(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

that transient, high peak exposures may have a different (increased) toxicity profile compared to
lower, more continuous exposures. There is some biological rationale for this hypothesis,
because bone marrow damage can be correlated with the timing of treatment of myelotoxic
chemotherapeutic agents. Further, high-dose, acute exposure to ionizing radiation is
considerably more damaging to the bone marrow than the same cumulative dose spread out
over a longer time (NRC, 1990). The underlying biology is complex but likely results from cellcycle
kinetics and proliferative regeneration of different populations of hematopoietic progenitor
cells following toxic insult. Specifically with regard to benzene, the timing of exposures and
related effects on toxicity has been addressed experimentally, as well as in numerous
epidemiological investigations (Coffin et al., 1977; Luke et al., 1988a,b; Snyder et al., 1988;
Rinsky et al., 1981, 1987).
A few examples of experimental animal studies that have reported timing related effects are
presented. Coffin et al. (1977) determined that if the absolute dose of benzene was kept
constant, high-dose intermittent exposures of benzene were less toxic (leukopenia) to treated
mice than the same dose administered via continuous exposure. In contrast, Luke et al.
(1988a,b) evaluated dosing regimens in mice and concluded that cytotoxicity, as evidenced by a
decrease in erythrocyte precursors, was more pronounced in intermittent exposures. Synder et
al. (1988) reported that chronic exposures, even if administered intermittently, were more
tumorigenic than acute, high-dose exposures.
In humans, the majority of studies report that cumulative exposures, reported in ppm-years, are
the best predictor of AML risk (Rinsky et al., 1981; Wong et al., 1993; Tsai et al., 1983; Wen et
al., 1983). These include studies of the ‘pliofilm’ cohort, upon which EPA bases the cancer
potency factor for benzene (Infante et al., 1977; Rinsky et al., 1987). Additionally, more recent
epidemiological investigations from Australia indicate that peak exposures did not correlate with
increased risk of acute non-lymphocytic leukemia (ANLL), as well as cumulative exposures
(Glass et al., 2003). Wong et al. (1983, 1987a,b) reported on the mortality of male chemical
workers who had been exposed to benzene during 1946–1975. Cumulative exposure to
benzene, not peak exposure, was the best predicator of risk in these workers (Wong, 1983,
1987a,b). One study reported that intermittent, high-dose peak exposures were found to be a
better predictor of AML risk than were cumulative exposures (Collins et al., 2003). Collins et al.
(2003) evaluated the risk of AML in chemical workers and found an association between risk
and the number of days on which peaks of 100 ppm or higher occurred. In this study, even
when peak exposures occurred on more than 40 days, there was no significant elevation in AML
risk reported (Collins et al., 2003; Ireland et al., 1997). Recently, Rappaport et al. (2005) used
PBPK modeling to chacterize the effect of exposure variability to internal dose of benzene (and
other VOCs). The conclusion reached by these authors was that cumulative exposure was the
best predictor of internal dose of both the parent compound and the active metabolites of
benzene (Rappaport et al., 2005).
6.1.6 Non-Cancer
6.1.6.1 Critical Study for EPA’s Benzene RfC and RfD (Rothman et al., 1996)
The EPA oral reference dose (RfD) for benzene is 4.0×10 -3 mg/kg/day and is based on a doserelated
decrease in the absolute lymphocyte count (ALC) observed in benzene-exposed
workers (Rothman et al., 1996). The EPA inhalation reference concentration (RfC) for benzene
is 3×10 -2 mg/m 3 and is based on data from the same study. Rothman and co-workers
conducted a cross-sectional study of 44 workers exposed to benzene in the workplace
Benzene VCCEP Submission
March 2006
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