C H A P T E R
56
Tin
ELENA A. OSTRAKHOVITCH
ABSTRACT
Inorganic tin compounds occur naturally in the
Earth’s crust. In the environment, tin can be found in
both inorganic and organic forms. Inorganic tin com-
pounds are released from natural and anthropogenic
sources. The conversion of metallic tin forms to com-
pounds that may be more soluble increases the risk of
exposure and toxicity. Organotin compounds in the
environment largely originate from anthropogenic
activities. However, chemical and biochemical meth-
ylation reactions convert inorganic tin compounds into
methyltin form. Biomethylation of alkyltins results in
the accumulation of more toxic organotin compounds.
Tin is not regarded an essential nutrient for humans.
However, tin is considered an essential for the growth
of rats, with a requirement for tin of between 1 and
2 mg/kg in the diet. Elemental tin, inorganic tin com-
pounds, and long-chain alkyltins are poorly absorbed
when ingested, which accounts for their relatively
low toxicity. The toxicity of organotin compounds
depends on the length of alkyl chain, hydrophobicity,
and other physicochemical properties. Hydrophobic
organotins are toxic to a wide variety of organisms
owing to their high solubility in cell membranes. The
alkyl tins are more toxic than the aryl tins, whereas
the toxicity of short-chain alkyltin compounds such as
trimethyl- and triethyltin is higher than that of long-
chain compounds: toxicity increases with number of
alkyl groups. The excretory routes of tin compounds
may vary depending of the type of compounds and the
mode of exposure.
Insoluble inorganic tin compounds are largely
nontoxic. However, inhalation of tin dust results in
Handbook on the Toxicology of Metals 4E
http://dx.doi.org/10.1016/B978-0-444-59453-2.00056-1
its deposition in lungs and may cause “stannosis,” a
benign pneumoconiosis. Some tin salts are irritating or
can liberate toxic fumes during decomposition. Gas-
trointestinal absorption of soluble tin salts is only a
few percent of the ingested dose. In chronic exposure,
tin tends to accumulate in kidney, liver, and bones.
Bones comprise a major site of deposition of tin after
long-term exposure and intramuscular injection. The
biological half-life of tin in bone is approximately 100
days. Exposure to high concentrations of inorganic tin
may cause gastrointestinal illness, as well as liver and
kidney problems. No noteworthy histopathological
observations of nonneoplastic nature were reported in
a long-term study.
Short-chain alkyls are easily absorbed from gastro-
intestinal tract. Some alkyltin compounds, particularly
tributyltin and triphenyltin, have high toxicity. Chronic
exposure to butyltin compounds causes imposex,
a pathological condition characterized by develop-
ment of male sex characteristics in female gastropods.
Toxicity of organotins in humans is most frequently
reported as loss of memory and seizure, as well as
other symptoms including death. Short-chain alkyl-
tin, particularly the trialkyl derivatives, and aromatic
tin compounds are neurotoxic. Hydrophobic tri-
methyltin and triethyltin compounds readily diffuse
into richly lipophilic tissues such as brain and cause
encephalopathy, cerebral edema, and severe seizures.
Tetraalkyltins are enzymatically converted to the tri-
substituted form and exert delayed but similar neuro-
toxic effects. Tributyltin compounds are less toxic than
trimethyl- and triethyltins. They may be strongly irri-
tating to the skin in humans. It was reported that ship-
yard workers exposed to tributyltin oxide developed
1241 Copyright © 2015 Elsevier B.V. All rights reserved.
1242 Elena A. Ostrakhovitch
severe dermatitis, difficulty in breathing, and flu-like
symptoms. Trisubstituted organotin derivatives are
implicated in hepatotoxicity, immunodeficiency, endo-
crine disruption, and both reproductive anomalies
and infertility in laboratory animals. Monobutyltin
and dibutyltin show genotoxicity, while mono- and
dimethyltin are not genotoxic. Organotin compounds
penetrate the cell membrane and interrupt oxidative
phosphorylation, disturb calcium homeostasis, dam-
age mitochondria, and induce apoptosis.
1  PHYSICAL AND CHEMICAL PROPERTIES
Tin [from the Latin word stannum (Sn)] is a chemi-
cal element of Group 14 (previously Group IVA) of
the Periodic Table, with atomic number 50 and atomic
weight 118.71. Its abbreviated electron configuration
is [Kr]4d105s25p2. The melting point of tin is 231.93°C
(449.474°F) and the boiling point is 2586°C (4686.8°F)
(CRC Handbook, 2011). Tin has 10 stable isotopes and
exists in three allotropic forms known as gray tin (alpha
tin), with a cubic structure, white metallic tetragonal tin
(beta tin), and metallic rhombic tin (gamma tin or tin
brittle). When white tin cools below 13.2°C, it changes
from a white to a gray form, a change commonly called
“tin pest.” Tin is insoluble in water and is resistant to
oxygen. Because of its low electropositivity, tin may
be obtained from cassiterite (SnO2) by reduction with
carbon. Tin compounds exist in two main oxidation
states, +2 and +4, with the +4 state being more stable.
Tin forms inorganic (without a tin-carbon bond)
and organic compounds (with tin-carbon bonding).
Inorganic tin has four oxidation states: −2, 0, +2, and
+4. The Chemical Abstracts Service (CAS) registry
number for tin inorganic compounds (except oxides)
is 7440-31-5. Inorganic tin compounds are divided into
two classes: stannous, or tin(II), compounds; and stan-
nic, or tin(IV), compounds. Stannous compounds are
readily oxidized at high pH. Both stannous and stan-
nic compounds tend to hydrolyze in solution (Pettine
et al., 1981). Tin forms stannic acid, H2SnO4, when
heated in air or oxygen at high temperature and pro-
duces metastannic acid, H2SnO3, in concentrated nitric
acid. Tin dissolves in hydrochloric acid to form stan-
nous chloride (SnCl2). Among the widely used inor-
ganic tin compounds are stannous chloride (SnCl2),
stannous oxide (SnO), stannous fluoride (SnF2), and
stannic chloride (SnCl4). The CAS registry numbers
for stannous oxide (SnO) and stannic oxide (SnO2) are
21651-19-4 and 18282-10-5, respectively.
Organotin compounds are generally classified
according to the tin oxidation state. They are rep-
resented by the formula RxSn(L)(4 - x), where R is an
organic alkyl or aryl group and L is an organic or inor-
ganic ligand. The noncarbon-bonded anionic group is
commonly halide, oxide, hydroxide, carboxylate, or
mercaptide (Kirk-Othmer Encyclopedia of Chemical
Technology, 2000). Mono-, di-, tri-, and tetraorganotin
compounds can be formed (Alzieu et al., 1989; Alzieu
et al., 1986; Errecalde et al., 1995). Many diorganotin
oxides (R2SnO)n are oligomeric. The chemical proper-
ties of organotin compounds depend upon their struc-
tures; however, water solubility across the group is
very low. Tetraalkyl- and tetraaryltin compounds exist
under all conditions as tetrahedral monomers; all are
insoluble in water but are soluble in various organic
solvents. The tin-carbon bond in tetraorganotins is eas-
ily cleaved by mineral acids. For example, tetrabutyl-
tin is stable, combustible, and colorless liquid at room
temperature. Trisubstituted compounds usually give
five-coordinated complexes R3SnL. The triorganotin
halides are insoluble in water, except for trimethyltin
chloride, which is completely water soluble. Tributyl-
tin is unstable unless it forms an oxide [bis(tributyltin)
oxide], which is a colorless to pale yellow liquid with
a melting point of −45°C, a boiling point of 180°C,
and low water solubility (20 mg/kg). The diorganotin
chlorides, bromides, and iodides are soluble in many
organic solvents, whereas dimethyltin dichloride is
soluble in water. Commercial grades of diorganotin
carboxylates frequently have wider melting ranges
because of the use of less pure grades of carboxylic
acids. Unlike diorganotins, monoorganotins are hygro-
scopic, low-melting point solids or liquids, which can
be hydrolyzed in water that contains enough acid to
retard hydrolysis. Among the organotin compounds,
the most widely investigated are tributyltin oxide
(CAS registry number, 56-35-9), triphenyltin (CAS reg-
istry number, 76-87-9), dibutyltin dilaurate (CAS regis-
try number, 77-58-7), and tetramethyl tin (CAS registry
number, 594-27-4).
There are many naturally occurring organotin com-
pounds (mainly methylated forms) that are mostly
products of the methylation of inorganic tin observed in
estuarine, sewage waters, and sediment (Quevauviller
et al., 1989). However, most organotins entering the
environment are introduced deliberately as man-made
products (e.g. biocides or stabilizers).
2  METHODS AND ANALYSIS
A range of analytical methods, from the simple to
the more sophisticated, have been used to determine
inorganic tin and organotin compounds. Detection
methods include anodic stripping voltammetry, colo-
rimetry, spectrophotometry, fluorescence spectrometry,
 56 Tin
ion chromatography, polarography, titration, atomic
absorption spectrometry (AAS), gas chromatography
(GC), mass spectrometry (MS), and inductively cou-
pled plasma (ICP) techniques (Boa Morte et al., 2009;
Detcheva and Grobecker, 2006; Ozcan and Akman,
2000; Yu et al., 2010; Aghaie et al., 2005; Li et al.,
1999). Numerous techniques have been developed to
improve sample preparation and detection methods
to achieve better sensitivity, accuracy, precision, and
detection limits through the enhancement of features
such as miniaturization and the acceleration of ana-
lytical processes. However, despite great strides being
made, the detection of organotin compounds remains
a challenging task. A major challenge is the develop-
ment of effective diluted sample preparation strategies
that must be implemented before samples are actually
subjected to detection analysis. Therefore, the search
continues for sensitive analytical methods capable of
providing quantitative analysis for various classes of
organotin compounds at very low limits of detection.
In the past, many colorimetric methods have been
applied for the detection of tin, using dithiol, catechol
violet, phenylfluorone, oxine (8-quinolinol), dithi-
zone, and quercetin (Adcock and Hope, 1970; Corbin,
1973). However, these methods are not very sensitive
and they do not distinguish between the various tin
compounds that may be present in the sample. Thus,
for catechol violet, sensitivity was given as 0.1 μg tin
in the sample (Corbin, 1973). Compared with the con-
ventional spectrophotometer, charge-coupled device
diode array detectors can improve precision and the
signal-to-noise ratio and rapidly scan the absorption
spectrum. Application of the diode array detector in
the sequential injection analysis methodology devel-
oped for the determination of Sn in canned food gen-
erated data in good agreement with electrothermal
(ET)-AAS (Boa Morte et al., 2009).
Anodic stripping voltammetric analysis has shown
good sensitivity, for micromolar level detection of tri-
phenyltin (Booth and Fleet, 1970; Florence and Farrar,
1974). However, the critical step in stripping experi-
ments is the preconcentration (or deposition) step,
when analyte compounds are deposited on the elec-
trode from the solution, as well as the problem of
overlapping stripping signals (for example, stripping
signals for tin and lead) in multianalyte determina-
tion. The overlap problem can be overcome either
by chemical separation of tin or by using a stripping
voltammetric procedure at the bismuth film electrode
(in place of a mercury film electrode) in the presence
of a supporting electrolyte (Prior, 2010; Hutton et al.,
2006; Frena et al., 2011). This enhanced procedure
improves the detection limits for tin (to 1.9 μg/L) and
enables multielement detection. The modification of
1243
a glassy carbon electrode with bismuth and a film of
poly(bromophenol blue) allows one to measure tin in
canned food with a detection limit of 7 nM (Yang et al.,
2012). A linear sweep voltammetric approach was pro-
posed for gaining rapid information on tin release in
processed canned food (Toniolo et al., 2009). Although
this method does not provide quantitative data on
metal release, it determines the thermodynamic condi-
tions controlling a specific tinplate corrosion process
and allows one to establish whether epoxyphenolic
lacquered tinplates should be employed.
An AAS analytical method for the detection of tin
was widely used in the past for the detection of inor-
ganic tin in metallurgical samples and biological mate-
rials. However, in routine operations where tin level is
below 3-5 μg, flame AAS has an unsatisfactory detec-
tion power (Engberg, 1973). The replacement of flame
with an electrically heated graphite tube increases the
atom density and residence time, which improves
graphite furnace (GF)-AAS detection limits by a fac-
tor of up to 1000 times compared to flame AAS, thus
bringing the detection limits down to the 0.1-05 μg/L
range. Furthermore, GF-AAS allows the direct deter-
mination of tin in solid samples (Hirano et al., 2001)
However, because of the temperature limitation, the
refractory element performance is still somewhat lim-
ited. Furthermore, limitations of GF-AAS are the inter-
action of tin with graphite during the atomization step
and matrix interference. In electrothermal atomizers
(ET-AAS), which include GF, increased light absorp-
tion lowers the detection limits. This technique was
developed in the 1990s and was widely used for the
detection of tin in biological materials and sediments.
ET-AAS can be used for the analysis of tin in water
(NEMI, Standard Method 3113B; APHA, 1998a,b).
Combined with high-performance liquid chromatog-
raphy (HPLC) separation, ET-AAS showed higher
selectivity and sensitivity (Quevauviller et al., 1993).
In combination with a hydride generation system GF-
AAS technique (HG-GF-AAS), tin is reduced to its
volatile hydride, which allows direct analysis of solid
samples with higher sensitivity (Hirano Y. et al., 2001).
However, the dependence of the hydride species on
the acidity of the sample solution makes this technique
less reliable. The development of ICP atomic emission
spectroscopy (ICP-AES) reduced the interference of the
sample matrix, enhanced productivity, and improved
the detection limits and dynamic ranges for quantita-
tive multielement analysis. As with emission spectros-
copy, the samples are atomized in this method. The U.S.
Environmental Protection Agency (USEPA) approved
ICP-AES for the determination of metals in environ-
mental samples and drinking water analysis (USEPA,
1994a,b). ICP-AES environmental applications require
1244 Elena A. Ostrakhovitch
that (1) samples must be in a liquid form so as to be
aspired through a nebulizer to increase the mass trans-
fer efficiency and (2) suspended soils and sediments
must be first digested to extract the metal. Drinking
water with turbidity higher than one normal turbidity
unit must also be digested prior to analysis for the suc-
cessful separation of the analyte from the matrix. The
detection limit was determined as 30 μg/L (Perring and
Basic-Dvorzak, 2002). ICP-AES has been used for the
detection of tin in water, sediments, plants, animal tis-
sue, air filters, soil, leachates, effluents, food samples,
and biominerals (Yokoi et al., 1990a; Elekes et al., 2010;
Afonso et al., 2010; Perring and Basic-Dvorzak, 2002;
Boutakhrit et al., 2011). ICP-AES is the preferred method
for the routine analysis of tin in canned food due to its
good accuracy, reliability, and ease of use. The method
was recommended for measurements of airborne
inorganic tin and its compounds, except for oxides
(NIOSH, 1994). In 2002, a combined nebulizer/gas-
liquid separator design was introduced (McLaughlin
and Brindle, 2002). A multimode sample introduction
system (MSIS) was patented in 2005; it is capable of
operating as a conventional spray chamber, as a gas-
liquid separator, or both (McLaughlin et al., 2006). Gas
from the nebulizer strips the volatile species and deliv-
ers them to the plasma. The MSIS diminishes the sig-
nal noise and improves detection limits. The Canadian
Association for Environmental Analytical Laboratories
has approved the MSIS application for the detection
of elements in sludges, biosolids, soils, drinking water,
and wastewater.
ICP-MS also uses an ICP plasma source to dissoci-
ate the sample into atoms and ions. However, ICP-MS
detects ions separated on the basis of their atomic mass-
charge ratio rather than by the light they emit. ICP-MS
has been used for the detection of tin compounds in
urine samples, food samples, soils, waters, and sedi-
ments with high levels of precision and reproducibility
(Sieniawska et al., 2012; Millour et al., 2011; Boutakhrit
et al., 2011; APHA, 1998c). The ICP-MS detection limit
for tin in canned food was 0.1 μg/kg, as compared to
0.5 μg/kg for HG-ICP-AES and 2 mg/kg for ICP-AES
(Boutakhrit et al., 2011). Tin is not specifically listed as
an analyte for ICP-MS (NEMI, Standard Method 3125).
However, it can be quantified in water, canned milk,
and in fruits by ICP-MS (ISO, 2003a,b, 2004). Laser
ablation ICP-MS (LA-ICP-MS) allows mulielemental
analysis without extensive sample preparation with
a shortened analysis time. LA-ICP-MS was shown to
be an efficient method for the characterization of trace
metals in complex solid matrices such as heteroge-
neous domestic wastes and polymer waste, as well as
compost (Motelica-Heino et al., 1998; Jimenez et al.,
2007; Stehrer et al., 2010). Recently, a new technique
was developed to measure tin isotopic composition
with high precision: multicollector ICP-MS (MC-ICP-
MS) on a Nu Plasma 500 (Moynier et al., 2009). Tin
isotopes have been fractionated by liquid-liquid tin
isotope extraction with a crown ether, dicyclohexano-
18-crown-6 (or DC18C6).
Where determination of specific organotin com-
pounds is required, a separation technique such as GC
with a flame-ionization detector (FID), a flame pho-
tometric detector (FPD), a pulsed flame photometric
detector (PFPD), or a thermal conductivity detector
(TCD) is useful. The GC-FPD or GC-FID techniques
cannot provide structural information. However, GC-
PFPD offers a compromise between analytical cost and
satisfactory levels of sensitivity, selectivity, and reli-
ability for the detection of organotin compounds in a
broad range of soils (Jing and Amirav, 1998; H ­ eroult
et al., 2008). A method combining the advantages
of both GC and MS (i.e. GC-MS) has been accepted
as a “gold standard” technique for the detection of
volatile and semivolatile organic compounds. Meth-
ods most frequently used are GC-MS and HPLC-­
coupled MS (Kawaguchi et al., 2004; Devos et al., 2005;
Lopez de Alda et al., 2001). GC-coupled ICP-MS (GC-
ICP-MS) provides the possibility of applying species-
specific isotope dilution analysis for the quantification
organometallic compounds (Monperrus et al., 2003;
Pinel-Raffaitin et al., 2007). The detection limits of
alkylated tin compounds were in the range of 0.01 to
0.04 μg Sn/L, with the best detection limits for dibutyl-
and tributyltin compounds. A comparison of ICP-MS,
HG-ICP-AES, ETA-AAS, and ICP-AES techniques for
the routine analysis of tin in canned food demonstrated
that ICP-AES is the preferred method for the range of
50-200 mg/kg due to its good analytical performance,
reliability, and ease of use (Boutakhrit et al., 2011).
GC-MS analysis with FID was found to provide
adequate sensitivity for the detection of volatile alkyl-
tins. The detection limit of this analytical procedure
for alkyltins was calculated to be 4.8 pg, with the
detection limit of the overall procedure (measured as
mass per sample and expressed as equivalent air con-
centration) calculated as 0.21 μg/sample (4.3 μg/m3).
However, a major drawback of GC for tri-, di-, and
monosubstituted organotin detection is the require-
ment of a derivatization step because of the poor
volatility of these organotin compounds. GC-ICP-MS
has been employed for the detection of organometal-
lic compounds of tin (Rajendran et al., 2000; Uveges
et al., 2007; Inagaki et al., 2007; Pinel-Raffaitin et al.,
2007). A major challenge of the GC-ICP-MS techniques
is to avoid thermal degradation of analyzed com-
pounds in the injector and column and during trans-
port from the column to the ICP torch. Capillary GC
 56 Tin
coupled to a PFPD achieved a low ng/L detection level
range for pesticidal and nonpesticidal organotin com-
pounds (Evans et al., 2009). Derivatization of organo-
tin compounds with tetraethylborate was coupled to
liquid-liquid extraction. Capillary GC coupled to high
resolution double-focusing magnetic sector MS detec-
tion offers high resolution and sensitivity in the detec-
tion of tin species, bringing the detection limits below
3 ng/L for inorganic tin, monophenyltin, diphenyltin,
triphenyltin, and monobutyltin. For dibutyltin and
tributyltin, the detection limits were calculated to be
3.4 and 7.3 ng/L, respectively (McSheehy et al., 2012).
HR-ICP-MS detection shows a high resolving power,
high sensitivity, and an extremely low background,
exceeding the performance of a quadrupole instrument.
An alternative to GC analysis is liquid chromatogra-
phy (LC), which does not require the prior derivatiza-
tion of organotins. Ion exchange LC and reversed
phase LC have been proposed to achieve the separa-
tion of mono-, di-, and trialkyl tin derivatives. Origi-
nally, coupling GC with ultraviolet (UV) detection,
ICP optical emission spectrophotometry (ICP-OES),
flame atomic absorption spectrophotometry (FAAS),
or GF-AAS was discounted because of poor sensitivity
(Gonzalez-Toledo et al., 2003). In ICP-OES, the radiation
emitted is measured at a unique wavelength, whereas
in ICP-MS the tail flame of the plasma is extracted into
a low-pressure interface containing the sampler and a
skimmer. The ions are transmitted to a mass analyzer
via an ion lens system. Although ICP-OES allows one
to simultaneously detect metal ions at different concen-
tration, the detection limits are in the μg/L range. ICP-
MS offers the advantages of ICP-OES along with those
of mass spectral acquisition, such as excellent sensitiv-
ity, enhanced detection limits (reaching ng/L levels),
and isotopic analysis. LC-coupled electrospray ioniza-
tion MS (ESI-MS) was proven to be a powerful method
for detection of triorganotin compounds in water
samples. ESI-MS (Q, quadrupole, quadrupole ion trap,
QqQ, triple quadrupole, and QqTOF, and quadrupole-
time-of-flight detection) is suitable for both polar and
ionic organometallic compounds and allows the analy-
sis of highly dilute solutions (Henderson and ­Taylor,
1996; Henderson and McIndoe, 2005; Baul et al., 2008;
Chalupa et al., 2008). The ­limits of detection for tribu-
tyltin and triphenyltin were 10 and 20 pg, respectively
(Sano et al., 2010). However, ESI-MS detection also
imposes some restrictions related to chromatographic
separation. Fluorescence detection has found an
application in LC as a sensitive detection approach
to tin speciation. However, organotin compounds
are nonfluorescent, and derivatization reagents such
as ­flavone derivatives are required to allow their detec-
tion. The application of HPLC has the advantage of
1245
enabling the separation of nonvolatile species. HPLC
coupled to ICP-MS (HPLC-ICP-MS) or to ESI-MS, tan-
dem MS/MS, and AAS increase its application range.
LC-MS/MS can be performed without complete sep-
aration of the different compounds, which makes it
highly suitable for high-throughput analyses. The LC-
ESI-MS/MS method of detection allows quantification
in the low range of 0.01-0.02 μg/L. HPLC-coupled MS
(HPLC-MS) was developed for speciation analysis of
methylated tins, such as mono-, di- and trimethyl-
ated tin species, dibutyltin and triphenyltin (Wahlen
and Catterick, 2003; Wang et al., 2008; Yoo et al., 2007;
Suzuki et al., 2008). HPLC-ICP-MS was applied for the
simultaneous detection of dibutyl-, tributyl-, diphenyl-,
and triphenyl tin species in shellfish samples with
detection limits ranging from 0.24 to 0.37 μg/L and
recoveries of over 80% for dibutyl- and diphenyltins
(Yu, Z.H. et al., 2010). The limits of ESI-MS detection
were 0.4 μg/L for tributyltin and 20 μg/L for triphen-
yltin compounds (Wang et al., 2008). However, MS/
MS was proven to be insufficient for the detection of
di- and trimethylated tin compounds in diluted sam-
ples. Multiple reactions monitoring mode was applied
in order to achieve a higher sensitivity with MS/MS
detection and to reach the detection limit of 0.1 mg/L
or less for trimethylated tin (Suzuki et al., 2008). An
HPLC-coupled HG-ICP-MS system was developed
for rapid, direct, and sensitive speciation of methyl-
tins in seawater without any pretreatment step, with
detection limits of 0.266 and 0.095 ng/mL for mono-
dimethyltins, respectively, and as low as 0.039 ng/
mL for trimethyltin (Zhai et al., 2009). However, some
basic analytical problems such as incomplete separa-
tion, column packing, and column and buffer solu-
tions competing for bioinorganic ligands remain to be
solved. The development of hydrophilic interaction
LC-ESI-MS analysis allows one to analyze the concen-
trations of tributyltin and triphenyltin compounds in
seawater at parts-per-trillion levels (Sano et al., 2010).
Detection methods such as ICP-MS and ESI-MS are
extremely sensitive. However, there are several dis-
advantages. The presence of the organic phase and
the proportion of salt in the mobile phase during LC
separation may jeopardize accurate quantification by
ICP-MS and ESI-MS as a result of increased spectral
overlap, leading to positively biased results. There-
fore, restrictions are placed on the type of eluents and
concentration of salts that can be employed. Capillary
electrophoresis is an alternative to chromatography
for the separation of organometallic compounds. Elec-
trophoresis in conjunction with ICP-MS was devel-
oped for the separation and analysis of trimethyl-,
tributyl-, dibutyl-, and monobutyltin compounds
(Sun et al., 2010). The authors applied a semipermanent
1246 Elena A. Ostrakhovitch
coating of dioctadecyl dimethyl ammonium chloride
to enhance methyltin separation. The detection limits
for these organotin compounds ranged from 0.037 to
0.112 mg/L, with method accuracies of 8.6 and 7.8% for
tributyltin and dibutyltin, respectively.
Samples are commonly complex and heteroge-
neous, with low species concentration. Thus, for
sediment samples, sieving is often used to limit the
heterogeneity of samples (Quevauviller and Donard,
1990). Acidification of filtered water samples and
freezing followed by oven-drying of sediment samples
was shown to be suitable for preserving the stability
of organotin compounds. The samples often require
additional clean-up and preconcentration to obtain a
sufficiently high amount of sample for measurement.
Four main methods of sample digestion are commonly
reported by laboratories: dry ashing of the sample in a
conventional oven; microwave digestion of the sample
in a strong acid; acid digestion of the sample by heating
in a pressure vessel; and dissolving the sample directly
into acid. Some laboratories also extract the metals in
2-methylhexan-2-one isobutyl methyl ketone. Meth-
ods of sampling and analysis for the official control of
the level of inorganic tin was implemented by Euro-
pean Commission regulation No 836/2011 amend-
ing European Commission regulation No 333/2007
(European Commission, 2011). Microwave diges-
tion was approved by the USEPA using closed-vessel
method, which employs hydrofluoric acid, for the
solubilization of all suspended solids. It was speci-
fied by Occupational Safety and Health Administra-
tion (OSHA) that specific organotins must be sampled
and analyzed until a satisfactory procedure for sepa-
rating the organic tin compounds as a group from the
inorganic ones is found. The National Institute for
Occupational Safety and Health (NIOSH) method for
organotin compounds (NIOSH, 1994) recommended
sampling with a glass fiber filter/XAD-2 sorbent tube,
desorption with acetic acid/acetonitrile, and analysis
with HPLC and GF-AAS. In this procedure, specific
organotin compounds are used for calibration. How-
ever, this method is not suitable for volatile tetraethyl-
tin and tetramethyltin.
Preconcentration may involve hot trapping or ion
exchange materials combined with an extraction or
derivatization step. Organometallic species in envi-
ronmental samples are mostly ionic and nonvola-
tile. For organotin speciation analysis, especially for
GC separation, sample derivatization is crucial for
organotin extraction from the original matrix into non-
polar medium to facilitate preconcentration and subse-
quently provide volatile thermally stable compounds
for separation (Centineo et al., 2004; Penalver et al.,
2011). Alkylation of organotin salts for subsequent
GC analysis can be accomplished using either the
Grignard reaction or alkylation with sodium alkylbo-
rate. However, nonaqueous alkylation, such as the use of
Grignard reagent, is less used due to complex multistep
analytical procedure and the requirement for strictly
anhydrous conditions. The advantage of using alkylbo-
rate is its stability in water, compared to the hydrolytic
instability of Grignard reagents (Dabek-Zlotorzynska
et al., 1998). However, the main disadvantage of using
NaBEt4 is its short lifetime in the presence of oxygen
and moisture. The rate of derivatization depends on
the pH of the medium, metal ion concentration, and
temperature. The working pH range for the derivatiza-
tion reaction is between 4.0 and 5.0. Cai and Bayona
(1995) have optimized the pH range for the ethyl-
ation reaction of organotins by sodium tetraethylbo-
rate without any additional clean-up step. Tropolone
has been used as chelating agent for the derivatiza-
tion of tin ions (Lu and Whang, 1995; Inagaki et al.,
2007). However, the most widely used methods for
tin derivatization are ethylation and, to a lesser extent,
propylation using sodium tetraalkylborates [sodium
tetraethylborate (NaBEt4), tetrapropylborate (NaBPr4),
bromomagnesium tetrapropylborate (BrMgPr4B), and
bromomagnesium tetraethylborate (BrMgEt4B)] (de
Smaele et al., 1998; Ashby and Craig, 1988b; Bergmann
and Neidhart, 2001; Nsengimana et al., 2009). Methods
of organometallic tin extraction include liquid-liquid
extraction and solid-liquid extraction procedures.
However, both of these methods are time-consuming
and require high amounts of organic solvents in order
to isolate and preconcentrate the derivatized ana-
lytes (Zachariadis and Rosenberg, 2009a,b). However,
­liquid-liquid extraction in hexane after derivatization
by tetraethyl- or tetrapropylborate reagents was suc-
cessfully applied for the fast speciation of tributyltin
compounds in human urine (Kapsimali et al., 2012).
With regard to the trend toward sample size miniatur-
ization, avoiding hazardous solvents, and minimiz-
ing the number of steps, solid phase microextraction
methods have been developed in combination with a
derivatization reaction for total element determination
(Kaur et al., 2006; Centineo et al., 2004). The derivatized
species are moved into the vapor phase, therefore mini-
mizing interference from the sample matrix. The use of
tetraethylborate and solid phase microextraction, cou-
pled with GC, were recommended for the speciation
analysis of methyltin (Morcillo et al., 1995; Cui et al.,
2011). NaBPr4 has been used for the detection of tribu-
tyltin in sediments by solid phase microextraction com-
bined with isotope dilution GC-MS (Bancon-Montigny
et al., 2002). Butyltin and tetramethyltin compounds
were detected by headspace solid phase microextrac-
tion after derivatization with NaBEt4 combined with
 56 Tin
either GC-ion trap MS-MS, GC-PFPD, or capillary GC-
coupled microwave-induced plasma atomic emission
detection (Azenha and Vasconcelos, 2002; Carvalho
et al., 2007; Zachariadis and Rosenberg, 2009b; Le Gac
et al., 2003; Tzollas and Zachariadis, 2010). However,
despite the critical need for derivatization in GC, there
is always risk of NaBEt4 interaction with components
of the sample and of producing by-product deriva-
tives, which increases the complexity of their deter-
mination. Molecular imprinted solid phase extraction
was developed for organotin compounds (Puri et al.,
2004; Gallego-Gallegos et al., 2006). Rahmi et al. (2010)
developed syringe-based solid phase microextraction,
named “tip-in chelating monolith,” for trace elements
including tin in natural waters. The “tip-in chelat-
ing monolith” was prepared within a commercially
available syringe filter tip by polymerization of 22 5%
glycidyl methacrylate, 7.5% ethylene glycol dimethac-
rylate, 35% 1-propanol, and 28% 1,4-butanediol, and
subsequent modification with iminodiacetate solution.
The elements were detected by ICP-MS, with a detec-
tion limit for tin of 0.0015 μg/L. Tin speciation has been
also performed using polydimethylsiloxane (100 μm)
as a preconcentration polymer. The thickness of the
polymer coating plays an important role, since the
thicker the film employed, the slower the absorption
process and the higher the desorption temperature is
required.
The point of primary importance is the validation
of new or modified methods before their application.
The sampling procedures and methods of tin analy-
sis have been implemented by legislative acts of the
European Union No. 1881 and No. 333 (European
Commission, 2006a, 2007) for the official control of
the levels of tin. These legislative acts require valida-
tion of the methods through analysis of certified refer-
ence materials such as marine sediment, river water,
and certified biological reference materials to prevent
scattering of values. This also allows the comparison
of data obtained from different sources. Furthermore,
validation of the sample treatment step for specifica-
tion of tin species is crucial. A major problem is the
insufficient number of matrices that match certified
reference materials. For tin species, available matri-
ces are freshwater sediment (BCR 646), certified for
mono-, di- and tributyltin compounds, mono- and
diphenyltins; costal sediment (BCR 462), certified to
dibutyl-, tributyl-, and triphenyltins; and harbor sedi-
ment certified reference material (PACS-2) and mussel
tissue (ERM-CE477), which were certified for mono-,
di-, and tributyltin compounds, as well as the recently
added sewage sludge quality control material (Dietz
et al., 2007; Zuliani et al., 2012). However, new meth-
ods still need to be developed for the quantitative
1247
extraction, separation, and analysis of various inor-
ganic and organic tin compounds.
3  PRODUCTION AND USES
3.1 Production
Tin is a relatively rare element, with an abundance
in the Earth’s crust of about 2.2 parts per million or
2.2 mg/kg, which accounts for approximately 0.00022%
of the total mass of the Earth’s crust. Tin does not occur
as a free metal in nature. The major mineral source of
tin is cassiterite (SnO2) ore. However, small quantities
of tin are recovered from sulfide minerals containing
tin such as stannite (Cu2S-FeS-SnS2), cylindrite (Pb3Sn4
FeSb2S14), frankeite (Fe(Pb,Sn)6Sn2Sb2S14), and teallite
(PbSnS2). The world resources of tin, principally cassit-
erite, are located in western Africa, southeastern Asia,
Australia, Bolivia, Brazil, China, and Russia, whereas
at least half of the world’s supply of tin comes from
Southeast Asia. The world tin reserves are estimated
to be 5.2 million metric tons. In 2009, statistics for the
world’s major tin producing countries were estimated
as China (44%), Indonesia (21%), Peru (14%), Bolivia
(7%), and Brazil (5%). In response to higher tin prices
in 2011, tin producers opened new tin mines and tin
smelters and expanded the existing operations, includ-
ing those in Australia, Bolivia, Canada, and Thailand.
The total world mine production of tin reached 265,000
tons in 2010 and slightly decreased to 253,000 tons in
2011 (USGS, 2010).
The largest producers of recycled tin are France and
the United States. According to the most recent sur-
vey conducted by ITRL Ltd (2011), global refined tin
consumption was about 350,000 tons in 2011, whereas
about 12,500 tons of tin was recovered from second-
ary (old and new scrap) metal. In 2010, about 16% of
tin consumed in the United States was recovered from
secondary metal.
On 4 January, 2011, the “Reduction of Lead in Drink-
ing Water Act” (Public Law 111-380) was passed by the
U.S. Congress. The law lowers the national standard
for lead in faucets, pipe fittings, and pipes from 8.0% to
0.25%, which may lead to a greater use of tin in plumb-
ing fixtures (Plumbing Manufacturers International,
2011). ITRL Ltd (2011) estimated that the global tin
demand in 2015 would be about 400,000 metric tons
per year.
Organometallic tin compounds have been increas-
ingly produced since 1950, reaching 50,000 tonnes
pumped by the organotin industry each year between
1990 and 2003 (Fent, 1996). Twenty-five organotin
compounds are presently produced and used to any
great extent (Laughlin and Linden, 1985). Since the
1248 Elena A. Ostrakhovitch
ban on tributyltin-based, dibutyltin, and dioctyltin for-
mulations, the production of organotins has gradually
decreased. A major commercial application of organo-
tin compounds is in the production of polyvinyl chlo-
ride (PVC) plastic stabilizers. In Europe, the highest
use of organotin stabilizers is in calendered film (10,000
tons) and sheet and profile (1500 tons), according to
the European Council of Vinyl Manufacturers. In 2009,
8% of stabilizer production in the EU was organotin-
based (over 10,000 tons). However, dibutyltins will be
prohibited by 2015 for use in soft PVC profiles, coated
fabrics for outdoor use, outdoor pipes, and roofing
materials. The use of dioctyltins has been restricted
since January 2012 in skin contact textiles and wall and
floor coverings.
3.2 Uses
Industrial applications of inorganic tin chemicals
are classified as direct or indirect. Indirect applications
include tin salts used as electrolytes for tinplate and tin
compounds used as intermediates in the manufacture
of other compounds. Stannous chloride is the most
commercially used inorganic tin compound in organic
and inorganic synthesis and tin galvanizing. The major
uses of tin in 2003 were cans and containers, 27%; elec-
trical, 23%; construction, 10%; and others, 40% (Carlin,
2004). Tin is used in tin-plated food cans and in aerosol
containers for protection against corrosion of the base
metal. Tin alloys cover a wide range of compositions
and many applications. Solder, an alloy of 63% tin and
lead, is primarily used for electronic applications and
has consistently accounted for more than 50% of the tin
end-use market since 2005. Lead-free tin solders, con-
taining up to 5% silver or antimony, are used at high
temperatures. Tin alloys, including babbit (containing
copper, antimony, tin and lead), brasses and bronzes
(essentially tin-copper alloys), pewter (containing tin,
1-8% bismuth, and 0.5-3% copper), are widely used
(Bulten, 1991). Tin is also an important component
of dental amalgams (silver, tin, and mercury alloy),
which has been used for centuries. However, today’s
dental alloys exclude mercury and consist of silver, tin,
copper, indium, palladium, and zinc. Titanium alloys
are used in aircraft components, whereas tin alloys
with zinc, nickel, or copper are used in superconduct-
ing cables and magnets. Indium-tin oxide is used in
spectroelectrochemistry, metallic photonic crystals and
liquid crystal display, organic light-emitting diodes,
and photovoltaic and other applications. Direct appli-
cations include the use of mixed tin oxide-metal oxide
systems as pigments. Furthermore, SnO2 is used in the
manufacture of alabaster glass and enamels, dyeing
fabrics, and varnish, SnS2 in pseudogilding, SnF2 in
toothpastes because of its long-lasting inhibitory effect
on oral microflora, and SnCl2 in soft drinks. Inorganic
tin compounds are also used in the ceramic and glass
industries.
Organometallic tin compounds comprise mono-,
di-, tri-, and tetrabutyl and triphenyl tin compounds.
They are widely used as stabilizers for PVC (76%),
antifouling biocides (10%), agricultural biocides (8%),
and catalysts for the production of polyurethanes and
silicones (5%). These uses account for approximately
20,000 tons of tin consumption per year. Mono- and
dialkyltin compounds (RSnL3 and R2SnL2) are well-
established PVC stabilizers that have been used to
reduce polymer backbone degradation and inhibit
heat- and light-induced deterioration of plastic prod-
ucts since the mid-twentieth century. There are three
major types of tin stabilizers: octyltin, butyltin, and
methyltin. In chemical synthesis, the organotins (pre-
dominantly monobutyltin, dibutyltin, and dioctyltin)
are used for esterification and transesterification of
mono- and polyesters. Alkyltin chlorides are the main
industrial precursors of commercial organotin prod-
ucts. The major commercial application of organotin
compounds is as stabilizers of rigid PVC to prevent
photochemical and thermal transformation (Kizlink,
1996). Organotin stabilizers are mostly a mixture of
mono- and dialkyltins, ranging from 10 to 80% mono-
alkyl. The main consumer uses of octyltin stabilizers
are in the production of rigid packing materials such
as bottles and pots for food and cosmetics. Dibutyltin
stabilizers were used in soft PVC profiles, coated fab-
rics for outdoor use, and outdoor pipes and roofing
materials, whereas dioctyltins were applied in textiles,
and wall and floor coverings. However, the European
Commission banned dibutyltin compounds in mix-
tures, and dioctyltin compounds from 2012. In 2008,
Environment Canada implemented regulations to
improve management practice guidelines to minimize
the releases of organotin stabilizers. The compounds
have been used in PVC fabric coatings, shoe insoles,
and antimicrobial finishes for socks and sport clothes.
Monooctyltin stabilizers offer excellent transparency
for rigid PVC, with almost no discoloration. A methylt-
invinyl stabilizer was designed for demanding foam
extrusion applications, in particular rigid vinyl pipes.
Monoorganotins (predominantly monobutyltin) and
diorganotins are used on glass containers.
Trisubstituted organotin compounds (R3SnL) have
biocidal properties, whereas monobutyl- and dibutyl-
tins do not exhibit these properties. Trimethyltins are
highly insecticidal, and the tripropyl-, tributyl-, and
tripentyltin compounds have high fungicide and bac-
tericide activities. Among the trisubstituted organo-
tin compounds, the most important are tributyltin,
 56 Tin
triphenyltin, and tricyclohexyltin compounds. Tribu-
tyltin was used from the 1960s onward as a biocide anti-
fouling agent in paints for underwater structures and
on the hulls of ships to prevent the growth of barnacles,
seaweed, and other organisms (Granmo et al., 2002).
These antifouling paints contained approximately 20%
(w/w) tributyltin, and released about 4 μg/cm2/day
tributyltin into the surrounding water (Matthias et al.,
1988; Swennen et al., 1997). The application of tribu-
tyltin in antifouling paints was restricted throughout
the 1980s and early 1990s in many countries around
the world due to their high toxicity to aquatic organ-
isms (Okoro et al., 2011). The International Maritime
Organization proposed a worldwide ban on tributyl-
tin-containing paints, commencing with a ban on its
application on vessels in 2003 and a total ban on its
presence on vessel hulls by 2008 (Gipperth, 2009). The
European Commission banned the use of trisubstituted
organic tin compounds in 2010. Tributyltin and triphe-
nyltin compounds cannot be used after 1 July, 2010, on
articles where its concentration is greater than 0.1% by
weight of tin (European Commission, 2010). The ban
on the use of organotin compounds as antifoulants and
biocides worldwide has resulted in reduced release of
these compounds into the environment. The measures
taken so far have reduced imposex (a marine snail
disease) indices in the majority of location monitored.
However, the release of organotin compounds to water
continue as a result of redistribution and resuspension
of organotins through the dumping of contaminated
sediments from docks removing contaminated coat-
ings from ships.
Other applications include tributyltin and triphe-
nyltin use as industrial disinfectants in circulating
industrial cooling waters, for controlling slime in
paper mills, as a slimicide in masonry, as a biocide
disinfectant for textile and leather processing, and in
industrial wood treatment, paper mills, and the brew-
ing industry (Antizar-Ladislao, 2008). However, these
uses are minor and are declining. Triorganotins such
as triphenyltin hydroxide, tricyclohexyltin hydroxide,
tricyclohexyltin triazole, trineophenyltin oxide, and
triphenyltin acetate are used as agricultural fungicides
and acaricides (Isensee et al., 1994).
4  ENVIRONMENTAL LEVELS AND
EXPOSURES
4.1  General Environment
Tin is present in water, sediments, soils, dust and
air. The presence of inorganic tin and organotin stabi-
lizers was also documented in household dust. Dust
in homes of men employed as electric cable splicers
1249
contained tin at concentrations as high as 242 mg/kg,
with the highest concentration in the laundry area,
suggesting occupational contamination of the cloth-
ing (Rinehart and Yanagisawa, 1993). Organotins were
found in house dust at concentrations from 390 to
28,000 ng/g (Kannan et al., 2010). The relative abun-
dances of organotin compounds in house dust were
ranked in the order:
monobutyltin → monooctyltin → dibutyltin → dioctyl-
tin → tributyltin
with monobutyltin accounting for 50% of the total
organotin concentration. The abundance of monobutyl-
tin suggests that a major source of organotin compounds
in household dust is heat- and light-stabilized PVC
products. Concentrations of total organotin species var-
ied widely from 140 to 780,000 ng/g in wallpapers and
from 3700 to 120,000 ng/g in floor tiles. The calculated
maximum daily intake of organotin in children through
dust ingestion was 186 ng/kg body weight (b.w.), which
is below the tolerable daily intake of 250 ng/kg b.w. per
day. However, dietary intake combined with intake
through the dust digestion could reach the tolerable
daily intake value. Additional sources of tin include
mining, industrial production (foundries, smelters,
oil refineries, petrochemical plants, pesticide produc-
tion, chemical industry), untreated sewage sludge, and
diverse sources such as PVC piping, traffic, and com-
bustion by-products from coal-burning power stations.
An increasing global problem is the management of
electronic waste (e-waste), particularly the disposal of
old computers and mobile phones (UNEP, 2006).
Inorganic tin(II) can be methylated in the environ-
ment in the presence of methyl donors such as methyl-
cobalamine (Dizikes et al., 1978; Ashby and Craig, 1991;
Craig and Rapsomanikis, 1985; Chen et al., 2006). Both
estuary microorganisms and marsh grass exhibited the
ability to convert inorganic tin into methylated coun-
terparts (Hallas et al., 1982; Falke and Weber, 1994a).
Guard et al. (1981) also demonstrated that trimethyl-
tin compounds can be further methylated in estuarine
sediments. Methylation of tin(II) in the presence of
organic methyl donors occurs through oxidative trans-
fer of carbonium ethyl to yield monomethyltin, with
the highest yield obtained at pH 5 (Chen et al., 2012).
However, monomethyltin transforms to dimethyltin
as the pH increases. In aqueous solutions with low
acidity, tin transforms into dimethyltin, as well as tri-
methyltin as the minor product.
The widespread use of organotin antifouling paints
and biocides has introduced high levels of organo-
tin compounds into the aquatic system. Organotins
are hydrophobic and only slightly soluble in water.
Approximately 95% of tributyltin in water was found
1250 Elena A. Ostrakhovitch
to be bound to suspended particles and the remainder
was associated with dissolved organic matter and both
organic and inorganic ligands (Gadd, 2000; Fent, 1996).
Sorption of organotin compounds onto particles,
with sorption coefficients ranging from 100 to 10,000,
is mostly followed by sedimentation (Sanderson
et al., 2002; Weidenhaupt et al., 1997; Stewart and
Thompson, 1997; Stewart and Demora, 1992). Conse-
quently, trisubstituted organotin compounds and their
degradation products such as di- and monoorganotins
accumulate in marine sediments. The aqueous degra-
dation rates of triorganotin are faster than those found
in aerobic sediments, and faster again than those in
anaerobic sediments.
Since the ban on the use of organotin com-
pounds in the antifouling paint was introduced in
2008, remobilization of sediments with a high con-
tent of organotin compounds is the main source of
­contamination. Organotin toxicity is highest for trisub-
stituted species, and the ecotoxicity increases in order:
tributyltin → dibutyltin → monobutyltin. The high con-
centrations of organotins are extremely harmful to the
marine environment and have been linked to mass
mortalities of marine mammals, reproductive failure
related to imposex, and population decline in gastro-
pods, mussels, oysters, and other species (Horiguchi
et al., 2001a,b). Marine mollusks can accumulate up to
5 μg/g tributyltin (Hoch, 2001). Crustaceans and fish
accumulate much lower amounts of organotin due to
their ability to degrade tributyltin. The no observed
effect level (NOEL) for oyster spat is about 20 ng/L,
whereas the development of imposex is associated
with NOEL values as low as 1.5 ng/L (WHO, 1990).
Organic tin compounds accumulate in the tissue of
filter-feeding zooplankton, grazing vertebrates, fish,
water birds, and mammals (Berge et al., 2004; Borghi
and Porte, 2002; Harino et al., 2000; Ohji et al., 2007).
Organotin compounds were reported to negatively
affect the immune system of fish and seals (Allner
et al., 2010; Frouin et al., 2008).
4.1.1  Food and Daily Intake
Food is the main source of tin in humans. The
amounts found in fresh meat, cereals, and vegetables
depend on the concentration of tin in the soil of the
area in which the food is produced. Stannous chloride
(SnCl2) is a permitted food additive (E512). Further-
more, tin is present in some multivitamin and mineral
supplements at levels up to 0.01 mg in the daily recom-
mended dose. Larger amounts of tin may be found in
foods stored in plain cans and, occasionally, in foods
stored in lacquered cans and drink cans. Canned food
contains more or less dissolved tin, depending on the
pH of the content, storage temperature and time, and
the presence of nitrates used as fertilizers (Blunden
and Wallace, 2003). Exposure of the general popula-
tion to tin is essentially dietary in origin, deriving
particularly from the consumption of food stored in
cans. This may provoke gastric irritation in certain
susceptible groups. European Commission regulation
No. 242/2004 (­ European Commission, 2004) intro-
duces limits for inorganic tin in canned foods, canned
beverages, and canned infant foods. For canned solid
foods, the maximum levels are set at 200  mg/kg
and for canned beverages at 100 mg/kg (European
­Commission 2006a; JECFA, 2011). The acceptable level
of tin in cooked chopped meat, cooked ham, corned
beef, and luncheon meat is 50 mg/kg. For inorganic tin
in canned foods and canned beverages for children,
the maximum permissible level is 50 mg/kg of wet
weight, as covered by Directive 2003/13/EC, the latest
amendments to Regulation (EC) No 466/2001. Guid-
ance on food contaminants, including inorganic tin,
was published by the Food Standards Agency in 2009
in conjunction with the pertinent EU legislation (FSA,
2009b; European Commission, 2006a, 2009).
Tin in canned food is likely to be in the cationic form
or in the form of inorganic tin salts in +2 and +4 oxida-
tion states (stannous and stannic compounds), rather
than in covalently bound organometallic compounds.
The tin content of canned foods varies according to
whether the can is lacquered, the pH of the food in
the can, the presence of plant pigments, the storage
conditions (i.e. time and temperature) of the canned
foods, whether the food is stored in opened cans, and
the presence of oxygen, reducible organic compounds,
and food additives. The most obvious influence on
internal corrosion in plain tinplate cans is the chemis-
try of the food product. It should be noted that fruits
and vegetables (e.g. tomatoes) will have significant
natural variation in pH and acid type and concentra-
tion, depending on the variety, maturity, time, place,
and conditions of harvest, soil chemistry, and agri-
cultural practices. Acidic foods are more damaging to
the tin coating in metal cans, and canned acidic foods
have higher tin contents (Blunden and Wallace, 2003).
Tomato-based products tend to have high levels of tin
because the presence of nitrates in the food acceler-
ates corrosion of the tin. Tin may be present in food
stored in incorrectly manufactured tins (i.e. when the
alloy layer is not compact and continuous), causing tin
present in the interior coating of the can to leach into
the foodstuff. During food and beverage packaging in
tinplate cans, dissolution of tin into the food may occur
(Boogaard et al., 2003; Shimbo et al., 2007). The addi-
tion of essential onion oil to a tinplate can filled with
tomato puree (pH 4.3-4) prevents the corrosion process
 56 Tin
and leads to a significant decrease in the tin content
to 28 mg/kg, compared to 223 mg/kg in the absence
of onion oil (Nincevic Grassino et al., 2009; Grassino
et al., 2010). However, essential onion oil stimulates the
corrosion of iron, which results in an increase in iron
content from 15 to 46 mg/kg in the canned food. The
reported concentration of tin in foods is also affected
by the method of sample preparation and the analyti-
cal method used.
A provisional maximum tolerable daily intake for
tin of 2 mg/kg b.w. and a provisional tolerable weekly
intake (PTWI) for tin of 14 mg/kg b.w. (expressed as
Sn), equivalent to 12.0 mg/day for a 60 kg adult, were
determined by the Joint FAO/WHO Expert Commit-
tee on Food Additives (JECFA, 2001). Only limited
data are available on the toxicological effects of inor-
ganic tin present in canned food resulting from disso-
lution of the tin coating. The sixty-fourth JECFA (2006)
concluded that the available data indicate that it is
inappropriate to establish an acute reference dose for
inorganic tin because irritation of the gastrointestinal
tract depends on the concentration and nature of tin in
the product, rather than on the dose ingested on a body
weight basis. Short-term effects may occur in some
individuals at concentrations greater than 150 mg/
kg in beverages and over 250 mg/kg in canned food,
resulting in irritation of the mucosa of the gastroin-
testinal tract, which may lead to vomiting, diarrhea,
anorexia, depression, ataxia, and muscular weakness.
Organic tin compounds, which differ considerably
from inorganic tin with respect to toxicity, are consid-
ered separately (JECFA, 1978). Based on limited data,
preliminary short-term intakes of inorganic tin were
estimated to be between 0.004 and 3.3 mg/kg b.w. per
day, depending on the food considered (JECFA, 2006).
The total content of tin in canned pear nectar,
mango juice, and orange juice was below 70 mg/kg,
whereas the tin concentration was higher in pineap-
ple juice (77.8 mg/kg) and over 100 mg/kg in canned
fish, mango slices, fruit cocktail, fruit juice, and tomato
puree (Manzoori et al., 2006; Boutakhrit et al., 2011).
The content of tin did not exceed the maximum limit
for tin in canned food for adults. However, canned
pineapple juice and fish cannot be used for consump-
tion by children. The Sn content in the majority of
samples of canned juices and fruits was high, in par-
ticular in canned papaya (269.8 mg/L) and apricot
(153.4 mg/L) juices (Boa Morte et al., 2009). The levels
of tin in canned rainbow trout and anchovies produced
in Turkey were shown to average 0.023 and 0.14 mg/
kg, respectively (Mol, 2011). The estimated maximum
intake of tin in 1994 was in the range of 2.4-7.9 mg/
day, whereas intakes of tin were estimated to be 1.4
mg/kg in 2000 and 1.8 in 2006 based on consumption
1251
data from the UK National Food survey (MAFF, 1998;
FSA, 2009a). An estimate of the daily intake of tin by
French consumers was 2.32 mg in 2003; this was sig-
nificantly below the tolerable limits (Noel et al., 2003).
In 2006, dietary exposure to tin was estimated for UK
consumers: the concentration of tin was below the
limit of detection in most food groups (e.g. bread, fish,
and fruit) (Rose et al., 2010). Canned foods contained
higher concentrations of tin, presumably as a result of
slow dissolution of the tin coating. Tin concentrations
in canned vegetables and fruits were 36.1 mg/kg and
11.1 mg/kg, respectively. The concentration of tin in
the canned vegetables group was found to be higher
than the 2000 total diet study result (25.06 mg/kg) but
lower than the value reported for the 1997 total diet
study survey (44 mg/kg) (FSA, 2002). The population
dietary exposure was estimated to be 1.80-1.81 mg per
day. The highest estimated daily dietary exposure to
tin was for high-level consumers aged 1.5-4.5 years
(341.5 mg/kg b.w.). Although the daily intake of tin in
this group exceeded the guidance level set by Expert
Group on Vitamins and Minerals (220 μg/kg b.w. per
day), the UK Government’s Scientific Committee on
Toxicity of Chemicals in Food, Consumer Products
and the Environment (COT) concluded that the small
excess over the guidance level is within the area of
uncertainty and that the estimated dietary exposures
to tin were unlikely to be of toxicological concern
(FSA, 2003; COT, 2008). In Japan, the daily intake of
tin for children was estimated at 162 μg/day, and for
adults at 152 μg/day (Aung et al., 2006). However,
when the daily intake was corrected for body weight,
the weekly intake for children was calculated as 61 μg/
kg b.w., whereas for adults the weekly intake was
around 19.8 μg/kg b.w. For both children and adults,
the intake on a body weight basis was far below the
PTWI of 14 mg/kg b.w. per week (JECFA, 1989). The
study conducted by Shimbo and coauthors elucidated
the possible effect of canned food on tin consump-
tion between 1999 and 2004 in Japan. The intake of
tin by people eating canned food was 35.7 μg per day,
eight times higher than the level of 4.5 μg per day for
noncanned food consumers as measured by ICP-MS
(Shimbo et al., 2007). The distribution of tin varied, but
the highest detected value was 2291 μg per day. Intake
tended to be high among people consuming canned
food such as peach, pineapple, clementines, tuna
flakes, or mackerel. The tin intake by the adult popu-
lation living in Tarragona County (Catalonia, Spain),
as estimated by the duplicate method, was 69.2 μg/
day in 2010, which was two times higher than the
value found in 2003 (Domingo et al., 2012; Bocio et al.,
2005). In 2006, an estimated dietary intake of 37.9 μg/
day for an adult man of 70 kg was observed in various
1252 Elena A. Ostrakhovitch
localities near to a hazardous waste incinerator in
­Tarragona County (Marti-Cid et al., 2009). The daily
intake was calculated as the sum of the tin concentra-
tion in each food item (such as meat, fish and seafood,
cereals, vegetables, tubers, fruits, sugar, eggs, and
dairy products) multiplied by the weight of that food
consumed by an average individual. Cereals were the
food group that made the highest contribution to tin
intake. These studies show that there is a trend toward
an increased daily consumption of tin.
Organotin compounds reach humans primarily
through the diet, in particular through contaminated
water, meat, and fish products. Of about 100 existing
organostannic compounds, mono-, di-, and tributyltin
and mono-, di-, and triphenyltin are those most fre-
quently found in fishery products. These compounds
are widely present throughout the aquatic environ-
ment, resulting in the accumulation of organotins in
aquatic organisms and eventually in aquatic food
products such as fish, oysters, and crabs. Octyltins are
not detected in fishery products. A scientific panel has
assessed the health risks to consumers associated with
exposure to organotin compounds in food products
and the tolerable daily intake for the sum of tributyltin,
dibutyltin, triphenyltin, and di-n-octyltin was accepted
as 250 ng/kg b.w. by the World Health Organization
(WHO, 1999) and the European Food Safety Author-
ity (EFSA, 2004b). The PTWI of organotins (as the sum
of dibutyltin, tributyltin, triphenyltin, and dioctylodi-
etylotin) is 0.7 μg Sn/kg b.w., which, for an individual
weighing 70 kg, is 49.0 μg Sn per week (EFSA, 2004a).
The USEPA has established an oral reference dose of
300 ng/kg b.w. per day (USEPA, 1997).
In Japan in the early 1990s, the daily intakes of tri-
butyltin and triphenyltin from a market food basket
were on average 6.8 and 3.3 μg per person, respectively.
Seafood accounted for more than 95% of the intake of
organotins (Tsuda et al., 1995). By the late 1990s, daily
intakes had decreased and were 1.7 μg for tributyl-
tin, 0.09 μg for triphenyltin, and 0.45 μg for dibutyltin
(Toyoda et al., 2000). The tributyltin concentration
measured in 11 species of fish from the port of Osaka
and the Yodo River was in the range of 11-182 ng/g
wet weight (Harino, et al., 2000). The estimated daily
intake of butyltin compounds from seafood consump-
tion for the general population in Korea was assessed
as 17.2 ng/kg b.w. per day (Choi et al., 2012). Among
the seafood groups, fish contributed to the highest
intake of tributyltins (8.66 ng/kg b.w./day), followed
by cephalopods (4.39 ng/kg b.w./day). High concen-
trations of butyltins were found in shellfish. How-
ever, the contribution of shellfish to the total butyltin
intake was low (18%) because of the low consump-
tion rate of shellfish (3.9 g/day). In France, tributyltin
concentration in fish collected from the market dur-
ing 2005 ranged between 1.1 and 23 ng/g wet weight
(Guerin et al., 2007). In Portugal, the tributyltin con-
centration in shellfish was in the range of 43.2-317 ng/g
wet weight (Santos et al., 2009). The estimated average
daily intake of organotin compounds from the Finnish
market basket for the period 2000-2002 was determined
to be 5.95 ng/kg b.w., 81% of which originated from
fish (Rantakokko et al., 2006). The total daily intake of
monobutyltin, dibutyltin, and tributyltin was calcu-
lated to be 3.39, 0.61, and 1.30 ng/kg b.w., respectively.
However, for consumers eating large quantities of fish,
the intake may be much higher. Imported Norwegian
salmon contained a few ng/g fresh weight of tributyl-
tin, which was below the limit of quantification. How-
ever, in Finnish coastal areas with a high density of
shipping, the level of organotins (mostly trisubstituted
species) reaches several hundred ng/g fresh weight in
costal fish such as pike, perch, and turbot. The content
of organotin compounds in Baltic cod was within the
range of recommended permissible limits in force in
the European Union (European Union Commission,
2006a). The concentrations of tributyltin and triphen-
yltin species were above the limit of quantitation: they
were 1.10 μg Sn/kg and 3.21 μg Sn/kg in cod and her-
ring, respectively. Organotin daily intake through fish
consumption in 2005-2007 decreased to 3.2 ng/kg b.w.,
which is 1.3% of the tolerable daily intake (Airaksinen
et al., 2010). In total, fish (in particular, perch, salmon,
and rainbow trout) accounted for over 60% of the total
organotin intake. These data indicate that the fish
analyzed (especially Baltic salmon) do not pose a risk
to consumer health as far as the presence of organo-
tin compounds is concerned. Because tributyltin was
a common ingredient in antifouling paint and is still
present in sediments in the Bay of Islands (Northland,
New Zealand), it was expected that trace amounts of
tin might still be detectable in shellfish (Coelho et al.,
2002). However, as a result of restriction in 2003 and
complete prohibition in 2008 on the use of organotin-
containing antifouling agents on ships, tin was not
detectable in mussels from this area; thus, that there is
no risk to shellfish consumers among the general pub-
lic, and in particular, the Maori population and Pacific
Island peoples whose diet is based primarily on fish
and seafood (Whyte et al., 2009). The levels of mono-,
di-, and tri butyltin compounds were significantly
lower than the tolerable level of 100 ng/g wet weight
in mussels and frequently consumed fish species from
Iranian coastal waters of the Caspian Sea (Rastkari
et al., 2012). In China, high concentrations of butyltins
(10-200 ng Sn/g) were detected in beans, vegetables,
fruits, eggs, milk, sugar, meat, potatoes, and bever-
ages (Qunfang et al., 2004). In Brazil, the application of
 56 Tin
triphenyltin during rice sowing was shown to result in
the accumulation of triphenyltin and its degradation
products such as diphenyltin and monophenyltin in
the roots (Antes et al., 2011). However, the concentra-
tion of these compounds in rice grains was lower than
the detection limits.
Furthermore, dietary exposure to organotin com-
pounds may result from the backing on silicon-backed
parchment, certain brands of gloves, sponges, sanitary
napkins, food storage in containers made from PVC
polymers, and some brands of vine stored in PVC bot-
tles or barrels (Takahashi et al., 1999). Organotin species
also leach into water through PVC pipes (Sadiki and
Williams, 1999); contamination levels of 291 ng/L for
monomethyltin, 49.1 ng/L for dimethyltin, 28.5 ng/L
for monobutyltin, and 52.3 ng/L dimethyltin were
detected. The highest levels of monomethyltin,
dimethyltin, monobutyltin, and dibutyltin were
detected in PVC pipes subjected to deionized water
exposure during the first 1-5 days (Impellitteri et al.,
2007). Monobutyltin was the most prevalent kind of
organotin. The concentrations of organotin were 0.4-
2.4 μg/L for monobutyltin, 0.2-1.0 μg/L for dimethyl-
tin, and 0.04-0.01 μg/L for tributyltin. A similar pattern
of release from PVC pipes was found for dimethyltin
and dibutyltin, with an initial rapid increase in con-
centration (Adams et al., 2011). The diffusion coeffi-
cient for organotin in PVC pipe material was found
to be 9 × 10−18 m2/s. Butyltin species were detected
in vinegar stored in plastic bags: the concentration of
tributyltins ranged from 0.012 to 14.1 μg (Sn)/L (Cui
et al., 2012).
4.1.2  Water, Soil, and Air
Tin compounds occur naturally in the soil and water.
Trace quantities of tin can be measured in air. Compo-
nents of the soil may be released as dust and the wind
may carry airborne particles for long distances before
deposition. In the air, tin largely associates with small
respirable particles 1-3 μm in size (WHO, 1980a). Inor-
ganic tin is considered to be relatively immobile in
the environment. However, it may also undergo bio-
methylation in sediments, and redistribution between
alkylated species of tin has been observed in decay-
ing plant materials in the environment (Falke and
Weber, 1994a,b; Guard et al., 1981; Hallas, et al., 1982).
A large percentage of tin is present in particulate form
(­Langston et al., 1987). In soil-plant systems, trans-
port coefficients for inorganic tin were reported to be
0.01-0.1 (Kloke et al., 1984).
Organotin compounds can degrade into inor-
ganic forms or may remain unchanged for years in
sediments. The marine biota tends to accumulate the
1253
highest concentrations of organotin species. Organo-
tin compounds are hydrophobic substances and only
slightly soluble in water. Tributyltin is generally lipo-
philic in character, and has a high specific gravity and
low solubility in seawater (less than 10 mg/L at 20°C
and pH 7.0) (Fent, 1996). It was suggested that the high
concentrations of tributyltins in seawater result from
their release from sediments, which act as a long-term
source of dissolved-phase contamination in marine
environments (Ritsema et al., 1998). Tributyltin is
reported to be highly adsorbed in sediments with fine
texture and abundant organic matter (Burton et al.,
2004). Organotins are relatively stable under anoxic
conditions in sediments: they remain in sediments for
many years and slowly leach into surrounding water.
The half-life of tributyltin was calculated to be 6 days
in summer for turbid water and up to 127 days in
winter for nonturbid water; the half-life is much lon-
ger in sediments, and has been estimated to last sev-
eral years (Alzieu, 2000, 2006). Tributyltin degrades
to dibutyltin and monobutyltin species in the aquatic
system via dealkylation by UV photolysis and micro-
bial degradation. Biodegradation of tributyltin is faster
in organic-rich sediments than in sandy sediments
with little organic material (Landmeyer et al., 2004).
Furthermore, the toxicity of tributyltin in salt water
is less than in freshwater due to reduced microbial
degradation. The retention of trisubstituted organotin
compounds depends on temperature, pH, and light.
The retention time of tributyltin is approximately 2.1
years, whereas the retention times of dibutyl- and
monobutyltin are 1.9 and 1.1 years, respectively
(Sarradin et al., 1995). The half-life of methyltin and
butyltin compounds was estimated to be in the range
of 0.5-15 years in organic and mineral forest soils
(Huang and Matzner, 2004a,b). Degradation rates
were: monosubstituted → ­disubstituted  → ­trisubstituted
organotin compounds. A similar half-life was deter-
mined for dibutyltin in marine sediments (Almeida
et al., 2004). The half-life of dibutyltin in acti-
vated sludge was found to be 5.1 days (Stasinakis
et al., 2005).
Despite the global ban on organotin antifouling
paints, they are still common contaminants of marine
and freshwater suspended matter, sediments, biomass,
and coastal organisms around the world. In India,
there has been no legal ban on the use of tributyltin,
and organotin compounds are still used in antifoul-
ing paints (Garg et al., 2010). The total levels of butyl-
tins (tri-, di-, and monobutyltins) measured in 2007 in
the Mandovi and Zuari estuaries located on the west
coast of India were up to 77 ng/L in water and up to
120 ng/g in sediments. The highest concentration of
tributyltin (119 ng/g dry weight) was detected in the
1254 Elena A. Ostrakhovitch
Zuari Estuary. High tributyltin pollution was reported
in sediments in the Bitung ferry port in Manado, Indo-
nesia, where the concentration of tributyltin reached
a staggering 250 μg/kg dry weight and 4.25 μg/g wet
weight (Harino et al., 2012; Undap et al., 2013a). Rela-
tively high concentrations of organotin compounds
were measured in sediments and organisms in many
areas of the Brazilian coast, particularly in harbors and
shipyards (Liscio et al., 2009; Fernandez et al., 2005).
Organotin pollution was detected in the Bahia Blanca
Estuary in southwest Buenos Aires Province, Argen-
tina (Delucchi et al., 2007). Tributyltin concentrations
measured in the inner region of the estuary ranged
from below the detection limit to 170.3 ng/g sedi-
ments, whereas the concentration near the dry dock at
Puerto Belgrano Naval Base was 3288 ng/g. The con-
centration of dibutyltin was also the highest at Peuto
Belgrano, and was estimated to be 1645 ng/g. In the
Archipelago Sea in southwestern Finland, the concen-
tration of tributyltin in sediments was estimated to be
42 μg/kg, with higher levels found in the northern part
(71 μg/g) and reaching 1443 μg/kg in the vicinity of a
repair shipyard (the largest individual source of tribu-
tyltin) (Lilley et al., 2012b; Airaksinen et al., 2010). Stud-
ies in chironomid species, which are an important food
source for fish, birds, and bats, showed that increased
tributyltin concentration in sediment reduced spe-
cies diversity but did not markedly affect the number
of individuals in the Archipelago Sea in southwest-
ern Finland (Lilley et al., 2012a). Similar effects were
reported for marine periphyton (Sayer et al., 2006;
Smith et al., 2008). The reduced diversity of the spe-
cies along with the prevalence of tributyltin-resistant
species may lead to a transfer of organotin compounds
between the aquatic and terrestrial ecosystems.
The agricultural and biocidal applications of organo-
tin compounds resulted in their accumulation in soil,
water, and air through spraying, leaching, and runoff.
Triphenyltin has been excessively used to control fun-
gal diseases of potato, sugar beets, carrots, onions, and
rice, as well as peanuts, pecans, coffee, and cocoa, and is
currently approved for use as a fungicide (Jones-Lepp
et al., 2004). Due to the volatility of triphenyltin, it can
be transported long distances from treated fields. Accu-
mulation of triphenyltin and its degradation products in
the soil and underground water poses a serious risk to
the environment. The environmental Serious Risk Con-
centrations (SRCs) for soil are 28, 0.052, and 0.24 mg/kg
dry weight soil for dibutyltin, tributyltin, and triphen-
yltin, respectively. For groundwater, the SRCs are 50,
0.046, and 0.40 μg/L respectively. The maximum allow-
able concentration of tributyltin compounds in inland
surface waters, as proposed by the European Commis-
sion, is 0.0015 μg/L (European Commission, 2006b).
The fate of organotin compounds depends on the soil
composition, water pH, wetting and drying of the soil,
and temperature (Huang and Matzner, 2004a; Hoch
et al., 2002, 2003; Hoch and Schwesig, 2004). The high-
est level of contamination by organotin compounds
in a freshwater river system was reported in central
South Carolina in the United States in early 2000 (Land-
meyer et al., 2004). The concentrations of tetrabutyltin
and tributyltin were greater than 10 mg/kg in samples
of surface water bed sediments collected in 2000 and
2001 in deposition areas. In bed sediments of a pond
located about 1.6 km from the release of organotins, the
concentration of total organotins reached 40 mg/kg.
Contamination by organotin compounds was reported
in surface and ground waters in the Hérault water-
shed (in the Mediterranean Basin) (Bancon-Montigny
et al., 2008). The total organotin content ranged from
below the detection limit to 0.51 ng/L in 2005; how-
ever, the concentration of tributyltin, and occasionally
of phenyltin, in water was found to be up to 368 ng/L.
Di- and trisubstituted compounds were prevalent in
April, whereas monosubstituted compounds predomi-
nated in July. The degradation of organotin species in
the sludge via dealkylation depends on the nature of
the parent compound, the concentration, and the par-
ticulate phase. A number of studies have reported the
presence of octyltin in sewage sludge from wastewa-
ter treatment. The highest concentration of dioctyl-
tin reported in sludge was 0.56 mg/kg, whereas the
monooctyltin concentration was 0.715 mg/g (Summer
et al., 2003). Organotin stabilizers in PVC pose a public
health risk involving the workplace, consumer prod-
ucts, and the general environment.
The leaching of organotin compounds from PVC
pipes contributes to the accumulation of organotin
in the environment. On average, 35 mg/m3 tin were
released into the water from PVC pipes with a length
of 46 m after the first use. Analysis of environmental
samples such as water, sediments, plants, and algae
collected in Johannesburg (South Africa) showed high
concentrations of dibutyltin and monobutyltin in com-
parison with tributyltin (Nsengimana et al., 2009). The
lower concentration of tributyltin (22.3 μg/L in surface
water and 14.6 μg/kg in sediments) was attributed to
its degradation. The concentrations of monobutyltin
and dibutyltin in surface water were 25.1 μg/L and
38.7 μg/L, respectively, and reached 39.2 μg/kg and
42.4 μg/kg in sediments. The accumulation of dibu-
tyltin and monobutyltin compounds was suggested to
result from tributyltin degradation and the use of PVC
materials in the supply of water for mining.
Tin can be found near to tin mines and is also natu-
rally present as a result of burning fossil fuels such as
coal and oil or of burning organic and inorganic waste.
 56 Tin
The tin concentration also depends on the extent of
industrial activity. The content of tin-containing par-
ticles in airborne ash from coal-burning power plants
ranges from 7 to 19 mg/kg. According to the USEPA,
in 1997 more than 3.2 million tons of e-waste com-
prising electrical and electronic equipment had been
dumped in U.S. landfills. Today, the estimated amount
of e-waste is 20-50 million tons/year worldwide. It
has been estimated that, in the USA alone, over 30 mil-
lion computers and 100 million cell phones contribute
more than 10,000 tons of e-waste annually (BAN, 2004;
Cobbing, 2008). Printed circuit boards contain metal-
lic tin in the form of lead-tin alloy, and plastics, which
constitute more than 20% of e-waste, contain various
organotin species (Schlummer et al., 2007; IGES, 2009).
Due to the crude recycling process, tin may leak from
the residual ashes to the ground and to aquifers in the
surroundings (Bi et al., 2010).
It was reported that after 2 weeks of exposure to
atmospheric fallouts in the courtyard of a secondary
lead smelter that recycles car batteries, the content of
tin during the entire plant exposure period increased
from 1 mg/kg to 4.9 mg/kg in parsley and from 2 mg/
kg to 13.3 mg/kg in ryegrass, reaching 7.9 mg/kg in
parsley and 16.4 mg/kg in ryegrass in 4 weeks (Schreck
et al., 2012).
4.2  Working Environment
The OSHA (2013) established workplace permis-
sible exposure limits of 0.1 mg/m3 air for organotin
compounds, defined as the maximum recommended
worksite concentration for a conventional 8-h work-
day, and 2 mg/m3 for all inorganic tin compounds
except oxides. A value of 0.2 mg/m3 was specified as
the maximum worksite concentration for short period-
exposure by the American Conference of Industrial
Hygienists (ACGIH), providing that the daily limit
value is not exceeded. NIOSH recommends workplace
exposure limits of 2 mg/m3 for inorganic tin com-
pounds, except for SnH4, and 0.1 mg/m3 for organo-
tins, except for tricyclohexyltin hydroxide (NIOSH,
2013). NIOSH states that a tricyclohexyltin hydroxide
concentration of 25 mg/m3 should be considered as
immediately dangerous to life or health. The current
OSHA standard for inorganic tin compounds (as Sn) is
2 mg/m3 of air. In the Netherlands, the administrative
MAC value is 2 mg/m3 as Sn for tin and inorganic tin
compounds (Health Council of the Netherlands, 2005).
In Denmark, Finland, Iceland, Norway, the UK, and
the USA, 2 mg/m3 as Sn is recommended by ACGIH,
NIOSH, and OSHA as the occupational exposure limit.
In addition, in the UK a short-time value of 4 mg/m3 is
available (ACGIH, 2003).
1255
5 METABOLISM
5.1  Inorganic Tin
5.1.1 Absorption
5.1.1.1 Inhalation
Exposure to tin oxide dusts and fumes during fusion
operations, when tin reaches its melting temperature,
may cause benign pneumoconiosis known as stanno-
sis. Occupational stannosis was reported in nonmin-
ing industries such as grinding, briquette-making, and
casting processes. Long-term exposure to tin oxide
dust and fumes results in the deposition of particles in
lung phagocytes and lung tissue due to its insolubility
and poor absorption (Robertson et al., 1961; Brown-
ing, 1969; Krigman and Silverman, 1984). Thus, lungs
are the major target organ. Smooth muscle of the
bronchiole was shown to remain intact. Chronic expo-
sure to tin dust causes benign pneumoconiosis and
stannosis, without indications of fibrosis (Robertson
et al., 1961). Slius-Cremer and colleagues (1989) ques-
tioned whether abnormalities associated with tin
exposure could be called pneumoconiosis at all since
these abnormalities were not associated with fibrosis
and respiratory failure. Silicosis and pulmonary heart
disorders had been reported among Chinese workers
in tin mines in the late 1980s (Chen et al., 1992). An
increase of nearly sixfold in the death rate from pul-
monary heart disease was observed among workers
exposed to dust in mines. A 50% increase in mortality
was associated with nonmalignant respiratory dis-
eases caused by respirable silica dust in hard rock tin
mines (Chen et al., 2005). However, there was a trend
toward increased cancer risk among tin miners. Later
findings indicated a positive dose-response relation
between exposure to cumulative dust in tin mines
and mortality from lung cancer (Chen et al., 2006).
Some studies reported an increased risk of death from
gastric cancer among tin miners, especially in under-
ground workers (Raj et al., 2003). However, high
arsenic, crystalline silica, and radon content in dust
particles might be a cause of increased mortality from
lung cancer (Chen et al., 2006; Hodgson and Jones,
1990; Raj et al., 2003).
Inhalation of tin oxides in molten metal-refining
furnaces can lead to the same conditions. Micro-
scopic analysis revealed dark dust foci in the lung tis-
sue of subjects employed in the tin-melting industry.
Recently, Yilmaz et al. (2009) described two cases of
stannosis associated with exposure to tin fume. Long-
term tin workers developed stannosis and died as a
result of respiratory failure. The subjects had numer-
ous small dense nodules in both lungs, with dense
1256 Elena A. Ostrakhovitch
nodular lesions. The authors suggested that tin fume
exposure may not be as benign as commonly believed.
Two cases of pulmonary alveolar proteinosis, includ-
ing one death, were reported in workers at a facility
producing indium-tin oxide (ITO), consisting of 90%
indium oxide (In2O3) and 10% tin oxide (SnO2), for flat
panel displays (Cummings et al., 2010). Both work-
ers were exposed to airborne ITO dust and developed
pulmonary alveolar proteinosis. However, it was sug-
gested that the exposure to indium compounds caused
pulmonary fibrosis, emphysema, and pneumothoraces
(Cummings et al., 2012).
5.1.1.2 Ingestion
Inorganic tin compounds are relatively harmless
due to their poor absorption, relative insolubility, and
low retention in the tissue (Johnson and Greger, 1982;
Krigman and Silverman, 1984; Winship, 1988). Several
cases of gastrointestinal manifestations of tin poison-
ing have been associated with high concentrations of
tin in drinks or solid foods. Vomiting, diarrhea, fatigue,
and headaches were recorded after the consumption
of canned orange beverages in 1963. The content of
tin ranged from 75 to 500 mg/kg. Over 100 cases of tin
poisoning were reported in Washington and Oregon in
1969 after ingestion of canned tomato juice. The toxic
effect of tin depends on the concentration in the food-
stuff ingested (WHO, 2001, 2006). Analysis of the juice
consumed showed a tin content of 477 mg/L. Five
adult participants of clinical study were given 240 mL
orange juice containing 0, 498, 540, or 1370 mg/kg tin.
Nausea and diarrhea were recorded in all participants
after ingestion of the orange juice with highest tin con-
centration, whereas lower concentrations equal to a
dose range of 1.6-3.6 mg/kg b.w. inorganic tin did not
induce any symptoms (Benoy et al., 1971). Ingestion of
fruit juice containing 342 mg caused symptoms of gas-
trointestinal irritation (MAFF, 1983); similar juice con-
taining between 125 and 182 mg had no effect. Peaches
containing 350-600 mg/kg tin and orange and grape-
fruit juices containing 330-400 mg/kg tin caused gastro-
intestinal effects (Blunden and Wallace, 2003). The level
of tin that may cause gastrointestinal irritation, nausea,
vomiting, and diarrhea varied from 250 to 2000 mg/kg.
Symptoms started within 0.5-3 h after consumption and
recovery occurred within 48 h. Dietary products more
likely to be responsible for gastrointestinal irritation are
acidic fruits and fruit juices packed in unlacquered, par-
tially unlacquered, or damaged tinplate cans (Schafer
and Femfert, 1984; Blunden and Wallace, 2003). The
presence of tin at levels up to 250 mg/kg in canned food
caused no adverse effects in healthy adults (Boogaard
et al., 2003). In cans containing tomato puree and potas-
sium nitrate, dissolution of tin started after 30 days (at
36°C) and 60 days (at 20°C) of storage as a consequence
of nitrate action, which act as a corrosion accelerator
(Nincevic Grassino et al., 2009). The addition of essen-
tial onion oil as a potential corrosion inhibitor was sug-
gested to avoid leaching of tin (Grassino et al., 2010).
Studies in animals and human subjects demon-
strated that the absorption rate of ingested inorganic
tin is approximately 5% in mice, rats, dogs, and mon-
keys, but is influenced by dose and the presence of
other substances. In humans, absorption rate is 3%
or less from a diet supplemented with 50 mg tin per
day (Johnson and Greger, 1982). Similar to symptoms
in humans, gastrointestinal irritation such as vomit-
ing was observed in cats (but not dogs) receiving 5
or 10 mL/kg b.w. of an orange juice containing over
450 mg/kg tin by stomach tube. Cats fed orange juice
containing 540 mg/kg tin, providing a dose of 5.4 mg/
kg weight, showed vomiting, and the incidence of
vomiting increased with high doses (Benoy et al.,
1971). Ingestion of stannous chloride (SnCl2) for 4-13
weeks resulted in gastrointestinal irritation, anemia,
and reduced bone strength.
5.1.2  Skin Contact
Inorganic tin has been used in cosmetics for many
years, in particular as toothpaste abrasive (tin fluo-
ride) and in nail care (tin oxide). Dermal toxicity of
tin fluoride and tin oxide was not reported. However,
tin tetrachloride or stannic chloride (SnCl4), stannous
chloride (SnCl2), and stannous sulfate (SnSO4) can
cause skin irritation due to their acidic nature. These
compounds absorb moisture from the air and become
dissolved in it to form an acidic solution. Contact with
these substances may cause severe burns to the skin
and eyes. Sodium stannate and potassium stannate are
strong alkalis. Tin salts are skin irritants, especially in
the form of dusts or mists, because of acidic or alkaline
reactions. Persons with existing skin disorders may
be more susceptible to the effect of these compounds.
However, only occasional cases of allergic dermatitis
in human have been reported. In rabbits, it has been
shown that a 1% solution of SnCl2 applied to dermal
scratches for 18 h generated a reaction with intraepi-
dermal pustules (Stone and Willis, 1968).
5.1.3 Distribution
Tin is present in small amounts in animals and
humans in nearly all organs, with a total content of
approximately 352 mg in adult men (Kehoe et al.,
1940). The highest accumulation of tin was observed
in the bone and thymus, but also occurs in the lungs,
liver, kidney, spleen, lymph nodes, and other organs.
Thus, in tissue samples from adults who died in acci-
dents the concentration of tin was found to be as high
as 4.1 mg/kg in bone ash, whereas in muscle and
 56 Tin
brain tin levels were 0.07 and 0.06 mg/kg wet weight,
respectively (Hamilton and Minski, 1972). In other
studies, tin concentration in the bone was determined
to be as high as 6.2 mg/kg and as low as 0.47 mg/kg
(Garcia et al., 2001; Llobet et al., 1998; Tipton and Cook,
1963; Teraoka 1981; Chiba et al., 1990). Tin concentra-
tion in lung samples from deceased subjects without
known occupational tin exposure varied between 0.24
and 3.4 mg/kg. In blood, tin concentrations of 2-9 μg/L
were reported. In subjects occupationally exposed
to tin, tin concentrations were elevated in the lungs,
spleen, liver, and kidney (Teraoka, 1981).
The application of tin fluoride solutions leads to tin
deposition onto the tooth surface and its incorporation
into carious enamel and dental hard tissue (Ellingsen,
1986). The administration of highly concentrated solu-
tions of tin (2100 mg/kg Sn2+) led to its incorporation to
a depth of 20 μm; a less-concentrated solution (400 mg/
kg Sn2+) led to small amounts of tin being incorporated
into the outer 10 μm (Schlueter et al., 2009).
In mice intraperitoneally injected with stannous
chloride, tin accumulated in all organs except the tes-
tis (Chiba et al., 1990). However, the most tin was
retained in bone, followed by muscle, liver, and kidney
­(Furchner and Drake, 1976). Following a single gavage
dose of 20 mg/kg b.w. of tin(II) or tin(IV) as fluoride or
citrate, the main deposition of tin was observed in the
skeleton (1 and 0.24%, respectively), followed by the
liver and kidney (Hiles, 1974). A single oral administra-
tion of tin salt at a dose of 20 mg/kg for 4 weeks resulted
in the predominant accumulation of tin in the bone.
Tin concentration in bone tissue of healthy unexposed
mice was reported to be 0.69 mg/kg dry weight, which
drastically increased after tin administration. Lifelong
exposure of mice to stannous chloride (SnCl2) in drink-
ing water resulted in tin accumulation in the kidney,
liver, heart, lungs, spleen, and thyroid (Schroeder et al.,
1968). In pregnant rats fed with stannous chloride, tin
has been found in embryos (Chmielnicka et al., 1981).
However, in pregnant rats exposed to tin fluoride, no tin
was detected in fetal or placental tissues (Hiles, 1974).
5.1.4 Excretion
Inorganic tin is mainly excreted in the feces (about
95-99%), with additional slow elimination in the urine
(Winship, 1988; WHO, 2001). Bile excretion is less than
15% (WHO, 2003, 1980a,b). The average tin concentra-
tion in the urine was approximately 0.023 mg/L, with
a range of 0-0.004 mg/L (Baselt and Cravey, 1989). Tin
concentration in the urine of adult human males receiv-
ing food containing 0.11 mg or 50 mg tin per day for 20
days was around 30 μg/L and 120 μg/L, respectively
(Johnson and Greger, 1982). Fecal excretion accounted
for 55% at the low dosage of tin and 97% at the high
1257
dosage. The tin concentration in urine samples from
miners after a work shift in Brazilian mines was shown
to be 0.45 μg/L, compared to 0.13 μg/L before the shift
and 0.08 μg/L in the control group, suggesting that the
workers have a daily intake of tin (Juliao et al., 2007). In
human and animals, the concentration of tin is higher
in urine than in hepatic bile (Ishihara and Matsushiro,
1986).
In laboratory animals, gastrointestinal absorption of
inorganic tin is reported to be extremely low (Ishihara
and Matsushiro 1986). Rats and cats given orange juice
supplying tin at 7-20 mg/kg excreted 99% of tin in
feces within 48 h (Benoy, Hooper, and Schneider, 1971).
Tin chloride administered at a dose of 50 mg/kg in
water was mainly (90-99%) excreted in the feces within
48 h (Fritsch et al., 1977). Traces of tin were found
in the urine and in the organs. Tin(II) or tin(IV) given at
single oral dose of 20 mg/kg as fluoride or citrate was
mainly excreted in feces (99%), with less than 1% in the
urine (Hiles, 1974). After a single intravenous dose of
tin(II) at 2 mg/kg, 35% of the tin was found in the urine
and 12% in feces, whereas 40% of tin was excreted in
urine and 3% in the feces after single intravenous dose
of tin(IV). However, intravenous injection of mice with
1% tin citrate did not result in tin excretion in the feces
or urine. Observed differences in the excretion routes
for tin may be due to the differences in the form of tin,
the dose, and the administration route. For example,
the biliary route was shown to be more important for
tin(II) than for tin(IV) compounds.
5.1.5  Biological Half-Life
The half-life of tin in the femur was estimated to be
34-40 days (Hiles, 1974). For liver and kidney, the half-
life of tin(II) has been estimated as 10-20 days. In later
studies, the biological half-life of inorganic tin in rats
was reported to be approximately 85 days in the liver
and 50 days in the spleen (Marciniak, 1981). In mice, a
biological half-life of approximately 30 days was shown
using a whole-body counting method (Brown et al.,
1977). Complete elimination of tin(II) has been observed
after 90-100 days (Furchner and Drake, 1976). Stannous
and stannic compounds show differences in blood clear-
ance, excretion, and soft tissue uptake (Srivastava et al.,
1985). Thus, Sn (IV) shows higher bone uptake and less
soft tissue accumulation than Sn (II). Such differences in
cation affinity between Sn (II) and Sn (IV) are attributed
to slow oxidation or reduction during their absorption
and transport in the organism.
5.1.6 Biotransformation
Inorganic tin may undergo oxidation-reduction,
ligand exchange, and methylation reactions. In extremely
anaerobic conditions inorganic tin may be converted into
1258 Elena A. Ostrakhovitch
stannane (SnH4) by decaying algal material (Donard and
Weber, 1988). Biomethylation of inorganic tin has been
shown in bacterial cultures, sediments, marsh grass,
decaying plant materials, soils, and household and indus-
trial composts (Braman and Tompkins, 1979; Furuhashi
et al., 2008; Donard et al., 1986; Ashby and Craig, 1988a;
Falke and Weber 1994a; Duester et al., 2005). Methylation
of tin in sediments positively correlated with increasing
organic content in sediments (Hadjispyrou et al., 1998).
Ashby and Craig (1991) showed that tin(II) can be meth-
ylated by methylcobalamin under environmentally
relevant conditions; this depends on salinity, pH, and
whether conditions are aerobic or anaerobic (Chen
et al., 2007). In solutions with pH higher than 1.0,
monomethyltin was produced by carbonium trans-
fer and further methylated to dimethyltin by addi-
tional carbanion transfer. The highest concentrations
of methylated tin were observed in agricultural soils,
garden soils, and flood plain soils (Duester et al., 2005).
Concentrations of dimethylated species and mono-
methyltin were between < 0.01-7.6 μg/kg dry mass.
Soil parameters such as pH, water content, and tem-
perature did not correlate significantly with the degree
of biomethylation observed. However, it was shown
that the pH of the reaction solution was highly associ-
ated with photochemical methylation of tin(II) in the
presence of acetone under UV irradiation (Chen et al.,
2012). The highest yield of methyltin was observed at
pH 5.0. Furthermore, pH affected the redox potential
of tin(II) in aqueous solution. Transformation of stan-
nic chloride in landfills was also documented. Inor-
ganic tin is methylated if methyl donors are present.
Monomethyltin trichloride at an initial concentration
of 500 mg Sn/L found in landfills promoted methyla-
tion of inorganic tin present in the inoculum under
methanogenic conditions (Bjorn et al., 2011): the mono-
methyltin concentration increased by a factor of about
five over the 211-day incubation period. Methylation
of inorganic tin compounds also contributes to increas-
ing the volatility, toxicity, and mobility of tin in the
environment.
5.2  Organotin Compounds
5.2.1 Absorption
5.2.1.1 Inhalation
Cases of intoxication due to occupational exposure
to triphenyltin acetate have been documented. The
main route of absorption is reported to be the respira-
tory tract. In 1951, Zeman and others (1951) reported
four cases of employee exposure to unknown con-
centrations of tetramethyltin and tetraethyltin. Initial
symptoms in all four subjects exposed included severe
headaches and nausea. In the most severe cases of
organotin poisoning, bradycardia, hypotension, and
abrupt variations in the sinus rhythm of the heart were
observed. Common clinical symptoms of organotin
poisoning are headache, dizziness, photophobia, nau-
sea, and vomiting, with some incidences of temporary
loss in consciousness, epileptic seizures, dermatitis,
and asthenia (Manzo et al., 1981; Lyle, 1958). In 1981, six
workers were exposed to a mixture of dimethyltin and
trimethyltin vapor while cleaning a cauldron. One of
the workers died and two of surviving workers devel-
oped neurological problems including memory loss
(Rey et al., 1984). Symptoms preceding death included
respiratory depression and coma associated with high
levels of tin in the urine. The excretion rate of total tin
in the urine was reported to correlate with the sever-
ity of intoxication by dimethyltin and trimethyltin;
patients with an excretion level above 1 mg/L showed
severe neurological defects (Rey et al., 1984). Exposure
to a vapor of dimethyltin and trimethyltin for 3 months
resulted in mental confusion and epileptic seizures
in two chemists involved in dimethyltin synthesis
(Fortemps et al., 1978). Following a spillage in a plant in
the United States in 1978, 22 chemical workers exposed
to trimethyltin chloride developed forgetfulness,
fatigue, depression, and attacks of rage (Ross et al.,
1981). A patient who had been exposed to triphenyltin
also showed acute urticarial eruption, signs of hepatic
injury, and electroencephalographic abnormalities
(Colosio et al., 1991). In one report, a 27-year-old male
studying chemistry was exposed to trimethyltin chlo-
ride when he measured 300 mg (15 cm3) of a powdered
substance (Saary and House, 2002); he developed head-
aches, agitation, shortness of breath, chest discomfort,
and abdominal pain. Acute poisoning with dimethyltin
dichloride was reported in worker after cleaning a tank
used in the manufacture of this organotin. Although
the man wore personal protective clothes and an air
supply mask, he suffered from dizziness, disorienta-
tion, hallucination, irritability, and decreased memory
after 4 days of exposure (Yoo et al., 2007). The neuro-
logical manifestation was similar to trialkyltin enceph-
alopathy. Brain magnetic resonance imaging revealed
extensive symmetric lesions in the subcortical and deep
white matter of the bilateral cerebral hemispheres, pos-
terior rim of internal capsule, corpus callosum, cerebral
peduncle, and middle cerebellar peduncle. Analysis
showed dimethyltin levels to be as high as 47.6 μg/L in
blood and 779.4 μg/g Sn in urine 13 days after the ces-
sation of exposure, whereas the trimethyltin concentra-
tion was as high as 327.5 μg/L in blood and 946.3 μg/g
Sn in urine. A trace amount of urinary dimethyltin was
detected on day 27 after discharge from the hospital;
however, trimethyltin was not detected.
 56 Tin
A tributyltin aerosol at a concentration of 20 mg/m3
was lethal to guinea pigs within 1 h of exposure
(­Schweinfurth and Gunzel, 1987). Similarly, lethality
was recorded in mice following single or repeated
daily exposure to a mixture of tributyltin (81%) and
dibutyltin (3.7%) at a total concentration 5.65 mg/m3
Sn (Igarashi, 1959). Inflammatory changes consisting
of hyperemia and bronchitis were observed in the
respiratory system of rabbits exposed to 4-6 mg/m3
(0.30-0.45 mg/kg) tributyltin chloride for 95 days.
Rats exposed to 2 mg tin/m3 (0.41 mg/kg) an aero-
sol mixture of tributyltin bromide (0.39 mg/kg) and
dibutyltin dibromide (0.02 mg/kg) displayed severe
bronchitis and both vascular and alveolar edema
(Iwamoto, 1969).
5.2.1.2 Ingestion
Organotin compounds can be digested from the
gastrointestinal tract (Kimbrough, 1976). The degree of
tributyltin oxide absorption was shown to be 20-55%.
Human exposure to organotins occurs through con-
taminated dietary sources (e.g. seafood and shellfish),
fungicides on food crops, and water systems (Golub
and Doherty, 2004). High levels of tributyltin reaching
up to 11 mg/kg were found in bivalves, gastropods,
and fish, suggesting that human diet can contain high
levels of organotin compounds (WHO, 1990). The total
tolerable average level of tributyltin consumption in
Taiwan was calculated to be 243 ng/g wet weight (Lee
et al., 2005). The lowest observed adverse effect level
(LOAEL) value of 0.025 mg/kg per day for dibutyl-
tin for oral exposure was derived from the LOAEL of
2.5 mg/kg per day for rats in mid-term and long-term
toxicity tests. The maximum oral exposure value was
set at around 0.035 μg/kg per day. The half-life for the
gastric hydrolysis of dibutyltin ranges between 0.5 and
3.5 h. The absorption of dibutyltin and triphenyltin
compounds is approximately 10% in rats, whereas the
absorption of monoethyltin is approximately 8% and
of octyltin is less than 0.1% (Sole et al., 1998). Exposure
of rats to diets containing 50 mg bis(tributyltin)oxide/
kg for 4.5 months significantly reduced thymus weight
and suppressed natural killer (NK) cell activity in the
spleen after 16 months (Vos et al., 1990). Oral admin-
istration of tributyltin to mice at dose levels of 0.5, 5,
and 50 μg/kg b.w. for 45 days resulted in an increase
in body weight gain and hepatic steatosis, accompa-
nied by hyperinsulinemia and hyperleptinemia (Zuo
et al., 2011). The plasma levels of insulin, leptin, and
adiponectin in mice receiving 5 μg/kg tributyltin were
more than 1.5 times higher than in controls. In contrast,
a reduction in body weight gain was observed in rats
fed diets containing 15 mg/kg tributyltin or 6 mg/kg
triphenyltin (Grote et al., 2004). Dietary exposure to
1259
tributyltin and triphenyltin affected male sexual devel-
opment, associated with decreased serum testosterone
and luteinizing hormone.
The most toxic organotin compounds are trimethyl-
and triethyltin, which are easily absorbed from the
gastrointestinal tract (Winship, 1988). During the 1999
New Year holiday, over 1000 people in southeast China
were poisoned by dimethyltin-contaminated cooking
oil: of these, 100 people were hospitalized and three
people died. Urine samples of those poisoned with
dimethyltin contained dimethyltin and trimethyltin
at approximately 80 ng/mL (Jiang et al., 2000). The
overall no observed adverse effect level (NOAEL) for
neuropathological effects of dimethyltin chloride is
considered to be 0.6 mg/kg b.w.
5.2.1.3  Skin Contact
Organotins range in toxicity from nontoxic trioc-
tyltin acetate to the highly irritant tributyltins. Expo-
sure to dimethyltin at 80 mg/kg was shown to result
in skin necrosis and scar formation in rats. The mix-
ture of diethyltin diiodide and linoic acid used to treat
furuncles and other skin infections caused 217 poison-
ings and 111 deaths in 1954 (Barnes and Stoner, 1959).
However, the identified toxic component was triethyl-
tin. Short-chain alkyltin compounds can be absorbed
easily, which makes them the most toxic for dermal
application. Studies on rat dorsal skin demonstrated
that tributyltin is more irritating than dibutyltin
(Middleton and Pratt, 1978). The application of tribu-
tyltin at 33 nmol/cm2 produced epidermal necrosis
and dermal inflammation, whereas dibutyltin was
less irritating and caused a similar effect at concen-
tration 10 times higher. Contact with butyltin com-
pounds caused skin lesions in process workers (Lyle,
1958). Another report described irritant foot dermati-
tis caused by tributyltin oxide used to disinfect socks
(Molin and Wahlberg, 1975). Follicular inflammation
and skin lesions induced by butyltins were reported on
the skin of volunteers’ hands (Lyle, 1958). Workers of
a marine paint plant developed a sharply demarcated
skin rash 2 days after skin contact with a chemical
composed of 50% triphenyltin fluoride and 49% aro-
matic solvent (Andersen and Petri, 1982). A week after
exposure, skin biopsy showed follicular and perifollic-
ular lymphocytic infiltration. Several cases of contact
dermatitis caused by triphenyltin have been reported
(Goh, 1985; Lewis and Emmett, 1987). Application of
50% triphenyltin fluoride to the forearm skin of four
volunteers induced an intense burning sensation after
30 min; erythema developed, followed by epidermal
necrosis. A patient who had been exposed to triphe-
nyltin showed an acute urticarial eruption (Colosio
et al., 1991). Exposure to antifouling paints containing
1260 Elena A. Ostrakhovitch
tributyltin oxide resulted in irritation, erythema, and
mild pustule lesions (Lewis and Emmett, 1987). The
contact-sensitizing potential of tributyltin oxide was
studied in mice: mice sensitized with 0.25, 0.5, or 1%
tributyltin oxide showed increasing swelling reactions
24 h after challenge with 1% tributyltin (Stringer et al.,
1991). A single application of 1% tributyltin oxide to the
ears of mice led to increases in auricular lymph node
weight. The contact allergenicity of tributyltin oxide
reflects its immunosuppressive effects (Krajnc et al.,
1984; Vos et al., 1984). Spontaneous dermatitis and
dermatitis induced by sensitization with 2,4,6-trinitro-
chlorobenzene were observed in mice fed a diet con-
taining 100 mg/kg tributyltin for 30 days. Diminished
interferon gamma (IFN-γ) level and increased interleu-
kin-13 (IL-13) and IL-5 induced by tributyltin aggra-
vate atopic dermatitis-like lesions in mice treated with
2,4,6-trinitrochlorobenzene (Iwamura et al., 2006).
Acute dermal toxicity of 1000-3000 mg/kg triphenyltin
was reported in rabbits. Skin irritation in rabbit is min-
imal when triphenyltin was used as powder. However,
triphenyltin incorporated into paint becomes irritating
to the skin; an inflammatory reaction developed after
the daily application to the ears of rabbits for 2 days.
In vitro studies on dioctyltin absorption in rat and
human epidermis showed that amount absorbed after
24 h was 0.039 μg/cm2 for human skin and 4.14 mg/
cm2 for rat skin when dioctyltin was applied at a dose
equivalent to 17,007 mg/cm2 as tin (Ward, 2003).
5.2.2 Distribution
The accumulation of butyltin compounds such
as mono-, di, and tributyltin was reported in the
soft tissues, muscle, and feathers of wild migratory
birds (Guruge et al., 1996; Senthilkumar et al., 1998;
Senthilkumar et al., 2001). The highest concentrations
were found in feathers (ranging from 12 to 290 ng/g),
whereas concentrations recorded in tail feathers were
73-360 ng/g for monobutyltin, 29-56 ng/g for dibutyl-
tin, and 37-67 ng/g for tributyltin. These data indicate
that of the butyltins, monobutyltin is the predominant
compound retained in birds. It has been shown in fish
and marine mammals that tributyltin predominantly
accumulates in blubber and muscle, whereas dibutyltin
levels were shown to be highest in the liver and kidney
(Guruge et al., 1996; Kannan et al., 1996). Distribution
of tributyltin is rapid and reaches the maximum plasma
level in 1 day. In seven species of dolphin (bottlenose
dolphin, finless porpoise, Indo-Pacific humpbacked
dolphin, long-beaked common dolphin, pantropi-
cal spotted dolphin, spinner dolphin, and striped
dolphin), butyltin and phenyltin compounds were
found in the range of 16-1152 μg/kg and 1-62 μg/kg,
respectively (Harino et al., 2008b). Accumulation of
butyltin compounds was reported in the liver, kidney,
and brain tissue of adult southern sea otters found
dead along the coast of California during 1992-1996
(Kannan et al., 2004). The concentrations of butyl-
tins in liver, kidney, and brain tissues were 0.04-5.3,
0.004-0.265, and 0.0039-0.14 μg/g wet weight butyltin,
respectively. The highest concentrations of tributyltin
and dibutyltin were found in the liver, whereas mono-
butyltin was predominant in most tissues and organs,
except the liver. After single oral administration of
tributyltin (25 mg/kg b.w.), high levels of tributyltin
and its metabolites were found in the liver and kidney.
The liver predominantly (95%) contained dibutyl- and
monobutyltin compounds. Preferential accumulation
of butyltins in the liver and kidney may be associated
with the presence of increased amounts of metal-­binding
proteins, such as metallothionein-like proteins and glu-
tathione, which may play a role in the detoxification
of alkyltin agents. Furthermore, liver plays a key role
in detoxification. Lipid-soluble toxicants are detoxified
by cytochrome P450 family proteins. The distribution
of tributyltin within organism is rapid. After single
administration of a 25 mg/kg b.w. dose, high levels
were found within 1-3 days. In blood, tributyltin and
its metabolites were detected within 3 h of administra-
tion. In blood, tributyltin and its degradation metabo-
lites bind to serum albumin, which may determine the
fate, metabolism, and biological function of organotins
(Zhang et al., 2006). The equilibrium-binding constant
[log (Kb)] of tributyltin to the serum albumin complex
was calculated to be 7.3 (Sun et al., 2012). The percent-
age tributyltin in the serum was shown to be higher
than in tissues (Shim et al., 2002). Dibutyltin is mainly
distributed in the kidney, liver, and thymus follow-
ing dietary administration for 1 week at 100 mg/kg
(Arakawa et al., 1983). Intraperitoneal administration
of dibutyltin to rats led to accumulation of the dibu-
tyltin metabolite, butyl (3-hydroxybutyltin), in the
kidney at a relatively high concentration compared
with other metabolites; moreover, its concentration
increased with time (Ishizaka et al., 1989). Dibutyltin
and its metabolites were found in brain tissue, whereas
butyl-(3-hydroxybutyltin) was also found in urine.
Triphenyltin was mainly distributed in the kidney,
followed by liver, brain, and heart of rats a few days
after its administration (Eckert et al., 1989; Kellner
and Eckert, 1989). A similar distribution pattern was
observed after chronic exposure for 104 weeks (Dorn
and Werner, 1989; Tennekes et al., 1989). Relatively
high concentrations of triphenyltin were detected
in the liver, pancreas, kidney, and brain of hamsters
within 24 h of administration of 50 mg/kg triphenyltin
(Ohhira and Matsui, 1996). However, dearylation was
 56 Tin 1261

slower in hamsters than in rats. There was a high pan- tetraethyltin at 10 mg/kg accumulated in the kidney at
creatic accumulation of triphenyltin in hamsters. High relatively high concentrations, whereas only tetrabu-
levels of triphenyltin were found in the brain tissue of tyltin was retained in the liver.
both rats and hamsters after a single dose of 50 mg/
kg triphenyltin chloride or 6 mg/kg fungicide contain- 5.2.3 Excretion
ing 60% triphenyltin (Lehotzky et al., 1982; Ohhira
The excretion of organotins chiefly depends on
and Matsui, 1996). Triphenyltin was shown to cross
the type of compound. The major routes of elimina-
the blood-brain barrier due to its high lipophilicity.
tion from the body are urine, feces, and bile. Ethyl-
After percutaneous administration in guinea pigs, tri-
tin is almost exclusively excreted in the urine in rats,
phenyltin (2 mg/kg b.w.) was distributed to the high-
whereas diethyltin is excreted in the feces, urine, and
est extent in the liver, followed by the adrenal glands,
bile (Bridges et al., 1967; Cremer, 1957). After daily
kidney, brain, spinal cord, and pancreas (Nagamatsu
intravenous administration, carboxyethyltin is rapidly
et al., 1978). It was shown that tetraphenyltin accumu-
excreted unchanged in urine without the presence of
lates more rapidly than triphenyltin in the liver of rats
metabolites (Penninks and Seinen, 1985). However,
fed with 55.4 mg/kg of this compound (Ohhira and
carboxyethyltin was excreted in feces and urine after
Matsui, 2003).
daily oral administration at a dose of 15 mg/kg. Tri-
Dioctyltin is rapidly distributed to the liver and kid-
ethyltin can be eliminated in urine and milk, at least
ney, and to a lesser extent to the adrenal, pituitary, and
in lactating sheep. The excretion route for tributyltin
thyroid glands, with poor diffusion into the brain in
is the bile rather than the urine (Evans et al., 1979).
rats dosed orally at 6.3 mg/kg b.w. or intravenously at
Thus, approximately 90-95% of ingested tributyltin is
1.2 mg/kg (Penninks et al., 1987). There was no selec-
excreted in the feces. Similar to butyltin, fecal excretion
tive accumulation of dioctyltin in the thymus, despite
was predominant after oral administration of dodecy-
the fact that thymus atrophy is the most sensitive
ltin, ocyltin, and phenyltin compounds (Eckert et al.,
marker of dioctyltin toxicity in rats. Dodecyltin com-
1989; Penninks et al., 1987; IPCS, 1999). About 10% of
pounds were mainly found in the thymus and liver,
dioctyltin is excreted in the urine as the unchanged
followed by the kidney and bone marrow (Schering,
parental compound. Approximately 32-53% of tri-
1992). The concentration of this organotin in the brain
phenyltin orally and intravenously administered to
was only 1.4% of the amount found in the liver.
Wistar rats at a dose of 2 mg/kg b.w. was excreted in
The high concentrations of triethyltin were found in
the feces. Renal excretion was 12% after oral admin-
the liver of rabbits, with smaller quantities in the kid-
istration of triphenyltin, reaching 24% following
ney, brain, and blood 2 h after intravenous administra-
repeated administration. After intravenous adminis-
tion of triethyltin at 20 mg/kg for 5 days followed by
tration, approximately 30% was excreted renally. Tri-
10 mg/kg for another 2 weeks (Cremer, 1957). Accumu-
phenyltin administered for seven consecutive days
lation of triethyltin was observed in the kidney, blood,
was predominantly excreted fecally (96-100%) within
and lung 1 h after administration, with penetration into
7 days, with less than 1% excreted renally (Eckert et al.,
the brain and adipose tissue 12 h later (Doctor and Fox,
1989). Although some of the administered triphenyl-
1982). Other experiments have shown that exposure
tin was excreted unchanged, a significant portion was
to triethyltin or trimethyltin results in higher tin con-
excreted as diphenyltin and monophenyltin, along
centrations in brain, liver, and kidney tissues, with less
with other polar products (Kimmel et al., 1977).
accumulation in the heart and blood (Cook et al., 1984).
Rates of elimination were shown to be greater in all tis-
5.2.4  Biological Half-Life
sues following triethyltin exposure than following tri-
methyltin exposure. Administration of trimethyltin at Biodegradation of tributyltin differs in various
dosages of 3.0, 6.0, and 9.0 mg/kg led to its accumula- organs. The calculated half-life for elimination of
tion in the brain, reaching 4.4, 8.5, and 12.7 ng tin/mg injected tributyltin is a few days in mice, with initial
protein, respectively, 12 h after exposure. Trimethyltin rapid elimination being followed by slow elimina-
can easily cross the blood-brain barrier and becomes tion in the feces for up to 29 days (Brown et al., 1977).
evenly distributed across the cerebellum, medulla-pons, A half-life of 8.9 days was estimated for dioctyltin
hypothalamus, hippocampus, and striatum. Dimethyl- (Penninks et al., 1987). However, urinary excretion of
tin exposure caused hemorrhages in the digestive tract dioctyltin was continuous over a period of 25 days. For
and severe hepatic and spleen injury in both rats and diethyltin, the half-life was estimated at 3-4 days in the
mice (Tang et al., 2013b). The amount of triethyltin has liver and kidney, with a prolonged half-life in muscles
been shown to increase with time (­Arakawa et al., 1981). and bones after oral administration. The longest bio-
Orally administered tetrapropyltin, tetrabutyltin, and logical half-life was reported in the brain, compared
1262 Elena A. Ostrakhovitch
with other organs (WHO, 1980a). For tricyclohexyl-
tin, the half-life ranges from 5 to 40 days, with slow
removal from the brain. For triphenyltin, the biological
half-life was calculated to be approximately 3 days in
rat brain, with a much longer half-life in guinea pig
brain. The biological half-life of triphenyltin in guinea
pigs was estimated to be 9.4 days (Nagamatsu et al.,
1978). The biological half-life of triphenyltin in short-
necked clams and guppies was estimated to be 30 and
48 days, respectively (Tas et al., 1990). The estimated
half-lives of dimethyltin and trimethyltin in the urine
of mice were calculated to be 0.3 and 1.3 days, respec-
tively (Furuhashi et al., 2008). In rats, the half-lives of
dimethyltin and trimethyltin were estimated as 0.35
and 11.6 days, respectively. The half-life of trimethyltin
in rats was much longer than that in mice.
5.2.5 Biotransformation
Biotransformation of organotin compounds by ter-
restrial and aquatic organisms proceeds by successive
dealkylation and dearylation of tetra-, tri-, and disub-
stituted organotin compound, with each successive
breakdown intermediate being less toxic than the last.
In experiments conducted by Stasinakis et al. (2005)
in an activated sludge reactor, tributyltin and dibu-
tyltin biodegradation took 18 days. Biodegradation
of tributyltin occurs in lower organisms, but with an
elimination rate that is much slower than in mammals;
this suggests that organotin bioaccumulation is much
higher in lower organisms than in mammals. The half-
lives of tributyltin, dibutyltin, monobutyltin, and tri-
phenyltin are 1.4, 3.6, 9.8, and 5 days, respectively. The
metabolism of organotin compounds determines their
environmental fate and retention.
Dearylation reactions have been reported for triphe-
nyltin (Stasinakis et al., 2005). In sediments, triphen-
yltin degradation occurs relatively slowly through
photodegradation (Fent et al., 1991a,b; Kannan and Lee,
1996). Less than 2.5% of triphenyltin was found bio-
transformed in the goldfish Carassius auratus, whereas
triphenyltin biotransformation was not observed in
larvae of the minnow Phoxinus phoxinus. Only half of
the initial triphenyltin concentration remained; the
remainder was biotransformed into diphenyltin, mon-
ophenyltin, and inorganic tin. The ecological half-life
of triphenyltin in gastropods was estimated to be 347
days (Mensink et al., 1996).
The bioconcentration factor for tributyltin is highest
for organisms that lack efficient degradation systems,
but it is easily degraded by fish, birds, and mammals
(Walker et al., 2006). Exposure of Chlorella vulgaris to
tributyltin resulted in rapid biosorption, with sequen-
tial degradation to dibutyltin and monobutyltin (Tsang
et al., 1999). Exposure of the wharf roach (Ligia exotica
Roux) to a tributyltin-containing diet (0.1 mg/g food)
for 2 days resulted in the accumulation of tributyltin
and its metabolite dibutyltin. The highest tributyltin
concentration (2760 ng/g) was detected 1 day after
cessation of exposure, whereas the highest dibutyltin
concentration (2960 ng/g) was measured 2 days later
(Undap et al., 2013b). The concentrations of these com-
pounds gradually decreased during the depuration
period; the half-life of tributyltin was estimated to be
about 4 days for the wharf roach. Tributyltin rapidly
accumulates in the digestive and reproductive organs
of the sea snail (Thais clavigera; of the rock shell fam-
ily) and its degradation index ranged from 0.4 to 23.3
(Wang et al., 2010; Fang et al., 2011). However, biodeg-
radation of tributyltin was lower in female reproduc-
tive organs. Digestive and reproductive organs have
higher degradation indices than other tissues. The deg-
radation rate of tributyltin to dibutyltin is higher than
that of dibutyltin degradation to monobutyltin, or of
monobutyltin degradation to inorganic tin.
Butyltin and phenyltin compounds undergo deal-
kylation and dearylation by the microsomal cyto-
chrome P450 monooxygenase system (Fish, 1984;
Ueno et al., 1995; Appel, 2004). In the presence of
phenobarbital, which activates the cytochrome P450
system, triorganotin metabolism accelerates (Ohhira
et al., 1999b). The total yield of tributyltin and triphe-
nyltin metabolites increased by approximately 1.8
and 8.9 times, respectively, in rats, 2.1 and 1.2 times
in hamsters, and 1.6 and 1.5 times in human isolated
hepatic microsomes (Ohhira et al., 2003). Tributyltin
was metabolized more readily than triphenyltin in
all species. Dealkylation of dibutyltin to monobutyl-
tin by the monooxygenase system is slower than that
of tributyltin to dibutyltin (Kannan et al., 1996). Four
cytochrome P450 human isoforms (CYP2C9, CYP2C18,
CYP2C19, and CYP3A4) were shown to mediate deal-
kylation and dearylation of tributyltin and triphenyl-
tin compounds in isolated human hepatic microsomes
(Ohhira et al., 2006b). However, the CYP2C18 content
is low in human hepatic microsomes, whereas the per-
centages of CYP2C9 and CYP2C19 accounts for about
53 and 11% of the CYP2C subfamily. Therefore, it
was suggested that CYP2C9, CYP2C19, and CYP3A4,
which is the most abundantly expressed cytochrome
P450 in human liver, are the major isoforms involved
in the metabolism of organotins in the human liver. In
isolated liver microsomes, cytochrome P450 monooxy-
genases hydroxylate the principal carbon-hydrogen
bonds in tributyltin to produce hydroxylated alpha
metabolites, which rapidly split to form the dibutyl
derivative, followed by further oxidation to 1-butanol
and then to 1-butane and ketones (Kannan et al., 1996).
 56 Tin
In rats, CYP2C subfamily members have a key role in
tributyltin and triphenyltin metabolism (Ohhira et al.,
2004, 2006a). CYP2C6 was shown to be responsible
for dearylation of triphenyltin. However, triphenyl-
tin may also convert cytochrome P450 to cytochrome
P420, resulting in inactivation of monooxygenase sys-
tem (Prough et al., 1981). Dearylation was shown to be
slower in hamsters than in rats.
Dealkylation of diethyltin may occur in the liver, gut,
and other organs. Alkylated organotin compounds can
be demethylated by P450 monooxygenases in mam-
mals. Besides dealkylation, dimethyltin can be also
methylated to form trimethyltin in mice and rats, sug-
gesting that alkylation and dealkylation reactions can
co-occur (Furuhashi et al., 2008); however, the dealkyl-
ation rate is greater than the alkylation rate. The con-
version rate of dimethyltin to trimethyltin in rats was
estimated to be about 0.8%, resulting in about 2.4%
of trimethyltin being present in the blood following
exposure to dimethyltin (Tang et al., 2013b). However,
the mechanism of methylation is not understood.
6  LEVELS IN TISSUE AND BIOLOGICAL
FLUIDS
The average tin concentration in urine is about 4.2-
42.2 nmol/L, and in hair is about 0.42-3.37 nmol/g.
The average concentration of tin in the blood of nor-
mal subjects is 0.14 mg/L; it is found mainly in eryth-
rocytes (Baselt and Cravey, 1989). Tissue analyses have
shown that tin is present in lung, adrenal gland, and
liver tissues at concentrations of 37, 23, and 23 mg/kg,
respectively. The highest amount of tin (in dry ash) has
been found in the cecum (130 mg/kg), ileum (79 mg/
kg), rectum (57 mg/kg), and sigmoid colon (45 mg/
kg) (Schroeder et al., 1964). Inorganic tin does not
accumulate in soft tissues with increasing age (Baselt
and Cravey, 1989). A dose-dependent increase in the
tin content of the tibia and kidney of weaning rats has
been reported after administration of tin in the diet,
ranging from 1 to 2000 μg/g food (Johnson and Greger,
1985).
The level of organotin compounds in the environ-
ment have shown declining trends since the early
2000s as a result of the ban on tributyltin and triphen-
yltin use, but these compounds have still been detected
in a wide variety of organisms, and even in deep-sea
organisms. On the one hand, tributyltin, triphenyltin,
and their degradation products are still being released
from sediments and soils; on the other hand, dibutyl-
tin and monobutyltin are still in use in industrial pro-
cess in some parts of the world. Some studies reported
high levels of organotins in environmental samples,
1263
including water and sediments, near “hot spots” such
as boat marinas and shipyards. Concentrations of butyl-
tins > 1 μg/g wet weight were observed in the ovary,
digestive gland, kidney, heart, ctenidium, osphradium,
stomach, head ganglia, and penis of both imposex-
exhibiting female and male rock shells (T. clavigera) col-
lected at Jogashima, Japan, which is considered to be the
most highly organotin-contaminated site (Horiguchi
et al., 2012). About 90% of collected rock shells were
sterile. Concentrations of tributyltin and triphenyltin
in the ovaries were 2.46 and 2.28 μg/g wet weight. A
similar accumulation of tributyltin compounds was
observed in Ocenebra erinacea and T. clavigera (Horiguchi
et al., 2006). One-third of the total butyltin concentra-
tion was detected in the digestive glands. The total
concentration of organotins in different organs of the
cobia (Rachycentron canadum) collected from the waters
in southern Taiwan ranged between 206 and 859 ng/g
wet weight (Liu et al., 2011). Accumulation of tri- and
dibutyltin in the Queen conch (Strombus gigas) was
recorded at Road Harbour in the British Virgin Islands
(Titley-O’Neal et al., 2013). The tributyltin concentra-
tion was in the range of 8.3-23.7 ng Sn/g dry weight,
while the dibutyltin concentration was in the range of
84.2-88.9 ng Sn/g dry weight. Butyltin concentrations
in mussels collected from the Venetian Lagoon between
1999 and 2003, in particular those from the area around
the city of Chioggia, were in the range of 187-6666 for
tributyltin, 80-4187 for dibutyltin, and 31-1538 μg/kg
dry weight for monobutyltin. The detected values did
not significantly differ from those reported in 2000
(Zanon et al., 2009; Gallina et al., 2000). Butyltin com-
pounds in the tissue of mussels from Egremont were
shown to be in the range 0.217-0.508 mg/kg; these
values were higher than those of mussels from New
Brighton (0.11-0.201 mg/kg dry weight) (Harino et al.,
2005). Since the prohibition of organotin-based anti-
fouling paints on ships worldwide after January 2008,
the percentage of Nassarius reticulatus females affected
with imposex along the northern continental shelf of
Portugal decreased from 84% (in 2006) to 20% (in 2010)
in the same surveyed sites, suggesting recovery of the
ecosystem (Barroso et al., 2011). Considerable levels of
tributyltin (1.4-190 ng/mL) were reported in the blood
of various species of fish collected at costal sites near
Fukuoka in Japan in 2008 (Miki et al., 2011). Tributyltin
accumulation in ripe testes (over 50 ng/g wet weight)
was reported for male turbot (Scophthalmus maximus)
collected from the Gulf of Gdansk and the Pomeranian
Bay in the southern Baltic Sea (Gosz et al., 2011). The
high concentrations of tributyltin and its metabolites
were found in the liver and kidney of adult common
cormorants (Phalacrocorax carbo) collected from Lake
Biwa in Japan. The levels of butyltin compounds
1264 Elena A. Ostrakhovitch
in the liver were lower in 2007 (8 ng/g) than in 1993
(270 ng/g), but were still detectable (Mizukawa et al.,
2009). Diphenyltin and triphenyl tin were distributed
uniformly among organ and tissues, and their levels
significantly decreased from 130 ng/g in 1993 to 2 ng/g
in 2007. The level of tributyltin and its metabolites
in the blubber, liver, lung, and muscle of adult killer
whales (Orcinus orca) collected from Rausu, Hokkaido,
Japan, were in the range of 37-90, 385-676, 15, and
26-53 μg/kg wet weight, respectively (Harino et al.,
2008a). Phenyltin concentrations were below 4 mg/
kg in all tissues except the liver (58 mg/kg). Tributyl-
tin oxide can be transferred across from the placenta
to the fetus. However, total butyltin concentrations in
the blubber and liver of a whale calf were lower than
those in adult whales. It was shown that concentra-
tions of butyltin and phenyltin compounds were in the
range of 16-1152 μg/kg and 1-62 μg/kg in organs and
tissues of dolphins (bottlenose dolphin, finless por-
poise, Indo-Pacific humpbacked dolphin, long-beaked
common dolphin, Pantropical spotted dolphin, spin-
ner dolphin, and striped dolphin) from the coasts of
Thailand (Harino et al., 2008b).
The administration of 17.6 μg/mL of tributyltin in
drinking water leads to accumulation in the kidney at
concentration equivalent to 2.1 mg/g wet tissue and in
the brain to 0.36 mg/g wet tissue. The total butyl con-
tent in the liver of mice exposed to tributyltin is about
1000 ppb and remains unchanged 24 h after adminis-
tration. The content of tin in the liver of rats and guinea
pigs is lower at 3 h and higher at 24 h than those of mice
(Ueno et al., 2003). The main form of butyltin in the
liver of rats treated with tributyltin was dibutyltin.
After a single oral dose of tributyltin, high levels of tri-
butyltin were seen in the frontal and temporal lobes
and in the cerebellum of rabbits. Oral administration
of monooctyltin trichloride to rats at 25 mg/kg b.w.
resulted in an increased concentration of monooctyltin
in the blood, reaching 62 ng/mL within 3 h (Penninks
et al., 1987). Absorption was estimated at 0.03% of the
dose received. After a single oral dose of 55.4 mg/kg
tetraphenyltin in oil to Wistar rats, the highest concen-
tration of diphenyltin was observed in the liver and
kidney (Ohhira et al., 2003). Urinary dibutyltin excre-
tion rates in mice and rats after intraperitoneal injec-
tion of dimethyltin dichloride (10 mg/kg b.w.) for
four consecutive days were approximately 43% for
both species (Furuhashi et al., 2008). Dimethyltin was
detected until day 10, with the highest level of 98 μg
detected in the urine at day 3 in mice and of 845 μg
in the urine at day 4 in rats. Trimethyltin was absent
in the urine on day 0 but a time-dependent increase in
its concentration thereafter was observed. The highest
concentrations were 1.26 μg in mice and 3.49 μg in rats.
The number of studies that have examined organo-
tin compounds in human tissues is limited. It was
reported that the concentrations of butyltins in the
liver of ­Japanese subjects ranged from 59 to 96 ng/g
wet weight, whereas monobutyltin and dibutyltin,
degradation products of tributyltin, were predominant
(Takahashi et al., 1999). Hepatic deposition of butyltin
in a group of Danish men was in the range of 1-33 ng/g,
while total butyltin concentrations in human liver sam-
ples collected in Poland were in the range of 2.4-11 ng/g
(Nielsen and Strand, 2002; Kannan and Falandysz,
1997). Variations in concentrations butyltin among indi-
viduals from different countries probably reflect differ-
ences in their dietary intake of fish (Nielsen and Strand,
2002). Butyltin concentration in blood collected from
32 volunteers during a blood drive organized by the
American Red Cross in central Michigan in 1998 ranged
from 0 to 101 ng/mL (Kannan et al., 1999). After remov-
ing the highest concentration from the data, the aver-
age concentration was about 4.5 ng/mL. The amounts
of monobutyltin, dibutyltin, and tributyltin measured
in human blood collected from individuals in central
Michigan were 15.4 ± 5.2, 6.08 ± 3.33, and 10.5 ± 16.7 ng/
mL, respectively (Kannan et al., 1999). Whalen et al.
found a maximum concentration of 94 ng/mL dibutyltin
in human blood (Whalen et al., 1999). Analysis of urine
samples from four male volunteers aged 25-45 years
indicated the presence of tributyltin in two subjects at
a relatively low level (25 and 49 ng/L) (Zachariadis and
Rosenberg, 2009a). Monobutyltin was detected in one
sample at concentration of 34 ng/L. The occurrence of
butyl compounds in human blood suggests widespread
exposure to these compounds from a variety of sources.
When tributyltin in a mixture of 3 mL cherry brandy
and 7 mL ethanol was given orally to a volunteer, only
5.1-5.4% of the dose was excreted in the urine, mainly
as dibutyltin metabolites (Uhl, 1986). In 1999, more than
1000 people were exposed to methyltin in cooking oil
in southeast China. The concentration of trimethyltin
in blood samples from these people after the incident
was about 70 ng/g, whereas levels of di- and trimethyl-
tin in urine were about 80 ng/mL (Jiang et al., 2000). In
another study, the concentration of trimethyltin in urine
samples from 15 occupationally exposed volunteers
ranged from below the detection limit to 1277 ng/L
(Cui et al., 2011). Concentrations of dimethyltin were
in the range of 26-6353 ng/L, whereas monomethyl-
tin was detectable in less than half of the samples, and
ranged from 68 to 261.9 ng/L. Analysis of tin in organs
showed the highest methyltin concentrations in the liver
(1.93 μg/g dimethyltin and 1.42 μg/g trimethyltin), kid-
ney (1.05 μg/g dimethyltin and 0.47 μg/g trimethyltin),
and heart (0.1 μg/g dimethyltin and 1.48 μg/g trimeth-
yltin). In the Korean worker cleaning the tank used in
 56 Tin
production of dimethyltin chloride, the circulatory level
of trimethyltin was highest on day 12 after the 4-day
exposure to dimethyltin; it was 208.3 μg/L (Yoo et al.,
2007). The concentration of dimethyltin was lower than
the concentration of trimethyltin at all time points; they
were approximately 40 μg/L or slightly over from day
10 to day 15 after exposure. The highest urinary concen-
trations of dimethyltin and trimethyltin were 779.4 and
946.3 μg/g Sn, respectively. However, monomethyltin
was not detected in urine samples.
7  EFFECTS AND DOSE-RESPONSE
RELATIONSHIPS
Tin is not an essential element for humans and no
specific role for tin has been identified in human health.
However, tin has been established to be required for
some animals such as rats to grow and develop (Reicks
and Rader, 1990; Yokoi et al., 1990b).
7.1  Inorganic Tin
7.1.1  Local Effects and Dose-Response Relationships
7.1.1.1 Humans
Most natural food products contain tin in trace
amounts, but concentration may increase in canned food
as a result of dissolution of the tin coating or tin plate in
damaged or improperly stored cans. There have been
several reports on outbreaks of food poisoning. A case
was reported in which 31 persons experienced nausea,
abdominal cramps, and vomiting within 1-2 h of drink-
ing fruit punch containing 2000 mg/kg tin (Warburton
et al., 1962). Eight cases were reported in 1969 after
ingestion of tomato juice containing 250 mg/kg tin.
Acute gastrointestinal illness was reported among peo-
ple who ingested canned tomato juice contaminated
with tin in Washington and Oregon in 1969 (Barker and
Runte, 1972). The most commonly described symptoms
were bloating, abdominal cramps, headaches, fever,
and mouth lesions. Tin levels measured in the cans
implicated in outbreak ranged from 131 to 405 mg/kg.
The high concentrations of nitrate on the tomatoes used
to prepare the juice and the excessive nitrate fertiliza-
tion of tomato plants were associated with corrosion of
the can lining. Vomiting, diarrhea, and other digestive
problems have been observed in a large number of per-
sons after the consumption of canned orange juice and
apple juice containing 250-390 mg/kg tin in Kuwait
(Benoy, Hooper, and Schneider, 1971). Fifteen out of
26 persons who consumed orange juice containing
about 300 mg/kg tin showed gastric symptoms. Simi-
larly, canned peaches containing 563 mg/kg tin caused
1265
gastrointestinal disturbances (Nehring, 1972). A total
of 74 out of 78 people who ingested canned peaches
containing 100 mg or more of tin developed digestive
problems. In a randomized, double-blind study, 3 out
of 18 healthy volunteers of both sexes who consumed
250 mL tomato juice containing stannous chloride at
concentrations of 264 mg/kg developed gastrointesti-
nal symptoms (Boogaard et al., 2003). Consumption of
tomato juice to which stannous chloride was added at a
concentration of 529 mg/kg caused mild and moderate
gastrointestinal disturbances in four out of five volun-
teers. In a case-control study conducted in Belgium, an
increased risk of chronic failure was reported for occu-
pational exposure to tin (Nuyts et al., 1995).
Symptoms of gastrointestinal illness were reported
in five volunteers of each sex after drinking orange
juice containing tin at concentrations up to 1400 mg/
kg (Benoy et al., 1971). However, nine volunteers who
ingested tin at a dose of 120-200 mg/day did not show
adverse effects (Calloway and McMullen, 1966). Inges-
tion of a tin solution containing a dose of 700 mg/kg
caused nausea and diarrhea in two volunteers, whereas
six others did not experience adverse effects (WHO,
2001). Consumption of 36 mg tin with a meal resulted in
decreased zinc absorption in 10 volunteers aged 16-46
years (Valberg et al., 1984). A 40-day balance study
revealed an increase in fecal excretion of selenium by
30% in healthy volunteers after ingestion of food con-
taining tin at a dose of 50 mg (Greger et al., 1982).
Positive allergic reactions for metallic tin and stan-
nous chloride have been described in several case
reports (Menne et al., 1987; Fine Olivarius et al., 1993;
Gaddoni et al., 1993). Of 73 patients, six developed
reactions in patch tests with tin-plated copper disks.
Among 2205 people tested for allergic reaction to 1%
stannous chloride in petrolatum, 5 subjects produced
positive reaction, 15 showed questionable positive
responses, while 10 showed irritation to stannous chlo-
ride. Testing with 10% stannous chloride showed that
11 out of 19 subjects had irritant skin reaction.
7.1.2  Systemic Effects and Dose-Response
Relationship
7.1.2.1 Humans
There have been many case reports of acute gas-
trointestinal illness following the intake of canned
fruits and fruit juices (Blunden and Wallace, 2003). The
most frequently reported symptoms were abdomi-
nal cramps, nausea, vomiting, and diarrhea. Tin(II)
compounds (except for tin hydride) affect heme
metabolism. Gaseous tin hydride is neurotoxic when
inhaled: similar to arsine gas, tin hydride causes nerve
damage, but its effects are less profound because it does
1266 Elena A. Ostrakhovitch
not cause hemolysis (Baldwin and Marshall, 1999). Stan-
nane (SnH4) is an analog of methane and may cause
hemolytic anemia. Exposure to high doses of stannane
may cause gastrointestinal illness, skin rash, abdominal
pain, and headaches, whereas low levels of stannane
result in fatigue, depression, low cardiac output, short-
ness of breath, asthma, headaches, and insomnia. Tin at
concentrations found in the human diet can decrease
copper status, which in turn produces a wide variety
of anatomical, chemical, and physiological pathologies
in the cardiovascular system (Klevay and Combs, 2004;
Klevay, 2000; Pekelharing et al., 1994). It was suggested
that uremic patients might be prone to elevated tin levels
because tin was shown to affect kidney enzyme activity.
Increased risk of chronic renal failure was documented
for occupational exposure to tin (Nuyts et al., 1995).
7.1.2.2 Animals
Tin is considered an essential nutrient for rats. Rats
fed a tin-deficient diet containing 17 ng/g tin showed
poor growth, lowered response to sound, and alope-
cia, with decreased food absorption efficiency com-
pared with rats receiving a diet containing 1.99 μg/g
tin (Yokoi et al., 1990b). Tin deficiency in the diet led
to increased calcium concentration in the lung and
increased iron concentration in the spleen and kidney,
whereas zinc and copper concentrations in the heart
were reduced. A tin-deficient diet resulted in poor
growth, reduced feeding efficiency, and bilateral (male
pattern) hair loss. However, chronic administration of
tin chloride at a dose of 10 mg/100 g caused signifi-
cant but reversible growth retardation of Wistar-Kyoto
rats (Escalante et al., 1991). Feeding rats a diet supple-
mented with tin (10-200 mg/kg) for 28 days did not
affect body weight; however, there was a linear inverse
response with food intake (Pekelharing et al., 1994).
Marked differences in toxicity were shown for stan-
nic and stannous oxides and salts in Wistar rats when
administered orally (de Groot et al., 1973). Insoluble
tin compounds are relatively harmless if administered
orally, whereas cationic tin compounds that are soluble
in water or acids can be very toxic because of absorp-
tion from the gastrointestinal tract. The reported oral
median lethal dose (LD50) for stannous chloride is
250 mg/kg for mice and 700 mg/kg for rats (Registry
of Toxic Effects of Chemical Substance, 1979), with an
oral LD50 value of 775 mg/kg for stannous oxide in
deer mice (Schafer and Bowles, 1985; WHO, 1980a).
Rabbits are less sensitive to stannous chloride, with an
oral LD50 of 10000 mg/kg. Sodium pentafluorostan-
nite (NaSn2F5) showed higher toxicity, with an LD50 of
150 mg/kg in mice and 400 mg/kg in rats. The LD50 in
rats after intraperitoneal injection was determined to
be 43-50 mg/kg for pentafluorostannite and 136 mg/kg
for stannous chloride after 24 h. Cats are more sensitive
than rats to oral administration of tin. Vomiting and
diarrhea developed only in cats after the oral adminis-
tration to cats and rats of fruit beverages containing tin
at 472 mg/L or a complex of tin chloride and sodium
citrate (9 mg/kg b.w.) (JECFA, 1982).
Early reports showed tin-induced toxic pathological
changes in the liver and kidney and neurological dam-
age in rats, with an increased incidence of changes in
fatty acids (der Meulen et al., 1974; Conine et al., 1976).
The uptake and metabolism of iron, copper, zinc, and
manganese are influenced by dietary tin at concentra-
tions greater than 50 mg/kg. Significant effects of tin
on liver glutathione peroxidase and superoxide dis-
mutase activities and on liver iron and total glutathi-
one concentrations were observed (Reicks and Rader,
1990). A single intraperitoneal injection of tin tartrate at
20 mg/kg b.w. caused a decrease in glutathione, lead-
ing to lipid peroxidation that damaged hepatocytic
membranes (Dwivedi et al., 1983). Exposure to tin pro-
duced hematological changes in animals (ATSDR, 2005;
Pekelharing et al., 1994). In 4- and 13-week feeding stud-
ies in rats, oral administration of tin salts (especially the
more soluble tin salts, i.e. chloride, orthophosphate, and
sulfate) and tin oxides at concentrations above 3000 mg/
kg caused anemia and extensive damage to the liver
and kidney (de Groot et al., 1973; JECFA, 1982). Stan-
nous chloride administered at a dose of 10 mg/kg for 3
months caused hemolytic anemia, including decreased
hematocrit, erythrocyte number, and hemoglobin levels.
Intraperitoneal administration of tin for 3 months at a
dose of 17 mM/kg caused anemia after 2 weeks, whereas
anemia was observed 6-10 weeks after oral administra-
tion (Chmielnicka et al., 1993). Animal studies into the
effects of tin revealed that tin interacts with zinc ions
and blocks the activity of zinc-dependent proteins. Tin
was shown to interfere with heme synthesis by replac-
ing zinc in δ-aminolevulinic acid dehydratase (ALADH)
and thus decreasing activity of the enzyme. The effect of
tin on heme biosynthesis was shown to depend on the
concentration of zinc (Chmielnicka et al., 1992). Several
studies have reported an effect of tin on bone strength:
the calcium content and compressive strength of the
femoral bone were reduced in Wistar rats given 1, 3,
10, and 30 mg/kg b.w. of stannous chloride twice daily
for 3, 30, and 90 days (Yamaguchi and Okada, 1980;
­Yamaguchi et al., 1980, 1982). Stannous chloride admin-
istered at 1 mg/kg for 30 days produced a significant
decrease in alkaline phosphatase activity of the femo-
ral epiphysis. At 0.6 mg/kg b.w. per day, changes in the
calcium content in the femoral epiphysis were not sig-
nificant. The results suggested a lowest observed effect
level of 0.6 mg/kg b.w. per day for orally administered
inorganic tin. Decreased bone compressive strength
 56 Tin
was also observed in Wistar rats administered with
50-600 mg/kg stannous chloride in their drinking water
(Ogoshi et al., 1981). Calcium content in the tibia was
significantly decreased in rats fed 100 mg/kg of stan-
nous chloride for 28 days (Johnson and Greger, 1985).
The minimal risk level (MRL; defined as an estimate
of daily exposure to substance without appreciable risk
of adverse noncarcinogenic effects) was calculated to
be 0.3 mg/kg/day for intermediate-duration oral expo-
sure (15-364 days). The intermediate-duration MRL
was based on a NOAEL of 32 mg/kg for hematologi-
cal effects in Wistar rats fed a diet containing tin in a
13-week dietary study (de Groot et al., 1973). A dose of
95 mg/kg per day is considered the minimal LOAEL.
However, the Agency for Toxic Substances and Disease
Registry did not derive a chronic oral MRL for inorganic
tin because survival rate was reduced in a 42-month
drinking water study in rats at the lowest dose (0.7 mg/
kg per day as stannous chloride) tested. There were
no adverse effects when Wistar rats were fed stannous
chloride, stannous sulfate, stannous orthophosphate,
stannous oxalate, or stannous tartrate at amounts up
to 0.1% in the diet for 4 weeks. However, at 0.3% and
above, these compounds resulted in growth retarda-
tion, anemia, and histological changes in the liver. Like-
wise, there were no adverse effects in studies in which
stannous chloride was administered to F344 rats and
B6C3F1 mice at 1900, 3800, 7500, 15,000 and 30,000 (the
highest dose in mice only) mg/kg in the diet for 2 weeks
(NTP, 1982). At the highest dose, a loss of weight was
reported. No significant toxicity was observed in Wistar
rats given pentafluorostannite at 20 mg/kg b.w. per day
for 1 month by stomach tube (Conine et al., 1976). At a
dosage of over 100 mg/kg b.w. per day, degenerative
changes were detected in the kidney in 15-20% of the
animals. Long-term oral administration of tin salts may
increase the occurrence of tumors. Mammary adenocar-
cinoma, uterine sarcoma, and adenocarcinoma near the
jaw occurred in a group of 13 male and 17 female rats
fed on diet containing 2% chlorostannate for more than
1 year (Roe et al., 1965). Sixteen percent of B6C3F1 mice
fed stannous chloride at concentration 2000 mg/kg (or
0.2%) for 105 weeks developed hepatocellular carcino-
mas. An increased incidence of histolytic lymphomas
was reported in female mice fed a diet containing stan-
nous chlorite. Similarly, injection of metallic tin pow-
der into Lewis rats caused enlargement of the regional
draining lymph nodes, with epithelioid cell granulo-
mas around phagocytosed particles of tin and intense
hyperplasia of plasma cells (Levine and Saltzman,
1996). Injection of metallic tin powder into August rats
enlarged the lymph nodes, but the enlargement was
caused by granulomas without a major concomitant
plasma cell response.
1267
Stannous ions may cause genotoxicity, immuno-
toxicity, neurotoxicity, and oxidative stress. Evidence
suggests that stannous ions induce DNA damage via
the formation of reactive oxygen species, thus linking
tin-induced oxidative stress and genotoxicity (Mclean
et al., 1983a; Dantas et al., 1996, 1999). Oral adminis-
tration of SnCl2 led to the generation of free radicals
in rabbit liver, testes, kidney, lung, brain, and heart,
accompanied by diminished glutathione S-transferase
(GST) activity and a decreased level of sulfhydryl (SH-)
groups (El Demerdash et al., 2005). Histopathological
analysis revealed marked changes in hepatocytes, duct
epithelium, and kidney; dilatation and congestion of
blood vessels; and a mononuclear inflammatory infil-
trate. The volume of the Bowman space was increased,
with infiltration of renal parenchyma and changes in
cells lining the proximal and distal convoluted tubules.
Genotoxicity of stannous chloride has been shown in
various in vivo and in vitro systems. Genotoxicity was
demonstrated in the SOS chromotest, calf thymus DNA,
and isolated nucleotides (Olivier and Marzin, 1987;
de Mattos et al., 2005). Tin(II) ions form a complex with
DNA and generate reactive oxygen species, which
may be responsible for DNA lesions. Genotoxic and
comutagenic effects of stannous chloride were shown
in V79 Chinese hamster lung fibroblasts, Chinese ham-
ster ovary cells, and human blood cells (Mclean et al.,
1983a,b; Viau et al., 2009). Exposure of V79 cells to stan-
nous chloride resulted in a dose-dependent (at concen-
tration range of 100-1000 μM) increase in DNA damage.
Although 50 μM SnCl2 did not affect DNA migration in
the comet assay, it did inhibit the repair of DNA dam-
aged by methyl methanesulfonate, suggesting that tin
can interfere with steps of the DNA repair systems. Inter-
ference with the DNA repair system may contribute to
mutations by shifting the balance from error-free to error-
prone repair processes. Pungartnik et al. (2005) defined
SnCl2 (stannous chloride) as a moderate mutagen of low
toxicity in Saccharomyces cerevisiae. SnCl2 was reported
to induce a dose-dependent increase in the frequency of
chromosomal aberrations and teratogenic effects in mice
and zebrafish (El Makawy et al., 2008; Sisman, 2011). No
mutagenic and teratogenic effects were reported for stan-
nic chloride, stannous oxide, and stannic oxide.
It was determined that stannous chloride admin-
istered orally up to 50 mg/kg to pregnant mice for 10
days had no discernible effects on maternal or fetal sur-
vival. Similarly, when administered to pregnant rabbits
at 41.5 mg/kg for 13 days, maternal or fetal survival was
unaffected. Stannous chloride with casein in an aqueous
medium at dose levels of 200, 400, or 800 mg/kg did not
affect reproductive performance in rats, although ane-
mia developed in the offspring before weaning (JECFA,
1982). However, administration of stannous chloride at
1268 Elena A. Ostrakhovitch
a high dose of 20 mg/kg b.w. caused a reduction in the
rate of successful pregnancies in female rats, with no
adverse effects on the implantation number in females
achieving pregnancy (El Makawy et al., 2008). Further-
more, administration of tin decreased fetal body weight
and was associated with delayed bone ossification. Stan-
nous chloride reproductive toxicity was observed in
rabbits (Yousef, 2005). Teratogenic and genotoxic effects
of stannous chloride were also observed in zebrafish.
Exposure of zebrafish embryos to 10-250 μM tin for
120 h resulted in developmental delay, reduced body
weight, morphological malformation, and decreased
survival rate for embryos and larvae (Sisman, 2011).
Embryos exposed to 100 μM tin displayed tail deforma-
tion and larvae exposed to 50 μM tin showed reduced
body growth, smaller head and eyes, a bent trunk, mild
pericardial edema, and a smaller caudal fin.
Effects of SnCl2 include stimulation followed by
depression of the central nervous system (CNS) in
laboratory animals (Silva et al., 2002). A recent study
demonstrated a neuroprotective effect of stannous
chloride in the hippocampus of rats subjected to cere-
bral ischemia (Volti et al., 2011). The administration of
stannous chloride at 10 mg/100 g b.w. 18 h before the
induction of cerebral ischemia decreased inducible
nitric oxide synthase (iNOS) expression in ischemized
rats, increased cell survival, and improved short-term
memory recovery. The protective effect of SnCl2 (given
12 h before K2Cr2O7) against K2Cr2O7-induced neph-
rotoxicity in rats was associated with the induction of
heme oxygenase 1 (HO-1) activity (Barrera et al., 2003).
The simultaneous injection of SnCl2 and K2Cr2O7 had
no protective effect, whereas injection of SnCl2 12 h after
K2Cr2O7 exacerbated renal damage. Stannous chloride
is used as a reducing agent in nuclear medicine kits for
the binding between Tc-99m and a drug such as meth-
ylenediphosphonate (MDP) for bone scintigraphy and
diethylenetriaminepentaacetic acid (DTPA) for kidney
and brain scintigraphy to obtain the radiopharmaceu-
tical needs. It was shown that tin complexes with MDP
and DTPA to form atoxic compounds (Guedes et al.,
2006). DNA damage was detected in peripheral blood
nuclear cells from patients who had received endove-
nously injected radiopharmaceuticals containing stan-
nous chloride as a reducing agent (Dantas et al., 2002).
7.2  Organotin Compounds
7.2.1  Local Effects and Dose-Response Relationships
7.2.1.1 Humans
Several incidents were reported when residents and
workers were exposed to walls and joists treated with
tributyltin oxide wood preservative. The symptoms of
tributyltin poisoning were muscle weakness, tremors,
numbness in the extremities, eye irritation, respiratory
distress, chest pain, poor coordination, unsteadiness,
and even seizures. Organic tin compounds are toxic
because they (1) inhibit the synthesis of heme oxygen-
ase and (2) can also be genotoxic. They cause severe
irritation and burning to the skin because they are
absorbed through this route; this can lead to systemic
toxicity, which is also produced when these compounds
are inhaled or ingested. Major effects may be anemia,
as well as renal and hepatocellular damage. Catechol-
amine production may also be stimulated, which may
lead to hyperglycemia, changes in blood pressure, and
damage to the immune system. Alkyl and aromatic tin
compounds are highly potent neurotoxins. Trialkyltin
compounds, such as triethyltin, can cause encephalop-
athy and cerebral edema. Excessive industrial exposure
to triethyltin produces symptoms such as headaches,
visual defects, and nausea (Prull and Rompel, 1970).
Triethyltin uncouples oxidative phosphorylation,
which leads to mitochondrial damage, cerebral edema,
and nerve damage. Workers exposed to organic tin
compounds (trimethyl and triethyl derivatives) devel-
oped psychomotor disturbances, tremor, convulsions,
hallucinations, and psychotic behavior (Hu, 1998).
Occupational exposure to trimethyltin was associated
with an increased prevalence of nephrolithiasis (kidney
stones). Workers exposed to trimethyltin had a higher
prevalence of kidney stones (18.06%) in comparison
with unexposed workers (5.88%) (Tang et al., 2013a).
Patients who inhaled fungicide powder containing
60% triphenyltin or were exposed to triphenyltin while
spraying it complained of dizziness, nausea, and pho-
tophobia (Manzo et al., 1981). No neurobehavioral
studies have been done in children whose mothers
were exposed to organotins during pregnancy (Sokas,
1998). Skin burns and severe lesions on the hands have
been reported among workers occupationally exposed
to liquid tri- and dibutyltin chlorides because of leak-
ing gloves or a failure to wear hand protection (Lyle,
1958). The development of severe dermatitis has been
described in workers accidentally exposed to tributyl-
tin and in painters applying tributyltin formulations
(Baaijens, 1986; Goh, 1985; Lewis and Emmett, 1987).
Dermatitis and irritant and allergic reactions have been
reported among Italian agricultural and ex-agricultural
workers using triphenyltin-containing pesticide for-
mulations (Lisi et al., 1987).
7.2.1.2 Animals
Acute oral LD50 values for tributyltin in mice and
rats range from 44 to 234 mg/kg b.w., but LD50 val-
ues for intravenous and intraperitoneal injections are
much lower (Funahashi et al., 1980; Schweinfurth,
 56 Tin
1985; Pelikan and Cerny, 1968; Polster and Halacka,
1971). For rats, the intraperitoneal LD50 value is
10 mg/kg and for mice the intravenous LD50 is esti-
mated to be 6 mg/kg (Poitou et al., 1978; Truhaut
et al., 1976). In rats, LD50 values for oral tributyltin
administration range from 94 to 224 mg/kg, and LD50
values in mice range from 46 to 230 mg/kg. A single
dose of tributyltin at 500 mg/kg caused numerous
hemorrhagic lesions in the digestive tract in mice
(Pelikan and Cerny, 1968). Signs of toxicity such as
anorexia, emesis, tremor, and diarrhea have been
observed after a single oral administration of triphe-
nyltin. The oral LD50 for triphenyltin in rats ranges
from 140 to 300 mg/kg b.w., and is 81-93 mg/kg b.w.
for mice, whereas dermal the LD50 is 350 mg/kg
b.w. in mice and over 2000 mg/kg b.w. in rats (WHO,
1992). For oral ingestion of triphenyltin, the LD50
for mice, guinea pigs, and rabbits is estimated to be
80-1000, 10-41.2, and 30-140  mg/kg, respectively.
An acute dose of triphenyltin (50 mg/kg) produces
marked hyperglycemia in hamsters, but this was not
observed when hamsters were fed diets containing
phenyltin concentrations below 60 mg/kg (Matsui
et al., 1984; Ohhira and Matsui, 1996; Ohhira et al.,
1996). The hyperglycemic action of triphenyltin may
be an effect of its dose-dependent accumulation in
the pancreas. In rats, neither tributyltin nor dibutyltin
caused any abnormalities in the intestinal tract, despite
the fact that tributyltin is a potential inducer of intes-
tinal heme oxygenase (Krajnc et al., 1984; Rosenberg
et al., 1984). However, atrophy of hepatocytes in the
centrilobular region has been noted in liver at 80 mg/
kg and 320 mg/kg (Krajnc et al., 1984). Feeding rats
with dibutyltin caused inflammation and damage to
the bile duct (Gaunt et al., 1968; Krajnc et al., 1984).
Repeated exposure to dibutyltin at 50 mg/kg for
3 days produced severe damage of the bile duct, char-
acterized by complete deterioration of the luminary
epithelium, mainly in the pancreatic regions of the
bile duct (Barnes and Magee, 1958). The reported oral
LD50 for trimethyltin in rats was 14.7 mg/kg b.w. and
13 mg/kg b.w. for rats; the LD50 values for female and
male mice were estimated to be 3.16 and 4.64, respec-
tively (Tang et al., 2013b; Hoch, 2001). Oral LD50 val-
ues for dimethyltin were calculated to be between
147 and 383 mg/kg b.w. for rats and between 216 and
316 mg/kg b.w. for mice (Tang et al., 2013b).
Several studies suggest that the immune system is
the target organ for organotin toxicity (Snoeij et al.,
1985; Vos and Krajnc, 1983). Exposure to tributyltin is
reported to decrease the proportion of neutrophils and
diminish respiratory burst activity in Japanese floun-
ders (Paralichthys olivaceus) (Nakayama et al., 2007).
The neutrophil proportion of the total leukocytes
1269
in fish exposed to tributyltin at 20 μg/L for 5 days
decreased from 52.5 to 42.0%. Exposure of young rats
to low doses of tributyltin oxide resulted in functional
alterations to the immune system (­Smialowicz et  al.,
1989). Short-term exposure to tributyltin reduced
weight and caused morphological changes in lym-
phoid tissues, particularly the thymus, associated
with a reduction in circulating lymphocyte numbers
and total serum immunoglobulin levels (Penninks,
1993). Both triphenyltin and tributyltin have been
shown to induce thymus atrophy and to suppress
T-cell-induced immune responses (Seinen et al., 1979;
Snoeij et al., 1985, 1988). Tributyltin at a dietary level
of 20-320 mg/kg caused thymus weight loss and atro-
phy, leading to a reduction in peripheral lymphocytes
and T cells in the spleen (Krajnc et al., 1984). It has been
proposed that thymus atrophy is related to inhibition
of immature thymocyte proliferation and thymocyte
apoptosis (Gennari et al., 1997; Grundler et al., 2001;
Baken et al., 2007). Additionally, tributyltin represses
mitochondrial function and immune cell activation.
Triphenyltin intraperitoneally injected into mice for
14 days inhibited T-cell-dependent humoral and cel-
lular immune responses (Nishida et al., 1990). It was
shown that mice and other species appear to be more
resistant than rats to the effects of ingested organo-
tin compounds on the thymus. Thus, in rats, dietary
dibutyltin, at concentrations as low as 20 mg/kg,
caused thymus atrophy within 2 weeks (Seinen et al.,
1977b). Oral administration of tributyltin chloride at
20 mg/kg for 28 days caused weight loss of both the
thymus and spleen accompanied by reduced prolif-
erative activity of T lymphocytes and increased thy-
mocyte apoptosis in mice (Chen et al., 2011). Decrease
in weight and cellularity of the thymus has been seen
in rats fed with 50-150 mg/kg dibutyltin dichloride
or 150 mg/kg dioctyltin dichloride (Seinen et al.,
1977a). The lower molecular weight diethyltin and
dipropyltin compounds produced less pronounced
effects, and both octyltin and dioctadecyltin did not
have a measurable impact on the immune system
(Seinen et al., 1977b). The inter-species differences in
susceptibility to these compounds were attributed to
differences in their gastrointestinal absorption and
metabolism (Boyer, 1989). The effects of dialkyltin
compounds on the thymus are reported to be due to
their interference with thymocyte proliferation via
cytostatic rather than cytotoxic mechanism (Penninks
et al., 1985; Seinen et al., 1977b; Boyer, 1989). Tribu-
tyltins, in contrast to dialkyltins, induced immunode-
ficiency through direct action on lymphocytes in the
thymus (Vos et al., 1984). The reported NOAEL for
dioctyltin immunotoxicity is 0.23 mg/kg b.w./day,
based on the incidence of thymus lymphoma after
1270 Elena A. Ostrakhovitch
exposure for 2 years (Dobson et al., 2006). A 3-month
exposure period resulted in a NOAEL of 0.87 mg/kg
b.w./day based on decreased thymus weight. Dioc-
tyltin was reported to cause thymus atrophy and
dysfunction of the T-lymphocyte-mediated immune
response (Miller et al., 1986; Seinen et al., 1979).
Oral exposure to dioctyltin chloride for 6 weeks at
150 mg/kg was shown to increase relative liver and
kidney weights (Seinen and Willems, 1976). In rats
fed dioctyltin chloride from postnatal day 10, kidney
weight decreased at postnatal day 21, with a further
increase of 11 and 5% on postnatal days 21 and 90,
whereas relative liver weight showed a tendency to
increase at postnatal day 21 without further changes
(Tonk et al., 2011c). The developing immune system
is reported to show greater sensitivity to the immu-
nosuppressive effects of dioctyltin compared with
the fully developed immune system (Smialowicz
et al., 1988). Oral administration of dioctyltin chlo-
ride to rats from postnatal day 10 decreased white
blood cell concentrations and lymphocyte counts at
postnatal days 42 and 70 in dose-dependent manner
(Tonk et al., 2011a,c). Thymus weight, thymus cellu-
larity, and relative thymic cell count were decreased
at all time points evaluated, with the largest decrease
of 74% observed at postnatal day 21. While effects on
lymphocyte subpopulations in the thymus were only
observed in the 30-mg/kg group at postnatal day 42,
effects on lymphocyte subpopulations in the spleen
were found in the 30-mg/kg group at postnatal
days 42 and 70 (Tonk et al., 2011b). The delayed-type
hypersensitivity response was seen at a dose of 3 mg/
kg. Hematological changes such as anemia, lympho-
penia, and thrombocytosis have been noted in rats
fed tributyltin at a dose of 50 mg/kg (Wester et al.,
1990). It has also been shown in vitro that organotin
compounds decrease the survival, proliferation, and
differentiation of isolated human B lymphocytes (De
Santiago and Aguilar-Santelises, 1999). In another
study, tributyltin was shown to decrease the percent-
age of the CD19+CD22+ B cell subset in human bone
marrow cell cultures (Carfi et al., 2010).
Triethyltin-induced neurotoxicity in the brain
causes the formation of myelin edema and the loss of
both axons and myelin. Myelin deficits produced by
early postnatal exposure to triethyltin are permanent
and cannot be repaired as the brain matures. There-
fore, triethyltin is more toxic than trimethyltin to the
CNS of rodents. The LC50 values for trimethyltin were
estimated to be 335.5 and 609.7 μM for human pri-
mary neurons and astrocytes, respectively, after 24 h
of exposure (Cristofol et al., 2004). With the exception
of rat hippocampal neurons, triethyltin was more toxic
than trimethyltin, showing LC50 values of 3.5-16.9 μM
in human and rat neurons. The cytotoxic potency of
trimethyltin increased 70-fold in human cortical neu-
rons 5 days after exposure. Rat hippocampal neurons
were the most vulnerable to trimethyltin, exhibit-
ing a LC50 value of 1.4 μM; in contrast, a LC50 value
of 44.28 μM was calculated for rat cerebellar granule
cells. Behavioral disturbances were observed after
exposure to 10 mg/kg triethyltin (Reiter et al., 1980).
A diminished startle response to a puff of air or sud-
den noise proved to be a sensitive indication of tri-
ethyltin exposure (Squibb et al., 1980). Tributyltin
given as a single dose at 10-60 mg/kg to rat pups on
postnatal day 5 caused persistent alterations in motor
activity development and the acoustic startle response
(Crofton et al., 1989). Alterations in brain weight and
brain histology have been found after intraperitoneal
injection of tributyltin to 5-day-old rats (O’Callaghan
and Miller, 1988).
Oral administration of 2.5 and 5 mg/kg dibutyltin
in olive oil 3 days per week to pregnant rats increased
the incidence of apoptotic cell death in the neocortex
and hippocampus of offspring at postnatal day 38.
The NOAEL for maternal toxicity of dibutyltin was
reported to be 1 mg/kg b.w. and 5 mg/kg b.w. by dif-
ferent research groups (ORTEPA, 1994; Ema et al.,
1991b). Male rats exposed to 10 mg/kg per day of
tributyltin for 10 days exhibited histological altera-
tions in seminal vesicles and epididymis, as well as
reduced sperm counts. Lumen formation in the semi-
niferous tubule was remarkably delayed in response
to a single administration of 25, 50, or 100 mg/kg
tributyltin (Kim et al., 2008). Reduced serum testos-
terone concentration and downregulated expression
of 3-beta-hydroxysteroid dehydrogenase (3β-HSD II)
and estradiol 17-beta-dehydrogenase 1 (17β-HSD 1)
were associated with reduced male fertility. Wistar
females receiving 100 ng/kg tributyltin per day for 16
days by gavage had decreased cycle regularity, dura-
tion of the reproductive cycle, proestrus and diestrus
phases, and number of epithelial cells in the proestrus
phase (Podratz et al., 2012). Administration of phen-
yltins during early pregnancy led to implantation fail-
ure and increased resorption, and ­post-implantation
loss in rats (Noda et al., 1992b; Ema and Miyawaki,
2002; Adeeko et al., 2003). Oral administration of
triphenyltin chloride at 2 or 6 mg/kg b.w. caused
an increase in the number of oocytes at all follicle
stages at both dose levels, whereas no histological
changes were observed in the oviduct, uterus, vagina,
and mamma (Watermann et al., 2008). Exposure to
2 mg/kg triphenyltin led to a significant reduction in
the diameter of tertiary follicles, whereas the number
of atretic follicles was increased in tertiary and pre-
ovulatory follicles.
 56 Tin
7.2.2  Systemic Effects and Dose-Response
Relationships
7.2.2.1 Human
No human studies are available on chronic low-level
exposure to organotin compounds. However, some case
reports describe various health effects after accidental
exposure to tributyltin and triphenyltin compounds.
Patients who had been exposed mainly through cuta-
neous absorption developed acute nephropathy and
disorders of the CNS (Prull and Rompel, 1970; Colosio
et al., 1991; Grace et al., 1991; Manzo et al., 1981; Wax
and Dockstader, 1995). Exposure to triphenyltin causes
spontaneous involuntary movements of the hands,
facial twitching, and crying. Some of the patients expe-
rienced diplopia, drowsiness, giddiness, vertigo, bidi-
rectional nystagmus, impairment of numerical ability,
and disorientation in time and place (Lin et al., 1998).
In addition to CNS abnormalities, delayed peripheral
neuropathy, hepatitis, and leucopenia have been moni-
tored 6 and 9 days after triphenyltin consumption.
Two case reports of triphenyltin poisoning indicated
leucopenia, decreased neutrophil responsiveness,
elevated hepatic enzymes, hepatomegaly, and CNS
effects (encephalopathy and delayed neuropathy)
(Colosio et al., 1991; Lin et al., 1998). Liver damage has
been reported in people using triphenyltin acetate as
a spray (Horacek and Demcik, 1970). More than 100
deaths and over 200 cases of illness occurred in France
in 1954 due to ingestion of a preparation containing
diethyltin diiodide and triethyltin monoiodide. Doses
of diethyltin were estimated to be 45-675 mg in non-
fatal cases and 380-675 mg in fatal cases (Barnes and
Stoner, 1959). Severe headaches, vertigo, visual abnor-
malities, paralysis, and convulsions were reported
after only a few days of exposure. Death occurred from
coma and respiratory or cardiac failure (Gruner, 1958).
Pronounced edema of white matter of the brain was
seen in fatal cases.
7.2.2.2 Animals
While the inorganic forms of tin are generally consid-
ered nontoxic, its organic derivatives exhibit a complex
pattern of toxicity. The biological effects of organotin
species are mostly dependent on the number and kind
of organic moieties bound to the tin atom, with trisub-
stituted compounds being the most toxic. Trisubsti-
tuted organotin compounds are toxic to many aquatic
organisms, including fish. In some fish, acute toxic-
ity occurs at a few milligrams per liter, while chronic
toxicity can be found at concentrations in the order
of micrograms per liter. These compounds are also
highly toxic to mollusks, with chronic toxicity in oys-
ters and clams occurring at concentrations of fractions
1271
of micrograms per liter. The tendency of organotin
compounds to accumulate in organisms depends on
its partition between lipid and aqueous phases. The
octanol-water partition coefficient (Kow) for tributyltin
indicates a potential for bioaccumulation: the log Kow
values range from 3.2 to 4.1 but can be modified by
salinity (Laughlin et al., 1986). Studies in algae, aquatic
invertebrates, and fish have confirmed that tributyl-
tin bioaccumulation in these organisms is substantial.
Bioconcentration factor values range up to 10,000 in
periwinkles, 50,000 in fish, and 500,000 in clams. Expo-
sure to organotins such as tributyltin and triphenyltin
results in imposex. The imposition of male sexual char-
acteristics on female gastropod mollusks was linked to
the androgen signaling pathway because simultane-
ous injection of tributyltin with an androgen receptor
inhibitor, cyproterone acetate, diminished masculin-
ization in this species (Stange et al., 2012). Imposex
develops experimentally in mud snails (Nassarius
obsoletus) after 60 days exposure to tributyltin at con-
centrations of 4.5-5.5 mg/L.
With regard to dibutyltin toxicity, it was shown that
the acute half maximal effective concentration (EC50)
for growth inhibition in the diatom Skeletonema costa-
tum is 30 μg/L, whereas at 48 h the EC50 was calculated
to be 17 μg/L for swimming inhibition in the crustacean
Daphnia magna, with an LC50 of 980 μg/L for fish spe-
cies. Evidence of disruption of the endocrine system,
e.g. the induction of imposex, is seen at 0.5 ng Sn/L
in dogwhelks. Some marine benthic invertebrates are
also very sensitive to tributyltin in sediments. Popula-
tions of benthic invertebrates such as polychaetes and
amphipods have been shown to be reduced as a result
of exposure to tributyltin in sediments. Exposure to tri-
butyltin leads to masculinization in some fish species
(Shimasaki et al., 2003). In male and female mammals,
organotins also affect the reproductive system but do
not alter sex ratios (Omura et al., 2001; Ogata et al.,
2001). Exposure of zebrafish embryos to trimethyltin
up to 72 h postfertilization was shown to result in mal-
formation with an EC25 of 5.55 μM (Chen et al., 2011).
Exposure of zebrafish embryos to various organotin
compounds during very early development (< 100 h
postfertilization) revealed that dibutyltin dichloride
is the most potent (developmental) neurotoxic com-
pound (Beker van Woudenberg et al., 2013). Embryos
exposed to dibutyltin at a concentration of 8 μM had
reduced hatching rates; in contrast, dimethyltin
dichloride showed effects only at high concentrations
of 600 μM. Octyl derivatives (monooctyltin trichloride
and dioctyltin dichloride) were not identified as devel-
opmental toxicants due to their low solubility.
Tributyltin oxide is known to disrupt the endocrine
and reproductive system in rats. Maternal exposure to
1272 Elena A. Ostrakhovitch
organotin compounds such as triphenyltin and dibu-
tyltin caused embryonic death or suppressed embry-
onic growth (Tryphonas et al., 2004). Reduction of fetal
ossification was observed at doses that are nontoxic to
the mother. Intraperitoneal injection of tributyltin to
pregnant C57BL/6 mice, providing a dose of 0.05 or
0.5 mg/kg b.w., from gestational day 12 to gestational
day 18 led to increased lipid accumulation in the pups
(Grun and Blumberg, 2006). Organotin compounds
were shown to cross the placental barrier and accu-
mulate in large quantities in placental and fetal tissues
(Cooke et al., 2008; Golub and Doherty, 2004). Accu-
mulation of organotins in the placenta was five times
higher than in the dam’s blood, whereas the level in
pups was half of that found in the placenta. The lev-
els of tributyltin compounds in the liver and brain tis-
sues of pups declined by days 6 and 12 after birth even
though they continue to ingest organotins with milk.
The toxic effects of tributyltin throughout the repro-
ductive cycle were attributed to a marked decrease in
ovary weight and in serum 17β-estradiol levels. Fur-
thermore, a significant increase in progesterone level
and an accumulation of apoptotic cells in the corpus
luteum and granulosa cell layer contributed to the toxic
effect. Tributyltin significantly increased the baseline
coronary perfusion pressure and impaired vasodila-
tion via suppression of 17β-estradiol accompanied by a
significant rise in serum progesterone after 100 ng/kg
tributyltin was orally administered daily to rats for 15
days (Dos Santos et al., 2012). Furthermore, tributyltin
promoted collagen deposition in the heart interstitium
and induced endothelium denudation and platelet
accumulation. Treatment with triphenyltin chloride at
6 mg/kg b.w. caused a high mortality rate in dams and
decreased the survival rate of offspring (Grote et al.,
2007). A considerable number of pups from surviving
dams died up to postnatal day 4. In utero treatment
with 2 mg/kg triphenyltin also caused early postna-
tal mortality up to postnatal day 4 (Grote et al., 2009).
The surviving offspring developed sex-dependent
differences in response to developmental exposure
to triphenyltin: the body weight of female offspring
was unaffected, whereas male offspring exhibited
a decrease in body weight after the end of lactation.
Similarly, a decrease in body weight gain was reported
after tributyltin administration at similar dose levels
(Kimura et al., 2005; Makita and Omura, 2006). At high
doses of triphenyltin (6 mg/kg and 10 mg/kg b.w.),
delayed development of the vaginal opening was
observed in female offspring (Grote et al., 2006). Water-
mann et al. reported that triphenyltin chloride treat-
ment of adult or peripubertal female rats at doses of
2 mg/kg or higher increased the incidence of follicular
atresia (Watermann et al., 2008).
Dibutyltin is neurotoxic and exposure of rats during
development causes an increased incidence of apop-
totic cell death in certain brain tissues (Jenkins et al.,
2004). Furthermore, exposure to trimethyltin dur-
ing development affected the memory and impaired
learning capacity (Jenkins and Barone, 2004), as well
as having toxic effects on testes development in mice
(Kumasaka et al., 2002).
Numerous studies have reported teratogenic effects
of dibutyltins. Dibutyltins have been shown to cause
malformation of rat fetuses after oral administration to
pregnant rats on day 8 of gestation (Noda et al., 1992a,
1993, 1994). Dibutyltin at 7.6 mg/kg b.w. and above
caused implantation failure in rats exposed for up to
3 days (Ema et al., 2003). Dibutyltin affects the normal
development of embryos during embryogenesis and
its dysmorphogenic potential varies with develop-
mental stage. The NOAEL for fetus malformation was
defined as 45 mg/kg b.w.
Trimethyltins are the most toxic trialkyltins. These
compounds are neurotoxic, induce pathological lesions
in the mammalian brain, and lead to neurological and
behavioral changes associated with hypothermia and
inhibition of brain protein synthesis (Geloso et al.,
2011; Chang, 1986a, 1986b; Costa and Sulaiman, 1986).
Neurotoxicity of tributyltin compounds has been
shown in various systems. Intraperitoneal adminis-
tration of tributyltin at 2, 3, and 4 mg/kg on postna-
tal day 5 caused dose-dependent decreases in brain
weight (O’Callaghan and Miller, 1988). A single acute
exposure to nonlethal doses of tributyltin chloride
(50 mg/kg) led to significant changes in rat behavior
(Ema et al., 1991a). Dietary administration of tributyl-
tin chloride (125 mg/kg) for 30 days inhibited ligand
binding to the N-methyl-d-aspartate (NMDA) receptor
in mice, leading to depressed NMDA receptor func-
tion associated with an array of negative symptoms
(Konno et al., 2001). Symptoms of triethyl poisoning
in rodents include weakness of hindlimbs, dyspnea,
peripheral vasodilation, and transient edema of central
and peripheral nervous systems (Reuhl and ­Cranmer,
1984). These compounds also cause hemolysis of
erythrocytes (Ali et al., 1987). Alkyl radicals have been
shown to damage the erythrocyte membrane. A single
trimethyltin injection resulted in neuronal death in
the hippocampus (Balaban et al., 1988; Chang, 1986a;
O’Callaghan et al., 1989). Toxic doses of trimethyltin
were higher for rats than for mice, hamsters, or mar-
mosets. Both male and female rats developed seizures
with symptoms including convulsion, head tremors,
and salivation (Tang et al., 2013b). In mice, trimeth-
yltin severely affects dentate gyrus granule cells. In
rats, effects of trimethyltin are restricted to pyrami-
dal neurons in cornu ammonis (CA) areas CA1-CA3.
 56 Tin
Trymethyltin (7  mg/kg, intraperitoneally) reduced
neurotransmission at the CA3-CA1 synapse and
decreased cell numbers and the width of the CA1 pyra-
midal cell layer in the brain of Wistar rats (Gasparova
et al., 2012). Neurodegenerative effects of trimethyltin
were shown to be associated with the production of
inflammatory cytokines and oxidative stress (Harry
et al., 2008; Maier et al., 1995; Shuto et al., 2009; Corvino
et al., 2011). Triethyltins also affect protein phosphory-
lation in the rat brain. Neuronal death was shown to be
delayed for 2 days after a single intraperitoneal injec-
tion of trimethyltin but then developed progressively
over the course of 3 weeks (Whittington et al., 1989).
Neonatal exposure to trimethyltin delayed learning in
preweanling rats; this was associated with a reduction
in neuronal viability and a significant decrease in the
expression of the dopamine receptors in the hippocam-
pal area (Mignini et al., 2012). Tributyltins were shown
to be neurotoxic, causing impaired learning ability and
memory loss in rats (Elsabbagh et al., 2002). Compari-
son of the toxicity of monomethyltin, dimethyltin, and
dibutyltin compounds to the known neurotoxicant
trimethyltin in an in vitro model of neuronal devel-
opment in PC12 cells showed that dimethyltin is less
potent than trimethyltin and that monomethyltin is
not toxic at any concentration examined (Jenkins et al.,
2004). The toxicity of organotins correlated with their
lipophilicity. Dibutyltin has the highest octanol-water
partition coefficient (log Kow = 1.9), followed by tri-
methyltin (log Kow = 0.3), dimethyltin (log Kow = −1.1)
and monomethyltin (log Kow = −1.29). Tributyltin and
dibutyltin, but not monobutyltin, were shown to sup-
press acetylcholine synthesis in slices of the cortex and
to inhibit the activity of choline acetyltransferase, thus
affecting both high-affinity and low-affinity uptake of
choline into synaptosomes (Kobayashi et al., 1996). All
three butyltins at concentrations from 10 μM to 100 μM
had no effect on the activity of acetylcholinesterase.
Organotin compounds exert various toxic effects on
the thymus, liver, and immune system (Vos et al., 1990;
Pieters et al., 1994a; Grinwis et al., 2009; O’Callaghan
and Miller, 1988; Yoshizuka et al., 1992; Tsunoda et al.,
2004). In short-term feeding studies in rats, tributyltin
ingestion caused thymus atrophy, decreased numbers
of lymphocytes in spleen and lymph nodes, increased
serum immunoglobulin M (IgM) levels, and decreased
serum IgG levels (Krajnc et al., 1984; Snoeij et al.,
1987). In mice, tributyltins reduced spleen weight and
decreased the number of leukocytes (Ishaaya et al.,
1976). Mice receiving a 100-mg/kg tributyltin diet for
30 days had a decreased number of lymph node cells.
The production of IFN-γ, IL-3, IL-4, and IL-5 was also
reduced, indicating immunosuppressive effects of tri-
butyltin on mice (Iwamura et al., 2006). Exposure to
1273
dibutyltin dichloride-induced thymus atrophy in rats,
resulting from the depletion of small CD4+CD8+ thy-
mocytes (Pieters et al., 1994b). In addition, organotin
compounds have been reported to induce genotoxicity
and immunosuppression in aquatic organisms (Hagger
et al., 2005). Tributyltin may exert endocrine, bio-
transformation, and lipid peroxidative effects through
modulation of cyclic AMP/protein kinase A second
messenger signaling, with overt physiological conse-
quences (Pavlikova et al., 2010). Tributyltin was shown
to modulate multiple hepatic responses in salmon,
including effects on peroxisome proliferator-activated
receptors (PPARs), CYP19 isoforms, CYP3A, estrogen
receptor alpha (ERα), and nuclear receptor subfamily 1
group I member 2/pregnane X receptor (PXR) at both
the transcriptional and translational levels.
Organotin compounds, especially tributyltin and
triphenyltin, were shown to be endocrine disrupt-
ers (Bryan et al., 1989; Oberdorster and McClellan-
Green, 2002; Golub and Doherty, 2004; Horiguchi,
2009). Tributyltins are obesogens: they were shown
to promote adipogenesis in murine 3T3-L1 preadipo-
cyte cells and to induce the differentiation of multipo-
tent mesenchymal stem cells into adipocytes (Inadera
and Shimomura, 2005; Grun et al., 2006; Kirchner
et al., 2010; Carfi et al., 2008). Tributyltin compounds
were shown to activate PPARs/retinoic acid recep-
tors (RXRs), a transcriptional complex that plays a
critical role in energy balance, including effects on tri-
glyceride metabolism and both fatty acid and glucose
homeostasis (Grun and Blumberg, 2006; Kanayama
et al., 2005). Tributyltin induced activation of adipo-
genesis and adipogenic commitment in mesenchymal
stem cells is via activation of PPAR and suppression
of RXR function. Furthermore, tributyltin has a high-
binding affinity to RXR via bond formation between
butyltin and the Cys-432 residue of RXR (Le Maire
et al., 2009). Activation of RXR has been implicated in
the development of imposex in gastropods (Sternberg
et al., 2008; Urushitani et al., 2011). It was suggested
that RXR activation by organotins is induced in the
penis-forming area behind the right tentacle of female
T. clavigera (Horiguchi et al., 2012). Gene enrichment
analysis revealed that transcripts involved in biologi-
cal processes including general metabolism, immune
response, lipid metabolism, and stress response are
responsible for the development of imposex in the
Queen conch (S. gigas) (Titley-O’Neal et al., 2013) Tri-
butyltin induces adipogenesis, triglyceride storage,
and the expression of adipogenic marker genes in 3T3-
L1 cells in a PPAR-dependent manner (Li et al., 2011).
Lipid plasma triacylglycerols, cholesterol, and lipases
exhibited monotonic increases with enhanced body
weight in response to tributyltin (Meador et al., 2011).
1274 Elena A. Ostrakhovitch
Acute tributyltin and triphenyltin toxicity induces
hyperglycemia without abnormalities in islet tissue,
indicating that organotins have a direct effect on adi-
pose tissue (Inadera and Shimomura, 2005). Acute
triphenyltin toxicity induces hypertriglyceridemia in
the hamster (Ohhira et al., 1999a). Dialkyltins, such
as dibutyltin dichloride, induce acute intestinal pan-
creatitis in rats at approximately half the lethal dos-
age of 6 mg/kg b.w. (Merkord et al., 1998). Dibutyltin
induces the development of chronic pancreatitis in ani-
mal models, which imitates progression from the acute
to the chronic stage. A single intravenous application
of dibutyltin at a dose of 8 mg/kg resulted in a high
concentration in the bile, followed by necrosis of bilio-
pancreatic duct epithelial cells, chronic inflammation,
and acute interstitial pancreatitis (Merkord et al., 1997,
1998). In rats, dibutyltin dichloride-induced chronic
pancreatitis is used as an experimental model for the
observation of pancreatic edema, inflammatory cell
infiltration, and fibrosis (Stange et al., 2003; Yamashita
et al., 2007). Abnormal biliopancreatic duct fibrosis,
acinar degeneration, and inflammatory cell infiltra-
tion were observed in tributyltin-treated rats 28 days
after administration (Zhang et al., 2010; Glawe et al.,
2005). Apoptosis of single acinar cells was observed
in dibutyltin-induced pancreatitis. Fibrosis in dibutyl-
tin-treated rats peaked after 1 week and was limited
to areas around the pancreatic ducts after 2 weeks;
the fibrosis was composed of both type I and type III
collagen (Miyauchi et al., 2007). Overexpression of
transforming growth factor-beta receptor-associated
protein 1 (TGF-A1/TRAP1) was shown to contribute
to the pancreatic fibrogenesis in rats.
7.3  Mechanism of Action
Organotin compounds are highly lipophilic, and
can therefore permeate across biological membranes;
they target the plasma and mitochondrial membranes.
It was shown that organotins affect the lipid bilayer
by altering membrane fluidity and decreasing plasma
membrane potential, which leads to breakdown of
the plasma membrane (Boyer, 1989). Trialkyltin com-
pounds inhibit oxidative phosphorylation in mito-
chondria in vitro (Matsui et al., 1983). ATP levels are
severely depleted in response to tributyltin oxide
and tributyltin 3-hydroxyflavone exposure (Usta and
Griffiths, 1992). Organotin compounds inhibit both
ATP hydrolysis and ATP synthesis catalyzed by mem-
brane-bound and isolated complex V (F0F1 complex).
Organotin compounds react noncovalently with ATP
synthase, and the inhibitory effect of these compounds
is reversed by dithiothreitol or mercaptoethanol. In
addition, organotin compounds exert several other
cellular effects, including disorganization of the cyto-
skeleton, suppression of enzyme activity, and altered
expression of proteins involved in protein synthesis,
cellular trafficking, and proliferation (Osman et al.,
2009). Thus, tributyltin oxide was shown to suppress
transcription factors involved in energy homeostasis,
including PPARα/β (Colliar et al., 2011). Organotins
disrupt mitochondrial energy metabolism and block
mitosis by affecting spindle formation (Penninks et al.,
1983; Raffray and Cohen, 1991; Jensen et al., 1991).
However, the mechanism through which organotin
compounds affect so many cellular processes remains
unclear.
The toxic effects of organotins have been attributed
to changes in calcium homeostasis (Corsini et al., 1998;
Gennari et al., 2000). Trisubstituted organotin com-
pounds, such as tributyltin, triphenyltin, trimethyltin,
and triethyltin, increase calcium flux in mitochondria,
thus altering ATPase activity and ATP synthesis (Miura
et al., 1997; Viviani et al., 1995; Gasso et al., 2000; Nesci
et al., 2011a,b). Tributyltin compounds were shown to
increase intracellular calcium levels in rat thymocytes,
Jurkat (a human T lymphocyte cell line) cells, B lym-
phocytes, and NK cells (Grundler et al., 2001; Lane
et al., 2009; Bissonnette et al., 2010). The function of
ATPase activity and voltage-gated calcium channels is
affected by tributyltin, resulting in suppressed calcium
flow from the cytoplasm to the endoplasmic reticulum
(ER). Perturbation in calcium homeostasis was shown
to destabilize the interaction between calmodulin
(CaM) and its interaction partners, including matrin-3,
which is a substrate of caspase-3 and caspase-8
(Osman and van Loveren, 2012). Downregulation of
ribosomal protein S6 kinase alpha-1 (S6K-α1), a down-
stream effector of the serine/threonine-protein kinase
mTOR/mammalian target of rapamycin pathway and
target of AMP-activated protein kinase (AMPK), was
implicated in inhibiting protein synthesis in the pres-
ence of tributyltin oxide (Osman et al., 2009; Osman
and van Loveren, 2012). A dose- and time-dependent
interaction of tributyltin with CaM was also reported
(Cima et al., 2002). This interaction was hydrophobic
in nature, mediated by the aliphatic chains of tribu-
tyltin and the hydrophobic regions of Ca2+-activated
CaM. Both di- and monobutyltin were less capable
of inducing conformational changes in CaM, with no
significant differences between the two compounds.
Triethyltin at 50 μM rapidly increases the intracellular
calcium level in human osteoblasts via stimulation of
extracellular calcium influx and intracellular calcium
release (Lu et al., 2003). However, the triethyltin- and
trimethyltin-induced calcium influx was not sensi-
tive to voltage-gated calcium channel blockers. More-
over, triethyltin was shown to be more effective than
 56 Tin
trimethyltin in increasing intracellular calcium con-
centration in human and rat neurons (Cristofol et al.,
2004).
A prolonged calcium increase affects diverse cellu-
lar processes such as protein activation, gene expres-
sion, ion transport, and transmitter secretion and may
lead to cell death. Increased calcium efflux from the
ER to the cytoplasm and activation of calpain-2 cata-
lytic subunit (M-calpain), together with induction of
nuclear factor-kappa-B (NF-κB/p65) and activation
of nuclear factor of activated T cells (NFAT) and its
relocation to the nucleus, were reported to result in
T-cell activation and apoptosis in response to tribu-
tyltin oxide exposure (Osman and van Loveren, 2012;
van Kol et al., 2012). Low concentrations of tributyl-
tin (0.5 μM) caused the release of cytochrome c from
isolated liver mitochondria, which is indicative of the
induction of mitochondrial permeability transition
and apoptosis (Gogvadze et al., 2002). Both tributyltin
and triphenyltin suppressed DNA and protein synthe-
sis in choriocarcinoma cells (Nakanishi et al., 2002).
At concentrations above 1 μM, tributyltin compounds
inhibited activities of 3β-HSD II and 17β-HSD 1 (Ohno
et al., 2005). Components of the cellular cytoskeleton
are also targeted by organotins (Cima et al., 1998). Tri-
butyltin and triphenyltin compounds inhibit microtu-
bule assembly through direct interaction with tubulin
(Jensen et al., 1991). The toxic effects of triphenyltin
were linked to depolymerization of filamentous actin
in thymocyte (Chow and Orrenius, 1994). The effect of
tributyltin and dibutyltin on chondrogenesis varied
depending on the concentration of organotin applied.
Organotins at a low concentration of 0.016 ppb slightly
increased human chondrocyte proliferation and dif-
ferentiation, while these compounds demonstrated
strong inhibition of chondrogenesis at concentrations
of 0.16 and 7.5 ppb (Banu et al., 2006).
Organotin compounds were shown to affect the
CNS, disrupt components of glutamate homeostasis
in astrocytes, induce noradrenaline (norepinephrine)
release from rat hippocampal slices and norepineph-
rine release in PC12 chromaffin cells, and induce apop-
tosis in neuronal cells (Mizuhashi et al., 2000; Yamada
et al., 2010). Trialkyltin compounds are the most neu-
rotoxic. While trimethyltin showed localized neuronal
damage, triethyltin chloride showed a specific effect
on myelin formation. Exposure to trimethyltin dimin-
ished neuronal viability, accompanied by a significant
decrease in the expression of dopamine receptors (D1
and D2) and dopamine transporters (Mignini et al.,
2012). Several finding suggest that trimethyltin dam-
ages mitochondria and induces apoptosis or necrosis
in cultured cerebellar granule cell, depending on the
concentration used (Misiti et al., 2008; Morita et al.,
1275
2008). Tributyltin can be neurotoxic through the pro-
duction of peptide hormones in the brain (Santos et al.,
2005). Activation of M-calpain, together with induc-
tion of ER-mediated apoptosis, has been described in
rat hepatocytes and PC12 cells exposed to tributyltin
(Nakatsu et al., 2006; Grondin et al., 2007). Tributyltin
at concentrations ranging from 30 to 100 nM reduced
the frequency of GABAergic miniature postsynaptic
currents in immature neurons and decreased synapse
numbers via disruption of Cl homeostasis in embry-
onic cortical neurons (Yamada et al., 2010). However,
there were no changes recorded in gamma-aminobu-
tyric acid (GABAA) receptor function in response to
tributyltin. Trimethyltin and triethyltin, but not tri-
butyltin, were shown to induce activation of primary
microglial cells purified from neonatal rat brains in the
presence of astrocytes (Roehl et al., 2009). Triethyltin-
induced calcium overload was implicated in medi-
ating apoptosis in PC12 cells exposed to triethyltin
(Viviani et al., 1995). Diorganotin compounds were
also shown to induce apoptosis in PC12 cells, with a
displayed potency of cytotoxicity in the order: dibu-
tyltin → diphenyltin → dimethyltin (Liu et al., 2013).
Triethyltin was cytotoxic for oligodendrocytes, the
myelin-forming cells, and led to apoptotic cell death,
as indicated by DNA fragmentation along with con-
densed and fragmented nuclei (Stahnke and Richter-
Landsberg, 2004). Upregulation of HO-1, an indicator
of oxidative stress, as well as activation of extracellular
signal-regulated kinases (ERKs), was observed in oli-
godendrocytes treated with 0.2-1.5 μM triethyltin for
24 h. Trimethyltin toxicity was linked to secretion of
Cl− (Yu et al., 2010). Exposure to trimethyltin increased
Cl− secretion in a dose-dependent manner in rat colonic
mucosa. Cl− secretion was essentially regulated by
basolateral calcium-sensitive K+ channels in response
to trimethyltin. The LC50 for tetramethyltin in CaCo
cells was 170.7 μmol/L. In CHO-9 and HepG2 cells,
tetramethyltin at concentration of 429.4 μmol/L and
161.7 μmol/L did not reduce cell viability below 50%
(Dopp et al., 2011).
Tributyltin oxide inhibits cell proliferation and
cell cycle progression, and induces apoptosis. Tri-
butyltin treatment was shown to cause apoptosis in
human amnion cells (Zhu et al., 2007). Suppression of
matrin-3, mitogen-activated protein kinase (MAPK)
signaling, and ribonucleotide reductase (all implicated
in cell proliferation) was demonstrated in mouse thy-
moma cells treated with tributyltin oxide (Osman and
van Loveren, 2012). Exposure to tributyltin resulted
in upregulation of genes involved in ER stress, NF-κB
and tumor necrosis factor (TNFα) pathways, and genes
involved in DNA damage, p53 signaling, and apopto-
sis in primary mouse thymocytes (van Kol et al., 2012).
1276 Elena A. Ostrakhovitch
Both tributyltin and triphenyltin at 1 μM induced phos-
phorylation and MAPK activation (Yu et al., 2000).
Tributyltin organotins are known to induce immu-
nosuppression. They inhibit lymphocyte proliferation
and induce apoptosis in rat primary thymocytes, Jur-
kat cells, and platelets (Raffray et al., 1993; Grundler
et al., 2001; Berg et al., 2003). The percentage of early
apoptotic cells was increased by tributyltin oxide at
0.5 and 1.0 μM after 3 h of exposure; genes expressed
after 3 h were largely related to the apoptotic process
in primary rat thymocytes (Baken et al., 2007). It was
suggested that tributyltin oxide exerts its toxic effects
on the thymus primarily by affecting apoptotic pro-
cesses. Exposure of Jurkat cells to 0.5 μM tributyltin
oxide for 12 and 24 h resulted in reduced viability of
the cells to below 80% (Katika et al., 2011). Tributyltin
at concentrations of 0.2 μM or 119 ng/mL, which corre-
spond better to the butyltin concentration measured in
human tissues, did not dramatically affect Jurkat cell
viability. However, tributyltin at a low concentration
of 0.2 μM induced T-cell activation accompanied by ER
and oxidative stress (Katika et al., 2012). Exposure of
primary cultures of rat thymocytes to tributyltin oxide
at a concentration of 1 μM for 3 and 6 h led to reduced
cell viability (Baken et al., 2007). The major mode of tri-
butyltin action is suggested to be via targeting the ER.
Organotin compounds were shown to be cytotoxic
and genotoxic in several test systems (Hamasaki et al.,
1992; Florea et al., 2004; Florea et al., 2004). Dimethyltin
was found to be the most toxic in hamster fibroblasts
(CHO-9 cells), followed by trimethyltin, tetramethyl-
tin, and monomethyltin. Only dibutyltin, at the
relatively high concentration of 1 mM, induced a sig-
nificant increase in chromosome aberrations and sister
chromatid exchange after a 1-h exposure. Trimethyl-
tin did not exert a genotoxic effect. All butyltins (tri,
di, and mono) were found to be genotoxic; moreover,
dibutyltin was the most genotoxic, followed by tri-,
tetra-, and monobutyltin in the SOS chromotest (Kub-
alla et al., 1995). The greatest mutagenicity was shown
for tributyltin in the SOS chromotest with Escherichia
coli PQ37, whereas there was no evidence of mutagen-
icity for dibutyltin and dimethyltin (Hamasaki et al.,
1992). However, dibutyltin dichloride, tributyltin chlo-
ride, tributyltin oxide, dimethyltin dichloride, and
trimethyltin chloride were demonstrated to be as
genotoxic in the “rec assay.” The genotoxicity of tribu-
tyltin and triphenyltin was demonstrated in zebrafish
circulating erythrocytes by the erythrocytic nuclear
abnormalities assay (Micael et al., 2007). Triphenyltin
compounds induced micronuclei formation and sister
chromatid exchange in Chinese hamster ovary cells
(Chao et al., 1999). Triphenyltins were positive in the
Ames test and the mouse lymphoma TK+/mutation
assay (Oshiro, 1991). These data indicate that organo-
tin compounds are potential mutagens.
Despite intensive studies into the toxicity of organo-
tin compounds, the molecular mechanisms underlying
their toxicity and the molecular targets of organotins
have not yet been fully elucidated.
Acknowledgment
I wish to dedicate this chapter to my teacher Dr M. George Che-
rian and to the late Dr Magnus Piscator, who wrote the Tin chapter
in the earlier editions of this book.
References
ACGIH (American Conference of Industrial Hygienists), 2003. Tin.
In: Threshold limit values for chemical substances and physical
agents and biological exposure indices. American Conference of
Governmental Industrial Hygienists, Cincinnati, OH. 56.
Adams, W.A., Xu, Y., Little, J.C., et al., 2011. Environ. Sci. Technol.
45, 6902–6907.
Adcock, L.H., Hope, W.G., 1970. Analyst 95, 868–874.
Adeeko, A., Li, D.M., Forsyth, D.S., et al., 2003. Toxicol. Sci. 74,
407–415.
Afonso, D.D., Baytak, S., Arslan, Z., 2010. J. Anal. At. Spectrom. 25,
726–729.
Aghaie, H., Giahi, A., Monajjemi, M., et al., 2005. Sensors Actuat.
B-Chem. 107, 756–761.
Airaksinen, R., Rantakokko, P., Turunen, A.W., et al., 2010. Environ.
Res. 110, 544–547.
Ali, A.A., Upreti, R.K., Kidwai, A.M., 1987. Toxicol. Lett. 38, 13–18.
Allner, B., der Goenna, S., Griebeler, E.M., et al., 2010. Environ. Sci.
Pollut. Res. 17, 505–518.
Almeida, A.C., Wagener, A.D.R., Maia, C.B., et al., 2004. Appl.
Organomet. Chem. 18, 694–704.
Alzieu, C., 2000. Sci. Total. Environ. 258, 99–102.
Alzieu, C., 2006. In: The Energy and Resource Institute. Teri Press,
New Delhi, pp. 444–457.
Alzieu, C., Sanjuan, J., Deltreil, J.P., et al., 1986. Mar. Pollut. Bull. 17,
494–498.
Alzieu, C., Sanjuan, J., Michel, P., et al., 1989. Mar. Pollut. Bull. 20,
22–26.
Andersen, K.E., Petri, M., 1982. Contact Dermatitis 8, 173–177.
Antes, F.G., Krupp, E., Flores, E.M., et al., 2011. Environ. Sci. Technol.
45, 10524–10530.
Antizar-Ladislao, B., 2008. Environ. Int. 34, 292–308.
APHA (American Public Health Association), 1998a. Metals—­
electrothermal absorption spectroscopy, 3113B. American P ­ ublic
Health Association, Washington, DC. American Water Works
­Association, and Water Environment Federation.
APHA, 1998b. Metals—flame atomic absorption spectroscopy, 3111.
American Water Works Association, and Water Environment
Federation. American Public Health Association, Washington,
DC.
APHA, 1998c. Standard methods for the examination of water and
wastewater. Washington, DC.
Appel, K.E., 2004. Drug Metab. Rev. 36, 763–786.
Arakawa, Y., Wada, O., Yu, T.H., 1981. Toxicol. Appl. Pharmacol. 60,
1–7.
Arakawa, Y., Wada, O., Manabe, M., 1983. Anal. Chem. 55, 1901–1904.
Ashby, J.R., Craig, P.J., 1988a. Sci. Total Environ. 73, 127–133.
Ashby, J.R., Craig, P.J., 1988b. Sci. Total Environ. 73, 127–133.
 56 Tin
Ashby, J.R., Craig, P.J., 1991. Sci. Total Environ. 100, 337–346.
ATSDR (Agency for Toxic Substances and Disease Registry), 2005.
Toxicological profile for Tin, Agency for Toxic Substances and
Disease Registry. Atlanta, GA.
Aung, N., Yoshinaga, J., Takahashi, J., 2006. Food Addit. Contam. 23,
883–894.
Azenha, M., Vasconcelos, M.T., 2002. Anal. Chim. Acta. 458, 231–239.
Baaijens, P.A., 1986. Proceedings of an ORTEPA workshop,
­Berlin. ORTEP Association, Vlissingen-Oost, The Netherlands,
pp. 191–208.
Baken, K.A., Arkusz, J., Pennings, J.L., et al., 2007. Toxicology 237,
35–48.
Balaban, C.D., Ocallaghan, J.P., Billingsley, M.L., 1988. Neuroscience
26, 337–361.
Baldwin, D.R., Marshall, W.J., 1999. Ann. Clin. Biochem. 36, 267–300.
BAN (Basel Action Network), 2004. Mobile Toxic Waste: Recent
Findings on the Toxicity of End-of-Life Cell Phones. A Report by
Basel Action Network (BAN). http://ban.org/library/mobileph
onetoxicityrep.pdf (accessed 5.12.13).
Bancon-Montigny, C., Maxwell, P., Yang, L., et al., 2002. Anal. Chem.
74, 5606–5613.
Bancon-Montigny, C., Seidel, J.L., Brissaud, F., Elbaz-Poulichet, F.,
2008. J. Environ. Monitor. 10, 638–647.
Banu, N., Tsuchiya, T., Sawada, R., 2006. Animal Cell Technology: Ba-
sic and Applied Aspects: Proceedings of the 19th Annual Meeting
of the Japanese Association for Animal Cell Technology (JAACT).
Kyoto, Japan, pp. 181–187. September 25–28 2006 Springer.
Barker Jr., W.H., Runte, V., 1972. Am. J. Epidemiol. 96, 219–226.
Barnes, J.M., Magee, P.N., 1958. J. Pathol. Bacteriol. 75, 267–279.
Barnes, J.M., Stoner, H.B., 1959. Pharmacol. Rev. 11, 211–231.
Barrera, D., Maldonado, P.D., Medina-Camposa, O.N., et al., 2003.
Life Sci. 73, 3027–3041.
Barroso, C.M., Rato, M., Veríssimo, A., et al., 2011. J. Environ. Monit.
13, 3018–3025.
Baselt, R.C., Cravey, R.H., 1989. Deposition of toxic drugs and chemi-
cals in man, third ed. Year Book Medical Publ., Inc., Chicago IL,
USA.
Baul, T.S.B., Mizar, A., Chandra, A.K., et al., 2008. J. Inorg. Biochem.
102, 1719–1730.
Beker van Woudenberg, A., Wolterbeek, A., Te Brake, L., et al., 2013.
Reprod. Toxicol. 41, 35–44.
Benoy, C.J., Hooper, P.A., Schneider, R., 1971. Food Cosmet. Toxicol.
9, 645–656.
Berg, C.P., Rothbart, A., Lauber, K., et al., 2003. Oncogene 22, 775–780.
Berge, J.A., Brevik, E.M., Bjorge, A., et al., 2004. J. Environ. Monitor.
6, 108–112.
Bergmann, K., Neidhart, B., 2001. J. Sep. Sci. 24, 221–225.
Bi, X., Simoneit, B.R., Wang, Z., et al., 2010. Atmos. Environ. 44,
4440–4445.
Bissonnette, S.L., Haas, A., Mann, K.K., et al., 2010. Toxicol. Sci. 118,
108–118.
Bjorn, A., Horsing, M., Ejlertsson, J., et al., 2011. Waste Manag. Res.
29, 1327–1336.
Blunden, S., Wallace, T., 2003. Food Chem. Toxicol. 41, 1651–1662.
Boa Morte, E.S., Korn, M.G., Saraiva, M., et al., 2009. Talanta 79,
1100–1103.
Bocio, A., Nadal, M., Domingo, J.L., 2005. Biol. Trace Elem. Res. 104,
193–201.
Boogaard, P.J., Boisset, M., Blunden, S., et al., 2003. Food Chem. Toxi-
col. 41, 1663–1670.
Booth, M.D., Fleet, B., 1970. Anal. Chem. 42, 825.
Borghi, V., Porte, C., 2002. Environ. Sci. Technol. 36, 4224–4228.
Boutakhrit, K., Crisci, M., Bolle, F., Van Loco, J., 2011. Food Addit.
Contam. A 28, 173–179.
Boyer, I.J., 1989. Toxicology 55, 253–298.
1277
Braman, R.S., Tompkins, M.A., 1979. Anal. Chem. 51, 12–19.
Bridges, J.W., Davies, D.S., Williams, R.T., 1967. Biochem. J. 105,
1261–1266.
Brown, R.A., Nazario, C.M., de Tirado, R.S., et al., 1977. Environ. Res.
13, 56–61.
Browning, E., 1969. Toxicity of industrial metals, second ed. London
Butterworths, pp. 323–330.
Bryan, G.W., Gibbs, P.E., Huggett, R.J., et al., 1989. Mar. Pollut. Bull.
20, 458–462.
Bulten EJ, M.H., 1991. Metals and their compounds in the environ-
ment: Occurrence, analysis, and biological relevance. In: Merian,
E., VCH (Eds.) Weinheim, pp. 1243–1259.
Burton, E.D., Phillips, I.R., Hawker, D.W., 2004. Environ. Sci. Tech-
nol. 38, 6694–6700.
Cai, Y., Bayona, J.M., 1995. J. Chromatogr. Sci. 33, 89–97.
Calloway, D.H., McMullen, J.J., 1966. Am. J. Clin. Nutr. 18, 1–6.
Carfi, M., Croera, C., Ferrario, D., et al., 2008. Toxicology 249,
11–18.
Carfi, M., Bowe, G., Pieters, R., Gribaldo, L., 2010. Toxicology 276,
33–40.
Carlin Jr. J.F., 2004. U.S. Geological Survey, Mineral Commodity
Summaries.
Carvalho, P.N., Pinto, L.F., Basto, M., Vasconcelos, A., 2007. Micro-
chem. J. 87, 147–153.
Centineo, G., Gonzalez, E.B., Sanz-Medel, A., 2004. J. Chromat. A
1034, 191–197.
Chalupa, J., Hanlir, K., Padelkova, Z., et al., 2008. Appl. Organomet.
Chem. 22, 308–313.
Chang, L.W., 1986a. Fund. Appl. Toxicol. 6, 217–232.
Chang, L.W., 1986b. Neurotoxicol 7, 355.
Chao, J.S., Wei, L.Y., Huang, M.C., et al., 1999. Mutat. Res. 444,
167–174.
Chen, B., Zhou, Q., Liu, J., et al., 2007. Chemosphere 68, 414–419.
Chen, B., Thanh, W., Yin, Y., et al., 2012. Anal. Methods 4, 2109–2114.
Chen, B.W., Jiang, G.B., Yang, R.Q., Liu, J.Y., 2006. Appl. Organomet.
Chem. 20, 161–167.
Chen, J., Huang, C., Zheng, L., et al., 2011. Neurotoxicol. Teratol. 33,
721–726.
Chen, J.Q., Mclaughlin, J.K., Zhang, J.Y., et al., 1992. J. Occup. Envi-
ron. Med. 34, 311–316.
Chen, Q., Zhang, Z., Zhang, R., et al., 2011. Int. J. Hyg. Envir. Heal.
214, 145–150.
Chen, W., Hnizdo, E., Chen, J.Q., et al., 2005. Am. J. Ind. Med. 48, 1–9.
Chen, W.H., Yang, J., Chen, J.Q., Bruch, J., 2006. Am. J. Ind. Med. 49,
67–76.
Chiba, M., Kikuchi, M., Tohyama, C., Nishikawa, M., 1990. Biol.
Trace Elem. Res. 25, 137–147.
Chmielnicka, J., Szymanska, J.A., Sniec, J., 1981. Arch. Toxicol. 47,
263–268.
Chmielnicka, J., Zareba, G., Grabowska, U., 1992. Ecotox. Environ.
Safe 24, 266–274.
Chmielnicka, J., Zareba, G., Polkowskakulesza, E., et al., 1993. Biol.
Trace Elem. Res. 36, 73–87.
Choi, M., Moon, H.B., Choi, H.G., 2012. Arch. Environ. Contam.
Toxicol. 62, 333–340.
Chow, S.C., Orrenius, S., 1994. Toxicol. Appl. Pharmacol. 127, 19–26.
Cima, F., Ballarin, L., Bressa, G., Burighel, P., 1998. Ecotoxicol. Envi-
ron. Saf. 40, 160–165.
Cima, F., Dominici, D., Mammi, S., Ballarin, L., 2002. Appl.
Organomet. Chem. 16, 182–186.
Cobbing, M., 2008. Full Report, Greenpeace International. Report
Greenpeace International, The Netherlands. http://www.green
peace.org.
Coelho, M.R., Bebianno, M.J., Langston, W.J., 2002. Mar. Environ.
Res. 54, 179–192.
1278 Elena A. Ostrakhovitch
Colliar, L., Sturm, A., Leaver, M.J., 2011. Comp. Biochem. Physiol.
C Toxicol. Pharmacol. 153, 168–173.
Colosio, C., Tomasini, M., Cairoli, S., et al., 1991. Br. J. Ind. Med. 48,
136–139.
Conine, D.L., Yum, M., Martz, R.C., et al., 1976. Toxicol. Appl. Phar-
macol. 35, 21–28.
Cook, L.L., Stine, K.E., Reiter, L.W., 1984. Toxicol. Appl. Pharmacol.
76, 344–348.
Cooke, G.M., Forsyth, D.S., Bondy, G.S., et al., 2008. J. Toxicol. Env.
Heal. A 71, 384–395.
Corbin, H.B., 1973. Anal. Chem. 45, 534–537.
Corsini, E., Viviani, B., Marinovich, M., Galli, C.L., 1998. Toxicol.
Vitro 12, 551–556.
Corvino, V., Marchese, E., Zarkovic, N., et al., 2011. Neurochem. Res.
36, 1490–1500.
Costa, L.G., Sulaiman, R., 1986. Toxicol. Appl. Pharmacol. 86,
189–196.
COT (Committee on Toxicity of Chemicals in Food), 2008. COT
statement on the 2006 UK Total Diet Study of metals and other
­elements. Annual Report.
Craig, P.J., Rapsomanikis, S., 1985. Environ. Sci. Technol. 19, 726–730.
CRC Handbook of Chemistry and Physics, CRC Press, 2011.
Cremer, J.E., 1957. Biochem. J. 67, 87–96.
Cristofol, R.M., Gasso, S., Vilchez, D., et al., 2004. Toxicol. Lett. 152,
35–46.
Crofton, K.M., Dean, K.F., Boncek, V.M., et al., 1989. Toxicol. Appl.
Pharmacol. 97, 113–123.
Cui, Z., Zhang, K., Zhou, Q., et al., 2011. Talanta 85, 1028–1033.
Cui, Z., Zhang, K., Zhou, Q., et al., 2012. Sci. China Chem. 55,
323–328.
Cummings, K.J., Donat, W.E., Ettensohn, D.B., et al., 2010. Am. J.
Respir. Crit. Care Med. 181, 458–464.
Cummings, K.J., Nakano, M., Omae, K., et al., 2012. Chest 141,
1512–1521.
Dabek-Zlotorzynska, E., Lai, E.P.C., Timerbaev, A.R., 1998. Anal.
Chim. Acta 359, 1–26.
Dantas, F.J.S., Moraes, M.O., Carvalho, E.F., et al., 1996. Toxicology
34, 959–962.
Dantas, F.J.S., Moraes, M.O., de Mattos, J.C.P., et al., 1999. Toxicol.
Lett. 110, 129–136.
Dantas, F.J.S., de Mattos, J.C.P., Moraes, M.O., et al., 2002. Cell. Mol.
Biol. 48, 789–791.
de Groot, A.P., Feron, V.J., Til, H.P., 1973. Food Cosmet. Toxicol. 11,
19–30.
de Mattos, J.C.P., Lage, C., Dantas, F.J.S., et al., 2005. Mol. Cell. Bio-
chem. 280, 173–179.
De Santiago, A., Aguilar-Santelises, M., 1999. Hum. Exp. Toxicol. 18,
619–624.
de Smaele, T., Moens, L., Dams, R., et al., 1998. J. Chromat. A 793,
99–106.
Delucchi, F., Tombesi, N.B., Freije, R.H., et al., 2007. Environ. Monit.
Assess. 132, 445–451.
der Meulen, H.C., Feron, V.J., Til, H.P., 1974. Pathol. Eur. 9, 185–192.
Detcheva, A., Grobecker, K., 2006. Spec. Acta B. 61, 454–459.
Devos, C., Vliegen, M., Willaert, B., et al., 2005. J. Chromat. A 1079,
408–414.
Dietz, C., Sanz, J., Sanz, E., et al., 2007. J. Chromat. A 1153, 114–129.
Dizikes, L.J., Ridley, W.P., Wood, J.M., 1978. J. Am. Chem. Soc. 100,
1010–1012.
Dobson, S., Howe, P.D., Floyd, P., 2006. Concise International Chemi-
cal Assessment Document 73.
Doctor, S.V., Fox, D.A., 1982. J. Toxicol. Environ. Health 10, 43–52.
Domingo, J.L., Perello, G., Gine Bordonaba, J., 2012. Biol. Trace Elem.
Res. 146, 420–425.
Donard, O.F.X., Weber, J.H., 1988. Nature 332, 339–341.
Donard, O.F.X., Rapsomanikis, S., Weber, J.H., 1986. Anal. Chem. 58,
772–777.
Dopp, E., von Recklinghausen, U., Hippler, J., et al., 2011. J. Toxicol.
2011, 503576.
Dorn, E., Werner, H.J., 1989. Unpublished report CR077/88 (A41974)
of Analytisches Laboratorium Hoechst AG. Submitted to WHO
by Hoechst AG, Frankfurt-am-Main.
Dos Santos, R.L., Podratz, P.L., Sena, G.C., et al., 2012. J. Toxicol. Env.
Heal. A. 75, 948–959.
Duester, L., Diaz-Bone, R.A., Kosters, J., et al., 2005. J. Environ. Moni-
tor. 7, 1186–1193.
Dwivedi, R.S., Kaur, G., Srivestava, R.C., et al., 1983. Chemosphere
12, 333–340.
Eckert, H.G., Kellner, H.M., Beurkle, W.L., 1989. Unpublished Work.
EFSA (European Food Safety Authority), 2004a. European Food
Safety Authority (EFSa) 102, 1–114.
EFSA, 2004b. Opinion of the Scientic Panel on Contaminants in the
Food Chain on a request from the Commission to assess the health
risks to consumers associated with exposure to organotins in food-
stuffs.
El Demerdash, F.M., Yousef, M.I., Zoheir, M.A., 2005. Food Chem.
Toxicol. 43, 1743–1752.
El Makawy, A.I., Girgis, S.M., Khalil, W.K., 2008. Mutat. Res. Gen.
Tox. Environ. Mutagen 657, 105–110.
Elekes, C.C., Dumitriu, I., Busuioc, G., et al., 2010. Environ. Sci.
­Pollut. R 17, 1230–1236.
Ellingsen, J.E., 1986. Scand. J. Dent. Res. 94, 299–305.
Elsabbagh, H.S., Moussa, S.Z., El Tawil, O.S., 2002. Pharmacol. Res.
45, 201–206.
Ema, M., Miyawaki, E., 2002. Reprod. Toxicol. 16, 309–317.
Ema, M., Itami, T., Kawasaki, H., 1991a. Neurotoxicol. Teratol. 13,
489–493.
Ema, M., Itami, T., Kawasaki, H., 1991b. Toxicol. Lett. 58, 347–356.
Ema, M., Harazono, A., Hirose, A., et al., 2003. Toxicol. Lett. 143,
233–238.
Engberg, A., 1973. Analyst 98, 137–145.
Errecalde, O., Gommy, C., Maury, G., et al., 1995. Appl. Organomet.
Chem. 9, 525–529.
Escalante, B., Sacerdoti, D., Davidian, M.M., et al., 1991. Hyperten-
sion 17, 776–779.
European Commission, 2004. European Commission Regula-
tion 242/2004. http://eur-lex.europa.eu/LexUriServ/LexU
riServ.do?uri=OJ: L:2004:042:0003:0004:EN: PDF (accessed
29.11.13).
European Commission, 2006a. Commission Regulation (EC)
No 1881/2006. Official Journal of European Union l 364.
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:
L:2006:364:0005:0024:EN: PDF (accessed 29.11.13).
European Commission, 2006b. Commission of the European Com-
munities COM No 398. http://eur-lex.europa.eu/LexUriServ/
LexUriServ.do?uri=COM:2007:0398:FIN: EN:PDF (accessed
5.12.13).
European Commission, 2007. Commission Regulation (EC)No
33/2007. http://eur-lex.europa.eu/LexUriServ/LexUriServ.
do?uri=OJ: L:2007:010:0007:0008:EN: PDF (accessed 29.11.13).
European Commission, 2009. EU Commission Regulation (EC) No.
124/2009. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do
?uri=OJ: L:2009:040:0007:0011:en:PDF (accessed 29.11.13).
European Commission, 2010. EU Commission Regulation No
276/2010. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do
?uri=OJ: L:2010:086:0007:0012:en:PDF (accessed 29.11.13).
European Commission, 2011. European Commission r­egulation
No 836/2011 amending European Commission regulation No
333/2007. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?
uri=OJ: L:2011:215:0009:0016:EN: PDF (accessed 29.11.13).
 56 Tin
European Council of Vinyl Manufacturers (n.d.) Science—PVC,
Stabilisers and Plasticisers, paper produced by the European
Council of Vinyl Manufacturers (ECVM) in conjunction with the
European Stabilisers Producers Association (ESPA), E ­ uropean
Council of Vinyl Manufacturers. http://www.pvc.org/en
(accessed 10.12.13).
Evans, O., Kauffman, P., Vonderheide, et al., 2009. Microchem. J. 92,
155–164.
Evans, W.H., Cardarelli, N.F., Smith, D.J., 1979. J. Toxicol. Environ.
Health 5, 871–877.
Falke, A.M., Weber, J.H., 1994a. Appl. Organomet. Chem. 8, 351–359.
Falke, A.M., Weber, J.H., 1994b. Abstr. Papers Amer. Chem. Soc. 207.
75–GEOC.
Fang, C., Wang, X., Wang, W., et al., 2011. Asian J. Ecotoxicol. 6, 54–59.
Fent, K., Hunn, J., Sturm, M., 1991a. Naturwissenschaften 78,
219–221.
Fent, K., Lovas, R., Hunn, J., 1991b. Naturwissenschaften 78, 125–127.
Fent, K., 1996. Crit. Rev. Toxicol. 26, 3–117.
Fernandez, M.A., Wagener, A.D.R., Limaverde, A.M., et al., 2005.
Mar. Environ. Res. 59, 435–452.
Fine Olivarius, F., Balslev, E., Menne, T., 1993. Contact Dermatitis
29, 110–111.
Fish, R.H., 1984. Neurotoxicol 5, 159–161.
Florea, A.M., Dopp, E., Obe, G., et al., 2004. Organic Metal and
Metalloid Species in the Environment: Analysis, Distribution,
Processes and Toxicological Evaluation, 205–219.
Florence, T.M., Farrar, Y.J., 1974. J. Electroanal. Chem. 51, 191–200.
FSA (Food Standards Agency), 2002. Report No 2002-08-22.
FSA., 2003. Report of the Expert Group on Vitamins and Minerals.
Food Standards Agency, UK.
FSA., 2009a. Survey on measurement of the concentrations of metals
and other elements from the 2006 UK total diet study. Food Sur-
veillance Information Sheet No. 01/09. London (UK): FSA, Com-
mittee on Toxicity of Chemicals in Food, Consumer Products and
Environment (COT).
FSA, 2009b. The Contaminants in Food (England) Regulations 2009
(Statutory Instrument 2009 No. 1223).
Fortemps, E., Amand, G., Bomboir, A., et al., 1978. Int. Arch. Occup.
Environ. Health 41, 1–6.
Frena, M., Campestrini, I., de Braga, O.C., et al., 2011. Electrochim.
Acta. 56, 4678–4684.
Fritsch, P., de Saint, B.G., Derache, R., 1977. Toxicology 8, 165–175.
Frouin, H., Lebeuf, M., Saint-Louis, R., et al., 2008. Aquat. Toxicol.
90, 243–251.
Funahashi, N., Iwasaki, I., Ide, G., 1980. Acta Pathol. Jpn. 30, 955–966.
Furchner, J.E., Drake, G.A., 1976. Health Phys. 31, 219–224.
Furuhashi, K., Ogawa, M., Suzuki, Y., et al., 2008. Chem. Res. Toxicol.
21, 467–471.
Gadd, G.M., 2000. Sci. Total Environ. 258, 119–127.
Gaddoni, G., Baldassari, L., Francesconi, E., et al., 1993. Contact
­Dermatitis 28, 127–128.
Gallego-Gallegos, M., Liva, M., Olivas, R.M., et al., 2006. J. Chromat.
A 1114, 82–88.
Gallina, A., Magno, F., Tallandini, L., et al., 2000. Rapid. Commun.
Mass Spec. 14, 373–378.
Garcia, F., Ortega, A., Domingo, J.L., et al., 2001. J. Environ. Sci.
Health A 36, 1767–1786.
Garg, A., Meena, R.M., Bhosle, N.B., 2010. Environ. Monit. Assess.
165, 643–651.
Gasparova, Z., Janega, P., Stara, V., et al., 2012. Neuro. Endocrinol.
Lett. 33, 689–696.
Gasso, S., Sanfeliu, C., Sunol, C., et al., 2000. Toxicol. Appl. Pharma-
col. 162, 189–196.
Gaunt, I.F., Colley, J., Grasso, P., et al., 1968. Food Cosmet. Toxicol.
6, 599–608.
1279
Geloso, M.C., Corvino, V., Michetti, F., 2011. Neurochem. Int. 58,
729–738.
Gennari, A., Potters, M., Seinen, W., et al., 1997. Toxicol. Appl. Phar-
macol. 147, 259–266.
Gennari, A., Viviani, B., Galli, C.L., et al., 2000. Toxicol. Appl. Phar-
macol. 169, 185–190.
Gipperth, L., 2009. J. Environ. Manage. 90, S86–S95.
Glawe, C., Emmrich, J., Sparmann, G., et al., 2005. Lab. Invest. 85,
193–204.
Gogvadze, V., Stridh, H., Orrenius, S., et al., 2002. Biochem. Biophys.
Res. Commun. 292, 904–908.
Goh, C.L., 1985. Contact Dermatitis 12, 161–163.
Golub, M., Doherty, J., 2004. J. Toxicol. Environ. Health B Crit. Rev.
7, 281–295.
Gonzalez-Toledo, E., Compano, R., et al., 2003. Trac-Trends Anal.
Chem. 22, 26–33.
Gosz, E., Horbowy, J., Ruczynska, W., 2011. Mar. Pollut. Bull. 62,
2563–2567.
Grace, C.T., Ng, S.K., Cheong, L.L., 1991. Contact Dermatitis 25,
250–251.
Granmo, A., Ekelund, R., Sneli, J.A., et al., 2002. Mar. Pollut. Bull. 44,
1142–1148.
Grassino, A.N., Grabaric, Z., Pezzani, A., et al., 2010. J. Sci. Food.
Agric. 90, 2419–2426.
Greger, J.L., Smith, S.A., Johnson, M.A., et al., 1982. Biol. Trace Elem.
Res. 4, 269–278.
Grinwis, G., Wester, P., Vethaak, A., 2009. Environ. Pollut. 157,
2587–2593.
Grondin, M., Marion, M., Denizeau, F., et al., 2007. Toxicol. Appl.
Pharmacol. 222, 57–68.
Grote, K., Stahlschmidt, B., Talsness, C.E., et al., 2004. Toxicology 202,
145–158.
Grote, K., Andrade, A.J.M., Grande, S.W., et al., 2006. Toxicology 222,
17–24.
Grote, K., Hobler, C., Andrade, A.J., et al., 2007. Toxicology 238,
177–185.
Grote, K., Hobler, C., Andrade, A.J., et al., 2009. Toxicology 260,
53–59.
Grun, F., Blumberg, B., 2006. Endocrinology 147, S50–S55.
Grun, F., Watanabe, H., Zamanian, Z., et al., 2006. Mol. Endocrinol.
20, 2141–2155.
Grundler, W., Dirscherl, P., Beisker, W., et al., 2001. Cytometry 44, 45–56.
Gruner, J.E., 1958. Rev. Neurol. 98, 109–116.
Guard, H.E., Cobet, A.B., Coleman, W.M., 1981. Science 213, 770–771.
Guedes, A.P., Cardoso, V.N., De Mattos, J.C., et al., 2006. Nucl. Med.
Biol. 33, 915–921.
Guerin, T., Sirot, V., Volatier, J., et al., 2007. Sci. Total Environ. 388,
66–77.
Guruge, K.S., Tanabe, S., Iwata, H., et al., 1996. Arch. Environ. Contam.
Toxicol. 31, 210–217.
Hadjispyrou, S.A., Anagnostopoulos, A., Nicholson, K., et al., 1998.
Environ. Geochem. Hlth. 20, 19–27.
Hagger, J.A., Depledge, M.H., Galloway, T.S., 2005. Mar. Pollut. Bull.
51, 811–816.
Hallas, L.E., Means, J.C., Cooney, J.J., 1982. Science 215, 1505–1507.
Hamasaki, T., Sato, T., Nagase, H., et al., 1992. Mut. Res. 280, 195–203.
Hamilton, E.I., Minski, M.J., 1972. Sci. Total Environ. 1, 375–394.
Harino, H., Fukushima, M., Kawai, S., 2000. Arch. Environ. Contam.
Toxicol. 39, 13–19.
Harino, H., O’Hara, S.C.M., Burt, G.R., et al., 2005. Chemosphere 58,
877–881.
Harino, H., Ohji, M., Brownell, R.L., et al., 2008a. Arch. Environ.
Contam. Toxicol. 55, 137–142.
Harino, H., Ohji, M., Wattayakorn, G., et al., 2008b. Arch. Environ.
Contam. Toxicol. 54, 145–153.
1280 Elena A. Ostrakhovitch
Harino, H., Arifin, Z., Rumengan, F.M.J., et al., 2012. Arch. Environ.
Contam. Toxicol. 63, 13–21.
Harry, G., Funk, J.A., d’Hellencourt, C.L., et al., 2008. Brain Res. 1194,
8–20.
Health Council of the Netherlands, 2005. Dutch Expert Committee on
Occupational Standards. Tin and inorganic tin compounds; Health-
based recommended occupational exposure limit. Health Council
of the Netherlands, 2005; publication no. 2005/06OSH, The Hague.
Henderson, W., Taylor, M.J., 1996. Polyhedron 15, 1957–1964.
Henderson, W., McIndoe, J.S., 2005. Mass Spectrometry of inorganic,
coordination and organometallic compounds: Tools-Techniques-
Tips. John Wiley &Sons, LTD, Chichester.
Heroult, J., Zuliani, T., Bueno, M., et al., 2008. Talanta 75, 486–493.
Hiles, R.A., 1974. Toxicol. Appl. Pharmacol. 27, 366–379.
Hirano, Y., Yamamura, K., Oguma, K., et al., 2001. Anal. Sci. (Suppl. 17),
il295–il298.
Hoch, M., 2001. Appl. Geochem. 16, 719–743.
Hoch, M., Schwesig, D., 2004. Appl. Geochem. 19, 323–334.
Hoch, M., Alonso-Azcarate, J., Lischick, M., 2002. Environ. Toxicol.
Chem. 21, 1390–1397.
Hoch, M., Alonso-Azcarate, J., Lischick, M., 2003. Environ. Pollut.
123, 217–227.
Hodgson, J.T., Jones, R.D., 1990. Brit. J. Ind. Med. 47, 665–676.
Horacek, V., Demcik, K., 1970. Prac.Lék. 22, 61–66.
Horiguchi, T., 2009. Ecotoxicol. Antifouling Biocides, pp. 111–124.
Horiguchi, T., Cho, H., Shiraishi, H., et al., 2001a. RIKEN Review:
Focused on New Trends in Bio-Trace Elements Research 35, 9–11.
Horiguchi, T., Cho, H.S., Shiraishi, H., et al., 2001b. Otsuchi Mar. Sci.
26, 61–63.
Horiguchi, T., Kojima, M., Hamada, F., et al., 2006. Environ. Health
Perspect. 114, 13–19.
Horiguchi, T., Lee, J.H., Park, J.C., et al., 2012. Mar. Environ. Res. 76,
56–62.
Hu, H., 1998. Harrison’s principles of Internal medicine. In: Fauci,
A.S., Braunwald, E., Isselbacher, K.J., Wilson, J.D., Martin, J.B.
(Eds.). McGraw-Hill, New York, pp. 2564–2569.
Huang, J.H., Matzner, E., 2004a. Eur. J. Soil. Sci. 55, 693–698.
Huang, J.H., Matzner, E., 2004b. J. Plant Nutr. Soil Sci. 167, 33–38.
Hutton, E.A., Ogorevc, B., Hocevar, S.B., Smyth, M.R., 2006. Anal.
Chim. Acta. 557, 57–63.
Igarashi, I., 1959. J. Tokyo Med. Coll. 17, 1603–1632.
Impellitteri, C.A., Evans, O., Ravel, B., 2007. J. Environ. Monitor. 9,
358–365.
Inadera, H., Shimomura, A., 2005. Toxicol. Lett. 159, 226–234.
Inagaki, K., Takatsu, A., Watanabe, T., et al., 2007. Anal. Bioanal.
Chem. 387, 2325–2334.
IGES (Institute for Global Environmental Strategies). (2009).
Tsydenova O., Bengtsson M. Environmental and Human health
risks ­associated with the End-of life Treatment of electrical and
electronic equipment. http://pub.iges.or.jp/modules/envirolib/
view.php?docid=2519 (accessed 29. 11. 13).
IPCS (Programme on Chemical Safety), 1999. International Pro-
gramme on Chemical Safety, World Health Organization (WHO).
Document 13.
Isensee, J., Watermann, B., Berger, H.D., 1994. Germ. J. Hydrogr. 46,
355–365.
Ishaaya, I., Engel, J.L., Casida, J.E., 1976. Pestic. Biochem. Physiol.
6, 270–279.
Ishihara, N., Matsushiro, T., 1986. Arch. Environ. Health 41, 324–330.
Ishizaka, T., Suzuki, T., Saito, Y., 1989. J. Agric. Food. Chem. 37,
1096–1101.
ISO (International Organization for Standardization), 2003a. Report
No 9941:2003. Milk and canned evaporated milk. Determination
of tin content: Spectrometric method. International Organization
for Standardization, Geneva.
ISO, 2003b. Report No 17294-2:2003. Water quality: Application of
inductively coupled plasma mass spectrometry (ICP-MS). Part2:
Determination of 62 elements. International Organization for
Standardization, Geneva.
ISO, 2004. Report No 17240:2004. Fruit and vegetable products: De-
termination of tin content. Method using flame atomic absorp-
tion spectrometry. International Organization for Standardiza-
tion, Geneva.
I.T.R.L, Ltd, 2011. Tin industry review 2011. news release, Frogmore,
United Kingdom.
Iwamoto, I., 1969. J. Tokyo. Med. Coll. 18, 1351–1376.
Iwamura, C., Aihara, M., Nakazawa, M., et al., 2006. Int. Arch.
­Allergy Immunol. 141, 337–345.
JECFA, 1978. WHO Technical Report Series, No. 631 Report No 22.
(Twenty-second report of the Joint FAO/WHO Expert Commit-
tee on Food Additives).
JECFA, 1982. Joint FAO/WHO Expert Committee on Food Additives
(WHO Food Additives Series No. 17). Cambridge University
Press, Cambridge, pp. 297–319.
JECFA, 1989. Thirty-third Report of the Joint FAO/WHO Expert
Committee on Food Additives. WHO Technical Report Series No.
776. WHO, Geneva.
JECFA, 2001. Codex Alimentarius Comission-Foods and Agriculture
Organization of the UN/World Health Organization (Thirty-
third report of the Joint FAO/WHO Expert Committee on Food
Additives). Report No 33.
JECFA, 2006. Sixty-fourth report of the Joint FAO/WHO Expert
Committee on Food Additives. WHO Technical Report Series,
No. 930, Report No 64.
JECFA, 2011. Food standards programme codex committee on contami-
nants in foods. Joint Food and Agriculture Organization (FAO) of
United Nations/World Health Organization (WHO). Fifth session.
Jenkins, S.M., Barone, S., 2004. Toxicol. Lett. 147, 63–72.
Jenkins, S.M., Ehman, K., Barone, S., 2004. Dev. Brain Res. 151, 1–12.
Jensen, K.G., Onfelt, A., Wallin, M., et al., 1991. Mutagenesis 6,
409–416.
Jiang, G., Zhou, Q., He, B., 2000. Bull. Environ. Contam. Toxicol. 65,
277–284.
Jimenez, M.S., Gomez, M.T., Castillo, J.R., 2007. Talanta 72,
1141–1148.
Jing, H.W., Amirav, A., 1998. J. Chromatogr. A 805, 177–215.
Johnson, M.A., Greger, J.L., 1982. Am. J. Clin. Nutr. 35, 655–660.
Johnson, M.A., Greger, J.L., 1985. J. Nutr. 115, 615–624.
Jones-Lepp, T.L., Varner, K.E., Heggem, D., 2004. Arch. Environ.
Contam. Toxicol. 46, 90–95.
Juliao, L.M., Melo, D.R., Sousa, W.O., et al., 2007. Radiat. Prot. D
­ osim.
125, 513–515.
Kanayama, T., Kobayashi, N., Mamiya, S., et al., 2005. Mol. Pharma-
col. 67, 766–774.
Kannan, K., Falandysz, J., 1997. Mar. Pollut. Bull. 34, 203–207.
Kannan, K., Lee, R.F., 1996. Environ. Toxicol. Chem. 15, 1492–1499.
Kannan, K., Corsolini, S., Focardi, S., et al., 1996. Arch. Environ. Con-
tam. Toxicol. 31, 19–23.
Kannan, K., Senthilkumar, K., Giesy, J.P., 1999. Environ. Sci. Technol.
33, 1776–1779.
Kannan, K., Kajiwara, N., Watanabe, M., et al., 2004. Environ. Toxi-
col. Chem. 23, 49–56.
Kannan, K., Takahashi, S., Fujiwara, N., et al., 2010. Arch. Environ.
Contam. Toxicol. 58, 901–907.
Kapsimali, D., Rosenberg, E., Zachariadis, G., 2012. Anal. Lett. 45,
642–650.
Katika, M.R., Hendriksen, P.J., van Loveren, H., et al., 2011. Toxicol.
Appl. Pharmacol. 254, 311–322.
Katika, M.R., Hendriksen, P.J., de Ruijter, N.C., et al., 2012. Toxicol.
Lett. 212, 126–136.
 56 Tin
Kaur, V., Malik, A.K., Verma, N., 2006. J. Sep. Sci. 29, 333–345.
Kawaguchi, M., Inoue, K., Yoshimura, M., et al., 2004. J. Chromat. B:
Biomed. Sci. Appl. 805, 41–48.
Kehoe, R.A., Cholak, J., Story, R.V., 1940. J. Nutr. 20, 98.
Kellner, H.M., Eckert, H.G., 1989. Unpublished Report 01-L42-
582-90 (A43434) of Pharma Forschung GB-L Radiochemisches
Laboratorium Hoechst, Submitted to WHO by Hoechst AG.,
­Frankfurt-am-Main.
Kim, S.K., Kim, J.H., Han, J.H., et al., 2008. Int. J. Toxicol. 27, 175–182.
Kimbrough, R.D., 1976. Environ. Health Perspect. 14, 51–56.
Kimmel, E.C., Fish, R.H., Casida, J.E., 1977. J. Agric. Food Chem. 25,
1–8.
Kimura, K., Kobayashi, K., Naito, H., et al., 2005. Biosci. Biotechnol.
Biochem. 69, 1104–1110.
Kirchner, S., Kieu, T., Chow, C., et al., 2010. Mol. Endocrinol. 24,
526–539.
Kirk-Othmer Encyclopedia of Chemical Technology, 2000. Tin com-
pounds. Wiley, New York.
Kizlink, J., 1996. Chemicke Listy 90, 147–154.
Klevay, L.M., 2000. Clinical Nutrition of the Essential Trace Elements
and Minerals: The Guide for Health Professionals. In: Bogden,
J.D., Klevay, L.M. (Eds.). Humana Press Inc., Totowa, N.J, pp.
251–271.
Klevay, L.M., Combs, G.F., 2004. For World Health Organization,
­Geneva. http://www.who.int/water_sanitation_health/dwq/
nutrientsindw.pdf (accessed 29.11.13).
Kloke, A., Sauerbeck, D.R., Vetter, H., 1984. Changing metal cycles
and human health. In: Nriagu, J.O. (Ed.). Springer-Verlag, Berlin,
pp. 113–114.
Kobayashi, H., Suzuki, T., Kasashima, Y., et al., 1996. Jpn. J. Pharma-
col. 72, 317–324.
Konno, N., Tsunoda, M., Nakano, K., et al., 2001. Arch. Toxicol. 75,
549–554.
Krajnc, E.I., Wester, P.W., Loeber, J.G., et al., 1984. Toxicol. Appl.
Pharmacol. 75, 363–386.
Krigman, M.R., Silverman, A.P., 1984. Neurotoxicology 5, 129–139.
Kuballa, J., Wilken, R.D., Jantzen, E., et al., 1995. Analyst 120,
667–673.
Kumasaka, K., Miyazawa, M., Fujimaki, T., et al., 2002. J. Reprod.
Dev. 48, 591–597.
Landmeyer, J.E., Tanner, T.L., Watt, B.E., 2004. Environ. Sci. Technol.
38, 4106–4112.
Lane, R., Ghazi, S.O., Whalen, M.M., 2009. Arch. Environ. Contam.
Toxicol. 57, 816–825.
Langston, W.J., Burt, G.R., Zhou, M.J., 1987. Mar. Pollut. Bull. 18,
634–639.
Laughlin, R.B., Linden, O., 1985. Ambio 14, 88–94.
Laughlin, R.B., Guard, H.E., Coleman, W.M., 1986. Environ. Sci.
Technol. 20, 201–204.
Le Gac, M., Lespes, G., Potin-Gautier, M., 2003. J. Chromat. A 999,
123–134.
Le Maire, A., Grimaldi, M., Roecklin, D., et al., 2009. EMBO Rep 10,
367–373.
Lee, C.C., Wang, T., Hsieh, C.Y., et al., 2005. Environ. Pollut. 137,
198–208.
Lehotzky, K., Szeberenyi, J.M., Gonda, Z., et al., 1982. Neurobehav.
Toxicol. Teratol. 4, 247–250.
Levine, S., Saltzman, A., 1996. Biol. Trace Elem. Res. 52, 303–308.
Lewis, P.G., Emmett, E.A., 1987. Contact Dermatitis 17, 129–132.
Li, Q., Lu, G.H., Wu, H., et al., 1999. Food Chem. 64, 129–132.
Li, X., Ycaza, J., Blumberg, B., 2011. J. Steroid Biochem. 127, 9–15.
Lilley, T., Ruokolainen, L., Vesterinen, E., et al., 2012a. Ecotoxicol 21,
1333–1344.
Lilley, T.M., Meierjohann, A., Ruokolainen, L., et al., 2012b. Environ.
Toxicol. Chem. 31, 1781–1787.
1281
Lin, T.J., Hung, D.Z., Kao, C.H., et al., 1998. Hum. Exp. Toxicol. 17,
403–405.
Liscio, C., Di Carro, M., Magi, E., 2009. Comptes. Rendus Chimie 12,
831–840.
Lisi, P., Caraffini, S., Assalve, D., 1987. Contact Dermatitis 17,
212–218.
Liu, E., Du, X., Ge, R., et al., 2013. Food Chem. Toxicol. 60, 302–
308.
Liu, L.L., Wang, J.T., Chung, K.N., et al., 2011. Mar. Pollut. Bull. 63,
535–540.
Llobet, J.M., Granero, S., Schuhmacher, M., et al., 1998. Trace Elem.
Electroly. 15, 44–49.
Lopez de Alda, M.J., Barcelo, D., 2001. J. Chromat. A 938, 145–153.
Lu, T.C., Whang, C.W., 1995. J. Chin. Chem. Soc. 42, 515–520.
Lu, Y.C., Kuo, S.Y., Jiann, B.P., et al., 2003. Environ. Toxicol. Pharma-
col. 14, 1–7.
Lyle, W.H., 1958. Br. J. Ind. Med. 15, 193–196.
MAFF (Ministry of Agriculture, Fisheries and Food), 1983. Food Ad-
ditives and Contaminants Committee Report. Report on the re-
view of metals in canned foods. (FAC/REP/38).
MAFF, 1998. Lead, Arsenic and other metals in Food. Food Surveil-
lance Paper No. 52.
Maier, W.E., Brown, H.W., Tilson, H.A., et al., 1995. J. Neuroimmu-
nol. 59, 65–75.
Makita, Y., Omura, M., 2006. Basic Clin. Pharmacol. Toxicol. 99,
128–132.
Manzo, L., Richelmi, P., Sabbioni, E., et al., 1981. Clin. Toxicol. 18,
1343–1353.
Manzoori, J.L., Amjadi, M., Abolhasani, D., 2006. J. Hazard. Mater.
137, 1631–1635.
Marciniak, M., 1981. Acta Physiol. Pol. 32, 193–204.
Marti-Cid, R., Perello, G., Domingo, J.L., 2009. Biol. Trace Elem. Res.
131, 245–254.
Matsui, H., Wada, O., Ushijima, Y., et al., 1983. Arch. Toxicol. 54,
227–233.
Matsui, H., Wada, O., Manabe, S., et al., 1984. Experientia 40,
377–378.
Matthias, C.L., Bushong, S.J., Hall, L.W., et al., 1988. Appl. Organomet.
Chem. 2, 547–552.
McLaughlin, R.L.J., Brindle, I.D., 2002. J. Anal. At. Spectrom. 17,
1540–1548.
McLaughlin, R., Cheese, P., Ding, M., et al., 2006. Am. Lab. 38. 13-+.
McLean, J.R., Birnboim, H.C., Pontefact, R., et al., 1983a. Chem. Biol.
Interact. 46, 189–200.
Mclean, J.R., Blakey, D.H., Douglas, G.R., et al., 1983b. Mut. Res. 119,
195–201.
McSheehy, S., Hamester, M., Lindemann, T., et al., 2012. Application
note: 30153, Thermo Fisher Scientific, Bremen, Germany.
Meador, J.P., Sommers, F.C., Cooper, K.A., et al., 2011. Environ. Res.
111, 50–56.
Menne, T., Andersen, K.E., Kaaber, K., et al., 1987. Contact Derma-
titis 16, 9–10.
Mensink, B.P., HallersTjabbes, C.C., Kralt, J., et al., 1996. Mar. Envi-
ron. Res. 41, 315–325.
Merkord, J., Jonas, L., Weber, H., et al., 1997. Pancreas 15, 392–401.
Merkord, J., Weber, H., Sparmann, G., et al., 1998. Gastroenterology
114, A482–A483.
Micael, J., Reis-Henriques, M., Carvalho, A., et al., 2007. Environ. Int.
33, 1035–1039.
Middleton, M.C., Pratt, I., 1978. J. Invest. Dermatol. 71, 305–310.
Mignini, F., Nasuti, C., Artico, M., et al., 2012. Int. J. Immunopathol.
Pharmacol. 25, 1107–1119.
Miki, S., Ikeda, K., Oba, Y., et al., 2011. Mar. Pollut. Bull. 62,
2533–2536.
Miller, K., Maisey, J., Nicklin, S., 1986. Environ. Res. 39, 434–441.
1282 Elena A. Ostrakhovitch
Millour, S., Noel, L., Kadar, A., et al., 2011. J. Food Comp. Anal. 24,
111–120.
Misiti, F., Orsini, F., Clementi, A., et al., 2008. Neurochem. Int. 52,
1092–1099.
Miura, Y., Kato, M., Ogino, K., et al., 1997. Endocrinology 138,
2769–2775.
Miyauchi, M., Suda, K., Kuwayama, C., et al., 2007. Histol. Histo-
pathol. 22, 1119–1127.
Mizuhashi, S., Ikegaya, Y., Matsuki, N., 2000. Neurosci. Res. 38,
35–42.
Mizukawa, H., Takahashi, S., Nakayama, K., et al., 2009. Report,
153–161.
Mol, S., 2011. Food Chem. Toxicol. 49, 348–351.
Molin, L., Wahlberg, J.E., 1975. Berufs-Dermatosen 23, 138–142.
Monperrus, M., Martin-Doimeadios, R.C.R., Scancar, J., et al., 2003.
Anal. Chem. 75, 4095–4102.
Morcillo, Y., Cai, Y., Bayona, J.M., 1995. J. High Resol. Chromat. 18,
767–770.
Morita, M., Imai, H., Liu, Y., et al., 2008. Neuroscience 153, 1135–
1145.
Motelica-Heino, M., Le Coustumer, P., Thomassin, J.H., et al., 1998.
Talanta 46, 407–422.
Moynier, F., Fujii, T., Telouk, P., 2009. Anal. Chim. Acta 632, 234–239.
Nagamatsu, K., Kido, Y., Urakubo, G., et al., 1978. Jap. J. Hyg. 33,
486–496.
Nakanishi, T., Kohroki, J., Suzuki, S., et al., 2002. J. Clin. Endocrinol.
Metab. 87, 2830–2837.
Nakatsu, Y., Kotake, Y., Ohta, S., 2006. Neurotoxicology 27, 587–593.
Nakayama, A., Kurokawa, Y., Harino, H., et al., 2007. Aquat. Toxicol.
83, 126–133.
Nehring, P., 1972. Ind. Obst. Gemusseverwert. 57, 489–492.
NEMI (National Environmental Methods Index). Standard Method:
3113B. https://www.nemi.gov/methods/method_summary/
4698/ (accessed 29.11.13).
NEMI. Standard Method: 3125. https://www.nemi.gov/methods/
method_summary/4796/ (accessed 29.11.13).
Nesci, S., Ventrella, V., Trombetti, F., et al., 2011a. Toxicol. in Vitro 25,
117–124.
Nesci, S., Ventrella, V., Trombetti, F., et al., 2011b. Biochimie 93,
1157–1164.
Nielsen, J.B., Strand, J., 2002. Environ. Res. 88, 129–133.
Nincevic Grassino, A., Grabaric, Z., Pezzani, A., et al., 2009. Food
Aaddit. Contam. A 26, 1488–1494.
NIOSH (National Institute for Occupational Safety and Health),
1994. NIOSH manual of analytical methods, Method No.7300
Department of Health andHuman Services, National Institute
for Occupational Safety andHealth (DHHS (NIOSH) Publication
94-113. Cincinnati, OH, US.
NIOSH, 2013. NIOSH Pocket Guide to Chemical Hazards. US
­Department of Health and Human Services. National Institute
for Occupational Safety and Health, (Publication no 97–140).
http://www.cdc.gov/niosh/npg/ (accessed 29.11.13).
Nishida, H., Matsui, H., Sugiura, H., et al., 1990. J. Pharmacobiodyn.
13, 543–548.
Noda, T., Nakamura, T., Shimizu, M., et al., 1992a. B Environ. Con-
tam. Tox. 49, 715–722.
Noda, T., Yamano, T., Shimizu, M., et al., 1992b. Arch. Environ. Con-
tam. Toxicol. 23, 216–222.
Noda, T., Morita, S., Baba, A., 1993. Toxicology 85, 149–160.
Noda, T., Morita, S., Baba, A., 1994. Food Chem. Toxicol. 32, 321–327.
Noel, L., Leblanc, J.C., Guerin, T., 2003. Food Addit. Contam. 20,
44–56.
Nsengimana, H., Cukrowska, E.M., Dinsmore, A., et al., 2009. J. Sep.
Sci. 32, 2426–2433.
NTP, 1982. National Institutes of Health, National ToxicologyPro-
gram (TR-231; NIH Publication No. 82-1787) Bethesda, MD.
Nuyts, G.D., Van Vlem, E., Thys, J., et al., 1995. Lancet 346, 7–11.
Oberdorster, E., McClellan-Green, P., 2002. Mar. Environ. Res. 54,
715–718.
O’Callaghan, J.P., Miller, D.B., 1988. J. Pharmacol. Exp. Ther. 246,
394–402.
O’Callaghan, J.P., Niedzwiecki, D.M., Means, J.C., 1989. Brain Res.
Bull. 22, 637–642.
Ogata, R., Omura, M., Shimasaki, Y., et al., 2001. J. Toxicol. Environ.
Health A 63, 127–144.
Ogoshi, K., Kurumatani, N., Aoki, Y., et al., 1981. Toxicol. Appl. Phar-
macol. 58, 331–332.
Ohhira, S., Matsui, H., 1996. Toxicol. Lett. 85, 3–8.
Ohhira, S., Matsui, H., 2003. J. Appl. Toxicol. 23, 31–35.
Ohhira, S., Matsui, H., Nitta, K., 1996. Vet. Hum. Toxicol. 38, 206–209.
Ohhira, S., Matsui, H., Watanabe, K., 1999a. Toxicology 137, 151–159.
Ohhira, S., Matsui, H., Watanabe, K., 1999b. Toxicology 137, 151–159.
Ohhira, S., Watanabe, M., Matsui, H., 2003. Arch. Toxicol. 77,­
138–144.
Ohhira, S., Watanabe, M., Matsui, H., 2004. Toxicol Lett. 148. 141-+.
Ohhira, S., Enomoto, M., Matsui, H., 2006a. Toxicol. Appl. Pharma-
col. 210, 32–38.
Ohhira, S., Enomoto, M., Matsui, H., 2006b. Toxicology 228, 171–177.
Ohji, M., Arai, T., Miyazaki, N., 2007. Estuar. Coast Shelf S. 72,
721–731.
Ohno, S., Nakajima, Y., Ohno, S., 2005. Steroids 70, 645–651.
Okoro, H.K., Fatoki, O.S., Adekola, F.A., et al., 2011. Rev. Environ.
Contam. Toxicol. 213, 27–54. 213.
Olivier, P., Marzin, D., 1987. Mut. Res. 189, 263–269.
Omura, M., Ogata, R., Kubo, K., et al., 2001. Toxicol. Sci. 64, 224–232.
ORTEPA (Organotin Environmental Programme Association), 1994.
For the organotin Environmental Programme Association (HD
Project No 380-211).
OSHA (Occupational Safety and Health Administration), 2013. U.S.
Department of Labor. Tin, organic compounds (as Sn). https://
www.osha.gov/dts/chemicalsampling/data/CH_271900.html
(accessed 29.11.13).
Oshiro, Y., Piper, C.E., Balwierz, P.S., Soelter, S.G., (1991). J Appl
Toxicol. 11, 167–177.
Osman, A.M., van Loveren, H., 2012. Toxicol. Sci. 126, 84–100.
Osman, A.M., van Kol, S., Peijnenburg, A., et al., 2009.
J. ­Immunotoxicol. 6, 174–183.
Ozcan, M., Akman, S., 2000. Spec. Acta B 55, 509–515.
Pavlikova, N., Kortner, T.M., Arukwe, A., 2010. Aquat. Toxicol. 99,
176–185.
Pekelharing, H.L., Lemmens, A.G., Beynen, A.C., 1994. Br. J. Nutr.
71, 103–109.
Pelikan, Z., Cerny, E., 1968. Arch. Toxikol. 23, 283–292.
Penalver, R., Campillo, N., Hernandez-Cordoba, M., 2011. Talanta
87, 268–275.
Penninks, A.H., 1993. Food Addit. Contam. 10, 351–361.
Penninks, A.H., Seinen, W., 1985. Toxicology 37, 285–295.
Penninks, A.H., Verschuren, P.M., Seinen, W., 1983. Toxicol. Appl.
Pharmacol. 70, 115–120.
Penninks, A., Kuper, F., Spit, B.J., Seinen, W., 1985. Immunopharma-
col 10, 1–10.
Penninks, A.H., Hilgers, L., Seinen, W., 1987. Toxicology 44,
107–120.
Perring, L., Basic-Dvorzak, M., 2002. Anal. Bioanal. Chem. 374,
235–243.
Pettine, M., Millero, F.J., Macchi, G., 1981. Anal. Chem. 53, 1039–1043.
Pieters, R.H.H., Bol, M., Penninks, A.H., 1994a. Toxicology 91,
189–202.
 56 Tin
Pieters, R.H.H., Bol, M., Seinen, W., et al., 1994b. Hum. Exp. Toxicol.
13, 876–879.
Pinel-Raffaitin, P., Rodriguez-Gonzalez, P., Ponthieu, M., et al., 2007.
J. Anal. At. Spectrom. 22, 258–266.
Plumbing Manufacturers International, 2011. Reduction in lead bill
is signed into law by President Obama: Plumbing Manufacturers
International press release, January 6, p. 2. htttp://www.pmiho
me.org/i4a/pages/index.cfm?pageID=3504 (accessed 03.02.11).
Podratz, P.L., Filho, V.S.D., Lopes, P.F.I., et al., 2012. J. Toxicol. Env.
Heal. A 75, 1035–1046.
Poitou, P., Marignac, B., Certin, C., et al., 1978. Ann. Pharm. Fr. 36,
569–572.
Polster, M., Halacka, K., 1971. Ernährungsforschung 16, 527–535.
Prior, C., 2010. Electroanalysis 22, 1446–1454.
Prough, R.A., Stalmach, M.A., Wiebkin, P., Bridges, J.W., 1981.
­Biochem. J. 196, 763–770.
Prull, G., Rompel, K., 1970. Clin. Neurophysiol. 29, 215.
Pungartnik, C., Viau, C., Picada, J., et al., 2005. Mutagenesis 583,
146–157.
Puri, B.K., Munoz-Olivas, R., Camara, C., 2004. Spec. Acta B 59,
209–214.
Quevauviller, P., Donard, O.F.X., 1990. Appl. Organomet. Chem. 4,
353–367.
Quevauviller, P., Lavigne, R., Pinel, R., et al., 1989. Environ. Pollut.
57, 149–166.
Quevauviller, P., Martin, F., Belin, C., et al., 1993. Appl. Organomet.
Chem. 7, 149–157.
Qunfang, Z., Guibin, J., Zhongyang, L., et al., 2004. Food Addit. Con-
tam. 21, 1162–1167.
Raffray, M., Cohen, G.M., 1991. Arch. Toxicol. 65, 135–139.
Raffray, M., Mccarthy, D., Snowden, R.T., et al., 1993. Toxicol. Appl.
Pharmacol. 119, 122–130.
Rahmi, D., Takasaki, Y., Zhu, Y., et al., 2010. Talanta 81, 1438–1445.
Raj, A., Mayberry, J.F., Podas, T., 2003. Postgrad. Med. J. 79, 252–
258.
Rajendran, R.B., Tao, H., Nakazato, T., et al., 2000. Analyst 125,
1757–1763.
Rantakokko, P., Kuningas, T., Saastamoinen, K., et al., 2006. Food
Addit. Contam. 23, 749–756.
Rastkari, N., Mesdaghinia, A., Yunesian, M., et al., 2012. Bull.
­Environ. Contam. Toxicol. 88, 74–77.
Reicks, M., Rader, J.I., 1990. Proc. Soc. Exp. Biol. Med. 195, 123–128.
Reiter, L., Kidd, K., Heavner, G., et al., 1980. Neurotoxicology 2,
97–112.
Reuhl, K.R., Cranmer, J.M., 1984. Neurotoxicology 5, 187–204.
Rey, C., Reinecke, H.J., Besser, R., 1984. Vet. Hum. Toxicol. 26,
121–122.
Rinehart, R.D., Yanagisawa, Y., 1993. Am. Ind. Hyg. Assoc. J. 54,
593–599.
Ritsema, R., de Smaele, T., Moens, L., et al., 1998. Environ. Pollut.
99, 271–277.
Robertson, A.J., Rivers, D., Nagelschmidt, G., et al., 1961. Lancet 1,
1089–1093.
Roe, F.J., Boyland, E., Millican, K., 1965. Food Cosmet. Toxicol. 3,
277–280.
Roehl, C., Grell, M., Maser, E., 2009. Toxicol. in Vitro 23, 1541–1547.
Rose, M., Baxter, M., Brereton, N., et al., 2010. Food Addit. Contam.
A 27, 1380–1404.
Rosenberg, D.W., Anderson, K.E., Kappas, A., 1984. Biochem. Bio-
phys. Res. Commun. 119, 1022–1027.
Ross, W.D., Emmett, E.A., Steiner, J., et al., 1981. Am. J. Psychiat. 138,
1092–1095.
Saary, M.J., House, R.A., 2002. Occup. Med. (Lond) 52, 227–230.
Sadiki, A.I., Williams, D.T., 1999. Chemosphere 38, 1541–1548.
1283
Sanderson, J.T., Boerma, J., Lansbergen, G.W., et al., 2002. Toxicol.
Appl. Pharmacol. 182, 44–54.
Sano, T., Takagi, H., Nagano, K., et al., 2010. J. Chromat. A 1217,
4344–4346.
Santos, M., Enes, P., Reis-Henriques, M., et al., 2009. Chemosphere
75, 661–666.
Santos, M.M., Castro, L.F.C., Vieira, M.N., et al., 2005. Comp.
­Biochem. Physiol.–C: Pharmacol. Toxicol. 141, 101–109.
Sarradin, P.M., Lapaquellerie, Y., Astruc, A., et al., 1995. Sci. Total
­Environ. 170, 59–70.
Sayer, C.D., Hoare, D.J., Simpson, G.L., et al., 2006. Environ. Sci.
Technol. 40, 5269–5275.
Schafer Jr., E.W., Bowles Jr, W.A., 1985. Arch. Environ. Contam. Toxi-
col. 14, 111–129.
Schafer, S.G., Femfert, U., 1984. Regul. Toxicol. Pharmacol. 4, 57–69.
Schering, A.G., 1992. Pharma Research Report No: IC-Kl 28. 19.8.
Schlueter, N., Hardt, M., Lussi, A., et al., 2009. Eur. J. Oral Sci. 117,
427–434.
Schlummer, M., Gruber, L., Maeurer, A., et al., 2007. Chemosphere
67, 1866–1876.
Schreck, E., Foucault, Y., Sarret, G., et al., 2012. Sci. Total Environ.
427, 253–262.
Schroeder, H.A., Balassa, J.J., Tipton, I.H., 1964. J. Chronic. Dis. 17,
483–502.
Schroeder, H.A., Kanisawa, M., Frost, D.V., et al., 1968. J. Nutr. 96,
37–45.
Schweinfurth, H., 1985. Tin Uses. Royal Society of Chemistry,
London, 143, 9–12.
Schweinfurth, H.A., Gunzel, P., 1987. Proceedings of the Oceans ‘87
Conference, Halifax, Nova Scotia.
Seinen, W., Willems, M.I., 1976. Toxicol. Appl. Pharmacol. 35, 63–75.
Seinen, W., Vos, J.G., van Krieken, R., et al., 1977a. Toxicol. Appl.
Pharmacol. 42, 213–224.
Seinen, W., Vos, J.G., van Spanje, I., et al., 1977b. Toxicol. Appl. Phar-
macol. 42, 197–212.
Seinen, W., Vos, J.G., Brands, R., et al., 1979. Immunopharmacol 1,
343–355.
Senthilkumar, K., Kannan, K., Tanabe, S., et al., 1998. Fresen. Envi-
ron. Bull. 7, 561–571.
Senthilkumar, K., Kannan, K., Subramanian, A., et al., 2001. Environ.
Sci. Poll. Res. 8, 35–47.
Shim, W.J., Jeon, J.K., Oh, J.R., Kim, N.S., Lee, S.H., 2002. Environ.
Toxicol. Chem. 21, 1451–1455.
Shimasaki, Y., Kitano, T., Oshima, Y., et al., 2003. Environ. Toxicol.
Chem. 22, 141–144.
Shimbo, S., Matsuda-Inoguchi, N., Watanabe, T., et al., 2007. Food
Add. Contam. 24, 535–545.
Shuto, M., Higuchi, K., Sugiyama, C., et al., 2009. J. Pharm. Sci. 110,
424–436.
Sieniawska, C.E., Jung, L.C., Olufadi, R., et al., 2012. Ann. Clin. Bio-
chem. 49, 341–351.
Silva, C.R., Oliveira, M.B.N., Melo, S.F., et al., 2002. Brain Res. Bull.
59, 213–216.
Sisman, T., 2011. Environ. Toxicol. 26, 240–249.
Sluis-Cremer, G.K., Thomas, R.G., Goldstein, B., et al., 1989. S. Afr.
Med. J. 75, 124–126.
Smialowicz, R.J., Riddle, M.M., Rogers, R.R., et al., 1988. J. Toxicol.
Environ. Health 25, 403–422.
Smialowicz, R.J., Riddle, M.M., Rogers, R.R., et al., 1989. Toxicology
57, 97–111.
Smith, R., Bolam, S., Rees, H., et al., 2008. Environ. Monit. Assess.
136, 245–256.
Snoeij, N.J., van Iersel, A.A., Penninks, A.H., et al., 1985. Toxicol.
Appl. Pharmacol. 81, 274–286.
1284 Elena A. Ostrakhovitch
Snoeij, N.J., Penninks, A.H., Seinen, W., 1987. Environ. Res. 44,
335–353.
Snoeij, N.J., Penninks, A.H., Seinen, W., 1988. Int. J. Immunopharma-
col. 10, 891–899.
Sokas, R.K., 1998. Reproductive hazards of the workplace. John Wiley
and sons, Inc., New York. 154–156.
Sole, M., Morcillo, Y., Porte, C., 1998. Environ. Pollut. 99, 241–246.
Squibb, R.E., Carmichael, N.G., Tilson, H.A., 1980. Toxicol. Appl.
Pharmacol. 55, 188–197.
Srivastava, S.C., Meinken, G.E., Richards, P., et al., 1985. Int. J. Nucl.
Med. Biol. 12 (3), 167–174.
Stahnke, T., Richter-Landsberg, C., 2004. Glia 46, 334–344.
Stange, B.J., Glanemann, M., Nuessler, N.C., et al., 2003. Liver Trans-
plant. 9, 612–620.
Stange, D., Sieratowicz, A., Oehlmann, J., 2012. Aquat. Toxicol,
106–107, 20–4.
Stasinakis, A.S., Thomaidis, N.S., Nikolaou, A., et al., 2005. Environ.
Pollut. 134, 431–438.
Stehrer, T., Heitz, J., Pedarnig, J., et al., 2010. Anal. Bioanal. Chem.
398, 415–424.
Sternberg, R.M., Hotchkiss, A.K., Leblanc, G.A., 2008. Environ. Sci.
Technol. 42, 1345–1351.
Stewart, C., Demora, S.J., 1992. Appl. Organomet. Chem. 6, 507–512.
Stewart, C., Thompson, J.A.J., 1997. Environ. Techn. 18, 1195–1202.
Stone, O.J., Willis, C.J., 1968. Toxicol. Appl. Pharmacol. 13, 332–338.
Stringer, C.P., Hicks, R., Botham, P.A., 1991. Contact Dermatitis 24,
210–215.
Summer, K.H., Klein, D., Grem, H., 2003. National Chemicals Inspec-
torate (report No 600). Stockholm.
Sun, J., He, B., Yin, Y., et al., 2010. Anal. Methods 2, 2025–2031.
Sun, J., He, B., Liu, Q., et al., 2012. Talanta 93, 239–244.
Suzuki, Y., Endo, Y., Ogawa, M., et al., 2008. J. Chromat. B, Analyt.
Technol. Biomed. Life Sci. 868, 116–119.
Swennen, C., Ruttanadakul, N., Ardseungnern, S., et al., 1997. Envi-
ron. Technol. 18, 1245–1254.
Takahashi, S., Mukai, H., Tanabe, S., et al., 1999. Environ. Pollut. 106,
213–218.
Tang, X., Li, N., Kang, L., et al., 2013a. Occup. Environ. Med. 70 (8),
561–567.
Tang, X., Wu, X., Dubois, A.M., et al., 2013b. Bull. Environ. Contam.
Toxicol. 90 (5), 626–633.
Tas, J.W., Opperhuizen, A., Seinen, W., 1990. Toxicol. Environ. Chem.
28, 129–141.
Tennekes, H., Horst, K., Luetkemeier, H., et al., 1989. Unpublished
report 046980 (A40468) of RCC Research and Consulting Com-
pany AG, Itingen. Submitted to WHO by Hoechst AG, Frankfurt-
am-Main.
Teraoka, H., 1981. Arch. Environ. Health 36, 155–165.
Tipton, I.H., Cook, M., 1963. Health Phys. 9, 103–145.
Titley-O’Neal, C..P., Spade, D.J., Zhang, Y., et al., 2013. Sci. Total
­Environ. 449, 52–62.
Toniolo, R., Pizzariello, A., Tubaro, F., et al., 2009. J. Appl. Electro-
chem. 39, 979–988.
Tonk, E., Verhoef, A., De la Fonteyne, L., et al., 2011a. Birth Defects.
Res. A 91, 343.
Tonk, E.C., de Groot, D.M., Penninks, A.H., et al., 2011b. Toxicol.
Lett. 204, 156–163.
Tonk, E.C., Verhoef, A., de la Fonteyne, L.J., et al., 2011c. Reprod.
Toxicol. 32, 341–348.
Toyoda, M., Sakai, H., Kobayashi, Y., et al., 2000. J. Food Hygienic
Soc. Japan 41, 280–286.
Truhaut, R., Chauvel, Y., Anger, J.P., et al., 1976. Eur. J. Toxicol. Envi-
ron. Hyg. 9, 31–40.
Tryphonas, H., Cooke, G., Caldwell, D., et al., 2004. Food Chem.
Toxicol. 42, 221–235.
Tsang, C.K., Lau, P.S., Tam, N.F.Y., et al., 1999. Environ. Pollut. 105,
289–297.
Tsuda, T., Inoue, T., Kojima, M., et al., 1995. J. Aoac Int. 78, 941–
943.
Tsunoda, M., Konno, N., Nakano, K., et al., 2004. Environ. Sci. 11,
209–219.
Tzollas, N.M., Zachariadis, G.A., 2010. J. Sep. Sci. 33, 1610–1616.
Ueno, S., Susa, N., Furukawa, Y., et al., 1995. Arch. Toxicol. 69,
655–658.
Ueno, S., Kashimoto, T., Susa, N., et al., 2003. Arch. Toxicol. 77,
173–181.
Uhl, S., 1986. ETH Thesis No. 8014. Zurich, Maus Offsetdruck
Konstanz.
Undap, S.L., Nirmala, K., Miki, S., et al., 2013a. J. Fac. Agric. Kyushu
Univ. 58, 131–135.
Undap, S.L., Matsunaga, S., Honda, M., et al., 2013b. Ecotoxicol.
­Environ. Saf. 96, 75–79.
UNEP (The United Nations Environment Programme), 2006. Global
Programme of Action for the Protection of the Marine Environ-
ment from Land-based Activities (GPA).
Urushitani, H., Katsu, Y., Ohta, Y., et al., 2011. Aquat. Toxicol. 103,
101–111.
USEPA (U.S. Environmental Protection Agency), 1994a.
EPA/600/R-94/111 Method 200.15, USEPA Office of Research and
Development. http://water.epa.gov/scitech/methods/cwa/
bioindicators/upload/2007_07_10_methods_method_200_15.p
df (accessed 29.11.13).
USEPA, 1994b. EPA/600/R-94/111 Method 200.2 USEPA Office of
Research and Development.
USEPA, 1997. EPA—U.S. Environmental Protection Agency. Stan-
dard Methods for the Examination of Water and Wastewater,
nineteenth ed.
USGS (U.S. Geological Survey), 2010. Commodity Statistics and
­Information. American Metal Market 118, 9.
Usta, J., Griffiths, D.E., 1992. Biochem. Biophys. Res. Commun. 188,
365–371.
Uveges, M., Abranko, L., Fodor, P., 2007. Talanta 73, 490–497.
Valberg, L.S., Flanagan, P.R., Chamberlain, M.J., 1984. Am. J. Clin.
Nutr. 40, 536–541.
van Kol, S.W., Hendriksen, P.J., van Loveren, H., et al., 2012. Toxicol-
ogy 296, 37–47.
Viau, C., Guecheva, T.N., Sousa, F., et al., 2009. Arch. Toxicol. 83,
769–775.
Viviani, B., Rossi, A.D., Chow, S.C., et al., 1995. Neurotoxicology 16,
19–25.
Volti, G.L., Zappala, A., Leggio, G.M., et al., 2011. Neurosci. Lett. 492,
33–38.
Vos, J.G., Krajnc, E.I., 1983. Dev. Toxicol. Environ. Sci. 11, 229–240.
Vos, J.G., de Klerk, A., Krajnc, E.I., et al., 1984. Toxicol. Appl. Phar-
macol. 75, 387–408.
Vos, J.G., Deklerk, A., Krajnc, E.I., et al., 1990. Toxicol. Appl. Pharma-
col. 105, 144–155.
Wahlen, R., Catterick, T., 2003. J. Chromat. B, Analyt. Technol.
Biomed. Life Sci. 783, 221–229.
Walker, C.H., Hopkin, S.P., Sibly, R.M., et al., 2006. Principles of
­Ecotoxicology. Taylor & Francis Group, Boca Raton, USA.
Wang, X., Jin, H., Ding, L., et al., 2008. Talanta 75, 556–563.
Wang, X., Fang, C., Hong, H., et al., 2010. Aquat. Toxicol. 99, 413–422.
Warburton, S., Udler, W., Ewert, R.M., et al., 1962. Public Health Rep.
77, 798–800.
Ward, R.J., 2003. Central Toxicology Laboratory, January (report No.
CTL/JV 1700) Report No CTL/JV 1700.
Watermann, B., Grote, K., Gnass, K., et al., 2008. Exp. Toxicol. Pathol.
60, 313–321.
Wax, P.M., Dockstader, L., 1995. J. Toxicol. Clin. Toxicol. 33, 239–241.
 56 Tin
Weidenhaupt, A., Arnold, C., Muller, S.R., et al., 1997. Environ. Sci.
Technol. 31, 2603–2609.
Wester, P.W., Krajnc, E.I., van Leeuwen, F.X., et al., 1990. Food Chem.
Toxicol. 28, 179–196.
Whalen, M.M., Loganathan, B.G., Kannan, K., 1999. Environ. Res.
81, 108–116.
Whittington, D.L., Woodruff, M.L., Baisden, R.H., 1989. Neurotoxi-
col. Teratol. 11, 21–33.
WHO (World Health Organization), 1980a. World health organiza-
tion: International program on Chemical Safety (WHO/IIPCS).
Environ. Health criteria 15.
WHO, 1980b. World Health Organization. International Programme
on Chemical Safety (WHO/IPCS). Tin and organotin com-
pounds. A preliminary review.
WHO, 1990. World Health Organization. International Programme
on Chemical Safety. Environ. Health Criteria 116.
WHO, 1992. World Health Organization. FAO Panel of Experts on
Pesticide Residues in Food and the Environment and the WHO
Expert Group on Pesticide Residues.
WHO, 1999. World Health Organization. Concise international
chemical assessment document 14.
WHO, 2001. World Health Organization. Food additives series 46.
WHO, 2003. World Health Organization. Committee on Updat-
ing of Occupational Exposure Limits. Health-based Reassess-
ment of Administrative Occupational Exposure Limits. No.
2000/15OSH/091, The Hague.
WHO, 2006. World Health Organization. Report Series 930.
Whyte, A.L., Hook, G., Greening, G.E., et al., 2009. Sci. Total Environ.
407, 4348–4355.
Winship, K.A., 1988. Adverse Drug React. Acute. Poisoning. Rev. 7,
19–38.
Yamada, J., Inoue, K., Furukawa, T., et al., 2010. Toxicol. Lett. 198,
282–288.
Yamaguchi, M., Okada, S., 1980. Toxicol. Lett. 6, 177–180.
Yamaguchi, M., Saito, R., Okada, S., 1980. Toxicology 16, 267–273.
1285
Yamaguchi, M., Sugii, K., Okada, S., 1982. Toxicol. Lett. 10, 7–10.
Yamashita, Y., Taketomi, A., Fukuzawa, K., et al., 2007. Am. J. Surg.
193, 454–459.
Yang, G., Wang, Y., Qi, F., 2012. Microchimica Acta 177, 365–372.
Yilmaz, A., Gocmen Ocal, S., Doruk, S., et al., 2009. Tuberkuloz ve
toraks 57, 422–426.
Yokoi, K., Kimura, M., Itokawa, Y., 1990a. Anal. Biochem. 190,
71–77.
Yokoi, K., Kimura, M., Itokawa, Y., 1990b. Biol. Trace Elem. Res. 24,
223–231.
Yoo, C.I., Kim, Y., Jeong, K.S., et al., 2007. J. Occup. Health 49,
305–310.
Yoshizuka, M., Hara, K., Haramaki, N., et al., 1992. Arch. Toxicol.
66, 182–187.
Yousef, M.I., 2005. Toxicology 207, 81–89.
Yu, H., Chen, S., Yang, Z., et al., 2010. Cell. Biol. Int. 34, 99–108.
Yu, Z.H., Sun, J.Q., Jing, M., et al., 2010. Food Chem. 119, 364–367.
Yu, Z.P., Matsuoka, M., Wispriyono, B., et al., 2000. Toxicol. Appl.
Pharmacol. 168, 200–207.
Zachariadis, G., Rosenberg, E., 2009a. Talanta 78, 570–576.
Zachariadis, G., Rosenberg, E., 2009b. J. Chromat. B, Analyt. Technol.
Biomed. Life Sci. 877, 1140–1144.
Zanon, F., Rado, N., Centanni, E., Zharova, N., et al., 2009. Environ.
Monit. Assess. 152, 35–45.
Zeman, W., Gadermann, E., Hardebeck, K., 1951. Deutsches Archiv
fur Klinische Medizin 198, 713–721.
Zhai, G., Liu, J., Li, L., et al., 2009. Talanta 77, 1273–1278.
Zhang, S.K., Tsui, N.C., Li, D.H., et al., 2010. Pancreas 39, 252–253.
Zhang, Z.H., Dong, B.B., Zang, S.L., et al., 2006. Acta Chim. Sin. 64,
953–958.
Zhu, X., Xing, M., Lou, J., et al., 2007. Toxicology 230, 45–52.
Zuliani, T., Milacic, R., Scancar, J., 2012. Anal. Bioanal. Chem. 403,
857–865.
Zuo, Z., Chen, S., Wu, T., et al., 2011. Environ. Toxicol. 26, 79–85.