Genotoxicity guidelines

Guidance on the evaluation of genotoxicity data is given in the two ICH genotoxicity guidelines. 

Second, meanwhile, no international guidelines have been provided for the manufacture, marketing, and distribution of household insecticides on such a level as those of agricultural chemicals, and not even manufacturing registration is required in some countries. Of course, the minimal required toxicity studies are conducted with synthetic pyrethroids for household insecticides to examine absorption, distribution, metabolism, and genotoxicity in animals. 

ICH guidelines specifically require three genotoxicity assays for all devices (see Table 6.2). The assays should preferably evaluate DNA effects, gene mutations and chromosomal aberrations, and two of the assays should preferably use mammalian cells. Guidance for providing tests for selection to meet these needs are the OECD guidelines, which include 8 in vitro and 7 in vivo assays. 

As performance data has become available on these strains, ICH (1997) has incorporated their use into pharmaceutical testing guidelines in lieu of the second rodent species tests (that is, to replace the long-term mouse bioassay when the traditional rat study has been performed). FDA has stated that they would accept such studies when performed in a validated model. In fact, CBER has accepted such studies as a sole carcinogenicity bioassay in some cases where there was negative traditional genotoxicity data and strong evidence of a lack of a mechanistic basis for concern. 

In the various OECD test guidelines for mutagenicity/genotoxicity testing, the definitions relevant for a specific test are provided in the Annex. 

The OECD, US-EPA, and EU have developed a number of specific test guidelines for in vitro testing of mutagenicity/genotoxicity, see Table 4.15. The EU Annex V methods are generally... 

Test Guidelines Adopted for In Vivo Testing of Mutagenicity/Genotoxicity... 

Overview of In Vivo Mutagenicity/Genotoxicity Test Guideline Studies... 

The WHO considers in its drinking-water quality guidelines, in relation to genotoxic carcinogens, that a lifetime cancer risk for consumers of less than 10 represents a tolerable risk (WHO 1996). Guideline values associated with excess lifetime cancer risks of 10 and 10 are also presented for the genotoxic carcinogens to emphasize the fact that each country should select its own appropriate risk level. 

In relation to their air quality guidelines, the WHO has estimated the risk associated with lifetime exposure to a certain concentration of a genotoxic carcinogen by linear extrapolation and the carcinogenic potency expressed as the incremental unit risk estimate. However, the guideline sections for carcinogenic pollutants also provide the concentration in air associated with an excess cancer risk of 10 ", 10 , and 10 , calculated from the unit risk, in order to support authorities in the decision-making process. 

An in vivo test for chromosomal damage using rodent haematopoietic cells. ICH guideline, Genotoxicity A Standard Battery for Genotoxicity Testing of Pharmaceuticals ... 

Reactive chemicals are used to manufacture drugs and a proportion of these are geno-toxic. A draft guideline has been issued by the Europe and CHMP that seeks to control patient exposure to most genotoxic contaminants to below a Threshold of Toxicological concern of 1.5 xg/day. This is based on modelling data on known human carcinogens where such concentrations for specific compoimds would not be expected to increase human cancer above 1 per 10 exposed individuals. ... 

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