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

DOI: 10.1016/j.yrtph.2014.07.001
Title: A constrained maximum likelihood approach to evaluate the impact of dose metric on cancer risk assessment: Application to β-chloroprene
Journal Title: Regulatory Toxicology and Pharmacology
Volume: 70
Issue: 1
Publication Date: October 2014
Start Page: 203
End Page: 213
Published online: online 7 July 2014
ISSN: 0273-2300
Author: B.C. Allena, C. Van Landinghamb, Y. Yangc, A.O. Youkd, G.M. Marshe, N. Esmenf, P.R. Gentryb, H.J. Clewell IIIc, M.W. Himmelsteing
Affiliations:

  • a Independent Consultant, 101 Corbin Hill Circle, Chapel Hill, NC 27514, United States

  • b ENVIRON International Corporation, 1900 North 18th St. Monroe, LA 71201, United States

  • c Center for Human Health Assessment, The Hamner Institutes for Health Sciences, 6 Davis Drive (PO Box 12137), Research Triangle Park, NC 27703, United States

  • d Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, 130 De Soto St., Pittsburgh, PA 15261, United States

  • e Center for Occupational Biostatistics and Epidemiology, Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, 130 De Soto St., Pittsburgh, PA 15261, United States

  • f Occupational and Environmental Health Sciences, School of Public Health, University of Illinois at Chicago, 2121 West Taylor Street, Chicago, IL 60622, United States

  • g DuPont Haskell Global Centers for Health & Environmental Sciences, PO Box 30, 1090 Elkton Road, Newark, DE 19711, United States
  • Abstract: prene (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.
    Received: 21 March 2014
    Keywords: Physiologically based kinetic modeling; Constrained likelihood approach; β-Chloroprene
    Corresponding information:
    Email: Bruce.C.Allen@outlook.com cvanlandingham@environcorp.com yyang@thehamner.org ayouk@pitt.edu gmar

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