Lesson 3 & 4 -CH4101

Chemical, Biological &

Plant Safety

Toxicology
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 Toxicology
Old definition: The science of poisons.
All substances are poisons; there is none which is not
a poison. The right dose differentiates a poison and a
remedy.
Paracelsus-The Father of Modern Toxicology (1493 1541)

Fundamental principle of toxicology:

There are no harmless substances, only harmless
ways of using substances.

Spanish physician Orfila (1815) established toxicology as

a distinct scientific discipline.

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 Toxicology - Modern definition
The qualitative and quantitative studies of the
adverse effects of toxicants on biological
organisms.
A toxicant is chemical or physical agent, including
dusts, fibres, noise and radiation.
The toxicity of a chemical or physical agent is a
property of the agent describing its effect on
biological organisms.
Toxic hazard is the likelihood of damage to
biological organisms based on exposure resulting
from transport and other physical factors of usage.
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 Toxicology Classification of Effects
1) Acute effects
Occur immediately on exposure or soon after
Usually from relatively high dose
Usually of short duration
Usually reversible but can be irreversible too

2) Chronic effects
Occur some time after exposure
Usually from repeated lower doses over many
months / years
Usually irreversible 4
 Toxicology - Classification of Effects
3) Local effects
Occur at the point of contact e.g.
Sulphuric acid causes irritation / burns on skin
Chlorine causes pulmonary inflammation

4) Systemic effects
Occur at target organ remote from point of
contact e.g.
Xylene causes dizziness / unconsciousness
Cadmium causes damage to kidney
Lead causes damage to blood forming process in
bones
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 Toxicology - Classification of Effects
5) Stochastic effects ("Stochastic" refers to the likelihood
that something will happen, may not be predicted precisely) Increased
levels of exposure make these health effects more likely to occur, but
do not influence the type or severity of the effect.
e.g. malignant disease such as cancer
Once it occurs consequence is independent of initiating dose
Stochastic effects do not have a threshold dose

6) Nonstochastic effects
1) e.g. inflammatory and degenerative diseases
2) severity and frequency of the effect varies with the dose
3) have a threshold dose below which they do not occur

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 Toxicology
Problems linking cause and effect:
1) The effect may not occur at time of exposure
By the time it occurs the person may not be
working with the substance anymore.
2) People vary in susceptibility (react differently)
Variations may be due to age, gender, health status
etc
3) Complications of combined effects
Exposure to different substances
Exposure to alcohol, tobacco or prescribed drugs
4) Detailed toxicological information is often not
available for many substances
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 Toxicology Today
Mechanistic toxicology: The study of how a
chemical causes toxic effects by investigating
its absorption, distribution, and excretion.
(characteristics)
Descriptive toxicology: The toxic properties
of chemical agents are systematically studied
for various endpoints using a variety of
different organisms.
Clinical toxicology: They study of toxic
effects of various drugs in the body, and are
also concerned with the treatment and
prevention of drug toxicity in the population.
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 Toxicology Today
Forensic toxicology: A branch of
medicine that focuses on medical
evidence of poisoning, and tries to
establish the extent to which poisons were
involved in human deaths.
Environmental toxicology: The study of
the effects of pollutants on organisms,
populations, ecosystems, and the
biosphere.
Regulatory toxicology: The use scientific
data to decide how to protect humans and
animals from excessive risk. Public or
Private Sector.
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Perceptions About Chemicals
What drives our perceptions? Are chemicals
bad?

HUMAN RISK PERCEPTION... is also affected

by the degree of like or pleasure or comfort
associated with every risk
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 Case history
Dupont plant in Belle, W. Virginia
23 January 2010
Phosgene
A transfer hose connected to a partially filled
phosgene cylinder failed catastrophically. When the
release occurred, an operator was in the phosgene shed.
He was sprayed across the chest and face with liquid
phosgene. He died the following day.
Its high toxicity arises from the action of the phosgene
on the proteins in the pulmonary alveoli, the site of gas
exchange: their damage disrupts the blood-air barrier,
causing suffocation. 11
 Case history

Fatal accident at Dupont

https://www.youtube.com/watch?v=uszxP
O9i0jI
3:50-13:00 (9.5 min)

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 Case history Discussion
What can we learn from this accident?

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 How Toxicants enter Biological organisms
Entry routes for Toxicants and Methods for Control
Entry route Entry organ Typical control measures
Ingestion Mouth or Enforcement of rules on
stomach eating, drinking and
smoking
Inhalation Mouth or Ventilation, respirators,
nose hoods and other personal
protection equipment
Injection Cuts in skin Proper protective clothing
Dermal Skin Proper protective clothing
absorption
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How Toxicants enter Biological organisms
Inhalation is a critical route.
Inhalation of vapors, gases, mists, dusts or fumes
May produce acute or chronic effects. Examples:
allergens, irritants, chemical or simple asphyxiants,
carcinogens and systemic toxicants (toxic to nerve
cells, liver, kidney etc)
Inhalation allows rapid entry to blood

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 How Toxicants enter Biological organisms
Inhalation
The respiratory system
plays an important role
in toxicants entering
the body through
inhalation.
Upper respiratory
system: nose, sinuses,
mouth, pharynx,
larynx, trachea.
Lower respiratory
system: lungs, bronchi,
alveoli.

"Respiratory system complete en" by LadyofHats - Licensed under Public Domain via Wikimedia Commons
- https://commons.wikimedia.org/wiki/File:Respiratory_system_complete_en.svg#/media/File:Respiratory_system_complete_en.svg 16
 How Toxicants enter Biological organisms
Asbestos a notorious dust.
In the past, used in construction
materials, e.g. walls and ceilings;
flooring; thermal insulation pipes,
roofing materials, fireproofing and
acoustic materials.
Asbestos-related diseases
Asbestosis (thickening of alveolar
walls)-Lungs disease
lung cancer (20-30 years after
exposure)
Malignant Mesothelioma (30-40
years after exposure)
https://en.wikipedia.org/wiki/Asbestos#Common_building_materials_containing_asbestos 17
 How Toxicants enter Biological organisms
Dermal absorption
Most chemicals are not readily absorbed by skin.
Exceptions: Phenol
Resorptive poisoning by a large quantity of
phenol can occur even with only a small area of
skin, rapidly leading to paralysis of the central
nervous system and a severe drop in body
temperature. Death can result.
The minimum lethal human dose was cited as
140 mg/kg.

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https://en.wikipedia.org/wiki/Phenol
How Toxicants enter Biological organisms
Dermal absorption

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 How Toxicants enter Biological organisms
Ingestion is usually associated with surface contamination,
poor housekeeping and hygiene, contaminated food and
drink, smoking, facial splashing, handtomouth behavior

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 How Toxicants are Eliminated
Toxicants are eliminated or rendered inactive by
1) Excretion: through kidneys (urine), liver (bile,
kidney), lungs, other organs (minor).
2) Detoxification (mainly liver): by changing the
chemical into something less harmful through
biotransformation.
3) Storage: in the fatty tissue, bones.

During massive exposures to chemical agents,

damage can occur to kidneys, liver or lungs,
significantly reducing the ability to excrete the
substance. 21
 Effects of Toxicants
Effects that may or may not be reversible:
Dermatotoxic affects skin
Hemotoxic affects blood
Hepatotoxic affects liver
Nephrotoxic affects kidneys
Neurotoxic affects nervous system
Pulmonotoxic affects lungs

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 Effects of Toxicants
Effects that are irreversible
Carcinogen causes cancer
Mutagen causes chromosome damage
Benzene, aromatic amines/amides, bromine etc.
Reproductive hazard causes damage to
reproductive system
Ethylene oxide; 1,2-dibromo-3-chloropropane
Teratogen causes birth defects
Ethanol

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https://en.wikipedia.org/wiki/Mutagen
Video to Watch- Toxicology Intro (8 mins)

Basic Principles Dr Ken from FLINN

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 Toxicological studies
Objective: To quantify the effect of the suspect toxicant
on a target organism dose-response curve
Usually animals are used. Hopefully the results can be
extrapolated to humans.
Key items:
1) The toxicant.
2) The target or test organism.
3) The effect or response to be monitored.
4) The dose range.
5) The period of the test.
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 Toxicological studies
The toxicant
Chemical composition
Physical state
The test organism
Single cell (usually cheaper and readily available)
Genetic effects
Higher organisms (usually more expensive)
Effects on specific organs (lungs, liver etc)
The response
Death.
Skin irritation.
Deafness.
Tumour formation. 26
 Toxicological studies
Dose units
1) mg of toxicant per kg of body weight (mg/kg)
For toxicants delivered via ingestion or injection.
Allows for applying results in mice (less than 1 kg)
to humans (~70 kg).

2) Parts per million (ppm) or mg of toxicant per m3 of air

(mg/m3)
For gaseous airborne toxicants or particulates.

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 Toxicological studies
Period of the test
1) Acute toxicity (Short term)
Duration: e.g. 14 days
Effect of a single exposure or a series of exposures
close together in a short period of time.

2) Chronic toxicity (Long term)

Duration: months or years
Effect of multiple exposures occurring over a long
period of time.
More difficult to perform due to time involved. 28
 Toxicological studies
Example of acute toxicity test:
1) Divide animals into several groups (10-40
animals per group).
2) One group (control group) is exposed to same
conditions except the toxicant.
3) Each of the remaining groups is exposed to a
specific dose of the toxicant.
4) The groups are observed for a fixed duration
(e.g. 14 days) and the number of responses (e.g.
deaths) in each group is recorded.

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 Toxicological studies

In a typical dose-response graph, the dose is plotted

against the number or proportion of animals exhibiting a
particular response (e.g. death).
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http://toxlearn.nlm.nih.gov/htmlversion/module1.html
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 Toxicological studies
In a lethal dose curve (where the measured response is
death), certain values are extracted:
LD50 dose: lethal dose for 50% of the subjects.
LDXX dose: lethal does of xx% of the subjects.
LC50 concentration: lethal concentration for 50%
of the subjects (for inhalation tests)
Threshold dose: the dose below which no effect
is detectable.
In an effective dose curve (where the measured
response is some other effects), we have:
ED50 dose: dose that affects 50% of the subjects.
Threshold dose: the dose below which no effect
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is detectable.
Toxicological studies

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 Relative Toxicity

Toxic response (%)

Dose

Which chemical is more toxic?

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https://en.wikipedia.org/wiki/Dose%E2%80%93response_relationship
Degree of Toxicity

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 Models for Dose Vs Response
Probit Equations/Correlations
Probits=Probability Units-
a method suited to provide
straight line equivalent to
response dose curves

Probit Variable Y
= k1+k2 ln V

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 Models for Dose Vs Response
Percentages to Probits

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 Models for Dose Vs Response
Example

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 Threshold Limit Values
Threshold Limit Values (TLV) are established by
the American Conference of Governmental
Industrial Hygienists (ACGIH) for many chemicals.
TLV refers to airborne concentrations that
correspond to conditions under which no adverse
effects are normally expected during a workers
lifetime.
The exposure occurs only during normal working
hours, 8 h per day, and 5 days per week.
For some toxicants (e.g. carcinogens) exposures at
any level are not permitted. These toxicants have
zero thresholds.
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 Threshold Limit Values
TLV-TWA: Time-weighted average for a normal 8-hour workday
or 40-hour work week, to which nearly all workers can be exposed, day
after day, without adverse effects. Excursions above the limit are allowed
if compensated by excursions below the limit.

TLV-STEL: Short-term exposure limit. The maximum

concentration to which workers can be exposed for a period of up to 15
minutes continuously without suffering (1) intolerable irritation, (2)
chronic or irreversible tissue change, (3) narcosis of sufficient degree to
increase accident proneness, impair self-rescue, or materially reduce
worker efficiency, provided no more than 4 excursions per day are
permitted, with at least 60 minutes between exposure periods, and
provided that the daily TLV-TWA is not exceeded.

TLV-C: Ceiling limit. The concentration that should not be

exceeded, even instantaneously. 40
 Threshold Limit Values
Units of TLV
ppm (parts per million by volume)
mg/m3 (mg of vapor/dust per m3 of air)
mppcf (millions of particles per ft3 of air)

22.4 T 1
To convert mg/m3 to ppm: C ppm Cmg / m3
MW 273 P

MW: molecular weight

T: absolute temperature in K
P: absolute pressure in atm.

Volume (m3) X C mg/m3 / Molecular Mass (mg/m mol)

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 Threshold Limit Values
The Occupational Safety and Health Administration
(OSHA) has defined its own threshold dose, called the
permissible exposure level (PEL).
PEL and TLV-TWA values are quite close.
There are not as many PEL values.
TLVs are more conservative.
Singapore uses the PEL (~700 substances)

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 PEL
PEL (Long Term) is the maximum time-weighted
average (TWA) concentration of a toxic substance
to which persons may be exposed over an 8-hour
workday or a 40-hour workweek.
similar to TLV-TWA

PEL (Short Term) is the maximum TWA

concentration to which persons may be exposed
over a period of 15 minutes during the workday
Similar to TLV-STEL

www.wshc.sg 43
 PEL
Units of PEL
ppm (parts per million by volume)
mg/m3 (mg of vapor/dust per m3 of air)

To convert mg/m3 to ppm:

24.5
C ppm Cmg / m3
MW
MW: molecular weight
Assumed to be at standard temperature and pressure
(i.e. T = 25C and P = 760 mmHg)

www.wshc.sg 44
PEL of various chemicals

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 Threshold Limit Values
Limitations of TLV
TLV are not consensus standards.
TLV should not be used as relative index of
toxicity.
TLV should not used for air pollution work.
TLV cannot be used to assess the impact of
continuous exposures to toxicants.
Assumes workers are exposed only during a
normal 8-hour workday.

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 Summary/Objective
Understand definitions and classifications of
Toxicology.
Understand how toxins enter a living organism.

Understand dose-response relationships / Effects.

Understand and able to use basic toxicological terms

and Probit Correlations.

Understand the toxic threshold and its use in

preventing diseases or toxic effects.

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 Case history
Dartmouth College
August 1996
Dimethyl mercury
Inorganic chemist Karen Wetterhahn died 10 months
after handling this compound on her latex-gloved hand.
Dimethyl mercury is extremely toxic and dangerous to
handle. Absorption of doses as low as 0.1 mL has
proven fatal.
Dimethyl mercury passes through latex, PVC, butyl,
and neoprene within seconds and is absorbed through
the skin.
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 Case history

Accidental poisoning at Dartmouth

https://www.youtube.com/watch?v=ALB
WxGik64A
7:49-11:11 (4 min)

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 Case history Discussion
What can we learn from this accident?

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