(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

(six rats) were injected with tyrosine hydroxylase inhibitor immediately following exposure, and
were sacrificed 2 hours later. Depletion of catecholamines was determined by calculating the
percent depletion in the + inhibitor group compared to levels of catecholamine in the benzene
(no–inhibitor) controls using quantitative microfluorimetry. Benzene (no-inhibitor) controls
produced increases in catecholamines in some hypothalamic regions, and the benzene +
inhibitor group enhanced disappearance in other regions. Benzene produced a pattern of
discrete changes in noradrenalin and dopamine turnover in certain areas of the hypothalamus.
Ungváry and Donath (1984) demonstrated that the noradrenergic innervation of reproductive
organs could be affected by benzene exposure. CFY rats were exposed to 1500 mg/m 3 ,
8 hours/day on GD 8–10. The abundance of fluorescent noradrenergic fibers normally found in
ovaries and uteri of pregnant rats decreased while background fluorescence increased,
interpreted to indicate an increased release of nonadrenalin. The authors concluded that
benzene has a selective and differential toxic effect on post-ganglionic neurons, with potential
for embryotoxicity.
Dempster et al. (1984) correlated behavior with hematological effects of inhaled benzene using
mice exposed to concentrations of 100—3000 ppm, 6 hours/day for the number of days
necessary to achieve (concentration × time) product of 3000 ppm-days. Lymphocyte counts
decreased to 68% of control after five exposures to 100 ppm, to 50% after two exposures to
300 ppm, or to one exposure of 1000 or 3000 ppm benzene. The maximum decrease occurred
in 10 days of 300-ppm exposure; lymphocyte counts remained depressed throughout each substudy.
Increased milk-licking from a sipper tube was statistically significantly increased following
1–2 days at 100 ppm, and after 4–5 days at 300 ppm, with the maximal effect at 7–8 days at
300 ppm, following a course similar to that of hematological changes. No effects on grip
strength were seen, except when 1000 ppm was administered for 1 day, causing reduced hindlimb
grip strength. All behavioral effects disappeared following termination of exposure. Other
behavioral effects were measured in male CD-1 and C57Bl/6 mice exposed to 300 or 900 ppm
(958 or 2875 mg/m 3 ) benzene, 6 hours/day for 5 days, with a 2-week recovery period, followed
by a repeat of the exposure regime (Evans et al., 1981). Behaviors monitored were: stereotypic
behavior, sleeping, resting, grooming, eating, locomotion, and fighting. For both strains, a
greater increase in activity was observed among 300-ppm mice, compared to the 900-ppm
mice, probably due to narcosis-like effects at the higher dose. Exposure of Wistar male rats for
4 hours to 929 ppm (2968 mg/m 3 ) benzene in glass chambers decreased evoked electrical
activity in the brain by 30%. A comparable 30% depression was produced in female H-strain
mice exposed to 856 ppm (2735 mg/m 3 ) benzene for 2 hours (Frantik et al., 1994).
Behavioral parameters, acetylcholine esterase (AChE) activity in blood and brain, organ weight,
and bone marrow cellularity were evaluated in male Kunming mice (five per group) exposed to
reported benzene concentrations of 0, 078, 3.13, or 12.52 ppm (0, 2.5, 10, or 40 mg/m 3 ) for
2 hours/day, 6 days/week for 30 days, under static conditions, in a 300-m 3 chamber (Li et al.,
1992). Benzene levels were monitored by gas chromatography every 30 min for 3 days but,
apparently, not thereafter. Forelimb grip strength and rapid response in running a Y-maze
increased at 0.78 ppm (2.5 mg/m 3 ) but declined significantly at higher concentrations. No
statistically significant differences were observed in AChE activity in blood or brain, or in
locomotor activity at any dose level. Relative liver weight increased, and relative spleen weights
decreased (p≤0.05) at 12.52 ppm. Bone marrow cellularity was affected only at 12.52 ppm
(40 mg/m 3 ), with reduction of 91% in myeloblasts, 64% in premyeloblasts, 77% in
metamyelocytes, 100% reduction in reticulum, and 100% in erythroblasts. The behavioral
effects follow the profile of hyperactivity at low doses demonstrated by Dempster et al. (1984)
and Evans et al. (1981) but at much lower doses and shorter duration of exposure. However,
Benzene VCCEP Submission
March 2006
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