Mutation as a Toxicological Endpoint for Regulatory Decision-Making.

Publisher: Wiley-Liss Country of Publication: United States NLM ID: 8800109 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-2280 (Electronic) Linking ISSN: 08936692 NLM ISO Abbreviation: Environ Mol Mutagen Subsets: MEDLINE

Publication: New York Ny : Wiley-Liss
Original Publication: New York, NY : Liss, c1987-

Mutagenicity Tests/*methods ; Mutagens/*toxicity; Animals ; Carcinogens/toxicity ; Germ Cells/drug effects ; Germ Cells/metabolism ; High-Throughput Nucleotide Sequencing ; Humans ; Mutation/drug effects ; Risk Assessment

Mutations induced in somatic cells and germ cells are responsible for a variety of human diseases, and mutation per se has been considered an adverse health concern since the early part of the 20th Century. Although in vitro and in vivo somatic cell mutation data are most commonly used by regulatory agencies for hazard identification, that is, determining whether or not a substance is a potential mutagen and carcinogen, quantitative mutagenicity dose-response data are being used increasingly for risk assessments. Efforts are currently underway to both improve the measurement of mutations and to refine the computational methods used for evaluating mutation data. We recommend continuing the development of these approaches with the objective of establishing consensus regarding the value of including the quantitative analysis of mutation per se as a required endpoint for comprehensive assessments of toxicological risk. Environ. Mol. Mutagen. 61:34-41, 2020. © 2019 Wiley Periodicals, Inc.
(© 2019 Wiley Periodicals, Inc.)

BfR (Bundesinstitut für Risikobewertung). 2006. Toxicological Assessment of Formaldehyde; Opinion of BfR No. 023/2006 of 30 March 2006. Available at: http://m.bfr-meal-studie.de/cm/349/toxicological_assessment_of_formaldehyde.pdf.
Boverhof DR, Chamberlain MP, Elcombe CR, Gonzalez FJ, Heflich RH, Hernandez LG, Jacobs AC, Jacobson-Kram D, Luijten M, Maggi A, et al. 2011. Transgenic animal models in toxicology: Historical perspectives and future outlook. Toxicol Sci 121:207-233.
Campbell IM, Shaw CA, Stankiewicz P, Lupski JR. 2015. Somatic mosaicism: Implications for disease and transmission genetics. Trends Genet 31:382-392.
Chuang JH, Li H. 2004. Functional bias and spatial organization of genes in mutational hot and cold regions in the human genome. PLoS Biol 2:253-263.
Cliet I, Melcion C, Cordier A. 1993. Lack of predictivity of bone marrow micronucleus test versus testis micronucleus test: Comparison with four carcinogens. Mutat Res 292:105-111.
COM (Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment). 2018. Statement 2018/S1: Statement on the quantitative approaches to the assessment of genotoxicity data. Available at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/704462/COM_statement_on_quantitative_approaches.pdf.
DeMarini DM. 2019. The mutagenesis moonshot: The propitious beginnings of the Environmental Mutagenesis and Genomics Society. Environ Mol Mutagen XX:XXX-XXX.
DeMarini DM, Brockman HE, de Serres FJ, Evans HH, Stankowski LF Jr, Hsie AW. 1989. Specific-locus mutations induced in eukaryotes (especially mammalian cells) by radiation and chemicals: A perspective. Mutat Res 220:11-29.
Doak SH, Jenkins GJS, Johnson GE, Quick E, Parry EM, Parry JM. 2007. Mechanistic influences for mutation induction curves after exposure to DNA-reactive carcinogens. Cancer Res 67:3904-3911.
Dong X, Zhang L, Milholland B, Lee M, Maslov AY, Wang T, Vijg J. 2017. Accurate identification of single-nucleotide variants in whole-genome-amplified single cells. Nat Methods 14:491-493.
Dourson M, Becker RA, Haber LT, Pottenger LH, Bredfeldt T, Fenner-Crisp PA. 2013. Advancing human health risk assessment: Integrating recent advisory committee recommendations. Crit Rev Toxicol 43:467-492.
ECHA (European Chemicals Agency). 2012. Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Available at: https://echa.europa.eu/documents/10162/13632/information_requirements_r8_en.pdf/e153243a-03f0-44c5-8808-88af66223258.
ECHA (European Chemicals Agency). 2018. Committee for risk assessment RAC: Opinion on scientific evaluation of occupational exposure limits for benzene. Available at: https://echa.europa.eu/documents/10162/13641/benzene_opinion_en.pdf/4fec9aac-9ed5-2aae-7b70-5226705358c7.
Environment Canada and Health Canada. 2016. Screening assessment, petroleum sector stream approach, natural gas condensates. Government of Canada, Ottawa. Available at: http://www.ec.gc.ca/ese-ees/default.asp?lang=En&n=7933A3C7-1#toc010.
Erickson RP. 2014. Recent advances in the study of somatic mosaicism and diseases other than cancer. Curr Opin Genet Dev 26:73-78.
Godschalk RWL, Yauk CL, van Benthem J, Douglas GR, Marchetti F. 2019. In utero exposure to genotoxins leading to genetic mosaicism: An overlooked window of susceptibility in genetic toxicology testing? Environ Mol Mutagen XX:XXX-XXX.
Gollapudi BB. 2017. An ongoing journey toward a risk-based testing in genetic toxicology. Curr Opin Toxicol 3:71-74.
Gollapudi BB, Johnson GE, Hernandez LG, Pottenger LH, Dearfield KL, Jeffrey AM, Julien E, Kim JH, Lovell DP, MacGregor JT, et al. 2013. Quantitative approaches for assessing dose-response relationships in genetic toxicology studies. Environ Mol Mutagen 54:8-18.
Guo X, Pan B, Seo JE, Chen Y, Yan J, Mei N, Chen T. 2018. Whole genome sequencing analysis of small and large colony mutants from the mouse lymphoma assay. Arch Toxicol 92:3585-3595.
Hardy A, Benford D, Halldorsson T, Jeger MJ, Knutsen KH, More S, Mortensen A, Naegeli H, Noteborn H, Ockleford C, et al. 2017. Update: Use of the benchmark dose approach in risk assessment. EFSA J 15(1):e04658.
Harris KL, Myers MB, McKim KL, Elespuru RK, Parsons BL. 2019. Rationale and roadmap for developing panels of hotspot cancer driver gene mutations as biomarkers of cancer risk. Environ Mol Mutagen XX:XXX-XXX.
Health Canada. 1993. The assessment of mutagenicity, Health Canada Health Protection Branch mutagenicity guidelines. Environ Mol Mutagen 21:15-37.
ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use). 2016. Q3C(R6): Impurities: Guideline for Residual Solvents. Geneva, Switzerland: ICH. pp. 1-34.
ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use). 2017. M7(R1): Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. Geneva, Switzerland: ICH. pp. 1-116.
Jenkins GJS, Zair Z, Johnson GE, Doak SH. 2010. Genotoxic thresholds, DNA repair, and susceptibility in human populations. Toxicology 278:305-310.
Johnson GE, Soeteman-Hernández LG, Gollapudi BB, Bodger OG, Dearfield KL, Heflich RH, Hixon JG, Lovell DP, MacGregor JT, Pottenger LH, et al. 2014. Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment. Environ Mol Mutagen 55:609-623.
Kucab JE, Zou X, Morganella S, Joel M, Nanda AS, Nagy E, Gomez C, Degasperi A, Harris R, Jackson SP, et al. 2019. A compendium of mutational signatures of environmental agents. Cell 177:821-836.
Lambert IB, Singer TM, Boucher SE, Douglas GR. 2005. Detailed review of transgenic rodent mutation assays. Mutat Res 590:1-280.
Luijten M, Ball NS, Dearfield KL, Gollapudi BB, Johnson GE, Madia F, Peel L, Pfuhler S, Settivari RS, ter Burg W, van Benthem J. 2019. Utility of a next generation framework for assessment of genomic damage: A case study using the industrial chemical benzene. Environ Mol Mutagen XX:XXX-XXX.
Lupski JR. 2013. Genome mosaicism-One human, multiple genomes. Science 341:358-359.
Luderer U, Meier MJ, Lawson GW, Beal MA, Yauk CL, Marchetti F. 2019. In utero exposure to benzo[a]pyrene induces ovarian mutations at doses that deplete ovarian follicles in mice. Environ Mol Mutagen 60:410-420.
Lynch M. 2010. Rate, molecular spectrum, and consequences of human mutation. Proc Natl Acad Sci USA 107:961-968.
MacGregor JT, Frötschl R, White PA, Crump KS, Eastmond DA, Fukushima S, Guérard M, Hayashi M, Soeteman-Hernández LG, Johnson GE, et al. 2015. 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. Mutat Res 783:66-78.
Marchetti F, Douglas GR, Yauk CL. 2019. A return to the origin of the EMGS: Rejuvenating the quest for human germ cell mutagens and determining the risk to future generations. Environ Mol Mutagen XX:XXX-XXX.
Marchetti F, Massarotti A, Yauk CL, Pacchierotti F, Russo A. 2016. The adverse outcome pathway (AOP) for chemical binding to tubulin in oocytes leading to aneuploid offspring. Environ Mol Mutagen 57:87-113.
Marchetti F, Aardema MJ, Beevers C, van Benthem J, Godschalk R, Williams A, Yauk CL, Young R, Douglas GR. 2018a. Identifying germ cell mutagens using OECD Test Guideline 488 (transgenic rodent somatic and germ cell gene mutation assays) and integration with somatic cell testing. Mutat Res 832-833:7-18.
Marchetti F, Aardema M, Beevers C, van Benthem J, Douglas GR, Godschalk R, Yauk CL, Young R, Williams A. 2018b. Simulation of mouse and rat spermatogenesis to inform genotoxicity testing using OECD Test Guideline 488. Mutat Res 832-833:19-28.
McConnell MJ, Moran JV, Abyzov A, Akbarian S, Bae T, Cortes-Ciriano I, Erwin JA, Fasching L, Flasch DA, Freed D, et al. 2017. Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network. Science 356:eaal1641.
Meier MJ, O'Brien JM, Beal MA, Allen B, Yauk CL, Marchetti F. 2017. In utero exposure to benzo[a]pyrene increases mutation burden in the soma and sperm of adult mice. Environ Helth Perspect 125:82-88.
Mittelstaedt RA, Dobrovolsky VN, Revollo JR, Pearce MG, Wang Y, Dad A, McKinzie PB, Rosenfeldt H, Yucesoy B, Yeager R, et al. 2019. Evaluation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) mutagenicity using in vitro and in vivo Pig-a assays. Mutat Res 837:65-72.
Monroe JJ, Kort KL, Miller JE, Marino DR, Skopek TR. 1998. A comparative study of in vivo mutation assays: Analysis of hprt, lacI, and cII/cI as mutational targets for N-nitroso-N-methylurea and benzo[a]pyrene in Big Blue™ mice. Mutat Res 421:121-136.
Moore MM, Harrington-Brock K, Doerr CL, Dearfield KL. 1989. Differential mutant quantitation at the mouse lymphoma tk and CHO hgprt loci. Mutagenesis 4:394-403.
Mortazavi Y, Merk B, McIntosh J, Marsh JCW, Schrezenmeier H, Rutherford TR. 2003. The spectrum of PIG-A gene mutations in aplastic anemia/paroxysmal nocturnal hemoglobinuria (AA/PNH): A high incidence of multiple mutations and evidence of a mutational hot spot. Blood 101:2833-2841.
Müller L, Singer T. 2009. EMS in Viracept-The course of events in 2007 and 2008 from the non-clinical safety point of view. Toxicol Lett 190:243-247.
Müller L, Gocke E, Lavé T, Pfister T. 2009. Ethyl methanesulfonate toxicity in Viracept-A comprehensive human risk assessment based on threshold data for genotoxicity. Toxicol Lett 190:317-329.
Nakamura J, Mutlu E, Sharma V, Collins L, Bodnar W, Yu R, Lai Y, Moeller B, Lu K, Swenberg J. 2014. The endogenous exposome. DNA Repair 19:3-13.
Nohmi T, Tsuzuki T. 2016. Possible mechanisms underlying genotoxic thresholds: DNA repair and translesion DNA synthesis. In: Nohmi T, Fukushima S, editors. Thresholds of Genotoxic Carcinogens, from Mechanisms to Regulation. Amsterdam: Elsevier. pp. 49-66.
Nohmi T, Masumura K, Toyoda-Hokaiwado N. 2017. Transgenic rat models for mutagenesis and carcinogenesis. Genes Environ 39:11-42.
OECD (Organisation for Economic Cooperation and Development). 2013. OECD Guidelines for the testing of chemicals: Transgenic rodent somatic and germ cell gene mutations assays. Test Guideline 488. Available at: http://www.oecd-library.org/docserver/download/9713251e.pdf?expires=1392571255&id=id&accname=guest&checksum=C7400BE10E1B8C223781FCB41BBB876B.
Revollo JR, Dad A, McDaniel LP, Pearce MG, Dobrovolsky VN. 2018. Genome-wide mutation detection by interclonal genetic variation. Mutat Res 829-830:61-69.
Russell WL, Bangham JW, Russell LB. 1998. Differential response of mouse male germ-cell stages to radiation-induced specific-locus and dominant mutations. Genetics 148:1567-1578.
Salk J, Kennedy SR. 2019. Next-generation genotoxicity: Using modern sequencing technologies to assess somatic mutagenesis and cancer risk. Environ Mol Mutagen XX:XXX-XXX.
Sasaki JC, Allemang A, Bryce SM, Custer L, Dearfield KL, Dietz Y, Elhajouji A, Escobar PA, Fornace AJ Jr, Froetschl R, Galloway S, Hemmann U, Hendriks G, Li H-H, Luijten M, Ouedraogo G, Peel L, Pfuhler S, Roberts D, Thybaud V, van Benthem J, Yauk CL, Schuler M. 2019. Application of the Adverse Outcome Pathway (AOP) Framework to genotoxic modes of action (MOA). Environ Mol Mutagen XX:XXX-XXX.
Snyder RD. 2009. An update on the genotoxicity and carcinogenicity of marketed pharmaceuticals with reference to in silico predictivity. Environ Mol Mutagen 50:235-250.
Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. 2017. The Human Gene Mutation Database: Towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis, and next-generation sequencing studies. Hum Genet 136:665-677.
Thilly WG. 1990. Mutational spectrometry in animal toxicity testing. Ann Rev Pharmacol Toxicol 30:369-385.
Tomasetti C. 2019. Mutated clones are the new normal. Science 364:938-939.
United Nations. 2017. Globally harmonized system of classification and labelling of chemicals (GHS), Part 3: Health Hazards. pp 115-216. Available at: https://www.unece.org/trans/danger/publi/ghs/ghs_rev07/07files_e.html.
Walker VE, Andrews JL, Upton PB, Skopek TR, deBoer JG, Walker DM, Shi X, Sussman HE, Gorelick NJ. 1999. Detection of cyclophosphamide-induced mutations at the Hprt but not the lacI locus in splenic lymphocytes of exposed mice. Environ Mol Mutagen 34:167-181.
Wang J, Sawyer JR, Chen L, Chen T, Honma M, Mei N, Moore MM. 2009. The mouse lymphoma assay detects recombination, deletion, and aneuploidy. Toxicol Sci 109:96-105.
White PA, Johnson GE. 2016. Genetic toxicology at the crossroads-From qualitative hazard evaluation to quantitative risk assessment. Mutagenesis 31:233-237.
White PA, Long AS, Johnson GE. 2019. Quantitative interpretation of genetic toxicity dose-response data for risk assessment and regulatory decision-making: Current status and emerging priorities. Environ Mol Mutagen XX:XXX-XXX.
WHO (World Health Organization). 2014. Guidance document on evaluating and expressing uncertainty in hazard characterization. IPCS Harmonization Project Document 11. WHO, Geneva, Switzerland. Available at: http://www.inchem.org/documents/harmproj/harmproj/harmproj11.pdf.
Yauk CL, Aardema MJ, van Benthem J, Bishop JB, Dearfield KL, DeMarini DM, Dubrova YE, Honma M, Lupski JR, Marchetti F, et al. 2015a. Approaches for identifying germ cell mutagens: Report of the 2013 IWGT workshop on germ cell assays. Mutat Res 783:36-54.
Yauk CL, Lambert IB, Meek ME, Douglas GR, Marchetti F. 2015b. Development of the adverse outcome pathway "Alkylation of DNA in male premeiotic germ cells leading to heritable mutations" using the OECD's users' handbook supplement. Environ Mol Mutagen 56:724-750.
Yizhak K, Aguet F, Kim J, Hess JM, Kübler K, Grimsby J, Frazer R, Zhang H, Haradhvala NJ, Rosebrock D, et al. 2019. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science 364:eaaw0726.
Zeiger E. 2004. History and rationale of genetic toxicity testing: An impersonal, and sometimes personal, view. Environ Mol Mutagen 44:363-371.
Zeiger E, Margolin BH. 2000. The proportions of mutagens among chemical in commerce. Regul Toxicol Pharmacol 32:219-225.
Zhang L, Dong X, Lee M, Maslov AY, Wang T, Vijg J. 2019. Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan. Proc Natl Acad Sci USA 116:9014-9019.

Keywords: error-corrected next-generation sequencing; germ cell mutation; point of departure; somatic cell mutation; somatic mosaicism

0 (Carcinogens)
0 (Mutagens)

Date Created: 20191011 Date Completed: 20200717 Latest Revision: 20200717

20231215

10.1002/em.22338

31600846