(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

absorption compared to inhalation, and divided by the standard default human body weight of
70 kg (equivalent oral dose = 1.2 mg/kg/day). The RfD was then derived by dividing the
equivalent oral dose by the overall uncertainty factor of 300 (4×10 -4 mg/kg/day). The UFs are
the same as described for the RfC above.
EPA considers the BMC to be an adverse-effect level; therefore, the effect-level extrapolation
analogous to the LOAEL-to-NOAEL UF was used. A factor of 3 (vs. 10) was selected, because
the BMD corresponded to an adverse effect that was not very serious. Second, a factor of 10
was used for intraspecies differences in response (human variability) as a means of protecting
potentially sensitive human populations. Third, a subchronic-to-chronic extrapolation factor was
applied, because the mean exposure duration for the subjects in the principal study was 6.3
years (7 years is the exposure duration used by EPA for deriving chronic RfDs). However, a
value of 3 (vs. 10) was selected, because it was very close to the 7-year cutoff. Finally, a UF of
3 was chosen to account for database deficiencies, because no two-generation reproductive
and developmental toxicity studies for benzene are available.
Importantly, decreased ALC is a very sensitive effect that can be measured in the blood, but
there is no evidence that it is related to any functional impairment at levels of decrement near
the benchmark response (U.S. EPA, 2003a). Further, WBC and ALC levels of the workers in
the Rothman study were still within the normal range for hematology parameters [WBC = 5.6 +/-
1.9×10 3 /mm 3 ; ALC = 1.6 +/- 0.3×10 3 /mm 3 ] (Bakerman, 2002). The normal range for WBC in
adults is 4.5–11.0×10 3 /mm 3 , and for lymphocytes, the range is 1–4.8×10 3 /mm 3 (Bakerman,
2002). Additionally, the levels of benzene reported in this study were not trivial, with the lowest
exposure group still exposed to a median benzene concentration of 7.6 ppm and the highest
group exposed to benzene concentrations in excess of 90 ppm (Rothman et al., 1996). Even
with prolonged, fairly significant exposures, there was no clinically relevant toxicity reported in
these workers, and marginally significant effects, especially in the lower exposure groups
(median benzene concentrations of 7.6 and 13.9 ppm). Finally, evidence in humans and
experimental animals indicates that cytopenias occur within weeks or months of exposure, and
upon removal from the environment or reduction in benzene concentration, small alterations are
likely to return to normal values (Green et al., 1981b; Snyder et al., 1981). Therefore, there is
no reason to suspect that the biological response from 6.3 years worth of exposure would be
quantitatively or qualitatively different from that expected to occur following 7 years of exposure.
This calls into question the biological rationale for EPA’s subchronic-to-chronic uncertainty
factor of 3.
6.1.6.2 Additional Literature for Non-Cancer Hematology Effects
A sufficient body of human data exists in the scientific literature to demonstrate the
hematopoietic toxicity of chronic exposure to benzene. The majority of these studies suggest
that this effect follows a predictable dose response, including the presence of a threshold, in
both experimental animals and humans. Doses of benzene required to suppress various cell
lineages vary to some degree from one study to another. Greenburg et al. (1939) reported clear
evidence of benzene hematotoxicity in the printing industry, with air concentrations of benzene
frequently in excess of 400 ppm and estimated to be as high as ~1000 ppm. Goldwater (1941)
also evaluated various industries with excessive benzene concentrations (10–1060 ppm) and
frequently observed cases of anemia and thrombocytopenia. Lymphocytopenia was also
commonly observed, but neutropenia was rare (Goldwater, 1941). Aksoy et al. (1971) reported
clear evidence of hematotoxicity (decreases in WBC) in Turkish shoe workers who were
exposed to air concentrations of benzene as high as 210 ppm. Kipen et al. (1988) evaluated
blood samples collected during medical surveillance from the ‘pliofilm’ cohort. Conclusions
Benzene VCCEP Submission
March 2006
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