Skip to main content
NCBI home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1996 Dec;104(Suppl 6):1413–1429. doi: 10.1289/ehp.961041413

Reassessing benzene risks using internal doses and Monte-Carlo uncertainty analysis.

L A Cox Jr 1
PMCID: PMC1469746  PMID: 9118928

Abstract

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 [Metabolite-based internal doses used in risk assessment of benzene. Environ Health Perspect 82:177-184 (1989)]. 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. This allows the probability of a positive low-dose slope to be quantified: It is about 10%. An upper 95% confidence limit on the low-dose slope of excess risk is also obtained directly from the posterior distribution and is similar to previous q1* values. This approach suggests that the excess risk due to benzene exposure may be nonexistent (or even negative) at sufficiently low doses. Two types of biological information about benzene effects--pharmacokinetic and hematotoxic--are examined to test the plausibility of this finding. A framework for incorporating causally relevant biological information into benzene risk assessment is introduced, and it is shown that both pharmacokinetic and hematotoxic models appear to be consistent with the hypothesis that sufficiently low concentrations of inhaled benzene do not create and excess risk.

Full text

PDF
1413

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aksoy M. Hematotoxicity and carcinogenicity of benzene. Environ Health Perspect. 1989 Jul;82:193–197. doi: 10.1289/ehp.8982193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bailer A. J., Hoel D. G. Metabolite-based internal doses used in a risk assessment of benzene. Environ Health Perspect. 1989 Jul;82:177–184. doi: 10.1289/ehp.8982177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cox L. A., Jr An exact analysis of the multistage model explaining dose-response concavity. Risk Anal. 1995 Jun;15(3):359–368. doi: 10.1111/j.1539-6924.1995.tb00329.x. [DOI] [PubMed] [Google Scholar]
  4. Cox L. A., Jr, Ricci P. F. Reassessing benzene cancer risks using internal doses. Risk Anal. 1992 Sep;12(3):401–410. doi: 10.1111/j.1539-6924.1992.tb00692.x. [DOI] [PubMed] [Google Scholar]
  5. Green J. D., Snyder C. A., LoBue J., Goldstein B. D., Albert R. E. Acute and chronic dose/response effect of benzene inhalation on the peripheral blood, bone marrow, and spleen cells of CD-1 male mice. Toxicol Appl Pharmacol. 1981 Jun 30;59(2):204–214. doi: 10.1016/0041-008x(81)90191-5. [DOI] [PubMed] [Google Scholar]
  6. Henderson R. F., Sabourin P. J., Bechtold W. E., Griffith W. C., Medinsky M. A., Birnbaum L. S., Lucier G. W. The effect of dose, dose rate, route of administration, and species on tissue and blood levels of benzene metabolites. Environ Health Perspect. 1989 Jul;82:9–17. doi: 10.1289/ehp.89829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Lee K. L., Harrell F. E., Jr, Tolley H. D., Rosati R. A. A comparison of test statistics for assessing the effects of concomitant variables in survival analysis. Biometrics. 1983 Jun;39(2):341–350. [PubMed] [Google Scholar]
  8. Luke C. A., Tice R. R., Drew R. T. The effect of exposure regimen and duration on benzene-induced bone-marrow damage in mice. I. Sex comparison in DBA/2 mice. Mutat Res. 1988 Aug;203(4):251–271. doi: 10.1016/0165-1161(88)90017-9. [DOI] [PubMed] [Google Scholar]
  9. Medinsky M. A., Sabourin P. J., Lucier G., Birnbaum L. S., Henderson R. F. A physiological model for simulation of benzene metabolism by rats and mice. Toxicol Appl Pharmacol. 1989 Jun 15;99(2):193–206. doi: 10.1016/0041-008x(89)90002-1. [DOI] [PubMed] [Google Scholar]
  10. Scheding S., Loeffler M., Schmitz S., Seidel H. J., Wichmann H. E. Hematotoxic effects of benzene analyzed by mathematical modeling. Toxicology. 1992;72(3):265–279. doi: 10.1016/0300-483x(92)90178-h. [DOI] [PubMed] [Google Scholar]
  11. Spear R. C., Bois F. Y., Woodruff T., Auslander D., Parker J., Selvin S. Modeling benzene pharmacokinetics across three sets of animal data: parametric sensitivity and risk implications. Risk Anal. 1991 Dec;11(4):641–654. doi: 10.1111/j.1539-6924.1991.tb00653.x. [DOI] [PubMed] [Google Scholar]
  12. Steinbach K. H., Raffler H., Pabst G., Fliedner T. M. A mathematical model of canine granulocytopoiesis. J Math Biol. 1980 Aug;10(1):1–12. doi: 10.1007/BF00276392. [DOI] [PubMed] [Google Scholar]
  13. Travis C. C., Quillen J. L., Arms A. D. Pharmacokinetics of benzene. Toxicol Appl Pharmacol. 1990 Mar 1;102(3):400–420. doi: 10.1016/0041-008x(90)90037-u. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES