Genotoxicity battery

If clear-cut evidence of genotoxic potential is obtained in the genotoxicity battery, especially via in vivo assays, then the potential for carcinogenicity in humans is highly suspected. In that case, drug development is discontinued. For compounds with negative or equivocal results in the genotoxicity battery and positive results in the Standard Chronic Bioassay, interpretation can be difficult. 

Standard genotoxicity battery. One-month toxicity (rodent and nonrodent by intended route). Single-study rodent assay to evaluate all phases of reproductive toxicity and a teratology study in a nonrodent... 

Kirkland, D., Reeve, L., Gatehouse, D., Vanparys, P. (2011). A core in vitro genotoxicity battery comprising the Ames test plus the in vitro micronucleus test is sufficient to detect rodent carcinogens and in vivo genotoxins. Mutation Research, 721, 27-73. 

S1 C(R1) Dose Selection for Carcinogenicity Studies of Pharmaceuticals Limit Dose S2A Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals S2B Genotoxicity A Standard Battery for Genotoxicity Testing of Pharmaceuticals Toxicokinetics and Pharmacokinetics... 

Genotoxicity studies are required to identify compounds that can induce genetic damage ranging from single point gene mutations to gross alterations of chromosomal structure. Such effects are taken as indicative of the potential to cause cancer or heritable defects in humans. A standard battery of three types of test is recommended ... 

Matheson et al. (1978) reported the results of a battery of in vivo and in vitro assays to assess the genotoxicity of 1,1-dimethylhydrazine. Included were the Ames Salmonella microsome assay, a microbial suspension assay, mutation induction at the TK locus in L5178Y mouse lymphoma cells, stimulation of UDS in WI-38 cells, and a dominant lethal assay in mice. 1,1-Dimethylhydrazine was active in all of the tests except the dominant lethal assay. 

A battery of different biochemical quantitative assays was applied to many different tissues and species. DNA damage and lipid peroxidation assays measure the direct impact of genotoxics and oxidant pollutants [16,17] whereas alteration of GSH levels in liver is a marker for oxidative stress [18]. Mercury and other heavy metals are known to induce metallothionein levels in different tissues although this effect is variable in different species and organs [19-22]. 

In a battery of mutagenicity and genotoxicity studies, PGDN tested negative except in L5178Y mouse lymphoma cells where it induced mutations at... 

S2B Guidance on Genotoxicity A Standard Battery for Genotoxicity Testing of Pharmaceuticals Availability Notice Nov 97... 

ICH (1997). Technical Requirements for Registration of Pharmaceuticals for Human Use. Genotoxicity A Standard Battery for Genotoxicity Testing of Pharmaceuticals. S2B document recommended for adoption at step 4 of the ICH process on July 16, 1997. Federal Register 62 16026-16030, November 21, 1997. 

Genotoxicity a standard battery for genotoxicity testing of pharmaceuticals... 

Genotoxicity. 1,2-Dibromoethane has been tested for mutagenic activity in a battery of in vitro and in vivo assay systems. It is mutagenic in bacteria, fungi, fruit flies, and cultured mammalian cells (Ames andYanofasky 1971 Barber 1981 Brimeret al. 1982 Crespi etal. 1985 Moriya etal. 1983 ... 

Professor Bruce Ames, a biochemist at the University of California at Berkeley is one of the pioneers of this type of short-term testing. The Ames Test, as it is called, is now widely used, typically as one of several short-term tests that constitute a series of tests, or battery. A battery is thought necessary because no single test is adequate to detect all types of genotoxicity. The Ames Test involves the use of mutant strains of a common bacterium. Salmonella typhimurium, that back-mutate to their normal state in the presence of a mutagenic chemical or metabolite. Many other bacterial and mammalian cell systems have been made available for this type of testing. 

Genotoxiciiy Studies ICH S2A Genotoxicity guidance on specific aspects of regulatory tests for pharmaceuticals ICH S2B Genotoxicity a standard battery for genotoxicity testing for pharmaceuticals Step 5 (1997) Step 5 (1997)... 

Genotoxicity. There are currently no in vivo or in vitro studies that address the genotoxic potential of 2-hexanone. A battery of in vitro genotoxicity tests with 2- hexanone would be useful as a preliminary step in assessing its mutagenic potential and determining if further genotoxicity tests would appear to be warranted. 

The current ICH harmonized tripartite guideline for genotoxicity testing of pharmaceuticals (S2B) defines a standard battery of tests, including both in vitro... 

Kirkland, D. and Speit, G. (2008) Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens III. Appropriate followup testing in vivo. Mutation Research, 654, 114-132. 

Single and repeat dose toxicity studies (with later mainly in the rat and dog by oral or intravenous route and up to 1 year duration), reproduction toxicity (embryo-foetal studies in the rat and rabbit), battery of genotoxicity assays, carcinogenicity studies (by diet route in mouse and rat) plus ADME studies (single and multiple dosing)... 

V. (1984) Evaluation of diallate and triallate herbicides for genotoxic effects in a battery of in vitro and short-term in vivo tests. Mutat. Res., 136, 173-183... 

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