Risk Analysis, zyxwvutsrq Vol. 12, No. 3, 1992 zyxwvutsr CBA Reassessing Benzene Cancer Risks Using Internal Doses Louis Anthony Cox, Jr.' and Paolo F. Ricci2 Received March 4, 1991; revised January 28, 1992 zyxwv Human cancer risks from benzene exposure have previously been estimated by regu based primarily on epidemiological data, with supporting evidence provided by animal bioas data. This paper reexamines the animal-based risk assessments for benzene using p based pharmacokinetic (PBPK) models of benzene metabolism in animals and humans. It dem- onstrates that internal doses (interpreted as total benzene metabolites formed) from or experiments in mice are well predicted by a PBPK model developed by Travis et al. Both the data and the model outputs can also be accurately described by the simple nonlinear re total metabolites zyxwvu CBA = zyxw RQPO 76.4x/(80.75 + zyxw PON x), where x = administered dose in mglkglday. Thus, PBPK modeling validates the use of such nonlinear regression models, previously used and Hoel. An important finding is that refitting the linearized multistage (LMS) model family to in doses and observed responses changes the maximum-likelihood estimate (MLE) do curve for mice from linear-quadratic to cubic, leading to low-dose risk estimates smaller than in previous risk assessments. This is consistent with the conclusion for mice from and Hoel analysis. An innovation in this paper is estimation of internal doses for humans based on a PBPK model (and the regression model approximating it) rather than zyx on interspecies dose con- versions. Estimates of human risks at low doses are reduced by the use of internal dose estimates when the estimates are obtained from a PBPK model, in contrast to Bailer and Hoel's findings based on interspecies dose conversion. Sensitivity analyses and comparisons with epidemiological data and risk models suggest that our finding of a nonlinear MLE dose-response curve at low doses is robust to changes in assumptions and more consistent with epidemiological data than earlier risk models. KEY WORDS: Benzene; PBPK modeling; quantitative risk assessment; statistical methods. 1. INTRODUCTION The use of biologically relevant internal dose sur- rogates is becoming increasingly accepted as a construc- tive approach for trying to increase the plausibility and accuracy of risk models. However,a perception is emerging among many practitioners that replacing ad- ministered doses with internal dose estimates often makes little difference in cancer risk estimates. This paper pre- sents a striking counterexample for benzene. It shows Cox Associates, 503 Franklin Street, Denver, Colorado, 80218. * Ricci & Molton, 685 Hilldale Ave., Berkeley, California 94708. that, for most choices of surrogate dose measures, the MLE estimate of low-dose risks decreases significantly when internal doses are used as the explanatory variable primarily because the dose-response relation becomes a nonlinear, upward-curving (quadratic or cubic) curve in- stead of an approximately straight line. When the inter- nal dose-response relation for mice is applied to humans, with the internal doses for humans also being calculated from a PBPK model, the resulting risk estimates are far lower than those previously accepted by regulatory agen- cies.(')This contrasts with conclusions from a recent analysis by Bailer and Hoel,(2) similar in many respects to this one, that extrapolated the relation between ad 0272-4332/9~900-01$06.50/1 0 1992 Society for Risk Analysis 401