(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

(Pedersen-Bjergaard et al., 1995; Pedersen-Bjergaard et al., 2002). It is also possible that
alternative pathways leading to AML development secondary to benzene exposure exist.
Currently, the mechanism(s) by which exposure to benzene and its metabolites leads to
carcinogenicity have not been defintively established. 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.
6.1.12b Human Reproductive Toxicity of Benzene
Very little published data is available to evaluate the potential reproductive toxicity of benzene.
Additionally, the few studies that have addressed this question possess significant shortcomings
and uncertainties. Vara and Kinnunen (1946) were the first to publish reproductive
effects associated with benzene exposure in women. The reported toxicity in exposed adult
subjects included hypermenorrhea, hypomenorrhea, ovarian hypoplasia and sterility (Vara et al.,
1946). The nature and severity of the symptoms were subjective and no attempt was made to
quantify exposure levels or rule out the effect of other potential confounding exposures.
Subsequent studies also had findings of menstrual abnormalities but failed to account for
potential effects from other chemicals or mixtures (Pushkina et al., 1968; Michon, 1965;
Mukhametova, 1972). Additionally, no information was presented on benzene exposure levels
associated with reported effects. Interpretation of these early studies is further complicated by
the lack of statistical analysis and appropriate comparison with control populations.
More recent studies partially overcome these deficiencies by providing some exposure data and
by attempts to address confounding chemical exposures. Yin et al. (1987) reported a
statistically significant increase in the incidence of hypermenorrhea in women exposed to
benzene concentrations (8 hr mean TWA = 59 ppm). Huang et al. (1991) evaluated Chinese
leather shoe workers and also reported elevated incidence rates of ‘dysmenorrhea’ in exposed
workers. Additionally, an increase in spontaneous abortions associated with employment
duration was observed in this study. Investigators did not quantify benzene exposures or
adequately account for potentially confounding influences from other chemical exposures in this
workplace on other non-chemical confounders (Huang, 1991). Historically, shoe workers have
experienced extremely high benzene levels as well as significant co-exposures to a variety of
other chemicals (Aksoy et al., 1976; Aksoy et al., 1974; Vigliani, 1976; Forni et al., 1974).
Another Chinese worker (petrochemical) study published in 2000 reported that women with
more than 7 years on a job with benzene exposure experienced a significantly increased
number of abnormal menstrual cycles compared to non-benzene exposed controls (OR = 1.71,
95% CI = 1.27-2.31) (Thurston et al., 2000). This increase was not observed in women
exposed for less than 7 years. Again, concomitant chemical exposures were not addressed and
no quantification of benzene air concentrations was provided.
Only one study was located that investigated the effect of occupational benzene exposure on
male reproductive function. Xiao et al. (1999) published an evaluation of benzene, toluene, and
xylene exposure on semen quality in exposed workers (shoe-making, paint manufacturing and
spray painting). Sperm vitality, motility and acrosin activity was reportedly decreased in
exposed workers compared to non-exposed controls (Xiao et al., 1999). It is not possible to
separate the effects of benzene, toluene and xylene on these parameters as co-exposures to all
three chemicals occurred continually (Xiao et al., 2001). Additionally, there was no
Benzene VCCEP Submission
March 2006
53