(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

aneuploidy), sister chromatid exchange (SCE) formation, single or double stranded DNA
breaks, unscheduled DNA synthesis, oxidative alterations to DNA and various gene mutations
(International Agency for Research on Cancer (IARC), 1987; Whysner et al., 1995; Whysner et
al., 2004). Benzene and its metabolites are generally negative in standard mutation assays
using the bacteria, yeast and fruit flies and results are inconclusive in mammalian cell lines
(ACGIH, 2001). Using human cells in the glycophorin A gene mutation assay, investigators
observed examples of benzene induced mutations that are likely associated with mitotic
recombination but not those typically associated with point mutations or deletions (Zhang et al.,
1995; Rothman et al., 1995). The majority of scientific evidence does not support benzene
acting as a mutagenic agent.
Consistent experimental proof for direct DNA reactivity is also lacking (Reddy et al., 1994;
Pathak et al., 1995). Benzene induced micronuclei formation has been generally positive in
rodents, but results from studies using human cells is less consistent (Zhang et al., 1993;
Eastmond et al., 1994; Liu et al., 1996). SCE assays have also produced highly variable results,
particularly in human cells (Clark et al., 1968; Watanabe et al., 1980; Funes-Cravioto et al.,
1977). Assays designed to measure benzene induced DNA strand breaks (single or double) or
induction of unscheduled DNA synthesis have also yielded inconsistent results in both humans
and experimental animals.
There is reliable scientific evidence for benzene induced clastogenicity or chromosome damage.
This ‘genotoxic’ event includes chromosome aberrations and/or aneuploidy. While there is
continuing scientific debate regarding specific chromosomal lesions that may or may not be
associated with benzene, there is solid evidence that excessive benzene exposure can result in
both structural and numerical chromosomal changes.
As early as 1964, studies of occupational workers exposed to benzene revealed positive
evidence of exposure-related chromosomal aberrations (Pollini et al., 1964; Forni et al., 1971;
Olweus et al., 1996; Tough et al., 1970). Many of these studies possess important confounders
such as smoking or co-exposures to other chemicals. Nonetheless, the overall pattern of
chromosomal changes observed in these early studies was consistent. Some investigators also
reported that decreases in exposure resulted in concomitant decreases in cytogenetic
abnormalities, which further strengthens the association (Tompa et al., 1994). Most of these
early studies reported gross structural changes, such as breaks and aneuploidy but stable and
unstable rearrangements were also commonly observed (Picciani, 1979; Erdogan et al., 1973;
Aksoy, 1989; Sarto et al., 1984; Yardley-Jones et al., 1990).
Data obtained from occupationally exposed workers have been corroborated and extended by
studies of human lymphocytes or hematopoietic progenitor cells following in vitro exposure to
hydroquinone or other metabolites. More recent laboratory based investigations benefit from
sophisticated techniques that allow researchers to detect highly specific cytogenetic lesions
(Stillman et al., 1999; Stillman et al., 1997; Niazi et al., 1997; Eastmond, Rupa, and Hasegawa,
1994; Smith et al., 2000; Zhang et al., 2002). Most of these in vitro analysis report involvement
of chromosomes 5, 7 and 8, with less frequently reported changes in chromosome 21 (Zhang et
al., 2005). In humans, chromosomes 5 , 7 or 8 appear to be the most commonly involved with
the best evidence supporting interstitial deletions and/or aneuploidy (Zhang et al., 2002). These
specific lesions have also been observed in workers (Zhang et al., 1998; Smith et al., 1998;
Zhang et al., 2002).
It has been generally recognized within the hematology and medical communities that treatment
of primary malignancies with drugs that act as alkylating agents can also result in the
Benzene VCCEP Submission
March 2006
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