Genetic test batteries

Griebel G, Moreau J-L, Jenck F, Martin JR, Misslin R (1993) Some critical determinants of the behavior of rats in the elevated plus-maze. Behav Process 29 37-48 Griebel G, Sanger DJ, Perrault G (1997) Genetic differences in the mouse defense test battery. Aggress Behav 23 10-31... 

Prenatal and postnatal development rats (abbreviated) Genetic toxicology battery of in vitro and in vivo tests Carcinogenicity none... 

The Ames test is recommended by the International Conference on Harmonisation Guidelines as part of a standard genetic toxicology battery. The other assays include the mouse lymphoma and micronucleus tests. This bacterial mutation test may not be appropriate for the evaluation of certain classes of chemicals, for example highly bactericidal compounds (e.g., certain antibiotics), any compounds that may interfere with cell division or replication, and possibly some peptides. In such cases, mammalian mutation tests may be more appropriate. 

The micronucleus assay is one type of study recommended by the FDA Redbook and ICH guidelines as part of a standard genetic toxicology battery. The other assays include the Ames (bacterial reverse mutation) and mouse lymphoma tests. 

Effluent test results support the use of Microtox as part of a test battery. Uniform response of sublethal effects to 50 effluents from pulp and paper mills was obtained with the Microtox test compared to the results with fish and algae, which varied greatly with age and genetic variation within the population. Microtox has also been used to detect other sublethal effects (e.g., chronic toxicity). For example, the bacterial response can be used to quantify the stress on the immunological defense systems of mussels exposed to toxins in polluted rivers or wastewaters. In... 

Genetic toxicity testing follows the reconmiended test battery as outlined in Option 1 of ICH S2(R1), employing two in vitro assays (bacterial reversion mutation and chromosomal aberrations in hPBLs, +/- S9 metabolic activation) and the in vivo rat bone marrow micronucleus assay. Intracellular exposure to the full-length parent drug product has been demonstrated in all three assay systems (thereby applicable across different sequences). 

Selection of a testing scheme or test battery to be employed must in most cases be based on the nature and use of the test substance. Testing schemes are probably as diverse as the laboratories that conduct the tests, although a battery of four or five tests selected from those listed in Table 2 would be expected to generate a reasonable data base for most chemicals under development. It is important, however, to select a battery that includes all possible types of genetic endpoints (e.g., gene mutation, chromosome alterations, and nonspecific DNA damage). 

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 ... 

Screening for the numerous disease of genetic origin on newborns will be expanded so that eventually a battery of tests will be utilized for the determination of the erythrocyte abnormalities and abnormalities of intermediate metabolism. 

Pharmacokinetic profiling (ICH-S3B 1995) may prove useful. Review of the battery of genetic toxicity tests ICH-S2B (1997) and the ICH reproduction toxicity guidances (S5A) (1994) and S5B (1996, 2000) are valuable. 

For a constituent of an additive with equivocal (mixed positive and negative) battery of genetic toxicity tests and a EDI of < 150 pg/p/d, SAR analysis for SAs and predictive software such as MDL QSAR (Contrera et al, 2005) and MultiCASE s MC4PC (Rosenkranz and Klopman, 1988 Matthews and Contrera, 1998) may be used as part of the weight of evidence approach in assessing the safety of the compound. If a constituent were of potential concern, a quantitative SAR analysis might be feasible to characterize the expected risk. 

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