Mutagenicity studies, requirements

The mouse micronucleus test or an in vivo chromosome aberration test will noimally be requited immediately after notification in the EC if any of the in vitro Base Set mutagenicity tests are positive. The third mutagenicity study required for notification in Canada can be either the mouse micronudeus test or the in vivo chromosome aberration test. 

An exhaustive review of the theory and mechanistic considerations of a mutagenicity evaluation are too lengthy for this discussion. ICH guidelines are available and include general principles and specifics related to the core battery of studies required.1617 Initial INDs are generally required to have two in vitro assays submitted, with the in vivo assay submitted prior to phase 2. 

The conduct of animal toxicity studies proceeds concurrently with and in advance of clinical studies. A certain amount of animal toxicity data is required for the IND. This often includes acute toxicity in two rodent species, mutagenicity screening studies, and one-month toxicity studies in a rodent and non-rodent species. After the clinical studies have begun, further animal studies are conducted, usually until the time for the NDA. These would include further mutagenicity studies, reproductive toxicity studies, and long-term toxicity studies, possibly including carcinogenicity studies. 

Animal toxicology a summary along with acute, long-term, reproduction, local toxicity and mutagenic/carcinogenic data. There are detailed requirements of toxicity studies in terms of time, dose, route of administration, which are beyond the scope of this article. Reproduction study requirements are also specified in terms of fertility studies, terato-genecity studies and perinatal studies. Local toxicity is limited to preparations intended for topical use. 

Especially when choosing in vivo assays and when proceeding into germ cell mutagenicity studies, expert judgment is required to select the appropriate test system(s) and to avoid uninformative and thus unnecessary animal experiments. 

Full notiHcation is required 60 days before a substance is to be supplied to the EC at an amount of one tonne a (or 5 tonnes cumulative). The information required for the notiHcation (the Base Set ) is specified in Annex VII of the Directive (see Table 34.1). It consists of the identity of the substance, commercial information, recommendations for safe handling and use, physico-chemical properties, animal toxicology, mutagenicity studies, ecotoxicology, recommendations for disposal, the proposed classification and labelling and a draft MSDS for dangerous substances. 

The information required for a notification is the chemical identity, amount manufactured or imported, use, physico-chemical properties, ecotoxicity studies, available mutagenicity studies and animal toxicity, indir t long-term effects on humans and recommendations for disposal and labelling. The data requirements for the notification of new substances are based on the OECD MPD and arc very similar to those in the EC. The minimum information required is listed in Table 34.1. There are no official reduced data requirements for notification of substances to be supplied only in low amounts, although FOEFL will negotiate on a case-by-case basis for certain of the standard tests to be omitted, especially if the substance is to be used in special applications or has special disposal methods which minimise environmental contamination. Studies are to be conducted in compliance with GLP to OECD guidelines or their equivalent. 

Nitroanthrafurans, required for mutagenic studies, were prepared by... 

Epidemiologic studies in Japan indicate an increased risk of stomach cancer owing to consumption of broiled fish and meats (116). In the United States, stomach cancer incidence has steadily declined since the 1940s, whereas consumption of broiled food has increased (108). In addition, the average human intake of PAHs is only 0.002 of that required to produce cancer in half of animals fed. Test results are often contradictory (117) and many components of food, such as vitamin A, unsaturated fatty acids, thiols, nitrites, and even saUva itself, tend to inhibit the mutagenic activity of PAHs (118—120). Therefore, the significance of PAHs in the human diet remains unknown (121,109). 

Considerable studies are required to establish the toxicological profile of the drug substance. These must assess its direct toxic effects, together with its potential as a reproductive toxin, mutagen, or carcinogen. 

Fluoranthenes. With the exception of 3-methylcholanthrene, much less work has been undertaken on nonalternant PAHs. Several recent studies have reported on the major metabolites and mutagenicity of various fluoranthenes (181-185), but little is known about the DNA adduct which they form. Some studies on dibenzo[a,e]fluoranthene showed that several adducts are formed by microsomal incubations (185) and additional studies will be required to provide complete structural elucidation of the products formed. 

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