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Title: Mechanistic considerations in benzene physiological model development

Abstract

Benzene, an important industrial solvent, is also present in unleaded gasoline and cigarette smoke. The hematotoxic effects of benzene in humans are well documented and include aplastic anemia, pancytopenia, and acute myelogenous leukemia. However, the risks of leukemia at low exposure concentrations have not been established. A combination of metabolites (hydroquinone and phenol, for example) may be necessary to duplicate the hematotoxic effect of benzene, perhaps due in part to the synergistic effect of phenol on myeloperoxidase-mediated oxidation of hydroquinone to the reactive metabolite benzoquinone. Because benzene and its hydroxylated metabolites (phenol, hydroquinone, and catechol) are substrates for the same cytochrome P450 enzymes, competitive interactions among the metabolites are possible. In vivo data on metabolite formation by mice exposed to various benzene concentrations are consistent with competitive inhibition of phenol oxidation by benzene. In vitro studies of the metabolic oxidation of benzene, phenol, and hydroquinone are consistent with the mechanism of competitive interaction among the metabolites. The dosimetry of benzene and its metabolites in the target tissue, bone marrow, depends on the balance of activation processes such as enzymatic oxidation and deactivation processes such as conjugation and excretion. Phenol, the primary benzene metabolite, can undergo both oxidation and conjugation. Thusmore » the potential exists for competition among various enzymes for phenol. Zonal localization of phase I and phase 11 enzymes in various regions of the liver acinus also impacts this competition. Biologically based dosimetry models that incorporate the important determinants of benzene flux, including interactions with other chemicals, will enable prediction of target tissue doses of benzene and metabolites at low exposure concentrations relevant for humans. 39 refs., 4 figs., 2 tabs.« less

Authors:
; ; ;  [1]
  1. Chemical Industry Institute of Toxicology, Research Triangle Park, NC (United States)
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
472192
Report Number(s):
CONF-9506288-
Journal ID: EVHPAZ; ISSN 0091-6765; CNN: Grant ES05630; TRN: 97:001626-0045
Resource Type:
Journal Article
Journal Name:
Environmental Health Perspectives
Additional Journal Information:
Journal Volume: 104; Journal Issue: Suppl.6; Conference: Benzene `95: international conference on benzene toxicity, carcinogenesis, and epidemiology, Piscataway, NJ (United States), 17-20 Jun 1995; Other Information: PBD: Dec 1996
Country of Publication:
United States
Language:
English
Subject:
02 PETROLEUM; 55 BIOLOGY AND MEDICINE, BASIC STUDIES; BENZENE; OCCUPATIONAL EXPOSURE; BIOLOGICAL EFFECTS; QUINONES; LEUKEMIA; PETROLEUM REFINERIES; CARCINOGENS; PETROLEUM PRODUCTS; BONE MARROW; DOSES; OXIDATION; UNLEADED GASOLINE; PHENOLS

Citation Formats

Medinsky, M A, Kenyon, E M, Seaton, M J, and Schlosser, P M. Mechanistic considerations in benzene physiological model development. United States: N. p., 1996. Web. doi:10.1289/ehp.961041399.
Medinsky, M A, Kenyon, E M, Seaton, M J, & Schlosser, P M. Mechanistic considerations in benzene physiological model development. United States. https://doi.org/10.1289/ehp.961041399
Medinsky, M A, Kenyon, E M, Seaton, M J, and Schlosser, P M. 1996. "Mechanistic considerations in benzene physiological model development". United States. https://doi.org/10.1289/ehp.961041399.
@article{osti_472192,
title = {Mechanistic considerations in benzene physiological model development},
author = {Medinsky, M A and Kenyon, E M and Seaton, M J and Schlosser, P M},
abstractNote = {Benzene, an important industrial solvent, is also present in unleaded gasoline and cigarette smoke. The hematotoxic effects of benzene in humans are well documented and include aplastic anemia, pancytopenia, and acute myelogenous leukemia. However, the risks of leukemia at low exposure concentrations have not been established. A combination of metabolites (hydroquinone and phenol, for example) may be necessary to duplicate the hematotoxic effect of benzene, perhaps due in part to the synergistic effect of phenol on myeloperoxidase-mediated oxidation of hydroquinone to the reactive metabolite benzoquinone. Because benzene and its hydroxylated metabolites (phenol, hydroquinone, and catechol) are substrates for the same cytochrome P450 enzymes, competitive interactions among the metabolites are possible. In vivo data on metabolite formation by mice exposed to various benzene concentrations are consistent with competitive inhibition of phenol oxidation by benzene. In vitro studies of the metabolic oxidation of benzene, phenol, and hydroquinone are consistent with the mechanism of competitive interaction among the metabolites. The dosimetry of benzene and its metabolites in the target tissue, bone marrow, depends on the balance of activation processes such as enzymatic oxidation and deactivation processes such as conjugation and excretion. Phenol, the primary benzene metabolite, can undergo both oxidation and conjugation. Thus the potential exists for competition among various enzymes for phenol. Zonal localization of phase I and phase 11 enzymes in various regions of the liver acinus also impacts this competition. Biologically based dosimetry models that incorporate the important determinants of benzene flux, including interactions with other chemicals, will enable prediction of target tissue doses of benzene and metabolites at low exposure concentrations relevant for humans. 39 refs., 4 figs., 2 tabs.},
doi = {10.1289/ehp.961041399},
url = {https://www.osti.gov/biblio/472192}, journal = {Environmental Health Perspectives},
number = Suppl.6,
volume = 104,
place = {United States},
year = {Sun Dec 01 00:00:00 EST 1996},
month = {Sun Dec 01 00:00:00 EST 1996}
}