title: Use of mode of action data to inform a dose-response assessment for bladder cancer following exposure to inorganic arsenic.
abstract: In the recent National Research Council report on conducting a dose-response assessment for inorganic arsenic, the committee remarked that mode of action data should be used, to the extent possible, to extrapolate below the observed range for epidemiological studies to inform the shape of the dose-response curve. Recent in vitro mode of action studies focused on understanding the development of bladder cancer following exposure to inorganic arsenic provide data to inform the dose-response curve. These in vitro data, combined with results of bladder cancer epidemiology studies, inform the dose-response curve in the low-dose region, and include values for both pharmacokinetic and pharmacodynamic variability. Integration of these data provides evidence of a range of concentrations of arsenic for which no effect on the bladder would be expected. Specifically, integration of these results suggest that arsenic exposures in the range of 7-43 ppb in drinking water are exceedingly unlikely to elicit changes leading to key events in the development of cancer or noncancer effects in bladder tissue. These findings are consistent with the lack of evidence for bladder cancer following chronic ingestion of arsenic water concentrations <100 ppb in epidemiological studies.
authors.affiliation: ENVIRON International Corporation, 1900 N. 18th Street, Suite 804, Monroe, LA 71201, United States. Electronic address: rgentry@environcorp.com.
authors.forename: P R
authors.initials: PR
authors.lastname: Gentry
authors.affiliation: ENVIRON International Corporation, 2200 Powell Street, Suite 700, Emeryville, CA 94608, United States; University of New Mexico, MSC 10 5550, 1 University of New Mexico, Albuquerque, NM 87131-0001, United States.
authors.forename: J W
authors.initials: JW
authors.lastname: Yager
authors.affiliation: The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709-2137, United States.
authors.forename: R A
authors.initials: RA
authors.lastname: Clewell
authors.affiliation: The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709-2137, United States.
authors.forename: H J
authors.initials: HJ
authors.lastname: Clewell
mesh_terms: D000818:Animals; D001151:Arsenic / Q000493:pharmacokinetics / Q000592:standards / Q000633:toxicity*; D002273:Carcinogens / Q000493:pharmacokinetics / Q000592:standards / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018570:Risk Assessment; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000453:epidemiology / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000493:pharmacokinetics / Q000592:standards / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D014874:Water Pollutants, Chemical; D001151:Arsenic
keywords: Arsenic; Bladder; Genomics; In vitro; Mode of action; Risk assessment