(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

enzene induced pancytopenias can progress to severe hematopoietic damage that can cause
bone marrow failure leading to aplastic anemia, a serious and often fatal disease. Suppression
of a type of white blood cell, the lymphocytes or lymphocytopenia, has been reported by many
independent investigators to be the most sensitive end-point for benzene induced
hematotoxicity. Chronic exposure to high concentrations of benzene has been positively
associated with the development of acute myelogenous leukemia (AML). Leukemias are a
diverse group of malignancies, with different cells of origins, clinical courses, prognosis and
treatments. Despite extensive investigations, the only hematopoietic malignancy positively
associated with benzene exposure is AML.
While there have been questions on the most applicable dose metric (numerical
characterization of the dose-response relationship) for benzene exposure, most studies rely on
cumulative exposure expressed as ppm-years. Intensity and frequency of exposure may also
be important variables in determining toxicity and risk, but they are only addressed indirectly in
cumulative exposure estimates. Accordingly, most studies have reported that cumulative
exposure correlates best with risk of AML.
Lymphocytopenia is considered by the US EPA to be the most sensitive toxic endpoint for
humans exposed to benzene and forms the basis for its non-cancer regulatory benchmark.
Rothman et al. (1996) was selected by the Agency as the critical study. The methodologies and
values are discussed as well as additional literature reporting cytopenias and hematopoietic
toxicity in benzene exposed workers. The cancer potency factor for benzene is based on a
variety of exposure estimates from a cohort of occupationally exposed workers involved with the
manufacture of rubber hydrochloride (Pliofilm) at one of three plants in Ohio. As a result, the
cancer potency or cancer slope factor (CSF) for benzene is presented as a range, based on the
risk associated with the varying exposures. Additional literature on AML and benzene are
briefly discussed to provide a better analysis of the dose response relationship between
benzene exposure and AML. An overview of the most pertinent epidemiology literature dealing
with refinery and petroleum workers, mechanics, and others was included to help understand
the dose response relationship. These additional data show that low levels of benzene exposure
have not been associated with an increased risk of AML.
Considerable research has been conducted to understand the mechanism of action for benzene
induced carcinogenicity, including an extensive evaluation of a genotoxic mechanism for
benzene and/or its reactive metabolites. There is still uncertainty regarding the human genotoxic
potential of benzene and its metabolites with inconsistent results reported. Therefore, it is not
possible to state with scientific certainty what role genotoxicity, including clastogenicity, plays in
benzene induced transformation. Further, epigenetic processes such as altered gene
regulation, cytotoxicity and cell proliferation are thought to be important, perhaps critical, for
benzene induced leukemogenesis.
In summary, benzene is toxic to the blood and bone marrow and can induce AML in a small
number of highly exposed individuals. A critical issue that has yet to be fully resolved is the
shape of the dose response curve at low doses. The available epidemiology data on both
cancer and non-cancer toxicity of benzene support the existence of a functional threshold (an
exposure level below which adverse health effects would not be expected). As a result, use of
a linear extrapolation to predict risk at low exposure levels is overly conservative and
biologically inappropriate.
Based on a recent review of available scientific evidence, it is not possible to reach definitive
conclusions regarding human developmental and/or reproductive toxicity associated with
Benzene VCCEP Submission
March 2006
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