title: 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.affiliation: Independent Consultant, 101 Corbin Hill Circle, Chapel Hill, NC 27514, United States. Electronic address: Bruce.C.Allen@outlook.com.
authors.forename: B C
authors.initials: BC
authors.lastname: Allen
authors.affiliation: ENVIRON International Corporation, 1900 North 18th St. Monroe, LA 71201, United States. Electronic address: cvanlandingham@environcorp.com.
authors.forename: C
authors.initials: C
authors.lastname: Van Landingham
authors.affiliation: Center for Human Health Assessment, The Hamner Institutes for Health Sciences, 6 Davis Drive (PO Box 12137), Research Triangle Park, NC 27703, United States. Electronic address: yyang@thehamner.org.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, 130 De Soto St., Pittsburgh, PA 15261, United States. Electronic address: ayouk@pitt.edu.
authors.forename: A O
authors.initials: AO
authors.lastname: Youk
authors.affiliation: 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. Electronic address: gmarsh@pitt.edu.
authors.forename: G M
authors.initials: GM
authors.lastname: Marsh
authors.affiliation: Occupational and Environmental Health Sciences, School of Public Health, University of Illinois at Chicago, 2121 West Taylor Street, Chicago, IL 60622, United States. Electronic address: nesmen@uic.edu.
authors.forename: N
authors.initials: N
authors.lastname: Esmen
authors.affiliation: ENVIRON International Corporation, 1900 North 18th St. Monroe, LA 71201, United States. Electronic address: rgentry@environcorp.com.
authors.forename: P R
authors.initials: PR
authors.lastname: Gentry
authors.affiliation: Center for Human Health Assessment, The Hamner Institutes for Health Sciences, 6 Davis Drive (PO Box 12137), Research Triangle Park, NC 27703, United States. Electronic address: hclewell@thehamner.org.
authors.forename: H J
authors.initials: HJ
authors.lastname: Clewell
authors.affiliation: DuPont Haskell Global Centers for Health & Environmental Sciences, PO Box 30, 1090 Elkton Road, Newark, DE 19711, United States. Electronic address: matthew.w.himmelstein@dupont.com.
authors.forename: M W
authors.initials: MW
authors.lastname: Himmelstein
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D002737:Chloroprene / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000139:chemically induced* / Q000453:epidemiology; D051381:Rats; D011916:Rats, Inbred F344; D018570:Risk Assessment / Q000379:methods*; D013045:Species Specificity
chemical_list: D002273:Carcinogens; D002737:Chloroprene
keywords: Constrained likelihood approach; Physiologically based kinetic modeling; β-Chloroprene