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Related Experiment Videos

Reassessing benzene cancer risks using internal doses.

L A Cox1, P F Ricci

  • 1Cox Associates, Denver, Colorado 80218.

Risk Analysis : an Official Publication of the Society for Risk Analysis
|September 11, 1992
PubMed
Summary
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Physiologically-based pharmacokinetic (PBPK) models refine human cancer risk assessments for benzene by using internal dose estimates. This approach, validated by animal studies, suggests lower low-dose cancer risks than previously estimated, aligning better with epidemiological data.

Area of Science:

  • Toxicology
  • Pharmacokinetics
  • Risk Assessment

Background:

  • Regulatory agencies historically estimated human cancer risks from benzene using epidemiological and animal bioassay data.
  • Previous risk assessments relied on interspecies dose conversions, which may not accurately reflect human metabolism.

Purpose of the Study:

  • To re-examine benzene cancer risk assessments using physiologically-based pharmacokinetic (PBPK) models.
  • To estimate human internal doses and associated risks more accurately.
  • To compare PBPK model-derived risks with existing regulatory estimates and epidemiological data.

Main Methods:

  • Utilized PBPK models to simulate benzene metabolism in mice and humans.
  • Applied nonlinear regression models to predict total benzene metabolites based on administered dose.

Related Experiment Videos

  • Refitted the linearized multistage (LMS) model to internal doses and observed responses in mice.
  • Estimated human internal doses using PBPK and regression models.

    • Main Results:

    • PBPK models accurately predicted internal benzene doses in mice from oral gavage experiments.
    • Nonlinear regression models effectively described the relationship between administered dose and metabolites.
    • Refitting the LMS model to internal doses resulted in a cubic dose-response curve for mice, lowering low-dose risk estimates.
    • PBPK-based human internal dose estimates led to reduced low-dose risk estimates compared to interspecies conversion methods.

    Conclusions:

    • PBPK modeling validates the use of nonlinear regression for risk assessment.
    • The study indicates a nonlinear maximum-likelihood estimate (MLE) dose-response curve at low benzene doses.
    • This revised approach provides more robust and epidemiologically consistent human cancer risk estimates for benzene.