Reassessing benzene risks using internal doses and Monte-Carlo uncertainty analysis
- Cox Associates, Denver, CO (United States)
Human cancer risks from benzene have been estimated from epidemiological data, with supporting evidence from animal bioassay data. This article reexamines the animal-based risk assessments using physiologically based pharmacokinetic (PBPK) models of benzene metabolism in animals and humans. Internal doses (total benzene metabolites) from oral gavage experiments in mice are well predicted by the PBPK model. Both the data and the PBPK model outputs are also well described by a simple nonlinear (Michaelis-Menten) regression model, as previously used by Bailer and Hoel. Refitting the multistage model family to internal doses changes the maximum-likelihood estimate (MLE) dose-response curve for mice from linear-quadratic to purely cubic, so that low-dose risk estimates are smaller than in previous risk assessments. In contrast to Bailer and Hoel`s findings using interspecies dose conversion, the use of internal dose estimates for humans from a PBPK model reduces estimated human risks at low doses. Sensitivity analyses suggest that the finding of a nonlinear MLE dose response curve at low doses is robust to changes in internal dose definitions and more consistent with epidemiological data than earlier risk models. A Monte-Carlo uncertainty analysis based on maximum-entropy probabilities and Bayesian conditioning is used to develop an entire probability distribution for the true but unknown dose-response function. 23 refs., 9 figs., 6 tabs.
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 472194
- Report Number(s):
- CONF-9506288-; ISSN 0091-6765; TRN: 97:001626-0047
- Journal Information:
- Environmental Health Perspectives, Vol. 104, 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
Similar Records
Limitations to benzene cancer risk assessment by Cox and Ricci
Translating dosimetry of Dibenzo[def,p]chrysene (DBC) and metabolites across dose and species using physiologically based pharmacokinetic (PBPK) modeling