(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

A fertility study in female rats exposed to benzene at vapor concentrations up to 300 ppm (960
mg/m 3 ) for 10 weeks prior to mating, and daily during gestation days (GD) 0-20 and lactation
days (LD) 5-20 did not demonstrate any effect on female fertility or maternal performance. No
effects on male reproductive capabilities were observed in a study of the performance of male
mice exposed up to 300 ppm (960 mg/m 3 ) benzene for 10 weeks (one spematogenic cycle) then
mated with untreated females. However, some effects on testicular weight, testicular atrophy
and abnormal sperm have been reported in a 90-day subchronic study in mice at similar doses;
whereas male rats were unaffected.
Benzene at high exposure concentrations typically causes maternal toxicity and stress, which
can affect developmental processes, reflected in fetal growth retardation and/or skeletal
variations. No benzene-induced malformations have been reported. Results of developmental
studies suggest a general toxicity leading to growth retardation and delays in maturation that
occur at levels considerably higher than those associated with hematopoietic toxicity.
Benzene has demonstrated transplacental effects on hematopoiesis and genotoxicity.
Exposure of pregnant mice to benzene on GD 6-15 produced hematopoietic changes that were
present 10 weeks after birth in bone marrow, spleen and liver. Clastogenicity of benzene in
fetuses is correlated with the gestational day of benzene administration. Exposure on GD13,
14–15 appears to result in cytogenetic damage, whereas treatment after this period had no
effect. These times of sensitivity correspond to the stages of hematopoiesis development in
rodents: initiation beginning on GD10 in the fetal liver, with maximum activity by GD12, followed
by initiation of hematopoiesis in bone marrow. Exposure on GD17-19 did not show adverse
cytogenetic effects in fetal livers.
Benzene immune system effects appear to be operative at doses that also produce
hematotoxicity. Studies address effects on lymphocyte proliferation, T and B cell lymphocyte
response, antibody response and resistance to pathogens by oral and inhalation routes of
exposure. Previous reviews by the EU and OECD concluded that benzene immunotoxic effects
are likely a reflection of bone marrow toxicity.
Neurotoxicity in adults resulting from benzene exposure has been demonstrated to diminish
and/or disappear with termination of exposure. Effects in animals including changes in activity
levels, grip strength, and clinical behaviors occur at doses generally above those that induce
hematologic effects.
Long term exposure to benzene has been evaluated in rats and mice in 2-year oral bioassays.
Survival was reduced in both sexes. Systemic effects included reduced body weight gain,
leukopenia in both sexes and lymphoid depletion in thymus and spleen of male rats. There are
no reliable animal models for benzene-induced leukemogenesis; however, 2-year bioassays of
benzene induced solid tumors in the zymbal gland, nasal and oral cavities, mammary gland
(female), and skin (male) of rats, and the zymbal gland, lung, Hardarian gland (male), preputial
gland, mammary gland (female) and ovaries of mice.
Metabolism and toxicokinetics of benzene have been studied in both animals and humans.
Benzene is absorbed by all routes of exposure (inhalation, dermal and oral) with inhalation as
the most important route. Benzene is rapidly distributed in the body and higher concentrations
are found in fat and in lipid rich tissues compared to blood. After absorption, most benzene is
metabolized and the metabolites are excreted after conjugation, mainly in the urine. Oxidative
metabolism of benzene is a prerequisite to repeat dose toxicity and follows similar pathways in
humans and animals. The liver is the major site of benzene metabolism, but metabolism in the
Benzene VCCEP Submission
March 2006
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