(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

WBC and RBC counts, Hgb and smears from femur bone marrow or spleen for number of cells
in DDP. No changes in hematopoietic parameters were seen in livers of 16-day-old fetuses, in
contrast to effects on CFU reported in 1986. The authors concluded that benzene-induced
hematotoxicity in offspring of mice exposed during pregnancy was evidenced by reduction in
number of early nucleated red cells in peripheral blood of 2-day-old neonates at all exposure
levels, and by increases in the number of dividing cells granulocytes in the livers of 2-day-old
neonates and spleens of 6-week-old adults (20 ppm). The only clearly dose-related response
was a decrease in early nucleated red cells in peripheral blood of 2-day-old neonates
(statistically significant at 20 ppm), present only in very young animals and not in 8-week-old
adults. In reviewing these Keller and Snyder studies (1986, 1988), Irons (2001) concluded that
these studies did not meet the minimal criteria necessary for use in risk assessment, citing the
variability of data, also addressed by IRIS (1998), the absence of a dose relationship, and the
facts that the biological significance of the endpoints has not been established and none of the
findings correlate with significant adverse health effects. Using exposure at 10 ppm to agematched
male, virgin female, and pregnant Swiss Webster mice, 6 hours/day for 10 consecutive
days (GD 6–15 for pregnant mice) and treatment of one-half of all mice with 5% ethanol in
drinking water, Corti and Snyder (1996) evaluated the influence of gender, development,
pregnancy, and ethanol consumption on hematotoxicity of inhaled benzene. On Day 11, bone
marrow cells from adults and liver cells from fetuses were examined for CFU-E and bone
marrow cells isolated from 6-week-old offspring of exposed mice that were allowed to deliver.
Depression of CFU-E cells was seen only in livers of male fetuses from dams exposed to
benzene, benzene+ethanol but not ethanol alone; in adult animals, CFU-E cells were depressed
in bone marrow of all treated males. The Keller and Snyder studies, and Corti and Snyder, are
cited prominently in the 2001 Office of Environmental Health Hazard Assessment (OEHHA)
draft on Prioritization of Toxic Air Contaminants under Children’s Environmental Health
Protection Act.
6.2.4.3 Genotoxicity
Significant increased incidence of micronuclei in fetal livers was observed when 80 mg/kg
benzene was administered orally to pregnant mice on GD 13 (Ciranni et al., 1988), and on
GD 14 or 15 at an i.p. dose of 1318 mg/kg (Xing et al., 1992), or at i.p. doses of 219–874 mg/kg
(Ning et al., 1991). However, oral exposure to 50 and 75 mg/kg benzene administered to
pregnant ICR mice on GD 17–19 did not induce increased micronuclei in fetal liver or adult bone
marrow erythrocytes (Harper et al., 1989); this result correlates with developing hematopoiesis.
When comparing genotoxic effects of benzene in males, females, and fetuses, Cirrani et al.
(1988) found slightly larger increases in micronucleated-PCE in virgin females than in pregnant
dams and fetuses exposed on GD 13, but a much larger effect in males. Harper et al. (1989)
reported large effects in males, smaller effects in virgin females, and no effects in pregnant
dams and fetuses exposed on GD 15–19.
Speculation has been advanced concerning the mechanisms of developmental and
reproductive toxicity of benzene. Pushkina et al. (1968), from a study of factory workers with
ovarian hypofunction related to benzene exposure, suggested that alteration in ascorbic acid
and RNA and DNA content are possible mechanisms. Ascorbic acid content decreased in
whole fetuses and in maternal organs as concentrations of benzene increased, first in maternal
liver and later in placenta and fetal livers. Benzene also increased DNA content and decreased
RNA content in placenta, fetal liver, and fetal brain, and decreased DNA content in maternal
liver. Ungváry and Donath (1984) suggested that damage to peripheral noradrenergic fibers in
pregnant rats might result in disturbed control of ovarian and uterine blood flow and steroid
production, contributing to the embryotoxic action of organic solvents. Tátrai et al. (1980)
Benzene VCCEP Submission
March 2006
81