title: IWGT report on quantitative approaches to genotoxicity risk assessment II. Use of point-of-departure (PoD) metrics in defining acceptable exposure limits and assessing human risk.
abstract: This is the second of two reports from the International Workshops on Genotoxicity Testing (IWGT) Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment (the QWG). The first report summarized the discussions and recommendations of the QWG related to the need for quantitative dose-response analysis of genetic toxicology data, the existence and appropriate evaluation of threshold responses, and methods to analyze exposure-response relationships and derive points of departure (PoDs) from which acceptable exposure levels could be determined. This report summarizes the QWG discussions and recommendations regarding appropriate approaches to evaluate exposure-related risks of genotoxic damage, including extrapolation below identified PoDs and across test systems and species. Recommendations include the selection of appropriate genetic endpoints and target tissues, uncertainty factors and extrapolation methods to be considered, the importance and use of information on mode of action, toxicokinetics, metabolism, and exposure biomarkers when using quantitative exposure-response data to determine acceptable exposure levels in human populations or to assess the risk associated with known or anticipated exposures. The empirical relationship between genetic damage (mutation and chromosomal aberration) and cancer in animal models was also examined. It was concluded that there is a general correlation between cancer induction and mutagenic and/or clastogenic damage for agents thought to act via a genotoxic mechanism, but that the correlation is limited due to an inadequate number of cases in which mutation and cancer can be compared at a sufficient number of doses in the same target tissues of the same species and strain exposed under directly comparable routes and experimental protocols.
authors.affiliation: Toxicology Consulting Services, Bonita Springs, FL, USA. Electronic address: jtmacgregor@earthlink.net.
authors.forename: James T
authors.initials: JT
authors.lastname: MacGregor
authors.affiliation: Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Frötschl
authors.affiliation: Health Canada, Ottawa, ON, Canada.
authors.forename: Paul A
authors.initials: PA
authors.lastname: White
authors.affiliation: Ruston, LA, USA.
authors.forename: Kenny S
authors.initials: KS
authors.lastname: Crump
authors.affiliation: University of California, Riverside, CA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Eastmond
authors.affiliation: Japan Bioassay Research Center, Hadano, Kanagawa, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharmaceutical Science and Early Development Innovation Center, Basel, Switzerland.
authors.forename: Melanie
authors.initials: M
authors.lastname: Guérard
authors.affiliation: Public Interest Incorporated Foundation BioSafety Research Center, Iwata, Shizuoka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: RIVM-National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Lya G
authors.initials: LG
authors.lastname: Soeteman-Hernández
authors.affiliation: Institute of Life Science, College of Medicine, Swansea University, Swansea SA2 8PP, UK.
authors.forename: George E
authors.initials: GE
authors.lastname: Johnson
authors.affiliation: Kao Corporation, Ichikai-Machi, Haga-Gun, Tochigi, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kasamatsu
authors.affiliation: U.S. Food and Drug Administration, College Park, MD, USA.
authors.forename: Dan D
authors.initials: DD
authors.lastname: Levy
authors.affiliation: National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Morita
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharmaceutical Science and Early Development Innovation Center, Basel, Switzerland.
authors.forename: Lutz
authors.initials: L
authors.lastname: Müller
authors.affiliation: U.S. Environmental Protection Agency, Washington, DC, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Schoeny
authors.affiliation: Pfizer, Inc., Groton, CT, USA.
authors.forename: Maik J
authors.initials: MJ
authors.lastname: Schuler
authors.affiliation: Sanofi, Vitry sur Seine, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Thybaud
mesh_terms: D002869:Chromosome Aberrations / Q000139:chemically induced*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009152:Mutagenicity Tests / Q000379:methods / Q000592:standards; D009153:Mutagens / Q000633:toxicity*; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects; D018570:Risk Assessment
chemical_list: D009153:Mutagens
keywords: Benchmark dose; Breakpoint dose; Extrapolation; Genotoxic risk assessment; Low-dose risk; Point of departure