title: Approaches for identifying germ cell mutagens: Report of the 2013 IWGT workshop on germ cell assays(☆).
abstract: This workshop reviewed the current science to inform and recommend the best evidence-based approaches on the use of germ cell genotoxicity tests. The workshop questions and key outcomes were as follows. (1) Do genotoxicity and mutagenicity assays in somatic cells predict germ cell effects? Limited data suggest that somatic cell tests detect most germ cell mutagens, but there are strong concerns that dictate caution in drawing conclusions. (2) Should germ cell tests be done, and when? If there is evidence that a chemical or its metabolite(s) will not reach target germ cells or gonadal tissue, it is not necessary to conduct germ cell tests, notwithstanding somatic outcomes. However, it was recommended that negative somatic cell mutagens with clear evidence for gonadal exposure and evidence of toxicity in germ cells could be considered for germ cell mutagenicity testing. For somatic mutagens that are known to reach the gonadal compartments and expose germ cells, the chemical could be assumed to be a germ cell mutagen without further testing. Nevertheless, germ cell mutagenicity testing would be needed for quantitative risk assessment. (3) What new assays should be implemented and how? There is an immediate need for research on the application of whole genome sequencing in heritable mutation analysis in humans and animals, and integration of germ cell assays with somatic cell genotoxicity tests. Focus should be on environmental exposures that can cause de novo mutations, particularly newly recognized types of genomic changes. Mutational events, which may occur by exposure of germ cells during embryonic development, should also be investigated. Finally, where there are indications of germ cell toxicity in repeat dose or reproductive toxicology tests, consideration should be given to leveraging those studies to inform of possible germ cell genotoxicity.
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada. Electronic address: Carole.Yauk@hc-sc.gc.ca.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
authors.affiliation: Marilyn Aardema Consulting, Fairfield OH, USA; Bioreliance, MD, USA.
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Aardema
authors.affiliation: National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Jan van
authors.initials: Jv
authors.lastname: Benthem
authors.affiliation: National Institute of Environmental Health Sciences, NC, USA.
authors.forename: Jack B
authors.initials: JB
authors.lastname: Bishop
authors.affiliation: USDA, Food Safety and Inspection Service, Washington DC, USA.
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Dearfield
authors.affiliation: University of North Carolina at Chapel Hill, NC, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: DeMarini
authors.affiliation: University of Leicester, United Kingdom.
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Dubrova
authors.affiliation: National Institute of Health Sciences, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Honma
authors.affiliation: Department of Molecular and Human Genetics, and Department of Pediatrics, Baylor College of Medicine, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchetti
authors.affiliation: University of Texas M.D. Anderson Cancer Center, USA.
authors.forename: Marvin L
authors.initials: ML
authors.lastname: Meistrich
authors.affiliation: ENEA, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pacchierotti
authors.affiliation: AstraZeneca Pharmaceuticals, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Stewart
authors.affiliation: Integrated Laboratory Systems, Incorporation, NC, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Waters
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada. Electronic address: George.Douglas@hc-sc.gc.ca.
authors.forename: George R
authors.initials: GR
authors.lastname: Douglas
mesh_terms: D000818:Animals; D004252:DNA Mutational Analysis / Q000379:methods / Q000592:standards; D004493:Education; D055106:Genome-Wide Association Study / Q000379:methods / Q000592:standards; D005854:Germ Cells / Q000378:metabolism / Q000473:pathology; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods / Q000592:standards; D006801:Humans; D009152:Mutagenicity Tests / Q000379:methods / Q000592:standards; D009153:Mutagens / Q000633:toxicity*; D018570:Risk Assessment
chemical_list: D009153:Mutagens
keywords: Chromosome aberrations; Copy number variants; Gene; Genetic disease; Germ cell mutation; Reproductive health; mutation