(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

LOAELs for carcinogenic effects in the oral rat and mouse studies (NTP, 1986; Huff et al, 1989):
Rat: LOAEL (male) = 36 mg/kg/day
LOAEL (female) = 18 mg/kg/day
Mouse: LOAEL (male) = 18 mg/kg/day
LOAEL (female) = 36 mg/kg/day
Overall, subchronic toxicity, chronic toxicity, and carcinogenicity of benzene have been
adequately addressed by researchers over the past 40+ years, such that there is little to be
gained by performing additional standardized toxicity testing.
6.2.6 Adult Neurotoxicity
Inhalation and oral (mostly acute) studies demonstrate the potential of benzene to affect the
nervous system at fairly high doses in animals, effects that are reduced or eliminated with
cessation of exposure.
6.2.6.1 Oral
Sprague-Dawley rats given a single oral dose of 1870 mg/kg exhibited tremors and tonic-clonic
convulsions, and died within minutes. A dose of 352 mg/kg to mice produced slight nervous
system depression (Cornish and Ryan, 1965). To evaluate effects of potential groundwater
contaminants, Hsieh et al (1988a) administered benzene to CD-1 male mice at concentrations
of 0, 40, 200, and 1000 mg/L benzene in drinking water (estimated daily doses of 0, 8, 40, and
180 mg/kg/day) for 4 weeks. Animals were euthanized after 4 weeks, and brains were
sectioned—hypothalamus, medulla oblongata, cerebellum, corpus striatum, cerebral cortex, and
mid-brain—and analyzed for catecholamines; norepinephrine, dopamine, and their metabolites;
and indoleamine seratonin and 5-hydroxyindoleacetic acid, by high-performance liquid
chromatography. No effects on behavior, body weight, and food or water consumption were
observed. Dose-related increases in levels of monoamine neurotransmitters occurred at 8 and
40 mg/kg/day, but no further increases were seen at 180 mg/kg. Increases in levels of parent
compounds were associated with increases in corresponding metabolites, reflecting increased
turnover of the amines. A NOAEL could not be determined; the LOAEL was 8 mg/kg/day.
Although a potential biomarker for exposure, the biological significance of these findings is
uncertain (ATSDR, 1997). Oral administration of 8, 40, or 180 mg/kg/day benzene in drinking
water to male CD-1 mice for 4 weeks markedly stimulated hypothalamic-pituitaryadrenocorticoid
activity (Hsieh et al., 1991). At all doses, serum corticosterone levels collected
at days 2, 7, and 14 of treatment were increased at day 7, decreased to control levels at day 14,
and were re-elevated at termination.
6.2.6.2 Inhalation
In an early study (Carpenter et al., 1944), rabbits exposed to approx. 45,000 ppm
(143,760 mg/m 3 ) benzene exhibited light narcosis after 3.7 minutes of exposure; tremors,
chewing, excitement, and running movements after 5 minutes; loss of pupillary reflex to strong
light, blink reflex, pupillary contraction, and involuntary blinking over 6.5–15.6 minutes; and
death after 36.2 minutes. Anderson et al. (1983) evaluated effects of high concentrations of
benzene in dopamine and noradrenaline turnover in parts of the hypothalamus in Sprague
Dawley rats exposed to 1500 ppm (4792 mg/m 3 ), 6 hours/day for 3 days. The benzene control
group (four rats, no inhibitor) were sacrificed immediately after exposure; the + inhibitor group
Benzene VCCEP Submission
March 2006
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