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June 3, 1991
JUSTIFICATION FOR THALLIUM SUBCHRONIC RfC
A subchronic inhalation Reference Concentration (RfC) has
been developed for soluble forms of thallium based on available
animal toxicological data. There are few available data
pertaining to inhalation effects of thallium in either humans or
animals. Thallium is a very toxic, cumulative poison. It is
known to attack the eyes, central nervous system, lungs, liver,
kidneys, gastrointestinal tract and body hair (Sittig, 1981).
Available occupational data indicate that moderate exposure to
thallium may produce fatigue, limb pain, metallic taste in the
mouth and loss of hair (Sittig, 1981). Later symptoms include
peripheral neuritis, proteinuria, and joint pains (Sittig, 1981).
Human occupational studies indicate possible effects on the
nervous system (ATSDR, 1990). Thallium can cross the human
placenta but there are no conclusive studies in humans regarding
developmental effects (ATSDR, 1990). A developmental study
conducted in rats (Bornhausen and Hagen, 1984) indicates a
potential performance deficit produced in newborn rats after
exposure to thallium sulfate. There were no studies located
regarding reproductive effects in humans after oral exposure to
thallium. Abnormalities in testicular morphology were found in
rats exposed to thallium sulfate for 60 days (Formigli et al.,
1986).
A thorough literature search produced a number of oral,
gavage and intraperitoneal studies conducted in animals. The
majority of the studies located are summarized in the Agency for
Toxic Substances and Disease Registry Toxicological Profile for
Thallium - Draft for Public Comment. (ATSDR, 1990). Other
noncarcinogenic studies identified which
were not cited in the above publication include:
Source
Species
H. Aoyama
et al.
male
oral
golden
(thallous
hamsters malonate)
M.S. Leloux Wistar
et al.
rats
Exp. Route
gavage
(thallium
nitrate)
Duration
male
albino
rats
Source
Species
F. Rossi
et al.
NOS
albino
rats
decr. GSH-Pactivity and
[NPSH] in kidney
10 mg/kg
(LOAEL)
one dose
incr. wt kidney
and adrenals
2 0 mg/kg
(LOAEL)
rats
i.p.
(thallous
acetate)
Exp. Route
in d.w.
(1 mg/dl)
(thallium
sulphate)
Exp. Level
one dose
4 consec.
days
M. Hasan
et al.
Effect
6 days
incr. wt kidney
and eyes
signif. decr. total
sulfhydryl radicals
in brain regions
(except cerebrum)
Duration
prenatal
(gest. to
22 d after
weaning)
1 mg/kg
(LOAEL)
5 mg/kg
(LOAEL)
Effect
Incompl.develop.
pila apparatus in
normotensive and z
DOCA©hypertensive
postnatal modifies develop.
(22nd d autonomic nervous
a.b. to system
60 d old)
Critical subchronic study (Formigli et al., 1986) from the
ATSDR list has been identified from this search. In this study,
male rats were administered thallium sulfate in drinking water at
0.74 mg/kg/day for 60 days, producing decreased sperm motility,
inhibition of glucuronidase activity and histopathological
Exp. Level
1 mg/dl
1 mg/dl
alteration of the testes. Based on these results, a LOAEL of
0.74 mg/kg/day was identified. In the absence of inhalation data
for this compound, this oral LOAEL was used as the basis for
developing an inhalation RfC using modified EPA RfC methodology
(EPA, 1990). Given that this study was conducted using a single
dose, the degree of confidence in this study is low; however, it
represents the best data currently available. A subchronic RfC
of 0.09 ug/m3 was developed using the following adjustments:
Animal LOAEL (60-day, adult) = 0.74 mg/kg/day
Converted to concentration (based on rat parameters inhal. rate: 0.29 m3/day and body weight: 0.35 kg)
= 0.89 mg/m3
Human-Equivalent Concentration (to account for
absorption: x 2.9*) = 2.6 mg/m3
According to EPA RfC methodology for particulates, the air
concentration should be adjusted to yield a human©equivalent concentration
based on the ratio of alveolar ventilation rate divided by the body weight of
the animal species to the same parameters for humans. Although the above
subchronic RfC was developed based on an oral LOAEL and any distribution of
particulates is theoretical (contributing to the uncertainty), the following
formula from the EPA RfC methodology was nevertheless used:
(Inhalation Rater at/Body Weight rat)/(Inhalation Rate human/Body Weight human)
The values used in the above formula include inhalation rate rat = 0.29 m3/day;
body weight rat = 0.35 kg;
inhalation rate human = 20 m3/day; body
weight human = 70 kg
Human-Equivalent Concentration (interspecies extrapolation adjustment factor to account for
distribution, metabolism and excretion (10) = 0.26 mg/m3
Human NOAEL (10) = 0.03 mg/m3
Adjust for sensitive individual (10) = 0.003 mg/m3
Low confidence in database (10) = 0.0003 mg/m3
SUBCHRONIC RfC = 0.3 ug/m3
JUSTIFICATION FOR THALLIUM CHRONIC TEL
The Chemical Health Effects Assessment Methodology and the
Method to Derive Allowable Ambient Limits (CHEM/AAL) can be used
to derive a threshold effects exposure limit (TEL) which
represents a concentration in air to which the general public can
be exposed day after day for a lifetime and experience no adverse
threshold health effects. The TEL therefore, is analogous to a
chronic RfC. However, occupational limits are used as the basis
for a TEL rather than primary toxicity studies. The most
appropriate occupational exposure limit (MAOL) for thallium was
selected and adjusted to account for continuous exposure and for
protection of children and high-risk groups. A TOX uncertainty
factor was applied to account for inadequacies in the
toxicological database used to derive the exposure limit. The
occupational exposure limit for this compound was actually
derived based on an analogy to other heavy metals. An adjusted
MAOL of 0.14 ug/m3 was derived.
MAOL = 0.1 mg/m3
Adjustment for continuous exposure (4.2) = 0.024 mg/m3
Adjustment for childhood exposure (1.75) = 0.014 mg/m3
Adjustment for high-risk groups (10) = 0.0014 mg/m3
Adjustment for inadequacies in database (TOX) (10) = 0.00014 mg/m3
Adjusted MAOL = 0.14 ug/m3
he adjusted MAOL was further modified to account for
reproductive/developmental effects not accounted for in setting
the occupational exposure limit and for relative source
contribution which is also not applied in the derivation of the
occupational limit. Based on available developmental and
reproductive studies, thallium was given a hazard score of "A"
and assigned a threshold effects uncertainty factor (TEUF) of 10.
TEUF adjustment (10) = 0.014 ug/m3
Relative source contribution (x 0.2) = 0.0028 ug/m3
TEL = 0.003 ug/m3
REFERENCES
Agency for Toxic Substances and Disease Registry, Toxicological
Profile for Thallium - Draft for Public Comment. U.S. Department
of Health and Human Services, Public Health Service. October
1990.
Aoyama, H., Yoshida, M. and Yamamura, Y. 1988. Induction of
lipid peroxidation in tissues of thallous malonate-treated
hamster. Toxicology 53: 11-18.
Bornhausen, M. and Hagen, U. 1984. Operant behavior performance
changes in rat after prenatal and post natl exposure to heavy
metals. IRCS Med Sci. 12: 805-806.
Environmental Protection Agency. 1990. Interim Methods for
Development of Inhalation Reference Concentrations.
Environmental Criteria and Assessment Office. EPA 600/8-90/066A.
Formigli, L., Scelsi, R. and Poggi, P. 1986. Thallium-induced
testicular toxicity in the rat. Environ. Res. 40: 531-539.
Hasan, M. and Haider, S. 1989. Acetyl-homocystein thiolactone
protects against some neurotoxic effects of thallium.
NeuroToxicol. 10: 257-262.
Leloux, M.S., Phu Lich, N. and Claude, J.R. 1987. Experimental
studies on thallium toxicity in rats. J. Toxicol. Clin. Exp. 7:
247-257.
Rossi, F., Marrazzo, R., Berrino, L., De Santis, D., Lisa, M.,
Susanna, V., Montanaro, C., Fici, F. and Marmo, E. 1988.
Prenatal and postnatal thallium exposure in rats: effect on
development of vasomotor reactivity in pups. Teratogenesis
Carcinogenesis and Mutagenesis. 8: 13-23.
Sittig, M. Handbook of Toxic and Hazardous Chemicals. Noyes
Publications. 1981.