Germ cell tests, genotoxicity testing

A positive response in the rodent dominant lethal test indicates that the test substance may be genotoxic in the germ cells of the treated sex of the test species as evaluated by an increase in the number of dominant lethals evaluated as the sum of pre- and postimplantation loss. A dominant lethal mutation is one occurring in a germ cell, which does not cause dysfunction of the gamete but which is lethal to the fertilized egg or developing embryo. 

Several assays in mammals permit a determination of the incidence of micronuclei 393 of these, the only one sufficiently developed to be a standard assay is the in vivo mammalian bone marrow polychromatic-erythrocyte assay.155 Micronuclei are formed from chromosomes or chromosomal fragments that are not incorporated into daughter nuclei at the time of cell division. Ihus, this very rapid test serves as an in vivo somatic cell screening test for finding genotoxic chemicals that might break chromosomes or cause nondisjunction in germ cells. It has been applied to more than 150 chemicals.158... 

This hazard class is primarily concerned with chemicals that may cause mutations in the germ cells of humans that can be transmitted to the progeny. However, mutagenicity/genotoxicity tests in vitro and in mammalian somatic cells in vivo are also considered in classifying substances and mixtures within this hazard class. 

Examples of mutagenicity/genotoxicity tests in germ cells are ... 

Shibamoto T, Wei Cl (1984) Mutagenicity of lichen constituents. Environ Mutagen 6(5) 757-762 Singh NP, McCoy MT, Tice RR et al (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175 184-191 Speit G, Vasquez M, Hartmann A (2009) The comet assay as an indicatra- test for germ cell genotoxicity. Mutat Res 681 3-12... 

Risk assessment is a quantitative analysis of the expression of inherent genotoxic activity of a suspect compound under defined test conditions in a suitable animal model followed by extrapolation of the results to human exposure conditions. This type of analysis is extremely difficult and costly and requires a careful analysis of the induction of somatic and germ cell alterations using mammalian species. The process implies that information related to the real dose received by the exposed animal can be measured. Studies employing large target populations and low exposure levels are necessary to conduct accurate risk estimations. Only a limited number of testing laboratories are currently prepared to conduct risk-assessment studies. 

Xripathy, N. K. Nabi, Md. J. Sahu, G. R Kumar, A. A. Genotoxicity testing of two red dyes in the somatic and germ line cells of Drosophila. Food Chem. Toxicol 1995, 33, 923-927. 

There are very few in vivo genotoxicity studies. Only two in vivo studies were located, and both assessed the dominant lethal effects. The results were negative for both studies, implying that neither heptachlor nor heptachlor epoxide are genotoxic to the germ-line cells of male mice when tested alone or as a mixture (Arnold et al. 1977 Epstein et al. 1972). Refer to Table 2- 3 for a summary of these results of in vivo studies. 

To arrive at a classification, test results are considered from experiments determining mutagenic and/or genotoxic effects in germ and/or somatic cells of exposed animals. Mutagenic and/or genotoxic effects determined in in vitro tests may also be considered. 

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