Pharmacokinetic studies in Tg.AC and FVB mice administered [14C] benzene either by oral gavage or intradermal injection.
Chronic benzene toxicity has been demonstrated to result in either aplastic anemia or acute myelogenous leukemia, a form of granulocytic leukemia, in exposed people (Snyder and Kalf, Crit. Rev. Toxicol. 24, 177-209, 1994). Aplastic anemia has been demonstrated in animal models following benzene exposure but, heretofore, it has not been possible to replicate benzene-induced granulocytic leukemia in animals. The Tg.AC mouse appears to be the first animal model in which a granulocytic leukemia was produced by treatment with benzene (Tennant et al., The Use of Short- and Medium-Term Tests for Carcinogenic Hazard Evaluation, 1999; French and Saulnier, J. Toxicol. Environ. Health 61, 377-379, 2000). Leukemia was observed in Tg.AC mice to which benzene was administered dermally. Neither orally dosed Tg.AC mice or mice of the parental FVB strain treated by either route of exposure developed leukemia. It is well established that benzene metabolism is required to produce benzene toxicity. To determine whether metabolic differences arising from differences in route of exposure or strain of mouse directed the development of leukemia, the pharmacokinetics of benzene were compared between the two strains and between the two routes of administration. Regardless of the route of exposure or the strain of mouse, seven major metabolites plus unmetabolized benzene were detected in most samples at most time points. Few differences were observed between the two strains following either route of administration. These results suggest that the genetic modification in the Tg.AC mouse, i.e., insertion of the v-Ha-ras construct into the genome, did not disrupt any major pathways involved in determining the pharmacokinetics of benzene. Two significant differences were observed between the two routes of exposure: first, benzene was absorbed more slowly after intradermal injection than after oral gavage, and second, the intradermally dosed mice produced more conjugates of hydroquinone than did the orally dosed mice. These differences in metabolism may be involved in the previously observed differences in hematotoxicity between the two routes of exposure.
Hoffmann
M J
MJ
Joint Graduate Program in Toxicology, Rutgers University, Piscataway, New Jersey 08854-8020, USA.
Sinko
P J
PJ
Lee
Y H
YH
Meeker
R J
RJ
Snyder
R
R
D000284:Administration, Oral; D000818:Animals; D001554:Benzene / Q000378:metabolism / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D006873:Hydroquinones / Q000097:blood; D007271:Injections, Intradermal; D008297:Male; D051379:Mice; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D006873:Hydroquinones; D001554:Benzene