(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

A second, original epidemiological investigation is being conducted by the Benzene Health
Research Consortium, a collaborative research program between the U.S. and China and
includes the following organizations: Applied Health Sciences, University of Colorado,
ExxonMobil Biomedical Sciences, Fudan University, Shanghai Municipal Institute of Public
Health Supervision, Shanghai Center for Disease Prevention and Control, and as many as 29
separate hospitals in Shanghai (Wong et al., 2005). The Shanghai Health Study is a large-scale
epidemiological investigation that includes a hospital-based, case-control study of NHL, MDS,
benzene poisoning, and AML. Additional components of this investigation will provide data to
better understand the progression and molecular epidemiology of benzene-related diseases, as
well as exposure analysis.
The ongoing epidemiology studies are using modern diagnostic and molecular techniques to
further study the molecular pathogenesis of benzene-associated diseases and the exposureresponse
relationship for benzene-related cancer and non-cancer effects.
6.1.9 Linear versus Non-Linear Extrapolation
Multiple epidemiological studies from the 1930s through the 1980s strongly support the
hypothesis that a threshold exists for benzene’s hematopoietic toxicity, including the risk for
developing AML. The EPA cancer slope factor is based on the Rinsky et al. (1987) study.
There have been at least three exposure analyses of this cohort (Rinsky, Crump, and
Paustenbach), and although they differ with regard to methodologies and conclusions, none has
reported an excess leukemia risk below 40 ppm-years, with an average value of ~200 ppmyears
(Paustenbach et al., 1992; Rushton and Romaniuk, 1997; Paxton et al., 1994; Wong,
1995; Aksoy, 1980). Other authors believe that the threshold could be much higher and that,
based on exposure estimates from Crump and Allen and Paustenbach, the AML threshold
would correspond to 370 or 530 ppm-years, respectively (Crump and Allen, 1984; Paustenbach
et al., 1992; Wong, 1995). In contrast, an analysis published by Glass et al. (2003) reports an
increased ANLL risk at lower levels of cumulative benzene exposures than previously reported,
but still published cumulative exposures to benzene that carried no elevated risk of ANLL (Glass
et al., 2003). Therefore, the majority of the existing epidemiology evidence on the relationship
between benzene and AML supports the existence of a threshold for this effect.
While the actual exposure/dose required for AML is not universally agreed upon, the existence
of a threshold for AML is consistent with epidemiological data, as well as clinical data obtained
from secondary leukemia arising from ionizing radiation and/or chemotherapy and the current
understanding of bone marrow patho-physiology and biology. Emerging evidence in the
biological mechanism of benzene-induced AML suggests that benzene and/or its metabolites
may induce AML via toxic disruption of the regulatory mechanism of cell growth and
differentiation (Irons et al., 1993; Irons et al., 1992; Snyder et al., 1994). Further, benzene
metabolism has been determined to follow non-linear Michaelis-Menton kinetics (Travis et al.,
1990). Given the non-linear nature of benzene metabolism, the use of a linear model for excess
cancer risk calculations will likely overestimate the risk, particularly at low exposure levels
(ACGIH, 2001). These observations provide a biological basis for the observed threshold
evident in epidemiological data (Wong et al., 1995; World Health Organization, 1993; ACGIH,
2001).
The ACGIH utilized a non-linear analysis in deriving the TLV ® for benzene and support a nonlinear
mechanism of benzene-induced leukemogenic transformation. The ACGIH concluded
that a linear non-threshold model of benzene risk would likely overstate the risk at low levels of
Benzene VCCEP Submission
March 2006
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