TOXICOLOGICAL PROFILE SUMMARIES FOR TARGET ANALYTES
http://www.epa.gov/ost/fishadvice/volume2/v2ch5.pdf
Based on the mutagenicity data results (discussed below), heritable defects may
result from exposure to cadmium. However, mutagenicity assays do not provide
dose-response data suitable for use for the calculation of a risk value. Calcium
deficiency has been shown to increase the fetotoxicity of cadmium, and lindane
exposure increased developmental toxicity in animal studies (ATSDR, 1997).
Neurological effects of dieldrin have been observed in experimental animals and
in humans exposed acutely and chronically. Wheat mixed with aldrin and lindane
was consumed for 6 to 12 months by a small human population. Effects were
attributed to aldrin (converted to dieldrin via metabolism) because the wheat had
been mixed with lindane in previous years without adverse effect. A variety of
CNS disorders were observed, and abnormal EEGs were noted. Some
symptoms (myoclonic jerks, memory loss, irritability) continued for at least 1 year
after cessation of exposure. A child is believed to have developed mild mental
retardation as a result of exposure. Quantitative exposure information was not
available in the data reviewed (ATSDR, 1991).
5.3.9 Lindane ( -hexachlorocyclohexane)
5.3.9.1 Background
Lindane is an organochlorine pesticide that is comprised of isomers of
hexachlorocyclohexane, with the isomer constituting the major (>99 percent)
component. There appears to be some difference in toxicity of the various
hexachlorocyclohexane isomers (U.S. EPA, 1993a). The following data assume
that lindane can be defined as the isomer. Lindane is used primarily for
controlling wood-inhabiting beetles and as a seed treatment. Lindane is also used
as a prescription pharmaceutical to control head lice and mites (scabies) in
humans.
5.3.9.2 Pharmacokinetics
Lindane is readily absorbed by the GI tract following oral exposure. Distribution
is primarily to the adipose tissue but also to the brain, kidney, muscle, spleen,
adrenal glands, heart, lungs, blood, and other organs. It is excreted primarily
through urine as chlorophenols. The epoxide metabolite may be responsible for
carcinogenic and mutagenic effects (ATSDR, 1994c).
Male exposure to lindane through the environment results in accumulation in
testes and semen in addition to the tissues listed above (ATSDR, 1994c). See
also a discussion in Section 5.3.9.5 of the accumulation of lindane by pregnant
women.
5.3.9.3 Acute Toxicity
The estimated human lethal dose is 125 mg/kg (HSDB, 1993). Occupational and
accidental exposures in humans have resulted in headaches, vertigo, abnormal
EEG patterns, seizures, and convulsions. Death has occurred primarily in
children.
5.3.9.4 Chronic Toxicity
IRIS provides an RfD of 3 × 10-4 mg/kg-d based on a NOAEL of 0.33 mg/kg-d
from a subchronic rat study that found liver and kidney toxicity at higher doses.
Uncertainty factors of 10 each for inter- and intraspecies variability and the use
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of a less-than-lifetime study were applied (IRIS, 1999). The confidence in the
principal study, database, and RfD are rated as medium. A recently completed
2-year study is under evaluation and may provide additional information regarding
toxicity (U.S. EPA, 1993i). Liver damage has been observed in many animal
studies and appears to be the most sensitive effect (U.S. EPA, 1993i). Immune
system effects have been observed in humans exposed via inhalation and in
orally dosed animals. A 5-week study in rabbits found immunosuppression at 1
mg/kg-d (ATSDR, 1994c).
Most observed effects in humans exposed accidentally to lindane are
neurological. Behavioral effects have also been noted in many studies on
experimental animals, and at relatively high levels seizures were reported. More
subtle behavioral effects were noted at an LOAEL of 2.5 mg/kg-d with 40 days of
exposure in rats. No NOAEL was reported (ATSDR, 1994c).
5.3.9.5 Reproductive and Developmental Toxicity
Two developmental toxicity studies in rats and rabbits both identified a NOAEL of
10 mg/kg (no effects were described for higher doses). A three-generation rat
study found no adverse reproductive effects at 5 mg/kg-d, the highest dose tested
(U.S. EPA, 1993i). A recent mouse study found increased resorptions at 5 mg/
kg-d. Studies in rats and mice have found increased incidence of extra ribs at 5
to 20 mg/kg-d (ATSDR, 1994c). There are multiple studies showing pre- and
postimplantation fetotoxicity and skeletal abnormalities resulting from prenatal
exposure at higher doses (HSDB, 1993).
Lindane accumulates in the fatty tissue of pregnant (and nonpregnant) women
where it can be transferred to the fetus through the placenta and to infants
through breast milk. Human milk concentrations are approximately five to seven
times greater than maternal blood levels. Concentrations in maternal blood are
proportional to the length of time over which exposure occurred, with older women
having higher blood levels. During pregnancy, the lindane concentration in blood
from fetal tissue, uterine muscle, placenta, and amniotic fluid was higher than
levels in maternal adipose tissue, and blood serum levels increased during
delivery (ATSDR, 1994c). There is little information on the effects of exposure
during lactation. One study (dose unspecified) in rats indicated that exposure
during gestation and lactation did not cause developmental effects; however, this
is not consistent with other studies that found effects associated with gestational
exposure.
Based on what is known regarding the transfer of lindane into human milk, nursing
infants must be considered at some risk if their mothers have been exposed to
significant amounts of lindane (lindane is a lipid-seeking chemical). Additional
information is needed to characterize the relationship between maternal intake,
body burden (blood or adipose levels), milk concentrations, and adverse effects.
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Multiple studies have reported that lindane exposure (as measured by body tissue
level of lindane) is associated with premature labor and spontaneous abortions.
The causal relationship has not been established for this action (ATSDR, 1994c);
however, the reproductive system effects discussed in Section 5.3.9.4 (bio-
chemical changes in uterine, cervical, and vaginal tissues and antiestrogenic
effects) may be involved.
As noted above, lindane accumulates in body tissue; consequently, exposure
occurring prior to pregnancy can contribute to the overall maternal body burden
and result in exposure to the developing individual. As a result, it is necessary to
reduce exposure to children and women with childbearing potential to reduce
overall body burden. If exposure is reduced during pregnancy but has occurred
prior to pregnancy, the pregnancy outcome may be affected, depending on the
timing and extent of prior exposure.
Two recent reproductive studies in rats found adverse effects on the male
reproductive system. In a 7-wk study, decreased sperm counts were noted at 50
mg/kg-d and, in a 180-d study, seminiferous tubular degeneration was noted at
6 mg/kg-d with a NOAEL of 3 mg/kg-d. An older study had identified the same
effects at 64.6 mg/kg-d in a 3-mo study. Experimental data indicate that the
female reproductive system may also be altered by lindane exposure. A study of
rats found uterine, cervical, and vaginal biochemical changes at 20 mg/kg-d in a
30-d study. Antiestrogenic effects were found at 20 mg/kg-d in female rats in a
15-wk study with a NOAEL of 5 mg/kg-d. This action was also found in two other
recent studies (ATSDR, 1994c).
5.3.9.6 Mutagenicity&
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In animals, ingestion of technical-grade hexachlorocyclohexane-induced dominant
lethal mutations in mice. Studies found that lindane binds to mouse liver DNA at
a low rate. Based on a review of genotoxicity studies, ATSDR concluded that
lindane "has some genotoxic potential, but the evidence for this is not conclusive"
(ATSDR, 1994c).
5.3.9.7 Carcinogenicity&
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Lindane has been classified as Group B2/C (probable/possible human
carcinogen) (U.S. EPA, 1999c) and a cancer potency of 1.3 per mg/kg-d has been
listed (HEAST, 1997). Lindane's related isomers, alpha and beta
hexachlorocyclohexane, are classified as probable human carcinogens and have
cancer potencies similar to that of lindane. In addition to tumors identified in
experimental animals, human study data indicate that this chemical may cause
aplastic anemia (U.S. EPA, 1993a).
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5.3.9.8 Special Susceptibilities&
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ATSDR has recommended that pregnant and/or lactating women should not be
exposed to lindane. The potential for premature labor and spontaneous abortion
is noted (ATSDR, 1994c). People with epilepsy, cerebrovascular accidents, or
head injuries who have lower thresholds for convulsions may be at greater risk of
lindane-induced CNS toxicity and seizures. Also, individuals with protein-deficient
diets, liver or kidney disease, or immunodeficiencies may be at greater risk from
lindane exposure than the general population (ATSDR, 1994c).
Children may also be at greater risk from lindane exposure because of the
immaturity of their immune and nervous systems. ATSDR has cautioned that:
Infants and children are especially susceptible to immuno-
suppression because their immune systems do not reach maturity
until 10 to 12 years of age (ATSDR, 1994c).
5.3.9.9 Interactive Effects&
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High- and low-protein diets and vitamin A and C deficiencies increased the toxicity
of lindane in experimental animals. Vitamin A supplements decreased toxicity.
Cadmium inhibited the metabolism of lindane. Combined cadmium and lindane
exposure caused significant embryotoxic and teratogenic effects in rats at
dosages that caused no effects when administered alone. Exposure to the , ,
and hexachlorocyclohexane isomers may reduce the neurotoxic effects of
lindane (ATSDR, 1994c).
MIXTOX has reported mixed results for studies of lindane and chlordane, lindane
and hexachlorobenzene, lindane and toxaphene, and lindane and mirex
interactions, including inhibition, no effect, and potentiation for these combinations
in rodents exposed via gavage (MIXTOX, 1992).
5.3.9.10 Critical Data Gaps&
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As discussed above, effects on both the male and female reproductive systems
have been evaluated in short-term studies. Evaluation of these effects in a
longer-term study and identification of the underlying mechanisms of toxicity
would provide information needed for a more complete evaluation of toxicity and
dose-response dynamics. Additional information is also needed, as noted in
Section 5.3.9.5, on the potential for exposure via lactation and on mechanisms
and dose-response for premature labor and spontaneous abortion.
ATSDR has identified data gaps that include chronic duration oral studies; in vivo
genotoxicity tests; reproductive, developmental immunotoxicity, and neurotoxicity
studies; human studies correlating exposure levels with body burdens of lindane
and with specific effects; and pharmacokinetic studies (ATSDR, 1994c).
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5.3.9.11 Summary of EPA Health Benchmarks&
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Chronic Toxicity 3 × 10-4 mg/kg-d
Carcinogenicity 1.3 per mg/kg-d.
5.3.9.12 Major Sources&
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ATSDR (1994c), HSDB (1993), IRIS (1999).
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