(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

cancer and cancer effects) has been definitively established. There have been numerous PBPK
models developed for benzene. These have been useful in assessing:
• species differences in benzene metabolism (McMahon et al., 1994; Spear et al., 1991),
• testing theories about non-linear dose-response relationships between benzene
exposures and hematopoetic/leukemogenic effects (Cox, 1996; Weisel et al., 1996;
Kenyon et al., 1996; Cox and Ricci, 1992),
• interpreting biomonitoring data collected from humans (Thrall et al., 2001; Sherwood
and Sinclair, 1999; Roy and Georgopoulos, 1998; Thomas et al., 1996),
• predicting concentrations of benzene in breast milk among exposed mothers (Fisher et
al., 1997),
• assessing potential gender differences in benzene metabolism (Brown et al., 1998), and
• for assessing the potential for co-exposures to toluene, ethyl benzene, and xylenes to
modulate the metabolism of benzene (Dennison et al., 2004; Krishnan et al., 2002;
Haddad et al., 2001; Tardif et al., 1997).
For PBPK models to form the basis for conducting a scientifically appropriate PBPK-based risk
assessment, the mechanism of action for the toxic endpoint of concern (e.g., hematopoetic
toxicity) must be known so that the critical dose measure can be established. While metabolism
seems to be a critical determinant for benzene’s hematopoetic toxic action, many questions
remain; 1) which specific metabolites or combinations of metabolites are critical, 2) whether
phase 1 metabolism or the bioactivation step of benzene must occur in the bone marrow or the
liver (or both) (Bird et al., 2005). Currently, the mechanism of action for benzene-induced AML
is still under investigation. Further, not enough is known at this time to choose a defensible
critical dose measure to form the basis of a PBPK-based risk assessment. Therefore, this
VCCEP risk assessment for benzene was conducted using absorbed doses of benzene as the
critical dose metric. This is consistent with USEPA’s approach used in developing their cancer
slope factors and Reference Dose and Reference Concentration. As mentioned in the exposure
assessment (Section 7.2.1.8), a PBPK model for benzene was used to calculate the dose of
benzene to an infant via breast milk from an exposed mother.
8.1.2 Mixed Exposures
Exposures to pure benzene rarely occur in environmental or occupational settings. More
commonly, benzene exposure will involve co-exposures to other chemicals, including complex
mixtures such as gasoline. BTEX (benzene, toluene, ethyl benzene, and xylenes) represent the
components that are most often focused on when assessing exposures to gasoline. It has been
shown in experimental animals and purified enzyme systems that co-exposures to toluene, ethyl
benzene or xylenes can inhibit the metabolism of benzene. However, this is only considered
relevant at high exposure concentrations (greater than 100 ppm) for each constituent, which
results in competitive inhibition of the metabolizing enzymes. Therefore, this competitive
inhibition is not likely to occur to any significant degree at environmentally relevant exposure
concentrations (e.g., less than 1 ppm). The ATSDR treats mixtures of BTEX as additive when
addressing neurological impairment (ATSDR, 2004). However, the ATSDR has stated that coexposures
with toluene, ethyl benzene or xylenes do not potentiate the hematopoetic or
leukemogenic effects of benzene (ATSDR, 2004). Thus, while exposures to benzene alone are
rare, it is not anticipated that other constituents in gasoline will potentiate or inhibit the
hematopoetic or leukemogenic effects of benzene, especially at environmentally relevant
exposure concentrations (ATSDR, 2004). Therefore, co-exposures are not quantitatively
addressed in this risk assessment.
Benzene VCCEP Submission
March 2006
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