title: Considering pharmacokinetic and mechanistic information in cancer risk assessments for environmental contaminants: examples with vinyl chloride and trichloroethylene.
abstract: Risk assessments for vinyl chloride (VC) and trichloroethylene (TCE) are presented as examples of approaches for incorporating chemical-specific pharmacokinetic and mechanistic information into a more scientifically plausible cancer risk assessment. For VC, the evidence regarding mode of action includes direct reaction of a metabolite with DNA, resulting in DNA adducts and mistranscription, and cross-species target-tissue correspondence of a rare tumor type. Risk estimates for human exposure to VC predicted with a physiologically-based pharmacokinetic (PBPK) model and the linearized multistage (LMS) model were lower than those currently used in environmental decision-making by a factor of 30 to 50, and were more consistent with human epidemiological data. For TCE, there is evidence of increased cell proliferation due to receptor interaction or cytotoxicity in every instance in which tumors are observed, and the tumors typically represent an increase in the incidence of a commonly observed, species-specific lesion. Virtually safe exposure estimates for human exposure to TCE predicted with a PBPK model and a margin of exposure (MOE) approach were higher than those obtained by the conventional LMS approach by roughly a factor of 100. The MOE approach is recommended as an alternative to the LMS approach for chemicals with a carcinogenic mode of action which entails increased cell proliferation, leading to the expectation of a highly nonlinear cancer dose-response.
authors.affiliation: K. S. Crump Group, ICF Kaiser International, Ruston, Louisiana 71270, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Clewell
authors.forename: P R
authors.initials: PR
authors.lastname: Gentry
authors.forename: J M
authors.initials: JM
authors.lastname: Gearhart
authors.forename: B C
authors.initials: BC
authors.lastname: Allen
authors.forename: M E
authors.initials: ME
authors.lastname: Andersen
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000009:adverse effects*; D006801:Humans; D009369:Neoplasms / Q000139:chemically induced* / Q000453:epidemiology; D018570:Risk Assessment; D014158:Transcription, Genetic / Q000187:drug effects; D014241:Trichloroethylene / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics; D014752:Vinyl Chloride / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D018736:DNA Adducts; D004785:Environmental Pollutants; D014241:Trichloroethylene; D014752:Vinyl Chloride