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
Citation:
MacGregor, J., R. Frötschl, P. White, K. Crump, D. Eastmond, S. Fukushima, M. Guérard, M. Hayashi, L. Soeteman-Hernandez, G. Johnson, T. Kasamatsu, D. Levy, T. Morita, L. Muller, R. Schoeny, M. Schuler, AND V. Thybaud. 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. Mutation Research/Genetic Toxicology and Environmental Mutagenesis . Elsevier Science Ltd, New York, NY, 783:66-78, (2015).
Impact/Purpose:
Peer reviewed publication on the quantitative assessment of genotoxicity risk. This paper is the consensus opinion of a committee of the International Workshop on Genotoxicity Testing. This group made recommendations for extrapolation from genetic toxicity testing to human health risk assessment, including some approaches for dose response assessment.
Description:
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.
URLs/Downloads:
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.PDF (PDF, NA pp, 944.372 KB, about PDF)http://dx.doi.org/10.1016/j.mrgentox.2014.10.008
