(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

6.1.2.2 Chronic Toxicity
Toxicity associated with chronic long-term exposure to benzene is primarily limited to the
hematopoietic and/or immune system. Manifestations can range from non-symptomatic,
reversible suppression of a specific blood cell (cytopenia) to permanent, often fatal, damage to
the bone marrow and resulting aplastic anemia (Irons, 1997; Rothman et al., 1996; Kipen et al.,
1988; Santesson, 1897; Selling, 1916). Scientific and medical evidence also supports a casual
link between benzene and the development of acute myelogenous leukemia (AML) (Rinsky et
al., 1987; Irons, 1997). The adverse health effects associated with chronic exposure to
benzene are discussed briefly below.
6.1.2.2a Peripheral Cytopenias
The first manifestation of chronic benzene toxicity is often some form of cytopenia (a significant
depression in one or more types of the peripheral blood cells). Existing data suggest that this
effect follows a predictable dose response in both experimental animals and humans. Early
work in rodents indicated that inhalation of 25 ppm benzene or higher for several weeks resulted
in suppression of white blood cells (WBC) (Cronkite et al., 1985; Cronkite et al., 1982; Snyder et
al., 1978a, 1979; Green et al., 1981a). Suppression of WBC or leukopenia has also been
observed in benzene-exposed humans, and in fact, alterations in WBC count were used
historically as a clinical biomarker for occupational physicians to screen workers for early
evidence of hematopoietic toxicity (Michiels, 1997; Ward et al., 1996; Kipen et al., 1988;
Rothman et al., 1996). It has also been reported in both experimental animal and human
studies that lymphocytes were highly sensitive to benzene toxicity (Irons et al., 1980; Pyatt et
al., 2000). Suppression of absolute lymphocyte count (ALC) by benzene is considered by EPA
to be the most sensitive non-cancer toxic endpoint in humans, and as such, forms the basis for
its regulatory non-cancer values (RfC and RfD) (Ward et al., 1996; U.S. EPA, 2000). A
depression in circulating red blood cells is also a common finding in highly exposed workers
(Aksoy, 1989; Aksoy et al., 1971; Snyder et al., 1978a; Snyder et al., 1982). However, frank
anemia usually occurs following higher doses or longer exposures to benzene than those
required to induce lymphocytopenia (Aksoy, 1989). Though less common, thrombocytopenia
(decrease in platelet production) has also been reported. In more severe exposure cases,
pancytopenias are observed, representing a significant suppression in all mature blood cells
found in the periphery (Aksoy, 1989; Aksoy et al., 1971).
6.1.2.2b Aplastic Anemia
At high enough concentrations, benzene can induce hematopoietic damage so severe that
complete bone marrow failure occurs, resulting in aplastic anemia (AA) (Vigliani et al., 1976; Erf
et al., 1939; Goldwater, 1941). This important adverse health effect will often present with
pancytopenia (a clinically significant suppression in the production of all mature blood cells),
which is clearly evident in the peripheral blood. Benzene-induced AA was frequently fatal, with
death resulting from severe hemorrhage, infection, or an additional secondary factor related to a
loss of mature blood cell function (Michiels, 1997). While a threshold for the development of AA
from benzene exposure likely exists, the exact value is not known. What is known is that cases
of AA were exposed to very high levels of benzene that caused frank cytotoxicity, often for
extended periods (Vigliani and Forni, 1976; Erf and Rhoads, 1939; Goldwater, 1941). By way of
an example, Turkish shoe workers who developed AA were often exposed to levels believed to
have been as high as 600 ppm for the entire 8- to 10-hour work shift (Aksoy et al., 1978).
Benzene VCCEP Submission
March 2006
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