Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment |
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| Authors: | G.E. Johnson L.G. Soeteman‐Hernández B.B. Gollapudi O.G. Bodger K.L. Dearfield R.H. Heflich J.G. Hixon D.P. Lovell J.T. MacGregor L.H. Pottenger C.M. Thompson L. Abraham V. Thybaud J.Y. Tanir E. Zeiger J. van Benthem P.A. White |
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| Affiliation: | 1. Institute of Life Science, College of Medicine, Swansea University, Swansea, Wales, United Kingdom;2. Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands;3. Exponent, Center for Toxicology and Mechanistic Biology, Midland, Michigan;4. U.S. Department of Agriculture, Food Safety and Inspection Service, Office of Public Health Science, Washington, District of Columbia;5. U.S. Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas;6. ToxStrategies, Austin, Texas;7. Division of Biomedical Sciences, St. George's University of London, Cranmer Terrace, London, United Kingdom;8. Toxicology Consulting Services, Bonita Springs, Florida;9. Dow Chemical Company, Midland, Michigan;10. ToxStrategies, Katy, Texas;11. Sanofi, Vitry‐Alfortville Research Center, Drug Disposition, Preclinical Safety and Animal Research, Vitry‐sur‐Seine, France;12. ILSI Health and Environmental Sciences Institute, Washington, District of Columbia;13. Errol Zeiger Consulting, Chapel Hill, North Carolina;14. Environmental Health Sciences and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada |
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| Abstract: | Genetic toxicology data have traditionally been employed for qualitative, rather than quantitative evaluations of hazard. As a continuation of our earlier report that analyzed ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) dose–response data (Gollapudi et al., 2013), here we present analyses of 1‐ethyl‐1‐nitrosourea (ENU) and 1‐methyl‐1‐nitrosourea (MNU) dose–response data and additional approaches for the determination of genetic toxicity point‐of‐departure (PoD) metrics. We previously described methods to determine the no‐observed‐genotoxic‐effect‐level (NOGEL), the breakpoint‐dose (BPD; previously named Td), and the benchmark dose (BMD10) for genetic toxicity endpoints. In this study we employed those methods, along with a new approach, to determine the non‐linear slope‐transition‐dose (STD), and alternative methods to determine the BPD and BMD, for the analyses of nine ENU and 22 MNU datasets across a range of in vitro and in vivo endpoints. The NOGEL, BMDL10 and BMDL1SD PoD metrics could be readily calculated for most gene mutation and chromosomal damage studies; however, BPDs and STDs could not always be derived due to data limitations and constraints of the underlying statistical methods. The BMDL10 values were often lower than the other PoDs, and the distribution of BMDL10 values produced the lowest median PoD. Our observations indicate that, among the methods investigated in this study, the BMD approach is the preferred PoD for quantitatively describing genetic toxicology data. Once genetic toxicology PoDs are calculated via this approach, they can be used to derive reference doses and margin of exposure values that may be useful for evaluating human risk and regulatory decision making. Environ. Mol. Mutagen. 55:609–623, 2014. © 2014 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc. |
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| Keywords: | benchmark dose ENU MNU alkylating agents margin of exposure |
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