A constrained maximum likelihood approach to evaluate the impact of dose metric on cancer risk assessment: application to β-chloroprene.

Abstract

β-Chloroprene (2-chloro-1,3-butadiene, CD) is used in the manufacture of polychloroprene rubber. Chronic inhalation studies have demonstrated that CD is carcinogenic in B6C3F1 mice and Fischer 344 rats. However, epidemiological studies do not provide compelling evidence for an increased risk of mortality from total cancers of the lung. Differences between the responses observed in animals and humans may be related to differences in toxicokinetics, the metabolism and detoxification of potentially active metabolites, as well as species differences in sensitivity. The purpose of this study was to develop and apply a novel method that combines the results from available physiologically based kinetic (PBK) models for chloroprene with a statistical maximum likelihood approach to test commonality of low-dose risk across species. This method allows for the combined evaluation of human and animal cancer study results to evaluate the difference between predicted risks using both external and internal dose metrics. The method applied to mouse and human CD data supports the hypothesis that a PBK-based metric reconciles the differences in mouse and human low-dose risk estimates and further suggests that, after PBK metric exposure adjustment, humans are equally or less sensitive than mice to low levels of CD exposure.

• Authors: B C Allen, C Van Landingham, Y Yang, A O Youk, G M Marsh, N Esmen, P R Gentry, H J Clewell 3rd, M W Himmelstein
• Journal: Regulatory toxicology and pharmacology : RTP (Regul Toxicol Pharmacol) Vol. 70 Issue 1 Pg. 203-13 (Oct 2014) ISSN: 1096-0295 [Electronic] Netherlands
• PMID: 25010378 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Carcinogens
• Chloroprene

Topics

• Animals
• Carcinogens (administration & dosage, pharmacokinetics, toxicity)
• Chloroprene (administration & dosage, pharmacokinetics, toxicity)
• Dose-Response Relationship, Drug
• Female
• Humans
• Likelihood Functions
• Male
• Mice
• Neoplasms (chemically induced, epidemiology)
• Rats
• Rats, Inbred F344
• Risk Assessment (methods)
• Species Specificity