Transgenic mouse mutation assay systems can play an important role in regulatory mutagenicity testing in vivo for the detection of site-of-contact mutagens

Abstract

Transgenic mouse mutation assays, such as MutaMouse (lacZ, CD2F1) and Big Blue (lacI, B6C3F1), afford the opportunity to evaluate the mutagenic potential of chemicals in any target organ in vivo. This paper discusses published data collected from the analysis of the skin, stomach and lung DNA after topical, oral and inhalation exposure, respectively. These data indicate that both MutaMouse and Big Blue should play an important part in the evaluation of genotoxicity in vivo, particularly where the endpoint or target tissue available in the more conventional tests is inappropriate. It is concluded that there is a distinct role for this type of assay in genetic toxicology testing. For substances applied to the skin or dosed orally or by inhalation and which are unlikely to reach either the bone marrow or the liver, then data derived from these assays may be more relevant to an assessment of possible risk to man than the currently used unscheduled DNA synthesis in liver and cytogenetics assays in bone marrow or peripheral blood.

Attempts at Organ-specific In Vivo Short-term Tests for Environmental Mutagens and Carcinogens in Rodent Liver and Stomach

“…Helicobacter pylori (H. pylori) is thought to be one of the most important factors for human stomach disorders, including neoplasia and a new animal model using H. pylori-infected Mongolian gerbils has been proposed (96). Only few organ-speciˆc in vivo short-term test methods for glandular stomach are available including transgenic rodent assay; only results of MNNG (97,98) and MNU (98) were reported and are consistent with our results. Rarely was 32 P-postlabeling analysis applied in the glandular stomach mucosa (99).…”

In vivo transgenic mutation assays

“…Shorter sample times might be appropriate after multiple dosing but sufficient data do not yet exist to confirm this. Tissues that turn over more rapidly, such as bone marrow, the stomach, and the intestinal epithelium, can be sampled within a few days of treatment whereas tissues that turn over slowly, such as liver, should be sampled at times longer than the recommended 35 days [Morrison and Ashby, 1994;Douglas et al, 1996;Brault et al, 1999;Dean et al, 1999]. It is acceptable to sample the tissues that turn over rapidly at the later times, so that all tissues can be sampled from one animal at the appropriate time for the slowest of the tissues, based on the data available.…”

“…Promising data have already been published describing the ability to detect mutagenicity in target tissues for which no models previously existed, such as site of contact tissues [Dean et al, 1999]. Good concordance with mutagenicity and carcinogenicity has also been reported (see Morrison and Ashby, 1994;Gorelick, 1995;Dean et al, 1999].…”

Test No. 488: Transgenic Rodent Somatic and Germ Cell Gene Mutation Assays

“…If studies are conducted to follow up carcinogenicity studies, target tissues for carcinogenicity should be considered. The choice of tissues for analysis should maximize the detection of chemicals that are direct-acting in vitro mutagens, rapidly metabolized, highly reactive or poorly absorbed, or those for which the target tissue is determined by route of administration (6).…”