci. 60: 139.

Hiszek, N., Horvath, F., Mandi, A. and Villanyi, G. 1971. Health hazards caused by
fluorine in aluminum plants. Internal. Chem. Eng. 11: 435-439.

Hitt, B., Mazze, R., Cousins, M. and Wilson, L. 1974. Differences in induction of
defluorination of methoxyflurane and isoflurane. Fed. Proc. 33: 495.

Hodge, H.C. 1952. The significance of the skeletal deposition of fluoride. In: "Metabolic
Interrelations with particular reference to Calcium". Trans. 4th Conf. Publ. by Josiah
Macy Foundation, New York. pp. 250-260.

Hodge, H.C. and Smith, F.A. 1977. Occupational fluoride exposure. J. Occup. Med. 19:
12-39.

Holaday, D.A. 1972. Metabolic production of toxic substances following general


anesthesia. In: "Cellular Biology and Toxicity of Anesthetics". Ed. B.R. Fink. Publ. by
Williams and Wilkins, Baltimore. pp. 215-220.

Hoover, R.N., McKay, F.W. and Fraumeni, J.F. 1976. Fluoridated drinking water and the
occurrence of cancer. J. Nal. Cancer Inst. 57: 757-768.

Horn, V. and Franke, J. 1976. Rasterelektonemikroskopische Untersuchen bei


menschlicher Industriefluorose. Z. Orthopadie u. ihre Grenzgebiete 114: 936-945.

Hortvedt, R. 1971. Fluoride injury to pine (Pinus sylvestrus) forests in Vettismorki,


Norway. Tidsskr. Skogbruk. 79:292-301.

Hosking, D.J. and Chamberlain, M.J. 1972. Studies in man with fluoride-18. Clinical Sci.
42: 153-161.

Huber, H. and Schurch, A. 1970. Some observations on the relationships between the
fluoride content of soil, fodder and bones and the effects on health and performance of
dairy cows. In: "Trace Elements Metabolism in Animals". Proc. WAAP/IBP Internal.
Symp., Scotland, July. pp. 482-486.

Hunter, D. 1969. The Diseases of Occupations. English Univ. Press, London, 1259 pp.
(cf. p. 691-692).

Husdan, H., Vogl, R., Oreopoulos, D., Gryfe, C. and Rapaport, A. 1976. Serum ionic
fluoride: Normal range and relationship to age and sex. Clin. Chem. 22: 1884-1888.

ICRP Publication 23. 1975. "Report of the Task Group on Reference Man". Pergamon
Press, Oxford.

ICRP Publication 26. 1977. Vol~ 1, No. 3, para. 216. Recommendations of the
International Commission on Radiological Protection. Pergamon Press, Oxford.

Inkovaara, J., Heikinheimo, R., Jarvinen, K., Kasurinen, U., Hanhijarvi, H. and lisalo, E.
1975. Prophylatic fluoride treatment and aged bones. Brit. Med. J., 12 July. pp. 73-74.

IJC 1971. International Joint Commission. Joint Air Pollution Study of St. Clair - Detroit
River Areas for International Commission, Canada and the United States. Ottawa and
Washington, January.

Ishio, S. and Nakagawa, H. 1971. Susceptibility of Alga, Porphyra tenera, to atmospheric


hydrogen fluoride. Bull. Jap. Soc. Sci. Fisheries 37: 105-110.

Israel, G.W. 1974a. Evaluation and comparison of three atmospheric fluoride monitors
under field conditions. Atmos. Environ. 8: 159-166.

Israel, G.W. 1974b. A field study of the correlation of static lime paper sampler with
forage and cattle urine. Atmos. Environ. 8: 167-181.

Jacks, 0. 1973. Geochemical viewpoints on fluoride in ground water. Swed. Dent. J.


66:211-215.
Jackson, D. and Weidmann, S.M. 1958. Fluorine in human bone related to age and the
water supply of different regions. J. Path. Bact. 76: 451-459.

Jacobson, J.S. and Weinstein, L.H. 1977. Sampling and analysis of fluoride: Methods for
ambient air, plant and animal tissues, water, soil and foods. J. Occup. Med. 19: 79-87.

Jagiello, G. and Lin, J-S. 1974. Sodium fluoride as potential mutagen in mammalian
eggs. Arch. Environ. Health 29: 230-235.

JAMA 1976. "National commission reports on the nation's third leading killer". J. Amer.
Med. Assoc. 235: 696-698.

Jardillier, J-C. and Desmet, G. 1973. Etude du fluor serique et de ses combinaisons par
une technique utilisant une electrode specifique. Clin. Chim. Acta. 47: 357-363.

Jenkins, S.H. 1972. Measures against water pollution in industries which perform metal
finishing. In: "Industrial Waste Water", Ed. B. Goransson. Butterworths, London. pp.
219-230.

Jenkins, G.N. 1973. Some observations on fluoride metabolism in Britain. J. Dent. Res.
(Suppl. to #5) 52: 984-985.

Jensen, K.F. 1975. Other Asymptomatic Physiological and Biochemical Alterations. In:
"Air Pollution and Metropolitan Woody Vegetation". Ed. W.H. Smith and L.S.
Dochinger. Yale Univ. Printing Service. pp. 31-33.

Jerard, E. and Patrick, J.B. 1973. The summing of fluoride exposures. Internal. J.
Environ. Studies 4: 141-155.

Johnson, W.J. and Taves, D.R. 1974. Exposure to excessive fluoride during
hemodialysis. Kidney Internal. 5: 451-454.

Jolly, S.S., Singh, B.M., Mathur, O.C. and Malhotra, K.C. 1968. Epidemiological,
clinical and biochemical study of endemic dental and skeletal fluorosis in Punjab. Brit.
Med. j. 16 Nov. pp. 427-429.

Jolly, S.S., Singla, V.P., Sharma, R., Ralhan, S.M. and Sandhu, S.S. 1974. Endocrine
aspects of endemic fluorosis. Fluoride 7(4): 208-219.

Jolly, S.S. 1976. Fluoride balance studies in endemic fluorosis. Fluoride 9(3):138-146.

Jones, C.M., Harries, J.M. and Martin, A.E. 1971. Fluoride in leafy vegetables. J. Sci.
Food Agric. 22: 602-605.

Jowsey, J., Johnson, W.J., Taves, D.R. and Kelly, P. 1972a. Effect of dialysate calcium
and fluoride on bone disease during regular hemodialysis. Lab. Clin. Med. 79: 204-214.

Jowsey, J., Riggs, B.L., Kelly, P.J. and Hoffman, D.L. 1972b. Effect of c~mbined
therapy with sodium fluoride, Vitamin D and calcium in osteoporosis. Amer. J. Med. 53:
43-49.

Juncos, L.I. and Donadio, J.V. 1972. Renal failure and fluorosis. J. Amer. Med. Assoc.
222: 783-785.

Kahl, S., Wojcik, K. and Ewy, Z. 1973. Effect of fluoride on some hematological indices
and iron-59 distribution in the blood and iron-storing tissues of rats. Bull. Acad.
Polonaise des Sci. (Ser. Sci. Biol.) 21: 389-393.

Kahl, S. and Ewy-Dura, A. 1976. Effect of fluoride on the red cells (5 1Cr label), plasma
(125IHSA label) and true blood volumes of rats. Bull. Acad. Polonaise des Sciences.
(Ser. Sci. Biol.) 24: 397-402.

Kathuria, A.K., Jain, A.K., Thergaonkar, V.P., Varandani, N. and Bhargava, R.K. 1974.
Fluorosis survey and preliminary report on urine analysis of fluorotic patients. Indian J.
Environ. Health 16: 222-232.

Kay, C.E. 1971. An inquiry into the distribution of fluoride in the environment of
Garrison, Montana. Dept. Environ. Studies, Univ. of Montana. 187 pp.

Kay, C.E. 1975. Fluoride distribution in different segments of the femur metacarpus and
mandible of mule deer. Fluoride 8(2): 92-97.

Kay, C.E., Tourangeau, P.C. and Gordon, C.C. 1975a. Fluoride levels in indigenous
animals and plants collected from uncontaminated ecosystems. Fluoride 8(3): 125-133.

Kay, C.E., Tourangeau, P.C. and Gordon, C.C. 1975b. Industrial fluorosis in wild mule
and whitetail deer from western Montana. Fluoride 8(4): 182-191.

Kay, C.E., Tourangeau, P.C. and Gordon, C.C. 1976. Population variation of fluoride
parameters in wild ungulates from the western United States. Fluoride 9(2): 73-90.

Keller, T. and Schwager, H. 1971. Der Nachweis unsichtbarer (physiologischer) Fluor-


Immissions-schadigungen an Waldbaumen durch eine einfache kolorimetrische
Bestimmung der Peroxidase-Aktivital. Europ. J. Pathol. 1: 6-18.

Keller, T. 1975. On the phytotoxicity of fluoride emissions for wood plants.


Schweizerische Amstalt fur das Forstliche Versuchswesen 51: 303-331.

Kilham, P. and Hecky, R.E. 1973. Fluoride: Geochemical and ecological significance in
east African waters and sediments. Limnol. Oceanography 18: 932-945.
King, W.R. and Ferrell, J.K. 1975. Wet process acid plant wastewater ponds, an
atmospheric fluoride pollution problem. Amer. Chem. Soc. Abst. 170: 5.

Kinlen, L. 1974. Cancer incidence in relation to fluoride levels in water supplies.


Community Health 6: 69-73.

Kinlen, L. 1975. Cancer incidence in relation to fluoride leyel in water supplies. Brit.
Dent. J. 138: 221-224.

Kitano, Y. and Furukawa, Y. 1972. Distribution of fluoride in waters of Tokyo Bay. J.


Oceanographic Soc. Japan 28: 121-125.

Klein, H. 1975. Dental fluorosis associated with hereditary Diabetes Insipidus. Oral Surg.
Oral Med. and Oral Pathol. 40: 736-741.

Knaus, R.M., Dost, F.N., Johnson, D.E. and Wang, C.H. 1976. Fluoride distribution in
rats during and after continuous infusion of sodium 18fluoride. Toxic. Appl. Pharmacol.
38: 335-343.

Kowalewska, M. 1974. Biopotentials of the hearing organ in chronic poisoning with


sodium fluoride. Otolaryngol. Pol. 28: 417-424.

Kramer, L., Osis, D., Wiatrowski, E. and Spencer, H. 1974. Dietary fluoride in different
areas in the United States. Amer. J. Clin. Nutr. 27: 590-594.

Kretchmar, L.H., Greene, W.M., Waterhouse, C.W. and Parry, W.L. 1963. Repeated
hemodialysis in chronic uremia. J. Amer. Med. Assoc. 184: 96-97.

Krishnamachari, K.A.V.R. and Krishnaswamy, K. 1973. Genu Valgum and osteoporosis


in an area of endemic fluorosis. The Lancet, 20 Oct. pp. 877-879.

Krishnamachari, K.A.V.R. and Krishnaswamy, K. 1974. An epidemiological study of the


syndrome of Genu Valgum among residents of endemic areas for fluorosis in Andhra
Pradesh. Indian J. Med. Res. 62: 1415-1423.

Krishnamachari, K.A.V.R. 1976. Further observations on the syndrome of endemic Genu


Valgum in south India. Indian J. Med. Res. 64: 284-291.

Kruggel, W.G. and Field, R.A. 1977. Fluoride content of mechanicallydeboned beef and
pork from commercial sources in different geographical areas. J. Food Sci. 42: 190-192.

Kuo, H.C. and Stamm, J.W. 1975. The relationship of creatinine clearance to serum
fluoride concentration and urinary fluoride excretion in man. Arch. Oral Biol. 20: 235-
238.

Kuo, H.C. and Wuthier, R.E. 1975. An investigation of fluoride protection against dietary
induced osteoporosis in the ral. Clin. Orthopaedics and Related Res. 110: 324-330.

Kuznetso, L.S. 1969. Fluorine level in maternal and fetal tissues in pregnant female
workers in the super-phosphate industry. Gigiena Truda Prof. Zabol. 13: 26-28.

Kyle, R.A., Jowsey, J., Kelly, P.J. and Taves, O.R. 1975. Multiplemyeloma bone disease.
The comparative effect of sodium fluoride and calcium carbonate or placebo. New
England J. Med. 293: 1334-1338.

Lakdawala, D.R. and Punekar, B.D. 1973. Fluoride content of water and commonly
consumed foods in Bombay and a study of the dietary fluoride intake. Indian J. Med. Res.
61: 1679-1687

LeBlanc, F., Comeau, G. and Rao, D.N. 1971. Fluoride injury symptoms in epiphytic
lichens and mosses. Can. J. Bot. 49: 1691-1698.

LeBlanc, F., Rao, D.N. and Comeau, G. 1972. Indices of atmospheric purity and fluoride
pollution pattern in Arvida, Quebec. Can. J. Bot. 50: 991-998.

LeBlanc, F. and Rao, D.N. 1975. Effect of air pollutants on lichens and bryophytes. In:
"Responses of Plants to Air Pollution". Ed. E.J. Mudd and T.T. Kozlowski. Academic
Press, N.Y. pp.237-269.

Lee, Y.K. and Whang, K.J. 1972. Geochemical investigation of contaminated river
waters. (Part IV): Fluorine contents of river water in Seoul. J. Korean Chem. Soc. 16:
219-228.

Lee, J.R. 1975. Optimal fluoridation. The Western J. Med. 122: 431-436.

Leloczky, M. 1971. Health-damaging effect of the fluorine pollution of the air around an
aluminum foundry. Egeszsegtudomany 15 (Suppl .) : 74-80.

Leonard, C.D. and Graves, H.B. 1970. Some effects of airborne fluoride on growth and
yield of six citrus varieties. Florida State Hort. Soc. Proc. 83: 34-41.

Leonard, C.D. and Graves, H.B. 1972. Effect of fluoride air pollution on Florida citrus.
Fluoride 5(3): 145-163.

Lillie, R.J. 1970. Air pollutants affecting the performance of domestic animals: A
literature review. U.S. Dept. Agric., Agric. Handbook No. 380. pp. 41-61.

Lindberg, G. 1971. Air pollution control in Swedish aluminum industry. Proc. 2nd
Internal. Clean Air Congr. Ed. H.M. Englund and W.T. Beery. Academic Press, London.
pp. 84-88.

Linzon, S.N. 1971. Fluoride effects on vegetation in Ontario. Proc. 2nd Internal. Clean
Air Congr. Ed. H.M. Englund and W.T. Beery. Academic Press, London. pp. 277-289.

Little, J.B., Radford, E.P., McCombs, L. and Hunt, V.R. 1965. Distribution of
polonium210 in pulmonary tissues of cigarette smokers. New England J. Med. 273:
1343-1354.

Lloyd, J.W., Lundin, F.E., Redmond, C.K. and Geiser, P.B. 1970. Long-term mortality
study of steel workers. IV. Mortality by work area. J. Occup. Med. 12: 151-157.

Loew, G., Motulsky, H., Trudell, J., Cohen, E. and Hjelmeland, L. 1974. Quantum
chemical studies of the metabolism of the inhalation anesthetics, methoxyflurane,
enflurane and isoflurane. Molecul. Pharmacol. 10: 406-418.

Lough, J., Noonan, R., Gagnon, R. and Kaye, M. 1975. Effects of fluoride on bone in
chronic renal failure. Arch. Pathol. 99: 484-487.

Lubinski, K.S. and Sparks, R.E. 1975. The use of toxicity indices to assess the quality of
the Illinois river. Assoc. Southeast Biol. Bull. 22: 64.

MacLean, D.C. and Schneider, R.E. 1973. Fluoride accumulation by forage: Continuous
versus intermittent exposure to hydrogen fluoride. J. Environ. Ouality 2: 501-503.

MacLean, D.C., Schneider, R.E. and McCune, D.C. 1976. Fluoride susceptibility of
tomato plants as affected by magnesium nutrition. J. Amer. Soc. Hort. Sci. 101: 347-352.

Macrae, S. 1975. Peripheral and metabolic effects of fenfluramine, 78OSE,


norfenfluramine and hydroxyethylnorfenfluramine: a review. Postgrad. Med. J. 51
(Suppl. 1): 13-17.

Mahaffey, K.R., Stone, C.L. and Fowler, B.A. 1976. Effect of high fluorine intake on
tissue lead (Pb) concentrations. Fed. Proc. 35: 256.

Mangold, C.A. and Beckett, R.R. 1971. Combined occupational exposure of silver
brazers to cadmium oxide, nitrogen dioxide and fluorides at a naval shipyard. Amer. Ind.
Hygiene Assoc. J. 32: 115-118.

Manocha, S.L., Warner, H. and Olkowski, Z.L. 1975. Cytochemical response of kidney,
liver and nervous system to fluoride ions in drinking water. Histochem. J. 7: 343-355.

Marier, J.R., Rose, D. and Boulet, M. 1963. Accumulation of skeletal fluoride and its
implications. Arch. Environ. Health 6: 664-671.

Marier, J.R. and Rose, D. 1966. The fluoride-content of some foods and beverages - a
brief survey using a modified Zr-SPADNS method. J. Food Sci. 31: 941-946.

Marier, J.R. 1968. The importance of dietary maqnesium with particular reference to
humans. Zeitschrift Vitalstoffe Zivilisationskrankheiten 13: 144-149.

Marier, J.R. 1971. Fluoride in the environment. Internal. Symp. on Identification and
Measurement of Environmental Pollutants. National Research Council, Ottawa, Canada.
June. pp. 404-406.

Marier, J.R. and Rose, D. 1971. Environmental Fluoride. Nal. Res. Council, Canada,
Public. No. 12226. (39 pp.).

Marier, J.R. 1977. Some current aspects of environmental fluoride. Sci . Tot. Environ. 8:
253-265.

Martindale, L. and Heaton, F.W. 1964. Magnesium deficiency in the adult ral. Biochem.
J. 92: 119-126.

Masironi, R. 1975. Drinking water quality and public health. Water Research Centre
Symp. Nov. WHO, Geneva. pp. 1-10.

Masuda, T.T. 1964. Persistence of fluoride from organic origins in waste waters. Devel.
Indust. Microbiol . 5: 53-70.

Mazze, R.I., Cousins, M.J. and Kosek, J.C. 1972. Dose-related methoxyflurane
nephrotoxicity in rats. Anesthesiology 36: 571-587.

Mazze, R.I. and Cousins, M.J. 1974. Biotransformation of methoxyflurane. Internal.


Anesthesiology Clinics 12: 93-105.

Mazze, R.I., Calverley, R.K. and Smith, N.T. 1977. Inorganic fluoride nephrotoxicity:
Prolonged enflurane and halothane anesthesia in volunteers. Anesthesiology 46: 265-271.

McCaull, J. 1972. The tide of industrial waste. Environment 14: 31-39.

McCune, D.C. and Hitchcock, A.E. 1971. Fluoride in forage: Factors determining its
accumulation from the atmosphere and concentration in the plant. Proc. 2nd Internal.
Clean Air Congr. Ed. H.M. Englund and W.T. Beery. Academic Press, London. pp. 289-
292.

McCune, D.C. and Weinstein, L.H. 1971. Metabolic effects of atmospheric fluorides on
plants. Environ. Pollut. 1 169-174.

McLaughlin, S.B. and Barnes, R.L. 1975. Effects of fluoride on photosynthesis and
respiration of some southeast American forest trees. Environ. Pollut. 8: 91-96.

Mernagh, J.R., Harrison, J.E., Hancock, R. and McNeill, K.G. 1977. Measurement of
fluoride in bone. J. Appl. Radiation Isotopes 28:581-583.
Merz, W.A., Schenk, R.K. and Reutter, F.W. 1970. Paradoxical effects of Vitamin D in
fluoride-treated senile osteoporosis. Calc. Tissue Res. 4 (Suppl.): 49-50.

Messer, H.H., Armstrong, W.D. and Singer, L. 1974. Effect of maternal fluoride intake
on preweaning bone fluoride concentration in mice. J. Dental Res. 53: 145.

Milham, S. 1976. Cancer mortality patterns associated with exposure to metals. Ann.
New York Acad. Sci. 271: 243-249.

Miller, G.W., Egyed, M.N. and Shupe, J.L. 1977. Alkaline phosphatase activity, fluoride,
citric acid, calcium and phosphorus content of bones of cows with osteoporosis. Fluoride
10(2): 76-82.

Miller, P.R. and McBride, J.R. 1975. Effect of Air Pollutants on Forests. In: "Responses
of Plants to Air Pollution". Ed. J.B. Mudd and T.T. Kozlowski. Academic Press, N.Y. pp.
195-236.

Mitchell, B. and Gerdes, R.A. 1973. Mutagenic effects of sodium and stannous fluoride
upon Drosophila melanogaster. Fluoride 6(2): 113-117.

Mohamed, A.H. and Kemner, P.A. 1970. Genetic effects of hydrogen fluoride on
Drosophila melanogaster. Fluoride 3(4): 192-200.

Mohamed, A.H. 1971. Induced recessive lethals in second chromosomes of Drosophila


melanogaster by hydrogen fluoride. Proc. 2nd Clean Air Congr. Ed. H.M. Englund and
W.T. Beery. Academic Press, London. pp. 158-161.

Mohamed, A.H. and Weitzenkamp-Chandler, M.E. 1976. Cytological effects of sodium


fluoride on mitotic and meiotic chromosomes of mice. Presented at Amer. Chem. Soc.
Meeting, San Francisco, Sept. (3 pp.).

Moore, D.J. 1971. The uptake and concentration of fluoride by the Blue crab, Callinectes
sapidus. Chesapeake Sci. 12: 1-13.

Mose, J.R., Fischer, G. and Brantner, H. 1969. Impurities in the urban atmosphere of
Graz, Austria. Archiv. fuer Hygiene und Bakteriologie 153: 234-238.

Murray, M.M. and Wilson, D.C. 1946. Fluoride hazards, with special references to some
social consequences of industrial processes. The Lancet, 7 Dec. pp. 821-824.

NAS 1971. U.S. National Academy of Sciences. "Fluorides". Committee on Biologic


Effects of Atmospheric Pollutants. Div. Med. Sci., National Research Council.
Washington, D.C. (295 pp.).

NAS 1973. U.S. National Academy of Sciences. "Manganese". Committee on Biol.


Effects of Atmospheric Pollutants. Div. Med. Sci., National Research Council.
Washington, D.C. (pp. 132-136).

NAS 1974. U.S. National Academy of Sciences. Effects of fluorides on animals. Comm.
on Animal Nutrition, Subcomm. on Fluorosis, National Research Council. Washington,
D.C. (70 pp.).

Newman, J.R. and Ming-Ho Yu. 1976. Fluorosis in black-tailed deer. J. Wildlife Disease
12: 39-41.

Newman, J.R. 1977. Sensitivity of the house martin, Delichon urbica, to fluoride
emissions. Fluoride 10(2): 73-76.

Nielsen, E., Solomon, N., Goodwin, N.J., Siddhivarn, N., Galonsky, R., Taves, D. and
Friedman, E.A. 1973. Fluoride metabolism in uremia. Trans. Amer. Soc. Artif. Internal
Organs 19: 450-455

Nikolaev, V.I. and Kas'Yanova, K.G. 1971. The role of manganese in the development of
occupational fluoride poisoning among workers in aluminum factories. Biol. Abst..52:
12769.

Nikolaev, V.I. and Sidorkin, V.I. 1973. Change of content of certain bioelements-metals
in the serum of workers in electrolytic shops. Biol. Abst. 56: 6460.

Nixon, J.M. and Carpenter, R.G. 1974. Mortality in areas containing natural fluoride in
their water supplies, taking account of socio-environmental factors and water hardness.
The Lancet, 2 Nov. pp. 1068-1071

Obel, A-L. 1971. A literary review of bovine fluorosis. Acta. Vet. Scand. 12: 151-163.

Obel, A-L. and Erne, K. 1971. Bovine fluorosis in Sweden. Acta. Vet. Scand. 12:164-
184.

O'Dell, B.L., Morris, E.R. and Regan, W.O. 1960. Magnesium requirement of Guinea
pigs and rats: Effect of calcium and phosphorus and symptoms of magnesium deficiency.
J. Nutr. 70: 103-111.

O'Dell, B.L., Moroni, R.I. and Regan, W.O. 1973. Interaction of dietary fluoride and
magnesium in Guinea pigs. J. Nutr. 103: 841-850.

OECD 1972. Organization for Economic Co-operation and Development. Report on air
pollution by fluorine compounds from primary aluminum smelting. Paris, France.
NR/ENV/72-7 (Final Rev.) Aug. (43 pp.).

Oelschlager, W. and Moser, E. 1969. The extent of plant damage caused by gaseous
fluoride as a function of environmental factors as well as by pulverulent fluorine and
fertilizer. StaubReinhalt Luft. 29: 38-40.
Oelschlager, W. 1974. Fluoride-containing mineral supplements in agriculture. Fluoride
7(2): 84-88.

Okamura, T. and Matsuhisa, T. 1965. The content of fluorine in cigarettes. J. Food


Hygiene Soc. Jap. 6: 382-385.

Ophaug, R.H. and Singer, L. 1976. Effect of fluoride on the mobilization of skeletal
magnesium and soft tissue calcinosis during acute magnesium deficiency in the ral. J.
Nutr. 106: 771-777.

Osag, T.R., Smith, J.A., Bunyard, F.L. and Crane, G.B. 1976. Fluoride emission control
costs. Chem. Eng. Progr. 72: 33-36.

Osis, D., Kramer, L., Wiatrowski, E. and Spencer, H. 1974. Dietary fluoride in man. J.
Nutr. 104: 1313-1318.

Pack, M.R. 1971a. Effects of hydrogen fluoride on production and organic reserves of
bean seeds. Environ. Sci. Technol. 5: 1128-1132.

Pack, M.R. 1971b. Effects of hydrogen fluoride on bean reproduction. J. Air Pollut.
Control Assoc. 21: 133-137.

Pack, M.R. 1972. Response of strawberry fruiting to hydrogen fluoride fumigation. J. Air
Pollut. Control Assoc. 22: 714-717.

Pack, M.R. and Sulzbach, C.W. 1976. Response of plant fruiting to hydrogen fluoride
fumigation. Atmosph. Environ. 10: 73-81.

Pantucek, M.B. 1975. Hygiene evaluation of exposure to fluoride fume from basic arc-
welding electrodes. Ann. Occup. Hyg. 18: 207-212.

Parkins, F.M., Timanoff, N., Moutinho, M., Anstry, M.B. and Waziri, M.H. 1974.
Relationship of human plasma fluoride and bone fluoride to age. Calcif. Tissue Res. 16:
335-338.

Parsonson, I.M., Carter, P.D. and Cruickshanks, J. 1975. Chronic fluorosis in laboratory
Guinea pigs. Australian Vet. J. 51: 362-363.

Pellissier, M. 1973. La pollution atmosph6rique et ses 6ffets sur la vegetation. Service de


Protection de l'Environment du Gouvernement du Quebec et de l'universite du Quebec A
Trois-Rivieres. 40 pp.

Peters, R.A. 1957. Mechanism of the toxicity of the active constituent of Dichapetalum
cymosum and related compounds. Adv. in Enzymol. 18: 113-159.
Peters, R.A. and Shorthouse, M. 1971. Oral toxicity of fluoracetate and fluorocitrate in
rats. J. Physiol. 216: 40P-41P.

Peters, R.A. and Shorthouse, M. 1972a. Fluorocitrate in plants and foodstuffs.


Phytochem. 11: 1337-1338.

Peters, R.A. and Shorthouse, M. 1972b. Formation of monofluorocarbon compounds by


single cell cultures of Glycine max growing on inorganic fluoride. Phytochem. 11: 1339.

Peters, R.A., Shorthouse, M., Ward, P.F.V. and McDowell, E.M. 1972. Observations
upon the metabolism of fluorocitrate in rats. Proc. Royal Soc. London. B-128: 1-8.

Pettyjohn, W.A. 1975. Picklinq liquors, strip mines and groundwater pollution. Ground
Water 1'3: 4-9.

Pilet, P.E. and Bejaoui, M. 1975. Interactions entre le fluor, le calcium et le magnesium
sur Vabsorption de l'oxygene par des tissues cultives in vitro. Biochen. Physiol. Pflanzen
168: 483-491.

Pita, M.L., Portela, M. de and Sanahuia, J.C. 1972. Efectos bioquimicos en la ingestion
prolongada de fluor en la rata. Arch. Latino-Americanos de Nutricion. 22: 291-308.

Poey, J., Elsair, J., Morgan, P., Reggabi, M. and Hattab, F. 1976. Evolution du bilan
biologique en fonction du stade radiologique chez une population vivant dans une zone
d'endemie fluor6e du sud algerien. Europ. J. Toxicol. 9: 179-186.

Polakoff, P.L., Busch, K.A. and Okawa, M.T. 1974. Urinary fluoride levels in
polytetrafluoroethylene fabricators. Amer. Ind. Hyg. Assoc. J. 35: 99-106.

Poovaiah, B.W. and Wiebe, H.H. 1973. Influence of hydrogen fluoride fumigation on the
water economy of soybean plants. Plant Physiol. 51: 396-399.

Popov, L.I., Filatova, R.I. and Shirshever, A.S. 1974. Characteristics of affections
involving nervous system in occupational fluorosis. Gig. Tr. Prof. Zabol. 1: 25-27.

Posen, G.R., Marier, J.R. and daworski, Z.F. 1971. Renal osteodystrophy in patients on
long-term hemodialysis with fluoridated water. Fluoride 4(3): 114-128.

Prival, M.J. and Fisher, F. 1974. Adding fluorides to the diet. Environment 16: 29-33.

Rak, M. 1969. Waste water from production of fluorine-containing chemicals. Vodni


Hospodarstyi B-19: 15-17.

Rantanen, N.W., Alexander, J.E. and Spencer, G.R. 1972. Interaction of fluoride,
calcium, phosphorus and thyroidectomy on porcine bone. Amer. J. Veterin. Res. 33:
1347-1358.
Rao, G.V.G.K., Ts'ao, K. and Draper, H.H. 1972. The effect of fluoride on some physical
and chemical characteristics of the bones of aging mice. J. Gerontol. 27: 183-187.

Rao, T.K.S. and Friedman, E.A. 1975. Fluoride and bone disease in uremia. Kidney
Internal. 7: 125-129.

Reddy, G.S. and Srikantia, S.G. 1971. Effect of dietary calcium, Vitamin C, and protein
in development of experimental skeletal fluorosis. I. Growth, serum chemistry, and
changes in composition and radiological appearance of bones. Metabolism 20: 642-649.

Reddy, G.S. and Narasinga Rao, B.S. 1972a. Effect of fluoride on the skeleton of rats
maintained on different levels of calcium in the diet. Indian J. Med. Res. 60: 481-487.

Reddy, G.S. and Narasinga Rao, B.S. 1972b. in vit2v biosynthesis of bone matrix in
bones of rabbits intoxicated with flUoride. Calc. Tissue Res. 10: 207-215.

Reddy, G.S., Sastry, J.G. and Narasinga Rao, B.S. 1972c. Radiographic
photodensitometric assessment of bone density changes in rats and rabbits subjected to
nutritional stresses. Indian J. Med. Res. 60: 1807-1815.

Reinert, R.A., Heagle, A.S. and Heck, W.W. 1975. Plant responses to pollutant
combinations. In: "Responses of Plants to Air Pollution". Ed. J.B. Mudd and T.T.
Kozlowski. Academic Press, N.Y. pp. 159-178.

Riggins, R.S., Zeman, F. and Moon, D. 1974. The effects of sodium fluoride on bone
breaking strength. Calc. Tissue Res. 14: 283-289.

Riggins, R.S., Rucker, R.C., Chan, M.M., Zeman, F. and Beljan, J.R. 1976. The effect of
fluoride supplementation on the strength of osteopenic bone. Clin. Orthcpaed. Related
Res. 114: 352-357

Riggs, B.L. and Jowsey, J. 1972. Treatment of osteoporosis with fluoride. Seminars in
Drug Treatment 2: 27-33.

Riggs, B.L., Jowsey, J., Kelly, P.J., Hoffman, D.L. and Arnaud, C.D. 1976. Effect of oral
therapy with calcium and Vitamin D in primary osteoporosis. J. Clin. Endocrin. 42: 1139-
1144.

Rippel, A., Balazova, G. and Bartosova, L. 1967. Hodnotenie prijmu fluoru u deti v okoli
zavodu na vyrobu hlinica. Lek. Obzor. 16: 369-372.

Rogler, J.C. and Parker, H.E. 1972. Effects of excess calcium on a fluoride-magnesium
interrelationship in chicks. J. Nutr. 102: 1699-1708.

Roman, R.J., Carter, J.R., North, W.C. and Kauker, M.L. 1977. Renal tubular site of
artion of fluoride in Fischer-344 rats. Anesthesiology 46: 260-264.

Rosenquist, J.B. 1974. Effects of supply and withdrawal of fluoride. 6. The mineral
content of microdissected fluorotic bone. Acta. Path. Microbiol. Scand. Sect. A, 82: 618-
622.

Rossano, A.T. and Pilat, M.J. 1971. Recent developments in the control of air pollution
from primary aluminum smelters' in the U.S. Proc. 2nd Internal. Clean Air Congr. Ed.
H.M. Englund and W.T. Beery. Academic Press, London. (pp. 701-706).

Royal College of Physicians, London, Committee on the Fluoridation of Water Supplies.


1976. "Fluoride, Teeth and Health". Pitman Medical, Tunbridge Wells.

Rush, D., Russell, J.C. and Iverson, R.E. 1973. Air pollution abatement on primary
aluminum potlines: Effectiveness and cost. J. Air Pollut. Control Assoc. 23: 98-104.

Said, A.N., Slagsvold, P., Bergh, H., and Laksesvela, B. 1977. High fluorine water to
Wether sheep maintained in pens. Nordisk Veterinaer Med. 29: 172-180.

Samuelson, P.N., Merin, R.G., Taves, D.R., Freeman, R.B., Calimlim, J.F. and
Kumazawa, T. 1976. Toxicity following methoxyflurane anesthesia. IV. The role of
obesity and the effect of low dose anesthesia on fluoride metabolism and renal function.
Canad. Anesthet. Soc. J. 23: 465-479.

San Filippo, F.A. and Battistone, G.C. 1971. The fluoride content of a representative diet
of the young adult male. Clin. Chim. Acta. 31: 453-457.

San Filippo, F.A., Battistone, G.C. and Chandler, D.W. 1972. Fluoride content of army
field rations. Official J. Assoc. Military Surgeons, U.S. 137: 11-12.

Sauerbrunn, B.J.L., Ryan, C.M. and Shaw, J.F. 1965. Chronic fluoride intoxication with
fluorotic radiculomyelopathy., Ann. Internal. Med. 63: 1074-1078.

Schellmann, B. and Zober, A. 1975. Normal values of fluoride from a defined region of
the human iliac crest. Internal. Arch. Occup. Environ. Health 35: 233-244.

Schlegel, H.H. 1974. Industrielle skelettfluorose vorlaufiger Bericht uber 61 Falle aus
Aluminiumhutten. Sozial und Praventivomedizen 19: 269-274.

Schmidt, C.W. 1976a. Auftreten von Nachbarschafts fluorose unter der Bevolkerung
einer sachsischen Kleinstadt. Deutsche Gesundheitswesen 31: 1271-1274.

Schmidt, C.W. 1976b. Nachbarschaftfluorose. Deutsche Gesundheitswesen 31: 1700-


1703.

Schuh, F.T. 1974. Enfluran (Ethrane) - Pharmakologie und klinische Aspekte eines neuen
inhalationsnarkoticums. Anesthesist 23: 273-280.

Schuldt, A.A. 1977. Personal communication, May 20.

Seidenberg, A., Flueler, U. and Binswanger, U. 1976. Serum fluoride concentrations in


renal insufficiency. Kidney Internal. 9: 454.

Shearer, T.R. and Suttie, J.W. 1970. Effect of fluoride on glycolytic and citric acid cycles
metabolites in rat liver. J. Nutr. 100: 749-756.

Shearer, T.R., Saouter, J.J. le and Suttie, J.W. 1971. Effect of toxic levels of dietary
fluoride on citrate metabolism in the ral. J. Nutr. 101: 1037-1044.

Shearer, T.R. 1972. Liver citrate levels in parathyroidectomized rats fed toxic amounts of
inorganic fluoride. Arch. Oral Biol. 17: 1629-1632.

Shen, Y-W. and Taves, D.R. 1974. Fluoride concentrations in the human placenta and
maternal and cord blood. Amer. J. Obstet. Gynecol. 119: 205-207.

Shupe, J.L. 1970. Fluorine toxicosis and industry. Amer. Indust. Hygiene 31: 240-247.

Shupe, J.L. and Olson, A.E. 1971. Clinical aspects of fluorosis in horses. J. Amer. Vet.
Assoc. 158: 167-174.

Shupe, J.L., Olson, A.E. and Sharma, R.P. 1972. Fluoride toxicity in domestic and wild
animals. Clin. Toxicol. 5: 195-213.

Sidhu, S.S. and Roberts, B.A. 1976. Progression of fluoride damage to vegetation from
1973 to 1975 in the vicinity of a phosphorus plant. Bi-monthly Res. Notes. Environment.
Canada. Forestry Service. Vol. 32. No. 6.pp. 30-31.

Sidhu, S.S. 1977a. Fluoride levels in air, vegetation and soil in the vicinity of a
phosphorus plant. Annual Meeting of the Air Poll. Contr. Assoc., June 20-24, Toronto.
Paper No. 77-30.2. (16 pp.).

Sidhu, S.S. 1977b. Personal communication, Sept. 2.

Sigler, W.F. and Neuhold, J.M. 1972. Fluoride intoxication in fish: a review. J. Wildlife
Disease 8: 252-254.

Singer, I. and Forrest, J.N. 1976. Drug-induced states of nephrogenic Diabetes Insipidus.
Kidney Internal. 10: 82-95.

Singer, L., Ophaug, R,.H. and Armstrong, W.D. 1976. Influence of dietary fluoride
restriction on regulation of plasma and soft tissue fluoride contents. Proc. Soc. Exp. Biol.
Med. 151: 627-631.
Singmaster and Breyer. 1973. Air pollution control in primary aluminum industry.
Singmaster and Breyer, 235 - East 42nd. St., N.Y. 10017. Vol. 1. 309 pp.

Sivakumar, B. and Krishnamachari, K.A.V.R. 1976. Circulating levels of


immunoreactive parathyroid hormone in endemic Genu Valgum. Horm. Metab. Res. 8:
317-319.

Soldatovic, D. and Nadeljkovic-Tomic, M. 1971. Influence of different concentrations of


sodium fluoride and sodium fluorosilicate -in cases of chronic intoxication -on the
number of erythrocytes and leucocytes and on the hemoglobin content and iron content of
rabbit blood. Acta. Pharm. Jug. 21: 181-186.

Soltero, R.A. 1969. Chemical and physical findings from pollution studies on the East
Gallatin river and its tributaries. Water Res. 3: 687-706.

Soriano, M. and Manchon, F. 1966. Radiological aspects of a new type of bone fluorosis,
Periostitis Deformans. Radiology 87: 1089-1094.

Speirs, R.L. and Adams, G. 1971. Effects of ingestion of low doses of fluoride on urinary
composition in human subjects. J. Dent. Res. 50: 1173.

Spencer, G.R., El-Sayed, F.I., Kroening, G.H., Pell, K.L., Shoup, N-, Adams, D.F.,
Franke, M. and Alexander, J.E. 1971. Effects of fluoride, calcium and phosphorus on
porcine bone. Amer. J. Veterin. Res. 32: 1751-1774.

Spencer, G.R., Cohen, A.L. and Garner, G.E. 1974. Effect of fluoride, calcium and
phosphorus on periosteal surfaces. Calc. Tissue Res. 15: 111-123.

Spencer, H., Lewin, I., Wiatrowski, E. and Samachson, J. 1970. Fluoride metabolism in
man. Amer. J. Med. 49: 807-813.

Spencer, H., Osis, D. and Wiatrowski, E. 1974. Intake, retention and release of retained
fluoride in man. Amer. J. Clin. Nutr. 27: 437.

Spencer, H., Osis, D. and Wiatrowski, E. 1975. Retention of fluoride with time in man.
Clin. Chem. 21: 613-618.

Spierdijk, J. 1972. The dangers of anesthetic agents to personnel working in operating


theatres. In: "Anesthesia and Pharmaceutics". Ed. J. Spierdijk and S.A. Feldman. Leiden
Univ. Press. (pp. 130-138).

Stepanek, D., Kuzelova, M., Vlasak, R. and Bryckova, E. 1972. Contamination of


irrigation waters by industrial wastes. Ceskoslovenska Hygiena 17: 25-29.

Stewart, W.H. 1969. Fluoridation and the use of fluoridated water in artificial kidneys. J.
Amer. Dent. Hyg. Assoc. 43: 152-153.

Stewart, D.J., Manley, T.R., White, D.A., Harrison, D.L. and Stringer, E.A. 1974. Natural
fluoride levels in Bluff area, New Zealand. I. Concentrations in wildlife and domestic
animals. New Zealand J. Sci. 17: 105-113.

Suketa, Y., Mikami, E., Sato, Y., Hayashi, M. and Yamamoto, T. Changes of ion
mobilizations and their related enzyme activities in the blood of fluoride-intoxicated rats.
J. Toxicol. Environ. Health 2: 301-309.

Suketa, Y., Mikami, E. and Hayashi, M. 1977. Changes in calcium and magnesium in the
kidneys of rats intoxicated with a single large dose of fluoride. Toxicol. Applied
Pharmacol. 39: 313-319.

Sulzbach, C.W. and Pack, M.R. 1972. Effects of fluoride on pollen germination, pollen
tube growth, and fruit development in tomato and cucumber. Phytopatholohy 62: 1247-
1253.

Sundstrom, B. 1972. On mild degreesof fluorosis. Acta. Path. Microbiol. Scand. Section
A, 80: 17-20.

Suter, C. and Klingman, W.O. 1955. Neurological manifestations of magnesium


depletion states. Neurology 5: 691-699.

Sutter, E. 1973. Fluoridmessungen in Aluminiumhutten. StaubReinhalt-Luft. 33: 114-


117.

Suttie, J.W. 1969a. Air quality standards for the protection of farm animals from
fluorides. J. Air Pollut. Control Assoc. 19: 239-242. Also available as "Air quality criteria
to protect livestock from fluoride toxicity", prepared for the Aluminum Assoc., 750 Third
Ave., New York 10017.

Suttie, J.W. 1969b. Fluoride content of commerci-al dairy concentrates and alfalfa forage.
J. Agric. Food Chem. 17: 1350-1352.

Suttie, J.W., Carlson, J.R. and Faltin, E.C. 1972. Effect of alternating high- and low-
fluoride ingestion on dairy cattle. J. Dairy Sci. 55: 790-803.

Suttie, J.W. and Faltin, E.C. 1973. Effects of sodium fluoride on dairy cattle: Influence of
nutritional state. Amer. J. Vet. Res. 34: 479-483.

Suttie, J.W. 1977. Effects of fluoride on livestock. J. Occup. Med. 19: 40-48.

Taft, W.H. and Martin, D.F. 1974. Sedimentary fluorite in Tampa Bay, Florida. Environ.
Letters 6: 167-174.
Takizawa, H., Igarashi, M., Hayashi, Y., Karube, S. and Okitzu, K. 1975. Effect of
combined therapy with fluoride in osteoporosis. Calc. Tissue Res. 19: 246.

Tal, E. and Guggenheim, K. 1965. Effect of manganese on calcification of bone.


Biochem. J. 95: 94-97.

Tamacas, J.C., Ramsay, A.C. and Hardwick, J.L. 1974. Fluoride content of beverages
commonly used in England. J. Dent. Res. (Suppl.) 53:1088.

Taves, D.R., Terry, R., Smith, F.A. and Gardner, D.E. 1965. Use of fluoridated water in
long-term hemodialysis. Arch. Internal Med. 115: 167-172.

Taves, D.R. 1968. Evidence that there are two forms of fluoride in human serum. Nature
217: 1050-1051.

Taves, D.R. 1970. New approach to the treatment of bone disease with fluoride. Fed.
Proc. 29: 1185-1187.

Taves, D.R. 1971. Comparison of "organic" fluoride in human and non-human serums. J.
Dent. Res. 50: 783.

Taves, D.R., Fry, B.W. and Merin, R.G. 1972. Role of metabolism in the nephrotoxicity
of methoxyflurane. Toxic. Applied Pharmacol. 23: 795-796.

Taves, D.R., Grey, W.S. and Brey, W.S. 1976. Organic fluoride in human plasma: Its
distribution and partial identification. Toxic. Applied Pharmacol. 37: 120-121.

Teotia, M., Teotia, S.P.S. and Kunwar, K.B. 1971. Endemic skeletal fluorosis. Arch.
Disease in Childhood 46: 686-691.

Teotia, S.P.S., Teotia, M., Burns, R.R. and Heels, S. 1974. Circulating plasma
immunoreaction parathyroid hormone levels in endemic skeletal fluorosis with secondary
hyperparathyroidism. Fluoride 7(4): 200-207.

Teotia, S.P.S. and Teotia, M. 1975. Dental fluorosis in areas with a high natural content
of calcium and magnesium in drinking water - an epidemiological study. Fluoride 8(l):
34-38.

Teotia, S.P.S., Teotia, M. and Teotia, N.P.S. 1976. Skeletal fluorosis: Roentgenological
and histopathological study. Fluoride 9(2): 91-98.

Teulon, F. 1971. Utilisation des vegetaux pour detecter la pollution fluoree autour d'une
usine susceptible d'emettre des effluents gaseux fluor6s. Commissariat a l'energie
atomique. Rapport CEA-R-4207. Aoal. Centre de Pierrelatte (29 pp.).

Teworte, W. 1972. Measures against water pollution in basic non-ferrous metal


industries. In: "Industrial Waste Water", Ed. B. Goransson. Butterworths, London. pp.
235-244.

Thergaonkar, V.P. and Bhargava, R.K. 1974. Water quality and incidence of fluorosis in
Jhunjhunu district of Rajasthan: Preliminary observations. Indian J. Environ. Health 16:
168-180.

Thompson, M.E. 1967. Fluoride in the Rappahannock River: Association with


magnesium. Report, Canada Centre for Inland Waters, Burlington, Ontario. (12 pp.).

Thompson, R.J., McMullen, T.B. and Morgan, G.B. 1971. Fluoride concentrations in
ambient air. J. Air Pollut. Control Assoc. 21: 484-487.

Tinker, J. 1972. Britain's environment - Nanny knows best. New Scientist. 9 March. 530-
534.

Toth, K. 1975. Optimum and tolerated intake of fluorine. Acta Med. Acad. Sci.
Hungaricae 32: 1-14.

Toth, K. and Sugar, E. 1975. Urinary fluoride levels after consumption of fluoride-poor
drinking waters in Hungary. Acta Physiol. Acad. Scientiarum Hungaricae 46: 37-49.

Tourangeau, P.C., Gordon, C.C. and Carlson, C.E. 1977. Fluoride emissions of coal-fired
power plants and their impact upon plant and animal species. Fluoride 10(2): 47-62.

Townsend, D. and Singer, L. 1977. Effect of fluoride on serum lipids of Guinea pigs. J.
Nutr. 107: 97-103.

Trautwein, K., Kopp, C. and Buchner, R. 1972. Fluorose und Umwelthygiene.


Tierartliche Umsuch. 27(l): 7-16.

Treshow, M. 1971. Fluorides as air pollutants affecting plants. Ann. Review Phytopath.
9: 21-44.

Tsunoda, F., Aizawa, E., Sakurai, S., Kunida, H. and Sasaki, K. 1973. On the fluoride
body-burden of residents living in fluoridepolluted areas. Air Poll. Abstr., June, 1973. p.
137. Abstr. No. 27978. APTIC No. 49607.

Tucker, W.K., Munson, E.S., Holaday, D.A., Fiserova-Bergerova, V. and Turner, B.M.
1973. Hepatorenal toxicity following fluroxene anesthesia. Anesthesiology 39:104-107.

Underwood, E.J. 1962. Trace elements in human and animal nutrition. (2nd ed.)
Academic Press, New York. pp. 260-261.

Underwood, E.J. 1977. Trace elements in human and animal nutrition. (4th ed.)
Academic Press, New York. pp. 355-356.
U.S. 1969. White House Conference on food and nutrition, Dec. 1969. Summarized in
National Dairy Council of Canada, Bulletin Service No. 198, Dec. 1, 1969.

Van Dyke, R.A. and Gandolfi, A.J. 1976. Anaerobic release of fluoride from halothane.
Drug Metabolism and Disposition 4: 40-44.

Vejrosta, Z., Sindelka, M., Feller, M. and Vilser, M. 1975. Study of dental caries in
children drinking water with a high content of magnesium. Ceskoslovenska Stomatologie
75: 346-354.

Vickery, B. and Vickery, M.L. 1972. Fluoride metabolism in Dichapetalum toxicarium.


Phytochem. 11: 1905-1909.

Vickery, B. and Vickery, M.L. 1975. The synthesis and defluorination of


monofluoroacetate in some Dichapetalum species. Phytochem. 14: 423-427.

Vins, B. and Mrkva, R. 1973. The diameter increment losses of pine stands as a result of
injurious immissions. Acta. Universitatis Agriculturae (Brno) Series C 42: 25-46.

Vishnevski, V.L. 196.9. Materials for setting standards of hydrogen fluoride in the air of
industrial areas. Gig. Tr. Prof. Zabol. 13: 60-62.

Voroshilin, S.I., Plotko, E.G., Gatiyatullina, E.A. and Gileva, E.A. 1973. Cytogenetic
effect of inorganic fluorine compounds on human and animal cells in vivo and in vitro.
Soviet Genet. (English translation of Genetika) 9: 492-496.

Voroshilin, S.I., Plotko, E.G. and Nikiforova, V.Y. 1975. Mutagenic effect of hydrogen
fluoride on animals. Cytol. Genet. (English translation of Tsitol. Genet.) 9: 40-42.

Vouilloz, R. 1975. Pollutions fluordes en Valais. Rapport de l'Assoc. de d6fense contre


les 6manations nocives en Valais. De'cembre. Martigny, Suisse. (16 pp.).

Waldbott, G.L. and Cecilioni, V.A. 1969. Neighborhood fluorosis. Clin. Toxicol. 2: 387-
396.

Ward, P.F.V. and Huskisson, N.S. 1972. The metabolism of fluoroacetate in lettuce.
Biochem. J. 130: 575-587.

Warner, T.B., Jones, M.M., Miller, G.R. and Kester, D.R. 1975. Fluoride in sea water:
Intercalibration study based on electrometric and spectrophotometric methods. Anal.
Chim. Acta 77: 223-228.

Weatherall, J.A. and Weidmann, S.M. 1959. The skeletal changes of chronic
experimental fluorosis. J. Pathol. Bact. 78: 233-241.
Weinstein, L.H. 1977. Fluoride and plant life. J. Occup. Med. 19: 49-78.

WHO 1970. World Health Organization. "Fluorides and human health" Monograph
Series. No. 59. (364 pp.).

Wiatrowski, E., Kramer, L., Osis, D. and Spencer, H. 1975. Dietary fluoride intake of
infants. Pediatrics 55: 517-522.

Widger, L.A., Gandolfi, A.J. and van Dyke, R.A. 1976. Hypoxia and halothane
metabolism in vivo. Anesthesiology 44: 197-201.

Williams, R.E. 10,75. Landfills, the 1977 fate of air and waterborne wastes. Ground
Water J. Jul.-Aug. pp. 367-371.

Wolinsky, I., Simkin, A. and Guggenheim, K. 1972. Effect of fluoride on metabolism and
mechanical properties of rat bones. Amer. J. Physiol. 9-23: 46-50.

Wright, D.A. and Davison, A.W. 1975. The accumulation of fluoride by marine and
intertidal animals. Environ. Pollut. 8: 1-13.

Wright, D.A. 1977. Toxicity of fluoride to brown trout fry (Salmo trutta). Environ. Pollut.
12: 57-62.

Yee-Meiler, D. 1974. Uber den Einflusz fluorhaltiger Fabrikabgase auf den Phenolgehalt
von Fichtennadeln. Europ. J. Forest Path. 4: 214-221.

Yiamouyiannis, J.A. and Burk, D. 1976. Fluoridation of public water systems and cancer
death rates in humans. Fed. Proc. 35: 1707.

Yiamouyiannis, J.A. and Burk, D. 1977. Fluoridation and cancer -- Age dependence of
cancer mortality related to artificial fluoridation. Fluoride 10:102-123.

Young, S.R., Stoelting, R.K., Peterson, C. and Madura, J.A. 1975. Anesthetic
biotransformation and renal function in obese patients during and after methoxyflurane or
halothane anesthesia. Anesthesiology 42: 451-457.

Zanzi, I., Aloia, J.F., Ellis, K.J., Vaswani, A., Wallach, S. and Cohn, S.H. 1975.
Treatment of osteoporosis with salmon calcitonin, sodium fluoride and calcium. Results
of in vivo neutron activation analyses. Clin. Res. 23: 335A

Zhavoronkov, S.A., Khovanskaya, M.G. and Korolenko, V.P. 1969. Condition of the
liver in fluorine poisoning. Vestnik Akademii Meditsinkikh Nauk SSSR 24(9): 39-42.

Zhavoronkov, A.A. and Dubynin, T.L. 1971. Changes in the kidneys in chronic fluorine
poisoning. Bull. Exp. Biol. Med. 72: 1094-1096. (Trans. Consultants Bureau, N.Y.).
Zucas, S.M. and Lajolo, F.M. 1975. Influencia da hypofise sobre a fixacao de fluor em
ossos de ratos. Rev. Farm. Bioquim. Univ. Sao Paulo 13: 103-116.

Zumpt, 1. 1975. Chronic fluoride poisoning in sheep. J. South African Vet. Assoc. 46:
161-163.

National Research Council of Canada - 1977


(back to top)
Part I Overview Information

Department of Health and Human Services

Issuing Organization
National Institute of Dental and Craniofacial Research (NIDCR), (http://www.nidcr.nih.gov/)

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov/)

Components of Participating Organizations


National Institute of Dental and Craniofacial Research (NIDCR), (http://www.nidcr.nih.gov/)

Title: Pharmacogenetics of Fluoride (R01)

Announcement Type
New

Update: The following update relating to this announcement has been issued:

• December 8, 2006 - The R01 portion of this funding opportunity has been replaced by PAR-
07-131, which now uses the electronic SF424 (R&R) application for February 5, 2007
submission dates and beyond.

Looking ahead: As part of the Department of Health and Human Services' implementation of e-
Government, during FY 2006 the NIH will gradually transition each research grant mechanism to
electronic submission through Grants.gov and the use of the SF 424 Research and Related (R&R)
forms. Therefore, once the transition is made for a specific grant mechanism, investigators and
institutions will be required to submit applications electronically using Grants.gov.. For more
information and an initial timeline, see http://era.nih.gov/ElectronicReceipt/. NIH will announce each
grant mechanism change in the NIH Guide to Grants and Contracts
(http://grants.nih.gov/grants/guide/index.html). Specific funding opportunity announcements will
also clearly indicate if Grants.gov submission and the use of the SF424 (R&R) is required.
Investigators should consult the NIH Forms and Applications Web site
(http://grants.nih.gov/grants/forms.htm) for the most current information when preparing a grant
application.
Program Announcement (PA) Number: PAR-06-214

Catalog of Federal Domestic Assistance Number(s)


93.121

Key Dates
Release Date: March 3, 2006
Letters of Intent Receipt Dates: April 17, 2006, 2007, 2008; August 17, 2006, 2007, 2008; December 17,
2006, 2007, 2008
Application Receipt Dates: May 15, 2006, 2007, 2008; September 15, 2006, 2007, 2008; January 15,
2007, 2008, 2009
Peer Review Dates: October-November 2006, 2007, 2008; February-March 2007, 2008, 2009; June-
July 2007, 2008, 2009
Council Review Dates: January 2007, 2008, 2009; May 2007, 2008, 2009; September 2007, 2008, 2009
Earliest Anticipated Start Dates: April 2007, 2008, 2009; July 2007, 2008, 2009; December 2007, 2008,
2009
Additional Information To Be Available Date (Url Activation Date): Not applicable
Expiration Date for R01 Non-AIDS Applications: November 2, 2006
Expiration Date for R01 AIDS and AIDS-Related Applications: January 3, 2007

Due Dates for E.O. 12372


Not Applicable

Additional Overview Content

Executive Summary

The National Institute of Dental and Craniofacial Research (NIDCR) invites applications for research
projects focusing on the genetic basis underlying individual responses to ingested fluoride in tooth
mineralized tissues and other physiological processes. Projects should aim to identify and
characterize fluoride-responsive genetic variations in humans or animal models. Applicants should
specifically address how pharmacogenetics data will be interpreted and translated into risk
assessment for public health.

• This funding opportunity will utilize the Individual Research Project Grant (R01) mechanism,
but runs in parallel with a funding opportunity announcement (FOA) of identical scientific
scope PAR-06-215 that will utilize the Exploratory/Developmental Research Grant (R21)
mechanism.
• Because the nature and scope of the proposed research will vary from application to
application, it is anticipated that the size and duration of each award will also vary. The total
amount awarded and the number of awards will depend upon the mechanism numbers,
quality, duration, and costs of the applications received.
• This FOA will use the Individual Research Project Grant (R01) mechanism.
• Eligible organizations include for-profit and non-profit organizations, public or private
institutions such as universities, colleges, hospitals and laboratories, units of State and
local governments including tribal governments, eligible agencies of the Federal
government, domestic or foreign institutions/organizations, or faith-based or community-
based organizations.
• Eligible principal investigators include any individual with the skills, knowledge, and
resources necessary to carry out the proposed research. Individuals from
underrepresented racial and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH programs.
• Applicants may submit more than one application, provided they are scientifically distinct.
• See Section IV.1 for application materials.
• Telecommunications for the hearing impaired is available at: TTY 301-451-0088

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description


1. Research Objectives

Section II. Award Information


1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information


1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information


1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt and Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information


1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information


1. Award Notices
2. Administrative and National Policy Requirements
3. Reporting

Section VII. Agency Contact(s)


1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement


Section I. Funding Opportunity Description

1. Research Objectives

Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to stimulate research on the
genetic basis underlying individual responses to ingested fluoride. Although there is a volume of
literature describing the effects of fluoride on both mineralized and non-mineralized tissues, the
genetic determinants of our physiological responses to fluoride is an unexplored research area.
Recent advances in genetic and genomic sciences provide unique opportunities to apply
pharmacogenetic approaches to fluoride research; how genetic variations determine heterogeneous
physiological responses to fluoride.

Projects should aim to identify and characterize fluoride-responsive genetic variations, e.g.
polymorphisms, in humans and animal models. Functional analyses of these variants will be
necessary in determining their contribution to differential phenotypes in tooth mineralized tissues or
other physiological processes in response to fluoride. Projects may test candidate genetic variants,
or search for genetic variants that are accountable for well characterized fluoride-responsive
phenotypes. Projects should explicitly state whether a causal relationship between fluoride-
responsive genotype and phenotype will be studied, and how this relationship will be established
with appropriate controls. Applicants should specifically address how pharmacogenetics data will
be interpreted and translated into public health risk assessment. The predicted relevance to human
conditions of data generated through animal studies should be addressed. Study design should
include fluoride exposure levels that are relevant and typical of human exposures. Gene expression
profiling studies are not responsive to this FOA unless there are data to suggest that changes in
gene expression level in response to fluoride are due to polymorphisms or epigenetic modifications
in the gene of interest.

Background

Since the introduction of fluoride in community drinking water in 1945, there has been a steady
decline in the prevalence and severity of dental caries among Americans living in fluoridated
communities. In fact, water fluoridation was touted by the Center for Disease Control and
Prevention as one of the top ten public health achievements of the twentieth century. However, with
this decline in caries prevalence, there has been an increase in dental fluorosis among children
living in fluoridated communities. It has been estimated that between 20-80% of these children have
mild fluorosis and 4% have moderate to severe fluorosis. A recent analysis of the NHANES datasets
indicated that the prevalence of fluorosis among 6-19 year old children increased by 9% since 1987.
This increase is thought to be due, in part, to the increase in fluoride intake from sources other than
drinking water including fluoridated beverages, supplements and topical fluoride-containing dental
products that may be ingested. Factors such as nutrition have been implicated in an increase in an
individual’s susceptibility to fluorosis but probably do not fully account for the prevalence observed
in the population. On the other hand, although the proper use of fluoride generally reduces dental
caries, the extent of its effectiveness varies among different communities.

Ingested fluoride is rapidly and efficiently absorbed through the gastrointestinal system and
approximately 35-70% is eventually cleared by the renal system. Most of the fluoride retained in the
body is incorporated into bones and teeth. The majority of fluoride related research efforts have
focused on tooth enamel. Enamel development begins with the secretion of a set of enamel matrix
proteins by ameloblasts that nucleates minerals. Matrix proteins continue to interact with minerals
and guide crystal growth. Crystals are aligned in parallel arrays, which further orient themselves to
form an interwoven superstructure of hydroxyapatite. Matrix proteins are degraded by proteolytic
enzymes and removed leaving enamel that contains 98% minerals. Fluoride is anticariogenic at low
concentration. Studies have shown that, during enamel mineralization, fluoride can be intercalated
into the enamel crystal structure as fluoroapatite which is more resistant to dissolution than
hydroxyapatite. However, excess fluoride results in dental fluorosis characterized by changes in
enamel that vary from barely discernible fine white striations to pitted brown lesions. Some studies
suggest that fluoride interferes with the activities of enamel matrix protein processing enzymes
resulting in a delay in the clearance of matrix proteins during the maturation phase of amelogenesis
and incomplete mineralization. Fluoride may also interfere with the maturation and differentiation of
ameloblasts.

In regard to its effects on bone, fluoride is considered anabolic in that it stimulates osteoblast
proliferation and mineral deposition. However, excessive fluoride can result in an increase in bone
density which can compromise bone quality and strength such that fluorotic bones have increased
fracture rates and delayed fracture repair.

Fluoride might also affect the physiological processes of non-mineralized tissues. Human and
animal studies of acute lethal or toxic levels of fluoride show that it affects the gastrointestinal,
cardiovascular, renal, reproductive, and neuroendocrine systems. It has also been proposed that
fluoride might increase the incidence of osteosarcomas in young males. Most of these studies have
been inconclusive and inconsistent. Animal experiments have used relatively high levels of fluoride,
whereas well controlled studies using relevant ranges that reflect more typical levels of human
exposure are lacking.
The involvement of genetic determinants in fluoride responsiveness has been implicated in several
studies. A number of ecological studies of populations around the world living in areas with
naturally high levels of fluoride in the water suggest that there is considerable variation in fluorosis
among and within these populations. Responsiveness to fluoride cannot be correlated with the total
bioburden of fluoride as assayed in urine samples. Heterogeneous responses to fluoride have also
been observed in different mouse strains with certain strains exhibiting fluorosis while other strains
are unaffected. Several fluoride-responsive genes have been identified but how these genes and
their gene products determine physiological responses to fluoride has not been clarified.
Nevertheless, these studies strongly suggest that there is a genetic basis underlying the effects of
fluoride.

With the completion of the Human Genome Project and rapid advancement of the International
HapMap Project, genomic science can begin to be translated into genomic medicine. On the
forefront of this progress is the emerging field of pharmacogenetics; an interdisciplinary study of
genetic variations that determine heterogeneous responses to drugs and other chemical
compounds. Global and high throughput map-based or sequence-based approaches, gene
expression profiling and proteomic studies can be utilized to ascertain functionally significant
genetic variations in drug responses and to identify polygenic interactions that determine complex
drug responses. Genetically engineered animals such as recombinant congenic strains of mice are
available to accelerate genetic dissection of complex traits. It is timely to apply these state-of-the-art
approaches to fluoride research and to attract new investigators and investigators with diverse
expertise to this area.

Scope and Objectives

This FOA encourages human and animal studies on: 1) whole genome approaches such as linkage
and mapping studies to identify fluoride-responsive genetic variations; 2) candidate gene strategies
based on existing knowledge of the mechanisms of fluoride action to identify and characterize
functional genetic variants; 3) the development of animal models with clearly defined differential
physiological responses to ingested fluoride at levels relevant to normal human exposures and the
association of these phenotypes with genotypes; 4) the development and validation of relevant
fluoride-responsive genetic variants into predictive genetic standards for an individual’s
physiological responses to fluoride; and 5) gene-gene and gene-environment interactions that
modify the function of fluoride-responsive genetic variants. Applicants are also encouraged to
consider the Nutritional Data System for Research with Fluoride (http://www.ncc.umn.edu/), a
software program designed to assess total fluoride exposure, to augment their research design
when applicable.
This FOA focuses on capturing emerging scientific opportunities and technologies to provide the
genetic and molecular basis for the physiological outcome of ingested fluoride. These studies will
pave the way for the identification of specific populations or individuals that will benefit from
fluoride supplement and/or exhibit other physiological consequences due to the action of fluoride.
The knowledge gained from these studies will serve as the basis for individualized
recommendations for total fluoride intake. This information will also elucidate fundamental
mechanisms by which fluoride influences biomineralization.

See Section VIII, Other Information - Required Federal Citations, for policies related to this
announcement.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the NIH Individual Research Project Grant (R01) award mechanism.

As an applicant, you will be solely responsible for planning, directing, and executing the proposed
project.

This funding opportunity uses just-in-time concepts. It also uses the modular as well as the non-
modular budget formats (see http://grants.nih.gov/grants/funding/modular/modular.htm).
Specifically, if you are submitting an application with direct costs in each year of $250,000 or less,
use the modular budget format described in the PHS 398 application instructions. Otherwise follow
the instructions for non-modular research grant applications.

2. Funds Available

The NIDCR has not set aside funds for this FOA. The number of awards will be dependent on their
scientific merit. Applicants may request up to five years of support. There is no cost limit for the
R01 mechanism.

Because the nature and scope of the proposed research will vary from application to application, it
is anticipated that the size and duration of each award will also vary. Although the financial plans of
the IC(s) provide support for this program, awards pursuant to this funding opportunity are
contingent upon the availability of funds and the receipt of a sufficient number of meritorious
applications.
Facilities and administrative costs requested by consortium participants are not included in the
direct cost limitation, see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

• For-profit organizations
• Non-profit organizations
• Public or private institutions, such as universities, colleges, hospitals, and laboratories
• Units of State government
• Units of local government
• Eligible agencies of the Federal government
• Foreign Institutions
• Domestic Institutions
• Faith-based or community-based organizations
• Units of State Tribal government
• Units of Local Tribal government

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed
research is invited to work with their institution to develop an application for support. Individuals
from underrepresented racial and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH programs.

2. Cost Sharing or Matching

Cost sharing is not required.

The most current Grants Policy Statement can be found at:


http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing
3. Other-Special Eligibility Criteria
Not applicable

Section IV. Application and Submission


Information

1. Address to Request Application Information

The PHS 398 application instructions are available at


http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must
use the currently approved version of the PHS 398. For further assistance contact GrantsInfo,
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-0088.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application
instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS)
number as the universal identifier when applying for Federal grants or cooperative agreements. The
D&B number can be obtained by calling (866) 705-5711 or through the web site at
http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS
398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the
application form and the YES box must be checked.

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

• Charge back of customs and import fees is not allowed.


• Format: every effort should be made to comply with the format specifications, which are
based upon a standard US paper size of 8.5" x 11."
• Funds for up to 8% administrative costs (excluding equipment) can now be requested
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-028.html)
• Organizations must comply with federal/NIH policies on human subjects, animals, and
biohazards.
• Organizations must comply with federal/NIH biosafety and biosecurity regulations. See
Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions
of Award".

Proposed research should provide a unique research opportunity not available in the U.S.

3. Submission Dates and Times

See Section IV.3.A for details.

3.A. Receipt, Review and Anticipated Start Dates

Letter of Intent Receipt Dates: April 17, 2006, 2007, 2008; August 17, 2006, 2007, 2008; December 17,
2006, 2007, 2008
Application Receipt Dates: May 15, 2006, 2007, 2008; September 15, 2006, 2007, 2008; January 15,
2007, 2008, 2009
Peer Review Dates: October-November 2006, 2007, 2008; February-March 2007, 2008, 2009; June-
July 2007, 2008, 2009
Council Review Dates: January 2007, 2008, 2009; May 2007, 2008, 2009; September 2007, 2008, 2009
Earliest Anticipated Start Dates: April 2007, 2008, 2009; July 2007, 2008, 2009; December 2007, 2008,
2009

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed research


• Name, address, and telephone number of the Principal Investigator
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

Although a letter of intent is not required, is not binding, and does not enter into the review of a
subsequent application, the information that it contains allows IC staff to estimate the potential
review workload and plan the review.
The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Lillian Shum, PhD


Director, Mineralized Tissue and Salivary Gland Physiology Program
Center for Integrative Biology and Infectious Diseases
National Institute of Dental and Craniofacial Research
45 Center Drive
Building 45, Room 4AN-18B
Bethesda, MD 20892-6402
Telephone: (301) 594-0618
Fax: (301) 480-8319
Email: ShumL@nidcr.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant application forms found in the PHS 398
instructions for preparing a research grant application. Submit a signed, typewritten original of the
application, including the checklist, and five signed photocopies in one package to:

Center for Scientific Review


National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see


http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

3.C. Application Processing

Applications must be received on or before the application receipt/submission date(s) described


above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant
without review .

Upon receipt applications will be evaluated for completeness by CSR. Incomplete applications will
not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the
same as one currently pending initial merit review unless the applicant withdraws the pending
application. The NIH will not accept any application that is essentially the same as one already
reviewed. This does not preclude the submission of a substantial revision of an application already
reviewed, but such application must include an Introduction addressing the previous critique.

Although there is no immediate acknowledgement of the receipt of an application, applicants are


generally notified of the review and funding assignment within eight (8) weeks.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations
described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at
http://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur
obligations and expenditures to cover costs up to 90 days before the beginning date of the initial
budget period of a new or competing continuation award if such costs: are necessary to conduct the
project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific
expenditures would otherwise require prior approval, the grantee must obtain NIH approval before
incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days
before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes


no obligation on NIH either to make the award or to increase the amount of the approved budget if
an award is made for less than the amount anticipated and is inadequate to cover the pre-award
costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing
against future support and that such borrowing must not impair the grantee's ability to accomplish
the project objectives in the approved time frame or in any way adversely affect the conduct of the
project. See NIH Grants Policy Statement
http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.
6. Other Submission Requirements

Specific Instructions for Modular Grant applications.

Applications requesting up to $250,000 per year in direct costs must be submitted in a modular
budget format. The modular budget format simplifies the preparation of the budget in these
applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000
modules. Section C of the research grant application instructions for the PHS 398 at
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for
preparing modular budgets. Applicants must use the currently approved version of the PHS 398.
Additional information on modular budgets is available at
http://grants.nih.gov/grants/funding/modular/modular.htm.

Specific Instructions for Applications Requesting $500,000 (direct costs) or More per Year.

Applicants requesting $500,000 or more in direct costs for any year must carry out the following
steps:

1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are
developing plans for the study;

2) Obtain agreement from the IC staff that the IC will accept your application for consideration for
award; and,

3) Include a cover letter with the application that identifies the staff member and IC who agreed to
accept assignment of the application.

This policy applies to all investigator-initiated new (type 1), competing continuation (type 2),
competing supplement, or any amended or revised version of these grant application types.
Additional information on this policy is available in the NIH Guide for Grants and Contracts, October
19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and
how the investigator is planning to share the data. Applicants who are planning to share data may
wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the
documentation to be provided, whether or not any analytic tools also will be provided, whether or
not a data-sharing agreement will be required and, if so, a brief description of such an agreement
(including the criteria for deciding who can receive the data and whether or not any conditions will
be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a
disk or posting data on their institutional or personal website, through a data archive or enclave).
Investigators choosing to share under their own auspices may wish to enter into a data-sharing
agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants must include a plan for sharing research data in their application. The data sharing
policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to
this funding opportunity should include a description of how final research data will be shared, or
explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be
assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into
the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available
for research purposes to qualified individuals within the scientific community after publication (NIH
Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and
http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators
responding to this funding opportunity should include a plan for sharing research resources
addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered
by Program staff of the funding organization when making recommendations about funding
applications. The effectiveness of the resource sharing will be evaluated as part of the
administrative review of each non-competing Grant Progress Report (PHS 2590,
http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.
2. Review and Selection Process

Applications submitted for this funding opportunity will be assigned to the ICs on the basis of
established PHS referral guidelines.

Appropriate scientific review groups convened in accordance with the standard NIH peer review
procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical
merit.

As part of the initial merit review, all applications will:

• Undergo a selection process in which only those applications deemed to have the highest
scientific merit, generally the top half of applications under review, will be discussed and
assigned a priority score.
• Receive a written critique
• Receive a second level of review by the National Advisory Dental and Craniofacial Research
Council.

The following will be considered in making funding decisions:

• Scientific merit of the proposed project as determined by peer review


• Availability of funds
• Relevance of program priorities

The goals of NIH supported research are to advance our understanding of biological systems, to
improve the control of disease, and to enhance health. In their written critiques, reviewers will be
asked to comment on each of the following criteria in order to judge the likelihood that the proposed
research will have a substantial impact on the pursuit of these goals. Each of these criteria will be
addressed and considered in assigning the overall score, weighting them as appropriate for each
application. Note that an application does not need to be strong in all categories to be judged likely
to have major scientific impact and thus deserve a high priority score. For example, an investigator
may propose to carry out important work that by its nature is not innovative but is essential to move
a field forward.

Significance: Does this study address an important problem? If the aims of the application are
achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of
these studies on the concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?
Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately
developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the
applicant acknowledge potential problem areas and consider alternative tactics? Are fluoride
exposure levels in the study design relevant and typical of human exposures? Will the study inform
a causal or associative relationship between fluoride-responsive genotype and phenotype? Are
there appropriate controls in the study design to demonstrate the specificity of the fluoride
response?

Innovation: Is the project original and innovative? For example: Does the project challenge existing
paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the
field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or
technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is
the work proposed appropriate to the experience level of the principal investigator and other
researchers? Does the investigative team bring complementary and integrated expertise to the
project (if applicable)?

Environment: Does the scientific environment in which the work will be done contribute to the
probability of success? Do the proposed studies benefit from unique features of the scientific
environment, or subject populations, or employ useful collaborative arrangements? Is there
evidence of institutional support?

Relevance to Public Health: Does the project have a clearly defined and acceptable standard on how
pharmacogenetics data will be interpreted and translated into public health risk assessment? If
animal studies were proposed, does the project discuss the predictive relevance to human
conditions of the data generated? Will the study generate interpretable and useful information
relevant to public health?

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the
determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and
protections from research risk relating to their participation in the proposed research will be
assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).
Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects
from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the
scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects
will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project,
the five items described under Section F of the PHS Form 398 research grant application
instructions will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research
personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation
to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing
research data will be assessed by the reviewers. However, reviewers will not factor the proposed
data sharing plan into the determination of scientific merit or the priority score. The presence of a
data sharing plan will be part of the terms and conditions of the award. The funding organization will
be responsible for monitoring the data sharing policy.

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available
for research purposes to qualified individuals within the scientific community after publication (See
the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr
and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding
opportunity should include a sharing research resources plan addressing how unique research
resources will be shared or explain why sharing is not possible.

Program staff will be responsible for the administrative review of the plan for sharing research
resources.

The adequacy of the resources sharing plan will be considered by Program staff of the funding
organization when making recommendations about funding applications. Program staff may
negotiate modifications of the data and resource sharing plans with the awardee before
recommending funding of an application. The final version of the data and resource sharing plans
negotiated by both will become a condition of the award of the grant. The effectiveness of the
resource sharing will be evaluated as part of the administrative review of each non-competing Grant
Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates


Not applicable

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the PI will be able to access his or her
Summary Statement (written critique) via the eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from
the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and
Conditions of NIH Grant Awards, Subpart A: General
(http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant
organization. The NoA signed by the grants management officer is the authorizing document. Once
all administrative and programmatic issues have been resolved, the NoA will be generated via email
notification from the awarding component to the grantee business official (designated in item 12 on
the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed
to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs
incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to
the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of
the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and
Conditions of NIH Grant Awards, Subpart A: General
(http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and
Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants,
Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590
annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in
the NIH Grants Policy Statement.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to
answer questions from potential applicants. Inquiries may fall into three areas: scientific/research,
peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Lillian Shum, PhD


Director, Mineralized Tissue and Salivary Gland Physiology Program
Center for Integrative Biology and Infectious Diseases
National Institute of Dental and Craniofacial Research
45 Center Drive
Building 45, Room 4AN-18B
Bethesda, MD 20892-6402
Telephone: (301) 594-0618
Fax: (301) 480-8319
Email: ShumL@nidcr.nih.gov

2. Peer Review Contacts:


Not applicable

3. Financial or Grants Management Contacts:


Mary Daley, Chief Grants Management Officer
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
Building 45, Room 4AN 44B
45 Center Drive
Bethesda, MD 20892-6402
Telephone: (301) 594-4808
FAX: (301) 480-3562
Email: daleym@mail.nih.gov

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:


Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS
Policy on Humane Care and Use of Laboratory Animals
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health
Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the
USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as
applicable.

Human Subjects Protection:


Federal regulations (45CFR46) require that applications and proposals involving human subjects
must be evaluated with reference to the risks to the subjects, the adequacy of protection against
these risks, the potential benefits of the research to the subjects and others, and the importance of
the knowledge gained or to be gained
(http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:


Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity
and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and
comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of
data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving
interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring,
NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).
Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single
year are expected to include a plan for data sharing or state why this is not possible
(http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies
and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy
Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination
of the scientific merit or the priority score.

Access to Research Data through the Freedom of Information Act:


The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to
research data through the Freedom of Information Act (FOIA) under some circumstances. Data that
are (1) first produced in a project that is supported in whole or in part with Federal funds and (2)
cited publicly and officially by a Federal agency in support of an action that has the force and effect
of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand
the basic scope of this amendment. NIH has provided guidance at
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place
data collected under this funding opportunity in a public archive, which can provide protections for
the data and manage the distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include information about this in
the budget justification section of the application. In addition, applicants should think about how to
structure informed consent statements and other human subjects procedures given the potential for
wider use of data collected under this award.

Sharing of Model Organisms:


NIH is committed to support efforts that encourage sharing of important research resources
including the sharing of model organisms for biomedical research (see
http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes
the rights of grantees and contractors to elect and retain title to subject inventions developed with
Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement
http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH
application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to
include in the application/proposal a description of a specific plan for sharing and distributing
unique model organism research resources generated using NIH funding or state why such sharing
is restricted or not possible. This will permit other researchers to benefit from the resources
developed with public funding. The inclusion of a model organism sharing plan is not subject to a
cost threshold in any year and is expected to be included in all applications where the development
of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:


It is the policy of the NIH that women and members of minority groups and their sub-populations
must be included in all NIH-supported clinical research projects unless a clear and compelling
justification is provided indicating that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43). All investigators proposing clinical research should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated
Guidelines is available at
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended
policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic
categories in compliance with the new OMB standards; clarification of language governing NIH-
defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and
responsibilities of NIH staff and the extramural community. The policy continues to require for all
NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must
provide a description of plans to conduct analyses, as appropriate, to address differences by
sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must
report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or
racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:


The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all
clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons
not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and
Guidelines" on the inclusion of children as participants in research involving human subjects
(http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:


NIH policy requires education on the protection of human subject participants for all investigators
submitting NIH applications for research involving human subjects and individuals designated as
key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-
039.html.
Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp
and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC
lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal
funding (http://escr.nih.gov/). It is the responsibility of the applicant to provide in the project
description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC
line(s)to be used in the proposed research. Applications that do not provide this information will be
returned without review.

NIH Public Access Policy:


NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system
(http://www.nihms.nih.gov/) at PubMed Central (PMC) an electronic version of the author's final
manuscript upon acceptance for publication, resulting from research supported in whole or in part
with direct costs from NIH. The author's final manuscript is defined as the final version accepted for
journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research
projects or 2) previously supported NIH research projects if they are accepted for publication on or
after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development
award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L.
Kirschstein National Research Service Awards, as well as NIH intramural research studies. The
Policy applies to peer-reviewed, original research publications that have been supported in whole or
in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or
conference proceedings. Publications resulting from non-NIH-supported research projects should
not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access
Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools
including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_Manual.htm).

Standards for Privacy of Individually Identifiable Health Information:


The Department of Health and Human Services (DHHS) issued final modification to the "Standards
for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002 .
The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability
Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is
administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and
his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy
Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?"
Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review,
funding, and progress monitoring of grants, cooperative agreements, and research contracts can be
found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:


All applications and proposals for NIH funding must be self-contained within specified page
limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not
be used to provide information necessary to the review because reviewers are under no obligation
to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be
compromised when they directly access an Internet site.

Healthy People 2010:


The Public Health Service (PHS) is committed to achieving the health promotion and disease
prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas.
This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of
"Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:


This program is described in the Catalog of Federal Domestic Assistance (CFDA# 93.121) at
http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and
conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage
the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994,
prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care, or early childhood development services are
provided to children. This is consistent with the PHS mission to protect and advance the physical
and mental health of the American people.

Loan Repayment Programs:


NIH encourages applications for educational loan repayment from qualified health professionals
who have made a commitment to pursue a research career involving clinical, pediatric,
contraception, infertility, and health disparities related areas. The LRP is an important component of
NIH's efforts to recruit and retain the next generation of researchers by providing the means for
developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is
not required for eligibility and concurrent career award and LRP applications are encouraged. The
periods of career award and LRP award may overlap providing the LRP recipient with the required
commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20
hours per week based on a 40 hour week) for two years to the research. For further information,
please see: http://www.lrp.nih.gov/.
FOR IMMEDIATE RELEASE: Roger Rensberger
April 29, 1994 (301) 975-2762

TN-5976

U.S./CANADA/MEXICO TO COOPERATE ON

MEASUREMENT AND CALIBRATION LAB PROGRAMS


http://www.nist.gov/public_affairs/releases/tn5976.htm

The U.S. Department of Commerce's National Institute of


Standards and Technology (NIST), the National Research Council of
Canada (NRC) and the Standards Council of Canada (SCC), the
National Center for Metrology (Centro Nacional de Metrologia--
CENAM) and the Director General for Standards (Direccion General
de Normas--DGN) of Mexico have signed memorandums of
understanding to establish two organizations: NORAMET and the
North American Calibration Cooperation (NACC).

The two organizations will serve as a framework to promote


closer North American cooperation between the three countries in
areas of metrology and calibration laboratory accreditation as
part of an overall effort to reduce non-tariff barriers to trade.

The inaugural meeting of representatives from the three


countries will take place April 30, 1994, at Quer‚taro, Mexico,
following the April 29 dedication of the new Mexican metrology
laboratory. A U.S. delegation will be led by George A. Sinnott,
director of the NIST Office of International and Academic
Affairs.

Sinnott points out that by signing the MOUs, the countries


declared their intention to cooperate in areas leading to mutual
recognition arrangements between the three nations concerning
metrological development and services and the development of
mutual confidence in national calibration laboratory
accreditation programs.

NORAMET will be a North American regional collaboration in


national measurement standards and services. It will be made up
of representatives of the primary reference laboratories of the
member countries, NIST, NRC and CENAM. The goals of NORAMET are:

o to develop closer collaboration between the members in


projects connected to measurement and metrological services
while respecting their obligations within their own
countries;

o to optimize the utilization of resources and services of the


members and to encourage the development of these toward
perceived metrological needs;

o to encourage the sharing of major facilities in order to


achieve efficiency and avoid duplication when feasible; and
o to improve measurement services and make them accessible to
all members within limits agreed upon by the members.

The North American Calibration Cooperation effort will be


directed to the development of mutual confidence in national
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Under NACC, the signatories NIST, NRC, SCC, DGN and CENAM,
recognize each other as having primary responsibility in their
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The NACC members intend to promote close collaboration


between the calibration laboratory accreditation and assessment
programs they have implemented, or intend to implement, such as
the Calibration Laboratory Assessment Service (CLAS) and the
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calibration program and National Voluntary Laboratory
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NOTE TO EDITORS: For information on NORAMET and NACC, contact


the Office of International and Academic Affairs, A505
Administration Building, NIST, Gaithersburg, Md. 20899-0001,
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(via Internet).
(C) Peter Meiers - http://www.fluoride-history.de

http://www.fluoride-history.de/p-dentpr.htm

Patents on ingestable dental preparations

see also:

- Early European fluoride research: http://www.fluoride-history.de/fteeth1.htm

1874

Alvaro Francisco Carlos REYNOSO, of Paris, France: "Improvement in medical


compounds", US Patent 146,781; filed Jan. 16, 1874, patented Jan. 27, 1874; ("Elixir"
and "Sirup" containing fluorides of either potassium, sodium or ammonium; "elixir" is
"invigorating, nutritious, and complemental to food", "fluorated sirup"
is "...for infants at the period when the bones and teeth are in process of formation"; also
contains "sugar in sufficient quantity"). Reynoso was a Cuban scientist who lived
for many years in France.

1909

Johann A. WÜLFING Company, of Berlin, Germany: "Verfahren zur Herstellung leicht


resorbierbarer Fluorpräparate", German Patent (DE) 222,716; filed June 29, 1909,
patented June 2, 1910; (Patent is based upon early European work, especially
experiments carried out by the chemist Deninger (1896). It is claimed that there´s
generally not enough fluoride in a normal diet. To produce an easily absorbable fluoride
preparation the company precipitates calcium fluoride (using sodium fluoride plus a
calcium salt) together with a protein like egg-white, albumin, casein, to which it
becomes adsorbed on co-precipitation.)
1911

Emil LANGER, of Wien, Austria: "Verfahren zur Herstellung leicht löslicher, haltbarer
Desinfektionsmittel zur Bereitung von Mund- und Spülwasser unter Verwendung von
Natriumfluorid und Natriumsiliciumfluorid", German Patent (DE) 281,148; filed Nov.
28, 1911, patented Dec. 14, 1914; (a mouthwash and disinfectant made of sodium
fluoride or sodium fluosilicate; tablets of 0.6 g each, containing 30 parts soda, 15 parts
sodium fluoride or sodium fluosilicate, 15 parts tartaric acid, and essential oils to give
them some taste: "... simply let the tablets slowly dissolve in the mouth as sodium
fluoride and sodium fluosilicate are not toxic to humans ...", the patent says.)

1919

Lecinwerk Dr. E. LAVES, Hannover, Germany: "Verfahren zur Herstellung


kolloidallöslicher Fluorcalcium-Amylodrextrinpräparate", German Patent DE 325,561;
filed March 12, 1919; patented Sept. 13, 1920 (calcium fluoride preparation made by
precipitation from a mixture of sodium fluoride, calcium chloride and amylodextrin; for
therapeutic and bakery technical use)

1927

Philip Adolph KOBER, Evanston, Illinois, assignor to G. D. Searle & Company, of


Chicago, Illinois, a corporation of Illinois: "Mineral Food Composition and Process of
Making Same", US Patent (US) 1,813,936; filed May 19, 1927, patented July 14, 1931
(a calcium, magnesium and phosphate preparation as a food supplement, also containing
350 mg NaF per 1,624 g of the product).

1935

Reinhol GRUETER, Berlin-Charlottenburg, Germany: "Herstellung von Zubereitungen,


die Calciumfluorid in leichter resorbierbarer Form enthalten", German Patent DE
695,874; filed October 22, 1935; patented August 8, 1940 (a preparation containing
calcium fluoride made from sodium fluoride and a calcium phosphate)

1944

Lyon P. STREAN, Montreal, Quebec, Canada, assignor, by mesne assignments, to


Ayerst, McKenna and Harrison Limited, New York, N.Y.: "Oral fluoride-vitamin
preparation", US Patent 2,449,184; filed March 8, 1944; patented Sept. 14, 1948
(calcium fluoride - containing preparation for the formation of fluor-apatite in bones and
teeth; author refers to Deaf Smith County where a low prevalence of caries has been
reported, and claims "the same is generally true with regard to the prevalence of
rickets.")

1954

Charles H. ELBREDER and Edward J. ROSS, St. Louis, Mo., assignors to Charles J.
Nemanick, St. Louis, Mo., "Therapeutic Composition", US Patent 2,967,131; filed Feb.
8, 1954, patented Jan. 3, 1961 (water-treating fluoride tablets)

1962

Riyad R. IRANI, assignor to Monsanto Company: "Fluoridation", US Patent 3,279,992;


filed May 18, 1962; pat. Oct. 18, 1966 (fluoridated table salt)

1981

Gert-Ulfert HEESE, of München, Gerhard Ferdinand SCHNEIDER, of Haar, Fritz


STANISLAUS, of München, Dietrich HENSCHLER, of Würzburg, Germany: "Orale
Arzneimittel für die Kariesprophylaxe", German Patent DE 3,127,984, filed July 15,
1981, patented Febr. 3, 1982

1996

Gunnar ABERG, Thomas Patrick JERUSSI, John R. McCULLOUGH, assignors to


Sepracor Inc., Marlborough, Mass.: "NSAID / Fluoride periodontal compositions and
methods", US Patent 5,807,541; filed Apr. 22, 1996; pat. Sept. 15, 1998 ("It is also
known that under certain circumstances sodium fluoride and fluoroaluminates can
activate G proteins and thereby induce prostaglandin production in endothelial cells and
leukotriene production in platelets, granulocytes and monocytes. The metabolites of
arachidonic acid have been implicated as important biochemical mediators of tissue
destruction in various inflammatory diseases. ... We have found that fluoride, in
the concentration range in which it is emplyed for the prevention of dental caries,
stimulates the production of prostaglandins and thereby exacerbates the inflammatory
response in gingivitis and periodontitis. The present invention is a method for
preventing dental caries by administering a fluoride salt into the oral cavity while at the
same time controlling periodontal bone loss by administering, in addition to the fluoride
salt, an amount of an NSAID sufficient to inhibit the production of prostaglandins
induced by the fluoride." NSAID = Non-steroidal aniti-inflammatory drug)

HOME
Potability of Water from the
Standpoint of Fluorine Content*
H. V. SMITH
University of Arizona, Tucson, Ariz.
MOTTLED enamel was first de- has impeded progress in determining the
scribed in the United States by toxic level.
Black and McKay' although it had At the time the original investigation
been described in 1901 by Eager,2 who was made in 1930 the most promising
found it in Italian immigrants. Their method available was that of Ross,
findings seemed to point to local water Reynolds, and Jacob,5 in which dry
supplies as responsible. It was not, silicon tetrafluoride was distilled into
however, until 1931 that it was found water and the resulting hydrofluosilicic
to be due to fluorine in the water. The acid determined by titration with a
proof 3 consisted of giving water which standard base. Using this method in a
was known to cause human mottled limited number of analyses, it appeared
enamel to rats, and also feeding to other that waters containing 2 p.p.m. or more
rats small amounts of sodium fluoride. of fluorine were associated with mottled
In both cases mottled enamel was pro- enamel as its cause. A year later an
duced. Added proof in the way of extensive investigation 6 was carried out
chemical analysis showed low concen- in Arizona for the twofold purpose of
trations of fluorine in waters not as- -disclosing endemic areas in the state and
sociated with enamel and high concen- obtaining evidence from analyses of
trations in waters which had produced water supplies from both endemic and
the defect. Churchill 4 added further non-endemic areas by which it would be
evidence by analyzing waters from possible to determine definitely the
several parts of the United States. concentrations of fluorides in drinking
High fluorine contents were found in water which interfere with normal
certain endemic regions. enamel development.
Since the volatilization method did
METHODS OF FLUORINE ANALYSIS not lend itself well to routine deter-
Since our proof of the causal rela- minations, another method of analysis
tionship of fluorine to mottled enamel, was sought, and the Fairchild method
the question of potability of water from was selected. In this method ferric iron
the standpoint of its fluorine content has in excess is added to the fluorine con-
become of prime importance. Lack of taining water. The iron combines with
accurate methods of fluorine analysis the fluorine, probably forming a com-
plex ion. The uncombined iron is then
determined iodimetrically and the
*
Read at a Joint Session of the Laboratory and amount of fluorine present calculated.
Public Health Engineering Sections of the American
Public Health Association at the Sixty-third Annual
The survey disclosed about 45 towns
Meeting in Pasadena, Calif., September 4, 1934. or rural districts in Arizona in which
[434]
POTABILITY OF WATER 435
mottled enamel is endemic. Analyses alizarine red-zirconium nitrate as an
of 110 public and 75 private water indicator in their determination of
supplies show a fluoride content ranging fluorine.
from 0.0 to 12.6 p.p.m. Concentra- The Willard and Winters method de-
tions above 2.7 p.p.m. were found to pends upon removing interfering ele-
be definitely toxic, that is, always as- ments by a preliminary distillation.
sociated with mottled enamel in its con- The fluorine in the distillate is titrated
sumers. with thorium nitrate, using the above
Because of the great interest in this mentioned indicator.
problem, several more sensitive methods The Sanchis method has been modi-
for fluorine determination have been fied from the Thompson and Taylor
developed recently, and the Fairchild method for fluorine in sea water and is
method has been shown to give results adaptable to the analysis of fresh
which are far too high. waters. Chloride and sulphate effects
The methods of Foster8 and of up to 500 p.p.M.. are nullified by the
Armstrong9 both depend upon the re- addition of hydrochloric and sulphuric
moval of fluorine by the addition of an acids.
excess of ferric chloride as in the Fair-
child method. The uncombined iron COMPARISON OF ANALYTICAL RESULTS
is determined colorometrically, Foster Analyses of many waters for fluorine
using ammonium sulphocyanate and using the Fairchild. Foster, Willard and
Armstrong acetylacetone. Winters, and Sanchis methods have been
Foster has also found that sulphates, made by the writer and the results
chlorides, and other ions act similarly compared. These data are presented in
to fluorine and withdraw a certain Table I. Further evidence is here given
amount of iron from solution. The that the results of the analysis of waters
effect of these ions is therefore nullified by the Fairchild method are abnormally.
by adding slight additional amounts of high.
ferric chloride. On the other hand, results by the
The Steiger method,10 one of the Foster, Willard, and Sanchis methods
older methods for fluorine, has been compare very closely with each other,
modified by both Wichmann 11 and the results obtained by any one of these
Boissevain.'2 In this a peroxidized 3 methods being practically the same.
titanium chloride solution is bleached by The results of the analysis of 54
fluorine, the amount of fading being waters by these 4 methods are grouped
proportional to the amount of fluorine into 2 classes: (1) waters which are
present. It is somewhat difficult to de- known to be associated with mottled
tect differences in the fading produced enamel, and (2) those which have been
by samples varying by 0.1 p.p.m. found not to cause mottled enamel.
fluorine in ordinary Nessler tubes. Un- This division is based on tooth examina-
doubtedly the photo-electric colorimeter tions made by M. C. Smith.
of Wilcox 13 used to compare the ferric It may be seen by inspection of
acetylacetone colors of Armstrong's Table I that the 33 waters associated
method would be more sensitive than with mottled enamel, as analyzed by the
comparisons in Nessler tubes. Sul- Foster, Willard, and Sanchis methods,
phates in excess are known to interfere have a fluorine content varying from
with this method, and correction is 0.7 p.p.m. to 13.2 p.p.m. Twenty-one
made if the concentration is too high. waters which did not cause mottled
Willard and Winters,14 Thompson enamel had fluorine contents ranging
and Taylor,'5 and Sanchis 16 use from 0.1 to 0.8 p.p.m.
436 AMERICAN JOURNAL OF PUBLIC HEALTH

TABLE I
WATERS ASSOCIATED WITH MOTTLED ENAMEL
Method
Lab. No. Location Fairchild Foster Willard Sanchis
p.p.m. p.p.m. p.p.m. p.p.m.
20487 Ajo 5.8 2.2
20670 Aztec 12.0 7.2 6.8 8.0
20853 Buckeye 2.4 1.5 1.2 1.3
20106 Cochise 2.0 0.9 0.9
20693 Concha 7.5 3.9 4.7
20104 Douglas 5.2 2.4 2.4 2.5
20663 Florence 2.8 0.8 0.8
20689 Gila Bend 10.6 6.8 6.7
F296 Gila Riv. 3.0 0.9 1.0
20708 Joseph Cy. 2.8 1.0 1.0
20482 Hayden 3.0 1.3 1.4
F73 Wilson, Idaho 16.8 13.2 11.1
20662 Laveen 2.5 1.2 1.3 1.7
20483 Mammoth 6.0 3.7 3.9 4.0
20121 Mesa (R) 3.1 1.0 1.1
19761 N. Gila Sch. 9.1 1.9 2.4
20486 Oracle 3.0 1.1 1.5
20487 Pinal Co. Hwy. Dept. *S.
5.0 -

Hayden 7.5 3.0


20690 Roll 8.7 4.7
19762 Roll Sch. 3.3 1.3
20664 Roosevelt
Sch. Dist. # 66 3.5 1.5 1.9 1.7
F82 San Xavier 3.0 0.9 1.0
20772 Sentinel 9.3 6.0 5.5
20673 Sentinel (R. R.) 7.7 5.9 4.5 1.0
F176 St. David, Merril Sr. 4.6 1.1 1.8
20694 Topock 4.7 1.0 1.1
20480 Tucson Brickyard 2.7 1.0 1.1 1.0
20489 Winkleman 2.8 1.1 1.1

WATERS NOT ASSOCIATED WITH MOTTLED ENAMEL


20683 Avondale 1.8 0.4
20656 Benson 0.9 0.4 0.3
20122 Chandler 2.1 0.7 0.8 0.8
20491 Clarkdale 1.2 0.3 0.5 0.3
20696 Concha 0.9 0.4 0.3 ...
21718 Fairbanks 0.3 0.1 -. 0.4 0.3
20699 Flagstaff 1.1 0.5 0.3 0.2
20490 Jerome 1.1 0.2 0.3 0.1
19769 Pomerene 1.4 0.5 0.3 ...
19770 Pomerene Sch. 0.9 0.5 0.6 ...
20661 Prescott 1.1 -0.2 0.6 0.1
20100 Tombstone 0.2 0.1 0.3 0.0
20665 Wickenburg 1.5 0.1 0.4 0.2
20475 Willcox, Stewart Sch. 1.2 0.3 0.4 0.25
20697 Winslow 0.7 0.2 0.2
20859 Yuma 2 .0 0.4 0.4 *
POTABILITY OF WATER 437
Severe mottled enamel of the deeply Willard method, and 1.9 p.p.m. by th-e
stained and pitted type appear to be as- modified Steiger method. Little dif-
sociated with waters containing well ference in results obtained by these 3
over 2.0 p.p.m. of fluorine. Waters methods was apparent. Therefore it is
containing from 1 to 2 p.p.m. were al- safe to conclude that the toxic concen-
ways found associated with a mild to tration of fluorine is similar when de-
moderate type of this dental defect. termined by the Foster, Willard,
That the lower limit of fluorine content Sanchis, or Steiger methods, and has as
in water which causes mottled enamel its lower limit 1 p.p.m. or slightly less.
probably is slightly less than 1 p.p.m. is
shown in Eagar, Tucson Brickyard, REMOVAL OF FLUORINE FROM WATER
Florence (private well), San Xavier, SUPPLIES
Cochise, and Springerville. These Because certain communities find it
waters were found to produce a very impossible to secure waters containing
mild type of mottled enamel. In Eagar too little fluorine to cause mottled
the effect was variable. About 50 per enamel, a practical method of treating
cent of the children in the community the water to remove fluorine must be
had chalky white patches on the teeth, developed. Many years ago Carnot 18
characteristic of mild mottling. Again reported that it was possible to remove
it may be noted that other waters with fluorine from water by the use of bone.
a fluorine content of 0. 7 to 0.8 p.p.m. This removal is probably due to
did not have a toxic effect upon the the fact that the CO3 in bone
teeth, as, for example, the city of Ca1oCO3(PO4)6 can be replaced with
Chandler. This community, however, fluorine. A single trial in our labora-
is surrounded bv areas in which mottled tory has been made of this method.
enamel does occur and in all proba- When 67.5 mg. of bone was used per
bility has a fluorine content which is liter of water, the original fluorine con-
just below the toxic concentration. It centration of 2.5 p.p.m. was reduced
is difficult to establish the exact to 1.7 p.p.m. The possibilities of this
fluorine concentration in a water supply method are under further investigation.
which will damage the teeth of its users. Willis of the Colorado Springs High
The evidence indicates strongly that any School 19 has studied the waters in the
water with a fluorine content of 0.9 mountains above Colorado Springs in
p.p.m. (when analyzed by the Foster, an attempt to determine the source of
Willard, or Sanchis methods) or over fluorine in Colorado Springs water
is dangerous from the standpoint of supply. Analyses of water from the
probable damage to the teeth. No same source showed lower concentra-
Arizona water has yet been found con- tions of fluorine during winter than
taining more than 1 p.p.m. of fluorine summer, hence the possibility of
which has not been shown to cause " freezing out " the fluorine suggested
mottled enamel. itself.
Dahle,'7 Associate Referee for the Through the courtesy of the Arizona
A.O.A.C. has compared the Foster, Ice and -Cold Storage Company in
Willard, and Steiger methods by means Tucson it was possible to conduct a
of analysis of synthetic waters made by freezing experiment under commercial
8 chemists in different parts of the conditions. Water originally containing
country. His synthetic water "A " 0. 7 p.p.m. fluorine was fortified with a
made up to contain 2.08 p.p.m. of sodium fluoride solution. A concentra-
fluorine was found to contain 2.08 tion of 3.4 p.p.m. resulted. The tank
p.p.m. by Foster method, 2.27 by the containing the mixture was placed in the.
438 AMERICAN JOURNAL OF PUBLIC HEALTH

brine to freeze. Agitation was obtained mained in the solution. Under these
with compressed air. Two cores were conditions fluorine results by the Foster
removed. The cake of ice was sampled method were lower than by the Willard
and analyzed for fluorine by the Sanchis and Winters method, and it is assumed
method. Results are shown in Table II. that aluminum sulphate was responsible
for this. Further studies are being con-
TABLE II ducted to discover the cause.
REMOVAL OF FLUORINE BY FREEZING McKee and Johnson 21 have recently
Fluorine in p.p.m. suggested the removal of fluorine by
Original Water . . ......... . 0. 7 the use of activated carbon after the pH
Water and added NaF ...... 3.4 of the water has been reduced below
First Core Removed ......... 6.0 3.0. Cost of carbon, acid, and lime
Second Core Removed ...... 4.0 will not permit the use of this method
Sample No. 1 Outer Portion.. 0.7 by a municipality. The practicability
Sample No. 2 Outer Portion.. 0.4
of any of the heretofore proposed
It is a well known fact that ice methods for the removal of fluorine from
freezes almost pure. In this case the municipal supplies seems doubtful.
impurities were concentrated in the When it is realized that only 1 p.p.m. of
ccre. It is doubtful whether this fluorine in water is necessary to cause
method of fluorine removal would be mottled enamel, it is not surprising that
any more practical than distillation. attempts to remove these small amounts
A verbal report of Dr. Frary of the have not met with greater success.
Aluminum Company of America, at the
meeting of the American Chemical SUMMARY
Society in Chicago in 1933-that acti- 1. A concentration of 0.8 to 0.9
vated aluminum would remove all traces p.p.m. of fluorine in water has been
of fluorine from solution-apparently found to cause mottled enamel if this
has not yet been published. water is consumed while the children
Boruff20 has reported the removal are of a susceptible age.
of fluorine from water by the use of 2. A comparison has been made of 4
aluminum sulphate. Water containing methods for the determination of
2 to 3 p.p.m. of fluorine required 85 fluorine in water.
p.p.m. of the anhydrous salt, or 165 of 3. Experimental work has shown the
the crystalline, to lower the fluorine Foster method to be unsatisfactory
concentration to the safe level of 0.5 when used for the fluorine determination
p.p.m. At $4.42 per 100 lb. for alu- on waters which have been treated with
minum sulphate, the cost of treating A12 (SO4) 3 for fluorine removal if con-
1,000,000 gallons of water would be siderable aluminum remains in solution.
$60.77. This cost is prohibitive for ACKNOWLEDGMENT-The writer is indebted
municipal supplies. If only drinking to Jane Rider in planning and executing part
water were treated, the cost of 6.07 of the experimental work presented here as
cents per 1,000 gallons for chemicals well as for a criticism of the manuscript, and
would be very economical. No reports to W. T. McGeorge and T. F. Buehrer for
of the use of this method have been suggestions and help in designing equipment
used.
noted. The writer has attempted to
corroborate Boruff's results and espe- REFERENCES
cially to modify his procedure to render 1. Black, G. V., and McKay, F. S. Mottled
teeth an endemic developmental imperfection of the
it more practical by securing more com- teeth heretofore unknown in the literature of dentistry.
plete removal with less aluminum. Dental Cosmos, 58:132-156, 1916.
2. Eager. Pub. Health Rep., 16:2576, 1901.
In some cases residual aluminum re- 3. Smith, M. C., Lantz, E. L., and Smith, H. V.
POTABILITY OF WATER 439
The cause of mottled enamel, a defect of human the water supply of Colorado and its relation to the
teeth. Univ. of Arizona Agri. Exper. Sta. Tech. occurrence of mottled enamel. Colorado Med., Apr.,
Bull. 32, 1931. 1933.
4. Churchill, H. V. Occurrence of fluorides in 13. Wilcox, L. V. A photronic colorimeter and its
some waters of the United States. J. Indust. & application to the determination of fluorine. Indust.
Eng. Chem., 23, 9:996-998, 1931. & Eng. Chem., 6:167-169, 1934.
S. Reynolds, P. S., Ross, W. H., and Jacob, L. D. 14. Willard, H. H., and Winters, 0. B. Volumetric
Volatilization method for the determination of method for determination of fluorine. Indust. & Eng.
fluorine with special reference to the analysis of rock Chem. Anal. Ed.., 5:7-10, 1933.
phosphate. J. Assn. Agri. Chem., 11:225, 1928. 15. Thompson, T. G., and Taylor, H. J. De-
6. Smith, H. V., and Smith, M. C. Mottled termination and occurrence of fluorides in sea water.
enamel in Arizona and its correlation with the con- Indust. & Eng. Chem., 5:87-89, 1933.
centration of fluorides in water supplies. Univ. of 16. Sanchis, J. M. Determination of fluorides in
Arizona Agri. Exper. Sta. Tech. Bull 43, 1932. natural waters. Indust. & Eng. Chem., 6:134-135,
7. Fairchild, John G. The volumetric determina- 1934.
tion. 17. Dable, Dan. Private correspondence.
8. Foster, Margaret D. Colorimetric determination 18. Carnot, A. Recherches sur la composition
of fluorides in water using ferric chloride. Indust. & generale et la teneur en fluor des os modernes et des
Eng. Chem., 5:234-236, 1933. os fossiles des differents ages. Ann. Mines, 9, 3:155-
9. Armstrong, W. D. Colorimetric Determination 195, 1893.
of Fluorine. Indust. & Eng. Chem. Anal. Ed. 19. Willis, Willet. The source of the fluorine in
5:300-302, 1933. some water supplies. Bull. Colorado State Dental
10. Steiger, G. Colorimetric determination of Assn., 1934, pp. 39-44.
fluorine. J. Am. Chem. Soc., 30:219, 1908. 20. Boruff, C. S. Removal of fluorides from drink-
11. Wichmann, H. G., and Dable, Dan. De- ing water. J. Indust. & Eng. Chem., 26, 1:69, 1934.
terminations of small quantities of fluorine. 21. McKee, R. H., and Johnston, W. S. Removal
J.A.O.A.C., Nov., 1933, p. 612. of fluorides from drinking water. Indust. & Eng.
12. Boissevain, D. H. The presence of fluorine in Chem., 26:849-851, 1934.

DISCUSSION
J. M. SANCHIS
Chemist, Bureau of Water Works and Supply, Los Angeles, Calif.
MR. SMITH has summarized effec- with zirconium in a hydrochloric acid
tively the extent of our present solution.
knowledge in regard to the various The Foster method is the best known
aspects of the problem presented by the of the procedures in which use is made
occurrence of fluorides in potable of the ferric ion reaction. This came
waters. at a time when the inconsistency of the
His timely remarks on the im- results obtained by the then available
portance of the part played by methods had thrown laboratory findings
analytical procedures in any attempt to into a hopeless state of confusion. Its
ascertain the toxic level of fluoride in relative superiority over the other
water, based on field observations, can- methods caused its ready acceptance by
not be overemphasized. Without a those confronted with the need of
reproducible unit of measure, little making fluoride determinations. How-
progress can be made in the evaluation ever, the results obtained by it were
of data obtained from widely scattered not always reliable nor easily dupli-
localities. cated. Boruff and Abbott I pointed out
As pointed out the methods which a number of theoretical considerations
have been used most generally in recent by which they proved the fundamental
years can be grouped into two main weakness of the method even in the ab-
classes. Those in one class make use sence of interfering substances. When
of the fact that fluorides interfere with to this is added the effect that reducing
the quantitative estimation of ferric agents such as hydrogen sulphide have
ions, while those in the other class de- upon ferric ions, the difficulty in which
pend on the effect of fluorides upon the the thiocyanate colors can be matched
color produced when alizarin reacts when using Nessler tubes or the
RULES
OF
TENNESSEE DEPARTMENT OF ENVIRONMENT AND CONSERVATION
BUREAU OF ENVIRONMENT
DIVISION OF WATER SUPPLY

CHAPTER 1200-5-1
PUBLIC WATER SYSTEMS

TABLE OF CONTENTS

1200-5-1-.01 Authority 1200-5-1-.23 Reserved


1200-5-1-.02 Purpose 1200-5-1-.24 Sodium Monitoring
1200-5-1-.03 Scope 1200-5-1-.25 Volatile Organic Chemicals
1200-5-1-.04 Definitions 1200-5-1-.26 Volatile Organic Chemical Sampling Analytical
1200-5-1-.05 Supervision of Design and Construction and Other Requirements
1200-5-1-.06 Maximum Contaminant Levels 1200-5-1-.27 Reserved
1200-5-1-.07 Monitoring and Analytical Requirements 1200-5-1-.28 Reserved
1200-5-1-.08 Turbidity Sampling and Analytical Requirements 1200-5-1-.29 Use of Non-Centralized Treatment Devices
1200-5-1-.09 Inorganic Chemical Sampling and Analytical 1200-5-1-.30 Reserved
Requirements 1200-5-1-.31 Filtration and Disinfection
1200-5-1-.10 Organic Chemical Sampling and Analytical 1200-5-1-.32 Fees for Public Water Systems
Requirements 1200-5-1-.33 Control of Lead and Copper
1200-5-1-.11 Radionuclide Sampling 1200-5-1-.34 Drinking Water Source Protection
1200-5-1-.12 Secondary Drinking Water Regulations 1200-5-1-.35 Consumer Confidence Reports
1200-5-1-.13 Alternative Analytical Techniques 1200-5-1-.36 Disinfectant Residuals, Disinfection Byproducts,
1200-5-1-.14 Laboratory Certification and Disinfection Byproduct Precursors
1200-5-1-.15 Monitoring of Consecutive Public Water Systems 1200-5-1-.37 Stage 2 Initial Distribution System Evaluation For
1200-5-1-.16 Siting Requirements Disinfection Byproducts
1200-5-1-.17 Operation and Maintenance Requirements 1200-5-1-.38 Stage 2 Disinfection Byproducts Requirements
1200-5-1-.18 Reporting Requirements (LRAA)
1200-5-1-.19 Notification of Customers 1200-5-1-.39 Enhanced Treatment For Cryptosporidium
1200-5-1-.20 Record Maintenance 1200-5-1-.40 Ground Water Rule
1200-5-1-.21 Monitoring For Corrosivity Chacteristics
1200-5-1-.22 Reserved

1200-5-1-.01 AUTHORITY.

(1) These Rules and Regulations are issued under the authority of Public Acts of 1983, Chapter
324.

(2) The Division of Water Supply is responsible for the supervision of public water systems.

Authority: T.C.A. §§ 4-5-201 et seq. and 68-221-701 et seq. Administrative History: Original rule
certified June 7, 1974. Repeal and new rule filed June 30, 1977; effective August 1, 1977. Amendment
filed February 3, 1984; effective February 12, 1985. Amendment filed September 26, 1988; effective
November 10, 1988.

1200-5-1-.02 PURPOSE.

(1) The purpose of these Rules and Regulations is to provide guidelines for the interpretation of
§68-221-701 et seq. of the Tennessee Code Annotated and to set out the procedures to be
followed by the Department in carrying out the State’s primary enforcement responsibility
under the Federal Safe Drinking Water Act. These Rules and Regulations set out the
requirements which agents, employees or representatives of public water systems must meet
in the following areas: in the preparation and submission of plan documents for public water
systems; in the supervision of all phases of construction; in supplying safe drinking water
meeting all applicable maximum contaminant levels or treatment technique requirements; in
providing adequate operation and maintenance of the system; and in complying with
procedural requirements for appealing orders issued by the Commissioner of the Tennessee
Department of Health and Environment against a public water system.

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(Rule 1200-5-1-.02, continued)

(2) Where the terms shall and must are used, practice and usage is sufficiently standardized to
indicate a mandatory requirement, insofar as any complaint action by the Department is
concerned. Other items, such as should, recommend, preferred, and the like, indicate
desirable procedures or methods.

Authority: T.C.A. §§4-5-201 et seq., 4-5-202, and 68-221-701 et seq. Administrative History: Original
rule certified June 7, 1974. Repeal and new rule filed June 30, 1977; effective August 1, 1977.

1200-5-1-.03 SCOPE.

These rules will apply to all public water supply systems that provide water for human consumption
through pipes or other constructed conveyances, if such system has at least fifteen (15) service
connections or regularly serves an average of at least twenty–five (25) individuals daily at least sixty (60)
days out of the year. A public water supply system is either a community water system or a non–
community water system. A community water system is a public water supply system which serves at
least fifteen (15) service connections used by year-round residents or regularly serves at least twenty–five
(25) year–round residents. A non–community water system is a public water supply system that is not a
community water system and which generally serves a transient population such as hotels, motels,
restaurants, camps, service stations churches, industry, etc. A Non-Transient Non–Community Water
System is a non–community water system that regularly serves at least 25 of the same persons over six
(6) months per year. These rules do not apply to public water systems which meet all of the following
criteria:

(1) consists only of distribution and storage facilities (and does not have any collection and
treatment facilities);

(2) obtains all of its water from, but is not owned or operated by, a public water system to which
such regulations apply;

(3) does not sell water to any person; and

(4) is not a carrier which conveys passengers in interstate commerce.

Authority: T.C.A. §§4-5-202, 68-221-701 et seq., and 68-221-704. Administrative History: Original
rule certified June 7, 1974. Repeal and new rule filed June 30, 1977; effective August 1, 1977.
Amendment filed February 3, 1984; effective February 12, 1985. Amendment filed September 26, 1988;
effective November 10, 1988. Repeal and new rule filed August 15, 2005; effective October 29, 2005.

1200-5-1-.04 DEFINITIONS.

(1) "Action level" is the concentration of lead or copper in water which may determine the
treatment requirements that a water system is required to complete.

(2) “Bag Filters” are pressure-driven separation devices that remove particulate matter larger
than 1 micrometer using an engineered porous filtration media. They are typically
constructed on a non-rigid fabric filtration media housed in a pressure vessel in which the
direction of flow is from the inside of the bag to outside.

(3) “Bank Filtration” is a water treatment process that uses a well to recover surface water that
has naturally infiltrated into ground water through a river bed or bank(s). Infiltration is
typically enhanced by the hydraulic gradient imposed by nearby pumping water supply or
other wells.

(4) “Benchmark” A disinfection benchmark is the lowest monthly average value of the monthly
logs of Garidia Lamblia inactivation.

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(Rule 1200-5-1-.04, continued)

(5) “Business Plan” means a document which identifies source(s) of income or revenue
sufficient to meet expenses over a three (3) year period. The business plan will identify
costs related to retaining a certified operator, estimated annual infrastructure repair costs,
depreciation, facility maintenance fees, estimated annual monitoring costs, estimated costs
of providing public notices, estimated administrative costs, and any and all other
operational, treatment, and related costs (e.g. chemicals and other supplies used to treat
water, etc.). The business plan must include the re-payment of borrowed and amortized
funds.

(6) “Capacity Development Plan” means a document(s) identifying what actions a public water
system is taking or shall take to become a “viable water system.” Such plan shall include
information concerning retention of a Certified Operator in direct charge; system ownership
and accountability; staffing and organizational structure; fiscal management and controls,
source water assessment and protection plan; “business plan;” and any and all other
information identifying any further action that shall be taken.

(7) “Cartridge filters” are pressure-driven separation devices that remove particulate matter
larger than 1 micrometer using an engineered porous filtration media. They are typically
constructed a rigid or semi-rigid self-supporting filter elements housed in pressure vessels in
which flow is from the outside of the cartridge to the inside.

(8) "Coagulation" means a process using coagulant chemicals and mixing by which colloidal
and suspended materials are destabilized and agglomerated into flocs.

(9) “Combined distribution system” is the interconnected distribution system consisting of the
distribution systems of wholesale systems and of the consecutive systems that receive
finished water.

(10) "Community Water System" means a public water system which serves at least fifteen (15)
service connections used by year-round residents or regularly serves at least twenty-five
(25) year-round residents.

(11) "Compliance cycle" means the nine-year calendar year cycle during which public water
systems must monitor for certain contaminants. Each compliance cycle consists of three
three-year compliance periods. The first calendar year cycle begins January 1, 1993 and
ends December 31, 2001; the second begins January 1, 2002 and ends December 31,
2010; the third begins January 1, 2011 and ends December 31, 2019.

(12) "Compliance period" means a three year calendar year period within a compliance cycle.
Each compliance cycle has three three-year compliance periods. Within the first
compliance cycle, the first compliance period runs from January 1, 1993 to December 31,
1995; the second from January 1, 1996 to December 31, 1998; the third from January 1,
1999 to December 31, 2001.

(13) “Comprehensive performance evaluation (CPE)” is a thorough review and analysis of a


treatment plant’s performance-based capabilities and associated administrative, operation
and maintenance practices. It is conducted to identify factors that may be adversely
impacting a plant’s capability to achieve compliance and emphasizes approaches that can
be implemented without significant capital improvements. For purposes of compliance, the
comprehensive performance evaluation must consist of at least the following components:
assessment of plant performance; evaluation of major unit processes; identification and
prioritization of performance limiting factors; assessment of the applicability of
comprehensive technical assistance; and preparation of a CPE report.

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(Rule 1200-5-1-.04, continued)


(14) "Confluent growth" means a continuous bacterial growth covering the entire filtration area of
a membrane filter, or a portion thereof, in which bacterial colonies are not discrete.

(15) "Connection" means the point at which there is a meter or service tap if no meter is present.

(16) “Consecutive system is a public water system that receives some or all of its finished water
from one or more wholesale systems. Delivery may be through a direct connection or
through the distribution system of one or more consecutive systems.

(17) "Contaminant" means any physical, chemical, biological, or radiological substance or matter
in water.

(18) "Conventional filtration treatment" means a series of processes including coagulation,


flocculation, sedimentation, and filtration resulting in substantial particulate removal.

(19) "Corrosion inhibitor" means a substance capable of reducing the corrosivity of water toward
metal plumbing materials, especially lead and copper, by forming a protective film on the
interior surface of those materials.

(20) "CT" or "CTcalc" is the product of "residual disinfectant concentration" (C) in mg/1
determined before or at the first customer, and the corresponding "disinfectant contact time"
(T) in minutes, i.e., "C" x "T". If a public water system applies disinfectants at more than one
point prior to the first customer, it must determine the CT of each disinfectant sequence
before or at the first customer to determine the total percent inactivation or "total inactivation
ratio". In determining the total inactivation ratio, the public water system must determine the
residual disinfectant concentration of each disinfection sequence and corresponding contact
time before any subsequent disinfection application point(s). "CT99.9" is the CT value
required for 99.9 percent (3-log) inactivation of Giardia lamblia cysts. CT99.9 for a variety of
disinfectants and conditions appear in Tables 1.1-1.6, 2.1, and 3.1 of 1200-5-1-.31(5)(b)3.

CTcalc
CT99.9

is the inactivation ratio. The sum of the inactivation ratios, or total inactivation ratio shown
as

(CTcalc)
Σ (CT99.9)

is calculated by adding together the inactivation ratio for each disinfection sequence. A total
inactivation ratio equal to or greater than 1.0 is assumed to provide a 3-log inactivation of
Giardia lamblia cyst. Disinfectant concentrations must be determined by tracer studies or
an equivalent demonstration approved by the Department.

(21) "Department" when used in these regulations shall mean the Division of Water Supply,
Tennessee Department of Environment and Conservation, or one of the Division's Field
Offices. The terms "State," "Department," and "Division" are often used interchangeably in
these Rules and Regulations.

(22) "Diatomaceous earth filtration" means a process resulting in substantial particulate removal
in which (1) a precoat cake of diatomaceous earth filter media is deposited on a support
membrane (septum), and (2) while the water is filtered by passing through the cake on the
septum, additional filter media known as body feed is continuously added to the feed water
to maintain the permeability of the filter cake.

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(Rule 1200-5-1-.04, continued)


(23) "Direct filtration" means a series of processes including coagulation and filtration but
excluding sedimentation resulting in substantial particulate removal.

(24) "Disinfectant" means any oxidant, including but not limited to chlorine, chlorine dioxide,
chloramines, and ozone added to water in any part of the treatment or distribution process,
that is intended to kill or inactivate pathogenic microorganisms.

(25) "Disinfectant contact time" ("T" in CT calculations) means the time in minutes that it takes
for water to move from the point of disinfectant application or the previous point of
disinfectant residual measurement to a point before or at the point where residual
disinfectant concentration ("C") is measured. Where only one "C" is measured, "T" is the
time in minutes that it takes for water to move from the point of disinfectant application to a
point before or at where residual disinfectant concentration ("C") is measured. Where more
than one "C" is measured, "T" is (a) for the first measurement of "C", the time in minutes
that it takes for water to move from the first or only point of disinfectant application to a point
before or at the point where the first "C" is measured and (b) for subsequent measurements
of "C", the time in minutes that it takes for water to move from the previous "C"
measurement point to the "C" measurement point for which the particular "T" is being
calculated. Disinfectant contact time in pipelines must be calculated based on "plug flow" by
dividing the internal volume of the pipe by the maximum hourly flow rate through that pipe.
Disinfectant contact time within mixing basins and storage reservoirs must be determined by
tracer studies or an equivalent demonstration.

(26) "Disinfection" means a process which inactivates pathogenic organisms in water by


chemical oxidants or equivalent agents.

(27) “Disinfection profile” is a summary of daily Giardia lamblia inactivation through the treatment
plant. The procedure for developing a disinfection profile is contained in 40CFR141.172.

(28) "Distribution System" means all water lines up to the point of a meter. For unmetered
systems distribution system includes all lines up to the customer's service tap.

(29) "Domestic or other non-distribution system plumbing problem" means a coliform


contamination problem in a public water system with more than one service connection that
is limited to the specific service connection from which the coliform-positive sample was
taken.

(30) "Dose Equivalent" means the product of the absorbed dose from ionizing radiation and such
factors as account for differences in biological effectiveness due to the type of radiation and
its distribution in the body as specified by the International Commission on Radiological
Units and Measurements (ICRU).

(31) “Dual sample set” is a set of two samples collected at the same time and same location,
with one sample analyzed for TTHM and the other sample analyzed for HAA5. Dual sample
sets are collected for the purposes of conducting an IDSE under the provisions of 1200-5-1-
.37 and determining compliance with the TTHM and HAA5 MCLs under the provisions of
1200-5-1-.38.

(32) "Effective corrosion inhibitor residual" for the purpose of the lead and copper rules only,
means a concentration sufficient to form a passivating film on the interior walls of a pipe.

(33) "Engineer" means the person or firm who designed the public water system and conceived,
developed, executed or supervised the preparation of the plan documents.

(34) “Enhanced coagulation” means the addition of sufficient coagulant for improved removal of
disinfection byproduct precursors by conventional filtration treatment

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(Rule 1200-5-1-.04, continued)

(35) “Enhanced softening” means the improved removal of disinfection byproduct precursors by
precipitative softening.

(36) “Filter profile” is a graphical representation of individual filter performance, based on


continuous turbidity measurements or total particle counts versus time for an entire filter run,
from startup to backwash inclusively, that includes an assessment of filter performance
while another filter is being backwashed.

(37) "Filtration" means a process for removing particulate matter from water by passage through
porous media.

(38) “Finished water” is water that is introduced into the distribution system of a public water
system and is intended for distribution and consumption without further treatment, except as
treatment necessary to maintain water quality in the distribution system (e.g., booster
disinfection, addition of corrosion control chemicals).

(39) "First draw sample" means a one-liter sample of tap water, for the purposes of the lead and
copper rules, that has been standing in plumbing pipes at least 6 hours and is collected
without flushing the tap.

(40) “Flocculation" means a process to enhance agglomeration or collection of smaller floc


particles into larger, more easily settleable particles through gentle stirring by hydraulic or
mechanical means.

(41) “Flowing stream” is a course of running water flowing in a definite channel.

(42) “GAC10” means granular activated carbon filter beds with an empty-bed contact time of 10
minutes based on average daily flow and a carbon reactivation frequency of every 180
days, except that the reactivation frequency for GAC10 used as best available technology
for compliance with disinfection byproducts shall be 120 days.

(43) “GAC20” means granular activated carbon filter beds with an empty-bed contact time of 20
minutes based on average daily flow and a carbon reactivation frequency of every 240
days.

(44) "Gross Alpha Particle Activity" means the total radioactivity due to alpha particle emission as
inferred from measurements on a dry sample.

(45) "Gross Beta Particle Activity" means the total radioactivity due to beta particle emission as
inferred from measurements on a dry sample.

(46) “Ground water under the direct influence of surface water” means any water beneath the
surface of the ground with significant occurrence of insects or other macroorganisms, algae,
or large-diameter pathogens such as Giardia lamblia or Cryptosporidium, or significant and
relatively rapid shifts in water characteristics such as turbidity, temperature, conductivity, or
pH which closely correlate to climatological or surface water conditions. Direct influence
must be determined for individual sources in accordance with criteria established by the
State. The State determination of direct influence may be based on site-specific
measurements of water quality and/or documentation of well construction characteristics
and geology with field evaluation.

(47) “Haloacetic acids (five) (HAA5)” mean the sum of the concentrations in milligrams per liter of
the haloacetic acid compounds (monochloroacetic acid, dichloroacetic acid, trichloroacetic
acid, monobromoacetic acid, and dibromoacetic acid), rounded to two significant figures
after addition.

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(Rule 1200-5-1-.04, continued)

(48) "Halogen" means one of the chemical elements chlorine, bromine or iodine.

(49) “Human Consumption” - means the use of water that involves any drinking or ingestion of
the water by humans, any human skin contact or food preparation where the food is not
brought to boiling temperatures after contact with the water..

(50) "Initial compliance period" means the first full three-year compliance period which begins
January 1, 1993. For public water systems having fewer than 150 service connections initial
compliance period shall be January 2, 1996, for the following contaminants:

(a) Antimony (m) endrin


(b) Beryllium (n) glyphosate
(c) Cyanide (o) oxamyl
(d) Nickel (p) picloram
(e) Thallium (q) simazine
(f) dichloromethane (r) benzo(a)pyrene
(g) 1,2,4-trichlorobenzene (s) di(2ethylhexyl)adipate
(h) 1,1,2-trichloroethane (t) di(2ethylhexyl)phthalate
(i) dalapon (u) hexachlorobenzene
(j) dinoseb (v) hexachlorocyclopentadiene
(k) diquat (w) 2,3,7,8 TCDD
(l) endothall

(51) “Lake/reservoir” refers to a natural or man made basin or hollow on the earth’s surface in
which water collects or is stored that may or may not have a current or single direction of
flow.

(52) "Large water system" for the purpose of lead and copper rule, means a water system that
serves more than 50,000 persons.

(53) "Lead service line" means a service line made of lead which connects the water main to the
building inlet and any lead pigtail, gooseneck or other fitting which is connected to such lead
line.

(54) "Legionella" means a genus of bacteria, some species of which have caused a type of
pneumonia called Legionnaires Disease.

(55) “Locational running annual average (LRAA)” is the average of sample analytical results for
samples taken at a particular monitoring location during the previous four calendar quarters.

(56) "Man-Made Beta Particle and Photon Emitter" means all radionuclides emitting beta
particles and/or photons listed in "Maximum Permissible Body Burdens and Maximum
Permissible Concentration of Radionuclides in Air or Water for Occupational Exposure, NBS
Handbook 69", except the daughter products of thorium-232, uranium-235 and
uranium-238.

(57) "Maximum Contaminant Level" means the maximum permissible level of a contaminant in
water which is delivered at the free flowing outlet of the ultimate user of a public water
system, except in the case of turbidity where the maximum permissible level is measured at
the point of entry to the distribution system. Contaminants added to the water under
circumstances controlled by the user, except those resulting from corrosion of piping and
plumbing caused by water quality, are excluded from this definition.

(58) “Maximum residual disinfectant level (MRDL)” means a level of a disinfectant added for
water treatment that may not be exceeded at the consumer’s tap without an unacceptable

August, 2008 (Revised) 7


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.04, continued)


possibility of adverse health effects. For chlorine and chloramines, a PWS is in compliance
with the MRDL when the running annual average of monthly averages of samples taken in
the distribution system, computed quarterly, is less than or equal to the MRDL. For chlorine
dioxide, a PWS is in compliance with the MRDL when daily samples are taken at the
entrance to the distribution system and no two consecutive daily samples exceed the
MRDL. MRDLs are enforceable in the same manner as maximum contaminant levels under
Section 1412 of the Safe Drinking Water Act. There is convincing evidence that addition of
a disinfectant is necessary for control of waterborne microbial contaminants.
Notwithstanding the MRDLs, operators may increase residual disinfectant levels of chlorine
or chloramines (but not chlorine dioxide) in the distribution system to a level and for a time
necessary to protect public health to address specific microbiological contamination
problems caused by circumstances such as distribution line breaks, storm runoff events,
source water contamination, or cross-connections.

(59) "Maximum Total Trihalomethane Potential (MTP)" means the maximum concentration of
total trihalomethanes produced in a given water containing a disinfectant residual after 7
days at a temperature of 25°C or above.

(60) "Medium-size water system" for the purpose of the lead and copper rule means a water
system that serves greater than 3,300 and less than or equal to 50,000 persons.

(61) “Membrane filtration” is a pressure or vacuum driven separation process in which particulate
matter larger than 1 micrometer is rejected by an engineered barrier, primarily through a
size exclusion mechanism, and which has a measurable removal efficiency of a target
organism that can be verified through the application of a direct integrity test. This definition
includes the common membrane technologies of microfiltration, ultrafiltration, nanofiltration,
and reverse osmosis.

(62) "Near the first service connection" means at one of the twenty percent of all service
connections in the entire system that are nearest the water supply treatment facility, as
measured by the water transport time within the distribution system.

(63) "Non-Community Water System" means a public water system that is not a community
water system.

(64) "Non-Transient Non-Community Water System" or NTNCWS" means a non-community


water system that regularly serves at least twenty-five (25) of the same persons over six (6)
months per year.

(65) "Optimal corrosion control treatment" for the purpose of lead and copper rule only means
the corrosion control treatment that minimizes the lead and copper concentrations at user's
taps while insuring that the treatment does not cause the water system to violate any
primary drinking water regulation.

(66) "Person" means any individual, corporation, company, association, partnership, State,
municipality, utility district, water cooperative, or Federal agency.

(67) "Picocurie" (pCi) means that quantity of radioactive material producing 2.22 nuclear
transformations per minute.

(68) "Plan Documents" mean reports, proposals, preliminary plans, survey and basis of design
data, general and detailed construction plans, profiles, specifications and all other
information pertaining to public water system planning.

(69) “Plant intake” refers to the works or structures at the head of a conduit through which water
is diverted from a source (e.g., river or lake) into the treatment plant.

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(Rule 1200-5-1-.04, continued)

(70) "Point of disinfectant application" is the point where the disinfectant is applied and water
downstream of that point is not subject to recontamination by surface water runoff.

(71) "Point-of-Entry Treatment Device" (POE) means a device applied to the drinking water
entering a house or building for the purpose of reducing contaminants in the drinking water
distributed throughout the house or building.

(72) "Point-of-Use Treatment Device" (POU) means a treatment device applied to a single tap
used for the purpose of reducing contaminants in drinking water at that one tap.

(73) ‘Presedimentation” is a preliminary treatment process used to remove gravel, sand and
other particulate material from the source water through settling before the water enters the
primary clarification and filtration processes in a treatment plant.

(74) "Primary Drinking Water Regulation" means a regulation promulgated by the Department
which:

(a) applies to public water systems;

(b) specifies contaminants which, in the judgment of the Department, may have any
adverse effect on the health of persons;

(c) specified for each such contaminant either;

1. a maximum contaminant level, if, in the judgment of the Department, it is


economically and technologically feasible to ascertain the level of such
contaminant in water in public water systems, or

2. if, in the judgment of the Department, it is not economically or technologically


feasible to so ascertain the level of such contaminant, each treatment
technique known to the Department which leads to a reduction in the level of
such contaminant sufficient to satisfy the requirements of Regulations
1200-5-1-.06; and

(d) contains criteria and procedures to assure a supply of drinking water which
dependably complies with such maximum contaminant levels; or treatment
techniques including quality control and testing procedures to insure compliance
with such levels and to insure proper operation and maintenance of the system, and
requirements to (i) the minimum quality of water which may be taken into the
system and (ii) siting for new facilities for public water systems.

(75) “Public Water System” means a system for the provision of piped water for human
consumption if such serves 15 or more connections or which regularly serves 25 or more
individuals daily at least 60 days out of the year and includes:

(a) any collection, treatment, storage or distribution facility under control of the operator of
such system and used primarily in connection with such system; and

(b) any collection or pre-treatment storage facility not under such control which is used
primarily in connection with such system,

The population of a water system shall be determined by actual count or by multiplying the
household factor by the number of connections in the system. The household factor shall be
taken from the latest federal census for that county or city. Water systems serving multi-

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PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.04, continued)


family residences such as apartment complexes and mobile home parks shall include each
individual residence unit as a connection in determining the population for the system.

(76) "Rem" means the unit of dose equivalent from ionizing radiation to the total body or any
internal organ or organ system. A "millerem (mrem)" is 1/1000 of a rem.

(77) "Repeat compliance period" means any subsequent compliance period after the initial
compliance period.

(78) "Residual disinfectant concentration" ("C" in CT calculations) means the concentration of


disinfectant measured in mg/l in a representative sample of water.

(79) "Safe Drinking Water Act" means the Federal law codified in 42 United States Code 300f et.
seq., Public Law 93-523, dated December 16, 1974 and subsequent amendments..

(80) "Sanitary Survey" means an on-site review of the water source, facilities, equipment,
operation and maintenance of a public water system for the purpose of evaluating the
adequacy of such sources, facilities, equipment, operation and maintenance for producing
and distributing safe drinking water.

(81) "Secondary Drinking Water Regulation" mean a regulation promulgated by the Department
which applies to public water systems and which specifies the maximum contaminant levels
which, in the judgment of the Department are requisite to protect the public welfare. Such
regulations may apply to any contaminant in drinking water

(a) which may adversely affect the odor or appearance of such water and
consequently may cause the persons served by the public water system providing
such water to discontinue its use, or

(b) which may otherwise adversely affect the public welfare. Such regulations may
vary according to geographic and other circumstances.

(82) "Sedimentation" means a process for removal of solids before filtration by gravity or
separation.

(83) "Service line sample" means a one-liter sample of water collected in accordance with
1200-5-1-.33(7)(b)3., that has been standing for at least 6 hours in a service line.

(84) "Single family structure" for the purpose of lead and copper rules means a building
constructed as a single-family residence that is currently used as either a residence or a
place of business.

(85) "Slow sand filtration" means a process involving passage of a raw water through a bed of
sand at low velocity (generally less than 0.4 m/h) resulting in substantial particulate removal
by physical and biological mechanisms.

(86) "Small water system" for the purpose of the lead and copper rules only, means a water
system that serves 3,300 or fewer persons.

(87) “Subpart H systems” means public water systems using surface water or ground water
under the direct influence of surface water as a source that are subject to the requirements
1200-5-1-.31, .39 and 1200-5-1-.17.

(88) "Supplier of Water" means any person who owns or operates a public water system.

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(Rule 1200-5-1-.04, continued)


(89) "Surface water" means all water which is open to the atmosphere and subject to surface
runoff.

(90) “SUVA” means Specific Ultraviolet Absorption at 254 nanometers (nm), an indicator of the
humic content of water. It is a calculated parameter obtained by dividing a sample’s
ultraviolet absorption at a wavelength of 254 nm (UV 254/ (in m) by its concentration of
dissolved organic carbon (DOC) (in mg/L).

(91) "System with a single service connection" means a system which supplies drinking water to
consumers via a single service line.

(92) "Too numerous to count" means that the total number of bacterial colonies exceeds 200 on
a 47 millimeter diameter membrane filter used for coliform detection.

(93) “Total Organic Carbon (TOC)” means total organic carbon in mg/L measured using heat,
oxygen, ultraviolet irradiation, chemical oxidants, or combinations of these oxidants that
convert organic carbon to carbon dioxide, rounded to two significant figures.

(94) "Total trihalomethane" (TTHM) means the sum of concentration in milligrams per liter of the
trihalomethane compounds-trihalomethane (chloroform), dibromochloromethane,
bromodichloro-methane and tribomomethane (bromoform), rounded to two significant
figures.

(95) “Transient Non-Community Water System” or “TNCWS” means a non-community water


system that regularly serves at least twenty-five (25) individuals daily at least sixty (60) days
out of the year. A transient non-community water system is a public water supply system
that generally serves a transient population such as hotels, motels, restaurants, camps,
service stations churches, industry, and rest stops.

(96) "Trihalomethane" (THM) means one of the family of organic compounds, named as
derivatives of methane, wherein three of the four hydrogen atoms in methane are each
substituted by a halogen atom in the molecular structure.

(97) “Two-stage lime softening” is a process in which chemical addition and hardness
precipitation occur in each of two distinct unit clarification processes.

(98) “Uncovered finished water storage facility” is a tank, reservoir, or other facility used to store
water that will undergo no further treatment except residual disinfection and is open to the
atmosphere.

(99) “Viable Water System” means a public water system which has the commitment and the
financial, managerial and technical capacity to consistently comply with the Tennessee Safe
Drinking Water Act and these regulations.

(100) "Virus" means a virus of fecal origin which is infectious to humans by waterborne
transmission.

(101) “Waterborne disease outbreak" means a significant occurrence of acute infectious illness,
epidemiologically associated with the ingestion of water from a public water system which is
deficient in treatment, as determined by the appropriate local or State agency.

(102) “Wholesale system” is a public water system that treats source water as necessary to
produce finished water and then delivers some or all of that finished water to another public
water system. Delivery may be through a direct connection or through the distribution
system of one or more consecutive systems.

August, 2008 (Revised) 11


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.04, continued)


Authority: T.C.A. § 68-221-704 and 4-5-202. Administrative History: Original rule certified June 7,
1974. Repeal and new rule filed June 30, 1977; effective August 1, 1977. Amendment filed February 3,
1984; effective February 12, 1985. Amendment filed September 26, 1988; effective November 10, 1988.
Amendment filed November 26, 1990; effective January 10, 1991. Amendment filed August 24, 1992;
effective October 8, 1992. Amendment filed October 22, 1993, effective January 5, 1994. Amendment
filed April 12, 1996; effective June 26, 1996. Amendment filed February 17, 1999; effective May 3, 1999.
Amendment filed October 31, 2000; effective January 14, 2001. Amendment filed July 15, 2002; effective
September 28, 2002. Amendment filed December 30, 2002; effective March 15, 2003. Amendment filed
July 31, 2006; effective October 14, 2006. Amendment filed June 12, 2008; effective August 26, 2008.

1200-5-1-.05 SUPERVISION OF DESIGN AND CONSTRUCTION.

(1) Engineering - Plan documents for public water systems shall be submitted to the Department
at least thirty (30) days prior to the date on which action by the Department is desired.

(2) Expiration of Approval - Approval of engineering reports, proposals, preliminary plans, survey
and basis of design data shall be null and void after a period of one year from the date
stamped on the documents, unless the general and detailed plan documents have been
submitted to the Department. Approval of all other plan documents by the Department shall
be null and void after a period of one year from the date stamped on the plan documents,
unless the construction is either underway or completed.

(3) General Practice - All plan documents for public water system design and construction shall
present all information in conformance with accepted engineering practices and the “Design
Criteria for community Public Water Systems” as published by the Department.

(4) Revisions to Plan Documents - Any deviations from plan documents approved by the
Department, which affect location, sanitary and/or mineral quality, capacity, hydraulic
conditions, operating units, or the function of unit processes or distribution and storage, must
be approved in writing before such changes are made. Any revisions must be made on the
master work, i.e., the original tracings. Revised plan documents must be submitted in time to
permit the review and approval of such revisions before any construction which will be
affected by such revisions is begun.

(5) Copies of Plan Documents - Generally, only two copies of the engineering report and two
sets of the preliminary plans shall be required by the Department for review and/or approval.
At least four complete sets of the detailed plan documents shall be required for final review.
Upon the granting by the Department of its approval for construction the documents shall be
so stamped and two sets returned to the engineer’s office, one set forwarded to the
appropriate Field Office for filing or use in field inspection of construction, and one set
retained for the Department files. Upon completion of the project, one set of “As Built” plans
and one copy of the executed contract documents shall be submitted to the Department and
one set each to the owner. In addition, shop drawings, instruction manuals, etc., on all
equipment furnished by the project shall be compiled into one or more documents and given
to the owner.

(6) Supervision of Construction - One set of the plan document stamped “APPROVED FOR
CONSTRUCTION” shall be available at the job sites at all times during construction. The
engineer or a person qualified other than the contractor or his representative, and approved
by the public water system shall provide continuous adequate inspection during construction
to assure that all work is done in accordance with approved plan documents. The
Department’s representative shall have access to the project at any time during construction.
If the Department’s representative observes work being done in a manner that does not
conform to the approved plan documents, he shall have the authority, through the engineer’s
representative, the water system’s agent or directly to the contractor, to order the cessation
of all work affected by the nonconformity until such discrepancies are rectified.

August, 2008 (Revised) 12


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.05, continued)

(7) Engineer’s Seal - Plan documents for non-transient non-community and community public
water systems shall be prepared by a person qualified under Section 62-2-101 et seq.,
Tennessee Code Annotated, and shall have the necessary professional seal affixed as
required by Section 62-2-306 of the Code.

(8) (a) Ownership and Operational Organization – No person shall operate a public water
system without notifying the Division of Water Supply prior to placing the new system in
operation. Any person operating a public water system other than an individual, a
municipality, any agency or instrumentality of the United States, any facility owned and
operated by the State of Tennessee, or any organization otherwise exempt by law must
have a charter or appropriate authorization lawfully issued as set forth in one or more of
the following:

Utility District – T.C.A. 7-82-101 et seq.


General Corporation Act – T.C.A. 48 -1-101 et seq.
Tennessee Regulatory Authority – T.C.A. 65-4-101 et seq.
Urban Type Public Facilities – T.C.A. 5-16-101 et seq.

(b) All public water systems shall comply with all laws, rules and regulations, and policies
of the Department. Construction modification and treatment processes must be
approved in accordance with all federally designated best available technologies and
Tennessee Laws. Every public water system shall, within thirty (30) days following any
change in ownership or operation of the system, file a written report of such change in
ownership or operation with the Department. Such report shall, at a minimum, contain
the name, home address, business address, and home and business phone numbers
of the person assuming ownership or operation of the system, and the date such
change of ownership or operation became effective.

(c) All persons owning or operating a public water system shall keep the Department
advised of their current address and must readily accept all mail sent to them by the
Department. For purposes of this Rule, registered or certified mail sent with proper
postage to the registered owner or operator’s last known address shall be considered
adequate notification regardless of whether is accepted or returned unclaimed.

(d) Because of the Department’s statutory duty to supervise the construction, operation,
and maintenance of public water systems, and because written communication is a
necessary aspect of such supervision, an owner or operator’s refusal to accept mail or
failure to claim registered or certified mail is a violation of this Chapter and may result
in enforcement action.

(9) Interconnection of Systems - Insofar as feasible, public water systems shall be connected
with a municipal, county, regional or other existing approved water system capable of
supplying the demand. Where such connection is not feasible, other approved sources may
be considered. Each public water system shall be designed in such a manner as will
facilitate the connection of the system at an appropriate time to an expanding municipal,
county or regional system. Each public water system shall be designed to provide service to
all service areas anticipated or projected by the owner.

(10) System Capacity - Whenever a public water system reaches eighty (80) per cent of the
design capacity based on average day usage, the supplier of water shall immediately obtain
the services of a competent engineer to prepare plan documents for expansion of said
system.

(11) Turbidimeters – All community water systems using ground water formations under the direct
influence of surface water, and serving more than 50 connections or 150 individuals, shall be

August, 2008 (Revised) 13


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.05, continued)


required to install turbidity monitoring equipment with power cutoff ability and recording unit.
Those systems not included in the above may be required to install turbidity monitoring
devices if the Department finds that the system cannot meet the microbiological standard, the
turbidity can be seen without an instrument, or there is an outbreak of illness that may be
water related. All filter plants serving community water systems shall be required to have
continuous recording turbidimeters on the filter effluent line(s). Such instrumentation may be
pen and ink, digital, computerized or other record keeping or recording devices approved by
the Division. If pen and ink recorders are used they shall be limited to two pens and two
filters and shall use a scale of 0 to 2.0 NTU unless specific alternatives are approved in
writing by the Division.

(12) Monitoring of new sources - All new surface or ground water sources added to an existing
water system or proposed for use by a new water system shall have the required biological
and chemical water quality monitoring completed prior to being placed in service. The
parameters to be monitored shall be those required for drinking water for the specific type of
system involved.

(13) Delegation of Plans Review Authority – Under Section 68–221–706 of the Tennessee Code
Annotated, any unit of local government may petition the Commissioner for certification to
review and approve plans for water distribution facilities within its jurisdiction. The unit of
local government must have adequate experience and expertise in water distribution and
must adopt standards and impose requirements which are at least as stringent as the
Department’s. The request for certification must be in writing and contain at least the
following:

(a) The names of the individual(s) responsible for the review and approval together with
his/her experience and education. This person(s) must be employed by the unit of
local government and be a registered professional engineer in Tennessee.

(b) A copy of the standards, requirements and design criteria legally adopted and
enforceable by the unit of local government.

(c) The type of projects the unit of local government wishes to receive certification to
review. This may include but is not limited to water lines, distribution pumping stations
and distribution storage tanks.

(d) Procedures for maintaining records of all projects reviewed and approved by the unit of
local government.

(e) The wording to be used on the approval stamp.

(f) Plans review authority fee.

The Division of Water Supply will be responsible for reviewing the application for certification
and shall have up to 60 days from the receipt of the complete application to make a written
response. Units of local government will not be certified to review projects involving state or
federal funds, raw water pump stations, new water sources, treatment facilities, sludge
handling facilities, or any project designed by the staff of the local government. Any unit of
local government which receives certification for plans review shall submit one copy of any
plan documents it has approved to the Division of Water Supply. This shall be done within 10
days of the local government’s approval. The commissioner may periodically review the unit
of local government’s plans review program and prescribe changes as deemed appropriate.
The Division of Water Supply may execute a written agreement with a unit of local
government which has received plans review certification. Failure to comply with the terms of
the agreement may result in revocation of the plans review certification.

August, 2008 (Revised) 14


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.05, continued)


Authority: T.C.A. §§4-5-201 et seq., 4-5-202, 68-221-701 et seq., and 68-221-704. Administrative
History: Original rule certified June 7, 1974. Repeal and new rule filed June 30, 1977; effective August
1, 1977. Amendment filed February 3, 1984; effective February 12, 1985. Amendment filed August 24,
1992; effective October 8, 1992. Amendment filed April 12, 1996; effective June 26, 1996. Amendment
filed October 31, 2000; effective January 14, 2001. Amendments filed August 15, 2005; effective October
29, 2005.

1200-5-1-.06 MAXIMUM CONTAMINANT LEVELS.

(1) Inorganic Chemicals

(a) The maximum contaminant level for fluoride applies to community water systems. The
maximum contaminant levels for nitrate, nitrite and total nitrate and nitrite are
applicable to both community water systems and non-community water systems. The
maximum contaminant levels for the remaining inorganic chemicals apply only to
community water systems and non-transient non-community systems. The effective
date for antimony, beryllium, cyanide, nickel and thallium shall be January 1, 1993, or
the effective date of this rule whichever is later. The arsenic maximum contaminant
level listed in subparagraph (b)2 is effective for the purpose of compliance January 23,
2006. Until January 23, 2006, the arsenic MCL is 0.05 mg/L.

(b) The following are the maximum contaminant levels for inorganic chemicals:

CONTAMINANT LEVEL, MILLIGRAMS PER LITER

1. Antimony 0.006
2. Arsenic 0.010
3. Asbestos 7 million fibers/liter
(longer than 10 microns)
4. Beryllium 0.004
5. Barium 2.0
6. Cadmium 0.005
7. Chromium 0.1
8. Cyanide (as free cyanide) 0.2
9. Fluoride 4.0
10. Mercury 0.002
11. Nickel 0.1
12. Nitrate 10.0 (as Nitrogen)
13. Nitrite 1.0 (as Nitrogen)
14. Total nitrate and nitrate 10.0 (as Nitrogen)
15. Selenium 0.05
16. Thallium 0.002

(2) Organic Chemicals - The following are the maximum contaminant levels for organic
chemicals.

(a) The following maximum contaminant levels for organic contaminants apply to
community water systems and non-transient non-community water systems. The
effective date of these MCLs shall be the effective date of this regulation.
CONTAMINANT LEVEL, MILLIGRAMS PER LITER

1. Alachlor 0.002
2. Atrazine 0.003
3. Carbofuran 0.04
4. Chlordane 0.002
5. Dibromo chloropropane (DBCP) 0.0002

August, 2008 (Revised) 15


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.06, continued)


6. 2,4 Dichlorophenoxyacetic acid 0.07
7. Ethylene dibromide 0.00005
8. Heptachlor 0.0004
9. Heptachlor epoxide 0.0002
10. Lindane 0.0002
11. Methoxychlor 0.04
12. Polychlorinated biphenyls 0.0005
13. Toxaphene 0.003
14. 2,4,5 Trichlorophenoxyproprionic
acid 0.05
15. Pentachlorophenol 0.001
16. Benzo(a)pyrene 0.0002
17. Dalapon 0.2
18. Di(2-ethylhexyl) adipate 0.4
19. Di(2-ethylhexyl)phthalate 0.006
20. Dinoseb 0.007
21. Diquat 0.02
22. Endothall 0.1
23. Glyphosate 0.7
24. Hexachlorobenzene 0.001
25. Hexachlorocyclopentadiene 0.05
26. Oxamyl (Vydate) 0.2
27. Picloram 0.5
28. Simazine 0.004
29. 2,3,7,8-TCDD (Dioxin) 0.00000003
30. Endrin 0.002

(3) Turbidity - The requirements of 1200-5-1-.06(3) apply to filtered surface systems until June
29, 1993. The requirements in this section apply to unfiltered systems that the State has
determined, in writing, must install filtration until June 29, 1993, or until filtration is installed,
whichever is later.

The maximum contaminant level for turbidity is applicable to public water systems using
surface water source(s) in whole or in part. Furthermore, the maximum contaminant level for
turbidity is applicable to those systems using ground water which are required to install
turbidimeters pursuant to Regulation 1200-5-1-.05(11). The maximum contaminant levels for
turbidity in drinking water, measured at a representative entry point(s) to the distribution
system are:

(a) One (1.0) turbidity unit, as determined by monthly average pursuant to Regulation
1200-5-1-.08.

(b) Two (2.0) turbidity units based on an average for two consecutive days pursuant to
Regulation 1200-5-1-.08.

To meet the maximum contaminant level for turbidity, a public water system must meet both
(a) and (b).

(4) Microbiological - The maximum contaminant levels for microbiologicals are applicable to both
community water systems and non-community water systems.

(a) The maximum contaminant level (MCL) is based on the presence or absence of total
coliforms in a sample, rather than coliform density.

The number of total coliform positive samples shall not exceed any of the following:

August, 2008 (Revised) 16


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.06, continued)


1. For a system which collects at least 40 samples per month, if no more than 5.0
percent of the samples collected during a month are total coliform-positive, the
system is in compliance with the MCL for total coliforms.

2. For a system which collects fewer than 40 samples/month, if no more than one
sample collected during a month is total coliform-positive, the system is in
compliance with the MCL for total coliforms.

3. A public water system which has exceeded the MCL for total coliforms must
report the violation to the State no later than the end of the next business day
after it learns of the violation and notify the public in accordance with the
schedule of 1200-5-1-.19 using the language specified in 1200-5-1-.19.

4. A public water system which has failed to comply with the coliform monitoring
requirements, including a sanitary survey requirement must report the monitoring
violation to the State within ten (10) days after the system discovers the violation
and notify the public in accordance with 1200-5-1-.19.

(b) Any fecal coliform-positive repeat sample or E-coli-positive repeat sample, or any total
coliform-positive repeat sample following a fecal coliform positive or E-coli positive
routine sample constitutes a violation of the MCL for total coliforms. For purposes of
the public notification requirements in 1200-5-1-.19 this is a tier 1 violation that may
pose an acute risk to health.

(c) Fecal coliforms/Escherichia coli (E. coli) testing

1. If any routine or repeat sample is total coliform-positive, the system must analyze
that total coliform-positive culture medium to determine if fecal coliforms are
present, except that the system may test for E. coli in lieu of fecal coliforms. If
fecal coliforms or E. coli are present, the system must notify the State by the end
of the day when the system is notified of the test result, unless the system is
notified of the result after the Department office is closed, in which case the
system must notify the State before the end of the next business day.

2. The State has the discretion to allow a public water system, on a case-by-case
basis, to forgo fecal coliform or E. coli testing on a total coliform-positive sample
if that system assumes that the total coliform-positive sample is fecal coliform-
positive or E. coli-positive. Accordingly, the system must notify the State as
specified in paragraph (c)(1) of this section and the provisions of 1200-5-1-
.06(4)(b) apply.

(d) A public water system must determine compliance with the MCL for total coliforms in
(a) and (b) of this section for each month in which it is required to monitor for total
coliforms.

(e) No variance or exemptions from the maximum contaminant level for total coliforms are
permitted.

(5) Radionuclides-

(a) The following maximum contaminant levels for radium-226, radium-228, and gross
alpha particle radioactivity are applicable to all community water systems:

1. Combined radium-226 and radium-228: The maximum contaminant level for


combined radium-226 and radium-228 is 5 pCi/L. The combined radium-226 and

August, 2008 (Revised) 17


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.06, continued)


radium-228 value is determined by the addition of the results of the analysis for
radium-226 and the analysis for radium-228.

2. Gross alpha particle activity (including radium-226 but excluding radon and
uranium): The maximum contaminant level for gross alpha particle activity
(including radium-226 but excluding radon and uranium) is 15 pCi/L.

(b) Maximum contaminant levels for beta particle and photon radioactivity from man-made
radionuclides in community water systems shall be as follows:

1. The average annual concentration of beta particle and photon radioactivity from
man-made radionuclides in drinking water shall not produce an annual dose
equivalent to the total body or any internal organ greater than four (4)
millirem/year.

2. Except for the radionuclides listed in Table A, the concentration of man-made


radionuclides causing four (4) mrem total body or organ dose equivalents shall
be calculated on the basis of a two (2) liter per day drinking water intake using
the 168 hour data listed in “Maximum Permissible Body Burdens and Maximum
Permissible Concentration of Radionuclides in Air or Water for Occupational
Exposure,” NBS Handbook 69 as amended August, 1963, U.S. Department of
Commerce. If two or more radionuclides are present, the sum of their annual
dose equivalent to the total body or to any organ shall not exceed four (4)
millirem/year.

Table A
Average Annual Concentrations Assumed
to Produce a Total Body or Organ Dose of a 4 mrem/yr.

Radionuclide Critical Organ pCi per Liter

Tritium Total Body 20,000


Strontium-90 Bone Marrow 8

(c) MCL for uranium. The maximum contaminant level for uranium is 30 micrograms per
liter.

(d) Compliance dates.

1. Compliance dates for combined radium-226 and -228, gross alpha particle
activity, gross beta particle and photon radioactivity, and uranium: Community
water systems must comply with the MCLs listed in subparagraphs (a), (b), and
(c), beginning December 8, 2003 and compliance shall be determined in
accordance with the requirements of 1200-5-1-.11. Compliance with reporting
requirements for the radionuclides under appendix A to Consumer Confidence
Reports (1200-5-1-.35) and Appendices A and B to Public Notification (1200-5-1-
.19) is required on December 8, 2003.

(e) Best Available Technologies

The Department hereby identifies as indicated in the following table the best technology
available for achieving compliance with the maximum contaminant levels for combined
radium-226 and -228, uranium, gross alpha particle activity, and beta particle and
photon radioactivity.

August, 2008 (Revised) 18


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.06, continued)

Table B.-BAT for Combined Radium-226 and Radium-228, Uranium, Gross


Alpha Particle Activity, and Beta Particle and Photon Radioactivity

Contaminant BAT
1. Combined radium-226 and radium- Ion exchange, reverse osmosis, lime
228 softening.

2. Uranium Ion exchange, reverse osmosis, lime


softening, coagulation/filtration
3. Gross alpha particle activity( Reverse osmosis
excluding Radon and Uranium)
4. Beta particle and photon radioactivity Ion exchange and reverse osmosis

(f) No variance or exemption for compliance with the MCLs listed in 1200-5-1-.06(5) are
allowed.

(g) Small systems compliance technologies list for radionuclides.

Table C.-List of Small Systems Compliance Technologies for Radionuclides


and Limitations to Use

Unit Technologies Limitations Operator skill level Raw water quality


(see foot- required 1 range
notes) and considerations.1
1. Ion Exchange (IE) (a) Intermediate All ground waters.
2. Point of use (POU2) IE (b) Basic All ground waters.
3. Reverse osmosis (RO) (c) Advanced Surface waters usually
require pre-filtration.
4. POU2 RO (b) Basic Surface waters usually
require pre-filtration.
5. Lime softening (d) Advanced All waters.
6. Green sand filtration (e) Basic
7. Co-precipitation with (f) Intermediate to Ground waters with
Barium Sulfate Advanced suitable water quality.
8. Basic to imtermediate All ground waters.
Electrodialysis/electrodialys
is reversal
9. Pre-formed hydrous (g) Intermediate All ground waters.
Manganese oxide filtration
10. Activated alumia (a)(h) Advanced All ground waters;
competing anion
concentrations may
affect regeneration
frequency.
11. Enhanced (i) Advanced Can treat a wide range
coagulation/filtration of water qualities
1
National Research Council (NRC). Safe Water from Every Tap: Improving Water Service to Small
Communities. National Academy Press. Washington, D.C. 1997.
2
A POU, or “point-of-use” technology is a treatment device installed at a single tap used for the purpose
of reducing contaminants in drinking water at that one tap. POU devices are typically installed at the
kitchen tap. See the April 21, 2000 NODA for more details.
Limitations Footnotes: Technologies for Radionuclides:

August, 2008 (Revised) 19


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.06, continued)


a
The regeneration solution contains high concentrations of the contaminant ions. Disposal options
should be carefully considered before choosing this technology.
b
When POU devices are used for compliance, programs for long-term operation, maintenance, and
monitoring must be provided by water utility to ensure proper performance.
c
Reject water disposal options should be carefully considered before choosing this technology. See
other RO limitations described in the SWTR Compliance Technologies Table.
d
The combination of variable source water quality and the complexity of the water chemistry involved
may make this technology too complex for small surface water systems.
e
Removal efficiencies can vary depending on water quality.
f
This technology may be very limited in application to small systems. Since the process requires static
mixing, detention basins, and filtration, it is most applicable to systems with sufficiently high sulfate levels
that already have a suitable filtration treatment train in place.
g
This technology is most applicable to small systems that already have filtration in place.
h
Handling of chemicals required during regeneration and pH adjustment may be too difficult for small
systems without an adequately trained operator.
i
Assumes modification to a coagulation/filtration process already in place.

Table D.-Compliance Technologies by System Size Category for Radionuclide NPDWR's

Contaminant Compliance Technologies 1 for system size categories


(population served)
25-500 501-3,300 3301-10,000
1. Combined radium- 1,2,3,4,5,6,7,8,9 1,2,3,4,5,6,7,8,9 1,2,3,4,5,6,7,8,9
226 and radium-228
2. Gross alpha 3.4 3.4 3,4
particle activity
3. Beta particle 1,2,3,4 1,2,3,4 1,2,3,4
activity and photon
acivity
4. Uranium 1,2,4,10,11 1,2,3,4,5,10,11 1,2,3,4,5,10,11

Note:1 Numbers correspond to those technologies found listed in table C.

(6) Disinfectant Residuals and Disinfectant Byproducts

(a) Bromate and chlorite. The maximum contaminant levels (MCLs) for bromate and
chlorite are as follows:

Disinfection by-product MCL (mg/L)


Bromate 0 .010
Chlorite 1 .0

1. Compliance dates for CWSs and NTNCWSs. Subpart H systems serving 10,000
or more persons must comply with this paragraph (a) beginning January 1, 2002.
Subpart H systems serving fewer than 10,000 persons and systems using only
ground water not under the direct influence of surface water must comply with
this paragraph (a) beginning January 1, 2004.

2. The Administrator, pursuant to section 1412 of the Act, hereby identifies the
following as the best technology, treatment techniques, or other means available
for achieving compliance with the maximum contaminant levels for bromate and
chlorite identified in this paragraph (a):

Disinfection Best available technology

August, 2008 (Revised) 20


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.06, continued)


by-product
Bromate Control of ozone treatment process to reduce production of
bromate
Chlorite Control of treatment processes to reduce disinfectant demand
and control of disinfection treatment processes to reduce
disinfectant levels

(b) TTHM and HAA5.

1. Subpart L— Running Annual Average compliance (1200-5-1-.36)

(i) Compliance dates. Subpart H systems serving 10,000 or more persons


must comply with subparagraph (b)1 beginning January 1, 2002. Subpart
H systems serving fewer than 10,000 persons and systems using only
ground water not under the direct influence of surface water must comply
with this subparagraph (b)1 beginning January 1, 2004. All systems must
comply with these MCLs until the date specified for Locational Running
Annual Average (subpart V) compliance in 1200-5-1-.38.

Disinfection by-product MCL (mg/L)


Total trihalomethanes (TTHM) 0.080
Haloacetic acids (five) (HAA5) 0.060

(ii) The Administrator, pursuant to section 1412 of the Act, hereby identifies
the following as the best technology, treatment techniques, or other means
available for achieving compliance with the maximum contaminant levels
for TTHM and HAA5 identified in this subparagraph (b)1.

Disinfection by-product Best available technology


Total trihalomethanes (TTHM) and Enhanced coagulation or enhanced softening
Haloacetic acids (five) (HAA5) or GAC10, with chlorine as the primary and
residual disinfectant

2. Subpart V—LRAA compliance (1200-5-1-.38)


.
(i) Compliance dates. The subpart V MCLs for TTHM and HAA5 must be
complied with as a locational running annual average (LRAA) at each
monitoring location beginning the date specified for subpart V compliance
in 1200-5-1-.38(1)(c).

Disinfection by-product MCL (mg/L)


Total trihalomethanes (TTHM) 0.080
Haloacetic acids (five) (HAA5) 0.060

(ii) The Administrator, pursuant to section 1412 of the Act, hereby identifies
the following as the best technology, treatment techniques, or other means
available for achieving compliance with the maximum contaminant levels
for TTHM and HAA5 identified in subparagraph (b)2 for all systems that
disinfect their source water:

Disinfection by-product Best available technology


Total trihalomethanes (TTHM) and Enhanced coagulation or enhanced softening
Haloacetic acids (five) (HAA5) or GAC10; nanofiltration and with a molecular
weight cutoff of equal to or less than 1000

August, 2008 (Revised) 21


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.06, continued)


Daltons; or GAC20

(iii) The Administrator, pursuant to section 1412 of the Act, hereby identifies
the following as the best technology, treatment techniques, or other means
available for achieving compliance with the maximum contaminant levels
for TTHM and HAA5 identified in subparagraph (b)2 for consecutive
systems and applies only to the disinfected water that consecutive systems
buy or otherwise receive:

Disinfection by-product Best available technology


Total trihalomethanes (TTHM) and Haloacetic Systems serving 10,000 or more: Improved
acids (five) -(HAA5). distribution system and storage tank
management to reduce residence time, plus
the use of chloramines for disinfectant residual
maintenance

Systems serving <10,000: Improved


distribution system and storage tank
management to reduce residence time

(c) Maximum residual disinfectant levels.

1. Maximum residual disinfectant levels (MRDLs) are as follows:

Disinfectant residual MRDL (mg/L)


Chlorine........................………..…….. 4.0 (as Cl2).
Chloramines........................……..….... 4.0 (as Cl2).
Chlorine dioxide.....................……..…. 0.8 (as ClO2).

(d) Compliance dates.

1. CWSs and NTNCWSs. Subpart H systems serving 10,000 or more persons must
comply with MRDLs beginning January 1, 2002. Subpart H systems serving
fewer than 10,000 persons and systems using only ground water not under the
direct influence of surface water must comply with MRDLs beginning January 1,
2004.

2. Transient NCWSs. Subpart H systems serving 10,000 or more persons and


using chlorine dioxide as a disinfectant or oxidant must comply with the chlorine
dioxide MRDL beginning January 1, 2002. Subpart H systems serving fewer
than 10,000 persons and using chlorine dioxide as a disinfectant or oxidant and
systems using only ground water not under the direct influence of surface water
and using chlorine dioxide as a disinfectant or oxidant must comply with the
chlorine dioxide MRDL beginning January 1, 2004.

(e) Best Available Control Technology

1. The following are identified as the best technology, treatment technology or other
means available for achieving compliance with the maximum residual
disinfectant level:

(i) Control of the treatment processes to reduce disinfectant demand and


control of disinfection treatment processes to reduce disinfectant levels.

August, 2008 (Revised) 22


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.06, continued)


Authority: T.C.A. §68-221-704. Administrative History: Original rule certified June 7, 1974. Repeal
and new rule filed June 30, 1977; effective August 1, 1977. Amendment filed February 3, 1984; effective
February 12, 1985. Amendment filed September 26, 1988; effective November 10, 1988. Amendment
filed November 26, 1990; effective January 10, 1991. Amendment filed August 24, 1992; effective
October 8, 1992. Amendment filed October 22, 1993; effective January 5, 1994. Amendment filed
October 31, 2000; effective January 14, 2001. Amendment filed November 21, 2001; effective February
4, 2002. Amendment filed April 12, 2002; effective June 26, 2002. Amendment filed July 15, 2002;
effective September 28, 2002. Amendment filed April 19, 2004; effective July 3, 2004. Amendment filed
July 31, 2006; effective October 14, 2006.

1200-5-1-.07 MONITORING AND ANALYTICAL REQUIREMENTS.

(1) Microbiological Contaminant Sampling

(a) Reserved

(b) Reserved

(c) The supplier of water for a community water system shall take coliform samples at
regular time intervals and in number proportional to the population served by the
system during the reporting period as set forth below:

TOTAL COLIFORM MONITORING FREQUENCY FOR COMMUNITY WATER


SYSTEMS

Minimum Number of
Population Served Samples Per Month

25 to 1,0001 ..................................................................................................1
1,001 to 2,500 ...............................................................................................2
2,501 to 3,300 ...............................................................................................3
3,301 to 4,100 ...............................................................................................4
4,101 to 4,900 ...............................................................................................5
4,901 to 5,800 ...............................................................................................6

Minimum Number of
Population Served Samples Per Month

5,801 to 6,700 ...............................................................................................7


6,701 to 7,600 ...............................................................................................8
7,601 to 8,500 ...............................................................................................9
8,501 to 12,900 ...........................................................................................10
12,901 to 17,200.........................................................................................15
17,201 to 21,500.........................................................................................20
21,501 to 25,000.........................................................................................25
25,001 to 33,000.........................................................................................30
33,001 to 41,000.........................................................................................40
41,001 to 50,000.........................................................................................50
50,001 to 59,000.........................................................................................60
59,001 to 70,000.........................................................................................70
70,001 to 83,000.........................................................................................80
83,001 to 96,000.........................................................................................90
96,001 to 130,000 ................................................................................................ 100
130,001 to 220,000 .............................................................................................. 120
220,001 to 320,000 .............................................................................................. 150
320,001 to 450,000 .............................................................................................. 180

August, 2008 (Revised) 23


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.07, continued)


450,001 to 600,000 .............................................................................................. 210
600,001 to 780,000 .............................................................................................. 240
780,001 to 970,000 .............................................................................................. 270
970,001 to 1,230,000 ........................................................................................... 300
1,230,001 to 1,520,000 ........................................................................................ 330
1,520,001 to 1,850,000 ........................................................................................ 360
1,850,001 to 2,270,000 ........................................................................................ 390
2,270,001 to 3,020,000 ........................................................................................ 420
3,020,001 to 3,960,000 ........................................................................................ 450
3,960,001 or more................................................................................................ 480
1
Includes public water systems which have at least 15 service connections, but serve
fewer than 25 persons.

1. Coliform samples shall be collected at sites which are representative of water


throughout the distribution system according to a written sample siting plan.

2. Sample siting plans shall be made available to the Department on request.


Plans determined to be deficient by the Department shall be revised by the
system on the basis of the Department’s findings.

3. Microbiological sampling shall be conducted in accordance with the approved


sampling plan.

(d) The monitoring frequency for total coliforms for non-community water systems is as
follows:

1. A non-community water system using only ground water (except ground water
under the direct influence of surface water) and serving 1,000 persons or fewer
must monitor each calendar quarter that the system provides water to the public.

2. A non-community water system using only ground water (except ground water
under the direct influence of surface water) and serving more than 1,000 persons
during any month must monitor at the same frequency as a like-sized community
water system, as specified in Rule 1200-5-1-.07(1)(c). For systems using ground
water under the direct influence of surface water, rule 1200-5-1-.07(1)(d)4.
applies.

3. A non-community water system using surface water, in total or in part, must


monitor at the same frequency as a like-sized community water system, as
specified in 1200-5-1-.07(1)(c), regardless of the number of persons it serves.

4. A non-community water system using ground water under the direct influence of
surface water must monitor at the same frequency as a like-sized community
water system, as specified in 1200-5-1-.07(1)(c). The system must begin
monitoring at this frequency beginning six months after the determination that the
ground water is under the direct influence of surface water.

5. A non-community water system must collect total coliform samples at sites which
are representative of water throughout the distribution system according to a
written sample site plan. These plans are subject to state review and revision.

(e) Public water systems must collect samples at regular time intervals throughout the
monitoring period. Those public water systems that use only ground water (except
ground water under the direct influence of surface water) and serve 4,900 or fewer
persons may collect all required samples on a single day if they are taken from different
sites.

August, 2008 (Revised) 24


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.07, continued)

(f) A public water system that uses surface water or ground water under the direct
influence of surface water, and does not practice filtration in compliance with Rule
1200-5-1-.31 must collect at least one sample near the first service connection each
day the turbidity level of the source water exceeds 1 NTU. This sample must be
analyzed for the presence of total coliforms. When one or more turbidity
measurements in any day exceed 1 NTU, the system must collect this coliform sample
within 24 hours of the first exceedance, unless the Department determines that the
system, for reasons outside the system’s control cannot have the sample analyzed
within 30 hours of collection. Sample results from this coliform monitoring must be
included in determining compliance with the MCL for total coliforms in 1200-5-1-.06(4).

(g) Special purpose samples, such as those taken to determine whether disinfection
practices are sufficient following pipe placement, replacement, or repair, shall not be
used to determine compliance with the MCL for total coliforms in Rule 1200-5-1-.06(4)
provided the water is not served to customers before negative analytical results are
obtained. Samples representing water served to customers prior to obtaining analytical
results shall not be special purpose samples and shall count toward compliance with
the MCL for total coliforms in Rule 1200-5-1-.06(4). Repeat samples taken pursuant to
paragraph (2) of this Rule are not considered special purpose samples, and must be
used to determine compliance with the MCL for total coliforms in Rule 1200-5-1-.06(4).

(2) Repeat Monitoring

(a) If a routine sample is total coliform-positive, the public water system must collect a set
of repeat samples within 24 hours of being notified of the positive result. A system
which collects more than one routine sample per month must collect no fewer than
three repeat samples for each total coliform-positive sample found. A system which
collects one routine sample per month or fewer must collect no fewer than four repeat
samples for each total coliform-positive sample found. The Department may extend
the 24-hour limit on a case-by-case basis if the system has a problem in collecting the
repeat samples within 24 hours that is beyond its control. In the case of an extension,
the Department must specify how much time the system has to collect the repeat
samples.

(b) The system must collect at least one repeat sample from the sampling tap where the
original total coliform-positive sample was taken, and at least one repeat sample at a
tap within five service connections upstream and at least one repeat sample at a tap
within five service connections downstream of the original sampling site. If a total
coliform-positive sample is at the end of the distribution system, or one away from the
end of the distribution system, the State may waive the requirement to collect at least
one repeat sample upstream or downstream of the original sampling site.

(c) The system must collect all repeat samples on the same day and within 24 hours of
being notified of a positive result, except that the State may allow a system with a
single service connection to collect the required set of repeat samples over a four
consecutive day period or to collect a larger volume repeat sample(s) in one or more
sample containers of any size, as long as the total volume collected is at least 400 ml
(300 ml for systems which collect more than one routine sample per month.)

(d) If one or more repeat samples in the set is total coliform-positive, the public water
system must collect an additional set of repeat samples in the manner specified in
paragraphs 1200-5-1-.07(2)(a), (b), and (c) of this section. The additional samples
must be collected within 24 hours of being notified of the positive result, unless the
State extends the limit as provided in 1200-5-1-.07(2)(a). The system must repeat this

August, 2008 (Revised) 25


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.07, continued)


process until either total coliforms are not detected in one complete set of repeat
samples or the system determines that the MCL for total coliforms in 1200-5-1-.06(4)
has been exceeded and notifies the State.

(e) If a system normally collecting fewer than five routine samples per monitoring period
has one or more total coliform-positive samples and the Department does not
invalidate the sample(s) under 1200-5-1-.07(3), it must collect at least five routine
samples during the next month the system serves water to the public.

(f) After a system collects a routine sample and before it learns the results of the analysis
of that sample, if it collects another routine sample(s) from within five adjacent service
connections of the initial sample, and the initial sample, after analysis, is found to
contain total coliforms, then the system may count the subsequent sample(s) as a
repeat sample instead of as a routine sample.

(g) Results of all routine and repeat samples not invalidated by the State must be included
in determining compliance with the MCL for total coliforms in 1200-5-1-.06(4).

(3) Invalidation of Total Coliform Samples. A total coliform-positive sample invalidated under
1200-5-1-.07(3) does not count towards meeting the minimum monitoring requirement for
microbiological contaminants.

(a) The state may invalidate a total coliform-positive sample only if the conditions of 1200-
5-1-.07(3)(a) 1., 2., or 3. are met.

1. The laboratory establishes that improper sample analysis caused the total
coliform-positive result;

2. The Department, on the basis of the results of repeat samples collected as


required by 1200-5-1-.07(2)(a), (b), (c), and (d), determines that the total
coliform-positive sample resulted from a domestic or other non-distribution
system plumbing problem. The Department cannot invalidate a sample on the
basis of repeat sample results unless all repeat sample(s) collected at the same
tap as the original total coliform-positive are also total coliform-positive, and all
repeat samples collected within five service connections of the original tap are
total coliform-negative (e.g., the Department cannot invalidate a total coliform-
positive sample on the basis of repeat samples if all the repeat samples are total
coliform-negative, or if the public water system has only one service connection).

3. The State has substantial grounds to believe that a total coliform-positive result is
due to a circumstance or condition which does not reflect water quality in the
distribution system. In this case, the system must still collect all repeat samples
required under 1200-5-1-.07(2)(a), (b), (c), and (d) and use them to determine
compliance with the MCL for total coliforms in 1200-5-1-.06(4). To invalidate a
total coliform-positive sample under this paragraph, the decision with the
rationale for the decision must be documented in writing, and approved and
signed by the supervisor of the Departmental official who recommended the
decision. The Department must make this document available to EPA and the
public. The written documentation must state the specific cause of the total
coliform-positive sample, and what action the system has taken, or will take, to
correct this problem. The Department may not invalidate a total coliform-positive
sample solely on the grounds that all repeat samples are total coliform-negative.

(b) A laboratory must invalidate a total coliform sample (unless total coliforms are
detected) if the sample produces a turbid culture in the absence of gas production
using an analytical method where gas formation is examined (e.g., the Multiple-Tube

August, 2008 (Revised) 26


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

(Rule 1200-5-1-.07, continued)


Fermentation Technique), produces a turbid culture in the absence of an acid reaction
in the Presence-Absence (P-A) Coliform Test, or exhibits confluent growth or produces
colonies too numerous to count with an analytical method using a membrane filter
(e.g., Membrane Filter Technique). If a laboratory invalidates a sample because of
such interference, the system must collect another sample from the same location as
the original sample within 24 hours of being notified of the interference problem, and
have it analyzed for the presence of total coliforms. The system must continue to re-
sample within 24 hours and have the samples analyzed until it obtains a valid result.
The Department may waive the 24-hour time limit on a case-by-case basis.

(4) Sanitary Surveys

(a) Public water systems which do not collect five or more routine samples per month must
undergo an initial sanitary survey by June 29, 1994 for community public water
systems and June 29, 1999 for non-community water systems. Thereafter, systems
must undergo another sanitary survey every five years, except that non-community
water systems using only protected and disinfected ground water, as defined by the
Department, must undergo subsequent sanitary surveys at least every ten years after
the initial sanitary survey. The Department must review the results of each sanitary
survey to determine whether the existing monitoring frequency is adequate and what
additional measures, if any, the system needs to undertake to improve drinking water
quality.

(b) In conducting a sanitary survey of a system using ground water having an EPA-
approved wellhead protection program under section 1428 of the Federal Safe Drinking
Water Act, information on sources of contamination within the delineated wellhead
protection area that was collected in the course of developing and implementing the
program should be considered instead of collecting new information, if the information
was collected since the last time the system was subject to a sanitary survey.

(c) Public water systems which do not collect five or more routine samples per month must
undergo a sanitary survey performed by the state at least once every five years. The
system is responsible for ensuring the survey takes place by informing the state within
30 days of the expiration of the 5-year period.

(d) Sanitary surveys conducted by the Department pursuant to Rule 1200-5-1-.40 may be
used to meet the sanitary survey requirements of Rule 1200-5-1-.07(4).

(e) A public water system may request a sanitary survey re-inspection of its water system
provided the public water system requests the re-inspection within sixty (60) days of
the receipt of the results of the initial sanitary survey. The public water system
requesting the sanitary survey re-inspection shall pay the costs of the re-inspection
incurred by the Department.

Authority: T.C.A. §§4-5-201 et seq., 4-5-202, 68-221-701 et seq., and 68-221-704 et seq.
Administrative History: Original rule certified June 7, 1974. Repeal and new rule filed June 30, 1977;
effective August 1, 1977. Amendment filed February 3, 1984; effective February 12, 1985. Amendment
filed November 26, 1990; effective January 10, 1991. Amendment filed August 24, 1992; effective
October 8, 1992. Amendment filed October 22, 1993, effective January 5, 1994. Amendment filed April
12, 1996, effective June 26, 1996. Amendment filed October 31, 2000; effective January 14, 2001.
Amendments filed August 15, 2005; effective October 29, 2005. Amendments filed June 12, 2008;
effective August 26, 2008.

August, 2008 (Revised) 27


PUBLIC WATER SYSTEMS CHAPTER 1200-5-1

1200-5-1-.08 TURBIDITY SAMPLING AND ANALTICAL REQUIREMENTS.

(1) Ground water sampling – Samples shall be taken by suppliers of water that serve more than
50 connections or that have been directed to conduct monitoring under Rule 1200-5-1-
.05(11) for both community water systems and non–community water system at a
representative entry point(s) to the water distribution system at least once per day for the
purpose of making turbidity measurements to determine compliance with Regulation 1200–
5–1–.06(3). Public water systems using water from a source not under the direct influence of
surface water are not required to monitor turbidity unless directed to do so under the
provisions of 1200-5-1-.05(11).

(2) Turbidity measurements of surface water and ground water under the direct influence that
employs filtration - The minimum sampling requirements for systems using filtration treatment
shall be as follows:

(a) Turbidity measurements must be performed on representative samples of the system’s


filtered water every four hours, (or more frequently, as authorized by the rules) that the
system serves water to the public. A public water system may substitute continuous
turbidity monitoring for grab samples if approved in writing by the Department. For
systems serving 500 or fewer persons per day, the Department may allow the sampling
frequency to be reduced to once per day if it determines that less frequent monitoring is
sufficient to indicate effective filtration performance. Systems filtering surface water
and ground water under the direct influence of surface water shall comply with the
treatment technique standards found in 1200-5-1-.31(4).

(3) Ground water systems under the direct influence of surface water and do not filter and have
qualified to avoid filtration - The minimum sampling requirements for ground water systems
under the direct influence of surface water and not employing filtration shall be as follows:

(a) Turbidity measurements must be performed on representative grab samples of source


water immediately prior to the first or only point of disinfectant application every four
hours (or more frequently, as authorized by the rules) that the system serves water to
the public. A public water system may substitute continuous turbidity monitoring for
grab sample monitoring if it validates the continuous measurement for accuracy on a
regular basis using a protocol approved by the State. Turbidity must comply with the
limits specified in 1200-5-1-.31(2)(a)2.

(4) Reporting

(a) Ground water systems - All community water systems using a ground water source
with turbidity removal facilities and not designated as ground water under the direct
influence of surface water shall be required, if the results of a turbidity analysis indicate
that the maximum allowable limit has been exceeded, to confirm by resampling as
soon as practicable and preferably within one (1) hour. If the repeat sample confirms
that the maximum allowable limit has been exceeded, the supplier of water shall report
to the Department within forty-eight (48) hours. The repeat sample shall be the sample
used for the purpose of calculating the monthly average. If the monthly average of the
daily samples exceeds the maximum allowable limit, or if the average of two samples
taken on consecutive days exceeds two (2) NTU, the supplier of water shall report to
the Department and notify the public as directed in Regulation 1200-5-1-.18 and 1200-
5-1-.19. All non-community water systems using ground water formations, other than