Toxicity tests metabolizers

Acute inhalation exposure of rats to 200,000 ppm VF for 30 minutes or more produced weak anaesthesia and no deaths (90). In rats VF is only slightly metabolized at a rate of one-fifth that of vinyl chloride (91—95). An extensive program of toxicity testing of vinyl fluoride is ia progress (96,97). 

In toxicity studies, acute toxicity tests are usually carried out in the rat, mouse, cat, and dog. Subacute toxicity studies for IM products are performed by giving SC injections to rats and IM injections to dogs. In IV studies the rat tail vein or a front leg is used. Deliberate overdosing usually washes out metabolism differences between species. In dogs it is common to give an IV dose five times that intended for humans. In rats this is increased to 10 times. 

The presence of chemically reactive structural features in potential drug candidates, especially when caused by metabolism, has been linked to idiosyncratic toxicity [56,57] although in most cases this is hard to prove unambiguously, and there is no evidence that idiosyncratic toxicity is correlated with specific physical properties per se. The best strategy for the medicinal chemist is avoidance of the liabilities associated with inherently chemically reactive or metabolically activated functional groups [58]. For reactive metabolites, protein covalent-binding screens [59] and genetic toxicity tests (Ames) of putative metabolites, for example, embedded anilines, can be employed in risky chemical series. 

The ability to introduce the lux phenotype into different bacterial species provides a convenient method for rapidly screening in a simple and sensitive way the presence of specific bacteria and for monitoring their growth and distribution in the environment [198], Another application of transformed bacteria deals with specific susceptibility in toxicity tests the presence of agents that disrupt or kill the bacteria destroys the metabolism, thus eliminating light emission. Some examples are listed in Table 7. 

Study Type. Metabolic and pharmacokinetic data from a rodent species and a nonrodent species (usually the dog) used for repeat dose safety assessments (14 days, 28 days, 90 days or six months) are recommended. If a dose dependency is observed in metabolic and pharmacokinetic or toxicity studies with one species, the same range of doses should be used in metabolic and pharmacokinetic studies with other species. If human metabolism and pharmacokinetic data also are available, this information should be used to help select test species for the full range of toxicity tests, and may help to justify using data from a particular species as a human surrogate in safety assessment and risk assessment. 

Metabolism and pharmacokinetic studies have greater relevance when conducted in both sexes of young adult animals of the same species and strain used for other toxicity tests with the test substance. The number of animals used in metabolism and pharmacokinetic studies would be sufficient to reliably estimate population variability. This usually means a separate (but parallel) set of groups of animals in rodent studies. A single set of intravenous and oral dosing results from adult animals, when combined with some in vitro kinetic results, may provide an adequate data set for the design and interpretation of short-term, subchronic and chronic toxicity studies. 

Therefore, information on the toxicological mode(s) of action as well as mechanistic data are essential in establishing the relevance to humans of the toxicological effects observed in experimental animals. The evaluation of the relevance for humans of data from smdies in animals is aided by use of data on the toxicokinetics, including metabolism, of a substance in both humans and the animal species used in the toxicity tests, when they are available, even when they are relatively limited. 

Currently, there are no validated and regulatory accepted in vitro methods for assessing repeated dose toxicity. Numerous in vitro systems have been developed over the last decades and have been discussed and summarized in recent ECVAM reports on repeated dose toxicity testing (Worth and Balls 2002, Prieto et al. 2005, Prieto et al. 2006). Human in vitro data, particularly on kinetics and metabolism, and in vitro test data from well-characterized target organ and target system models on, e.g., mode of action(s)/mechanism(s) of toxicity may be useful in the interpretation of observed repeated dose toxicity. 

Caldwell, J. (1992) Problems and opportunities in toxicity testing arising from species differences in xenobiotic metabolism. Toxicol. Lett., 64/65, 651-659 Caldwell, J., Anthony, A., Cotgreave, I.A. Sangster, S.A., Sutton, J.D., Bernard, B.K. Ford, R.A. (1985) Influence of dose and sex on the disposition and hepatic effects of cinnamyl anthranilate in the B6C3F1 mouse. Food chem. Toxicol., 23, 559-566 Cattley, R.C., DeLuca, J., Elcombe, C., Fenner-Crisp, R, Lake, B.G, Marsman, D.S., Pastoor,... 

Melnick, R.L. Tomaszewski, K.E. (1990) Triethanolamine. In Buhler, D.R. Reed, D.J., eds, Ethel Browning s Toxicity and Metabolism ofIndustrial Solvents, Vol. II, Nitrogen and Phosphorus Solvents, Amsterdam, Elsevier, pp. 441-450 Morin, R.J. Lim, C.T (1970) Inhibition in vitro of incorporation of [ P]-phosphate into rabbit and human endometrial phospholipids. J. reprod. Fert., 23, 456-462 Mortelmans, K., Haworth, S., Lawlor, T., Speck, W., Tainer, B. Zeiger, E. (1986) Salmonella mutagenicity tests II. Results from the testing of 270 chemicals. Environ, mol. Mutag., 8 (Suppl. 7), 1-119... 

The nature of metabolic reactions and their variations between species is detailed in Chapters 7, 8, and 9 with some aspects of toxicokinetics in Chapter 6. The methods used for the measurement of toxicants and their metabolites are detailed in Chapter 25. The present section is concerned with the general principles, use, and need for metabolic and toxicokinetics studies in toxicity testing. 

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