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Reassessing Benzene Cancer Risks Using Internal Doses

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  • Louis Anthony Cox
  • Paolo F. Ricci

Abstract

Human cancer risks from benzene exposure have previously been estimated by regulatory agencies based primarily on epidemiological data, with supporting evidence provided by animal bioassay data. This paper reexamines the animal‐based risk assessments for benzene using physiologically‐based pharmacokinetic (PBPK) models of benzene metabolism in animals and humans. It demonstrates that internal doses (interpreted as total benzene metabolites formed) from oral gavage 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 regression model total metabolites= 76.4x/(80.75 + x), where x= administered dose in mg/kg/day. Thus, PBPK modeling validates the use of such nonlinear regression models, previously used by Bailer and Hoel. An important finding is that refitting the linearized multistage (LMS) model family to internal doses and observed responses changes the maximum‐likelihood estimate (MLE) dose‐response 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 the Bailer 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 on interspecies dose conversions. 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.

Suggested Citation

  • Louis Anthony Cox & Paolo F. Ricci, 1992. "Reassessing Benzene Cancer Risks Using Internal Doses," Risk Analysis, John Wiley & Sons, vol. 12(3), pages 401-410, September.
  • Handle: RePEc:wly:riskan:v:12:y:1992:i:3:p:401-410
    DOI: 10.1111/j.1539-6924.1992.tb00692.x
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    References listed on IDEAS

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    1. Louis Anthony Cox, 1984. "Probability of Causation and the Attributable Proportion Risk," Risk Analysis, John Wiley & Sons, vol. 4(3), pages 221-230, September.
    2. Louis Anthony Cox, 1991. "Biological Basis of Chemical Carcinogenesis: Insights from Benzene," Risk Analysis, John Wiley & Sons, vol. 11(3), pages 453-464, September.
    3. Robert C. Spear & Frédéric Y. Bois & Tracey Woodruff & David Auslander & Jennifer Parker & Steve Selvin, 1991. "Modeling Benzene Pharmacokinetics Across Three Sets of Animal Data: Parametric Sensitivity and Risk Implications," Risk Analysis, John Wiley & Sons, vol. 11(4), pages 641-654, December.
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    1. Louis Anthony Cox, 1995. "Simple Relations Between Administered and Internal Doses in Compartmental Flow Models," Risk Analysis, John Wiley & Sons, vol. 15(2), pages 197-204, April.
    2. Louis Anthony Cox & Paolo F. Ricci, 1993. "Dose‐Response Nonlinearities for Benzene Revisited: A Reply to Crump et al," Risk Analysis, John Wiley & Sons, vol. 13(5), pages 485-486, October.
    3. A. Robert Schnatter & Mark J. Nicolich & Michael G. Bird, 1996. "Determination of Leukemogenic Benzene Exposure Concentrations: Refined Analyses of the Pliofilm Cohort," Risk Analysis, John Wiley & Sons, vol. 16(6), pages 833-840, December.

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