(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

enzene exposure. Relevant studies are limited by small size, inadequate exposure
information, confounding chemical exposure and other factors, as well as potential recall and
selection bias. For these reasons, the existing data on male and female reproductive toxicity or
developmental effects do not establish a causal relationship with benzene exposure. Studies
evaluating the role that paternal exposures may play in the development of childhood leukemia
do not support a casual link with the development of childhood acute lymphoblastic leukemia
(ALL). There is one study indicating that a potential association between maternal exposures to
benzene and childhood AML might exist. However, this finding has not been independently
confirmed and this single study is of insufficient quality to be used exclusively to support a
causal relationship. Therefore, in the absence of additional, more reliable data, it is not possible
to conclude that parental benzene exposure has not been showen to adversely affect the
developing fetus (including the development of childhood leukemia) or adversely affect
reproductive function in either exposed parent. The available studies on human reproductive
and developmental toxicity of benzene are discussed in this assessment.
Animal Hazard Assessment
While the human data summarized above are the key data supporting this and other risk
assessments and risk management decisions, benzene has also been studied extensively in
laboratory animals. Similar to humans, hematotoxicity is frequently the most sensitive effect
observed in animal studies; however, there is no animal toxicity model for benzene induced
AML.
Acute animal toxicity studies of benzene have been conducted by the oral, inhalation, and
dermal route. The results from these studies indicate that benzene is of a low order of acute
toxicity for the inhalation, oral and dermal routes or exposure. Skin and eye irritation studies
indicate that benzene is irritating to the skin and can cause damage to the eye.
In repeat dose studies, benzene effects depend on a variety of factors, including the animal
species and strain, exposure duration, and whether exposure is intermittent or continuous.
Serious toxicological effects are primarily confined to hematological parameters, from
depression of stem cells up to pancytopenia and histopathological alterations in the marrow.
Principal effects of subchronic treatment in rats and mice are hematotoxicity, reduction in body
weight and weight gain, and dose-related increases in mortality. Hematologic effects include
leukopenia, lymphocytopenia, lymphoid depletion in spleen, decreased incidence of primitive
progenitor cells and granulocyte-macrophage colony forming units (CFU-GM).
Benzene does not induce in vitro gene mutation in bacteria using the standard Ames test
conditions. Weakly positive effects were obtained in the presence of metabolic activation for
Salmonella typhimurium TA 1535 exposed to benzene vapor and in another study with TA100
exposed in microsuspension wells. Mammalian cell gene mutation tests give mixed results.
Chromosome aberrations and sister chromatid exchanges (SCE) have been reported in cultured
human lymphocytes and other mammalian cells exposed in vitro to benzene and/or its
metabolites. Further, oral doses of benzene induced dose-related increases in chromosome
aberrations in mice sperm and inhalation exposure lead to micronuclei induction in both rats and
mice and chromosome aberrations in rat bone marrow. However, in vivo exposuse to benzene
in other studies of laboratory animals did not induce chromosome aberrations, increased
incidence of micronuclei (MN), or SCE. Benzene and/or its metabolites have also been
reported to bind to DNA and protein forming adducts in the bone marrow and liver of treated
animals.
Benzene VCCEP Submission
March 2006
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