Animals chronic toxicity studies

The single-dose toxicity studies were performed in two mammalian species, rat and mouse, by the route used in clinical practice, that is oral, as well as that ensuring adequate systemic exposure to the drug, that is intravenous. The subacute (3 months) toxicity studies were correctly carried out in the two animal species (rat, dog) in which also the pharmacokinetics was studied. Since in accordance with the International Conference on Harmonization (CPMP/ICH/286/95), 3-month toxicity studies support clinical trials for up to 1 month s duration (the longest duration of drug administration in clinical use), chronic toxicity studies have not been performed. 

The duration of such toxicity tests varies. In the USA, the FDA usually recommends a period of up to 2 years, whereas in Europe the recommended duration is usually much shorter. Chronic toxicity studies of biopharmaceuticals can also be complicated by their likely stimulation of an immune response in the recipient animals. In the context of new chemical entities (NCEs, i.e. low molecular weight traditional chemicals), not only can the drug itself exhibit a toxic effect, but so potentially can drug breakdown products. As proteins are degraded to amino acids, any potentially toxicity associated with protein-based drugs is typically associated with the protein itself and not degradation products. 

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. 

Body Weight Effects. No specific effects on body weight have been noted in humans. Effects on body weight (decreases) in animals were usually associated with administration of high doses and were not observed in chronic toxicity studies (Chemoff et al. 1979a Deichmann et al. 1970 Goldenthal 1978a Kavlock et al. 1981 NCI 1978 Treon et al. 1955). 

Repeated dose chronic toxicity studies are performed on two species of animals a rodent and nonrodent. The aim is to evaluate the longer-term effects of the drug in animals. Plasma drug concentrations are measured and pharmacokinetics analyses are performed. Vital functions are studied for cardiovascular, respiratory, and nervous systems. Animals are retained at the end of the study to check toxicity recovery. Table 5.2 shows the duration of the animal studies, which depends on the duration of the intended human clinical trial. Appendix 6 summarizes the information to be submitted to regulatory authorities. 

Chronic-Duration Exposure and Cancer. No studies of chronic duration were found in humans or animals. Chronic toxicity information is important because people living near hazardous waste sites might be exposed to cresols for many years. Prolonged exposure to cresols in humans might occur by oral, inhalation, or dermal routes. Chronic studies would enable discovery of effects produced by long-term exposure to relatively low levels of cresols, which might not be detected in shorter-term studies. 

The duration of such toxicity tests varies. In the USA, the FDA usually recommends a period of up to 2 years, while in Europe the recommended duration is usually much shorter. Chronic toxicity studies of biopharmaceuticals can also be complicated by their likely stimulation of an immune response in the recipient animals. 

Considering the insensitivity of the decaBDE studies for MRL derivation, as well as the lack of cancer information on the lower brominated PBB mixtures that may have higher carcinogenic potency than decaBDE, there is a need for chronic toxicity studies on pentaBDE and/or octaBDE. Evaluations that include the thyroid would be particularly informative because the acute and intermediate-duration animal studies indicate that the thyroid is a particularly sensitive target organ for PBDEs. 

An MRL of 0.06 mg/kg/day was derived for chronic-duration ( 365 days) oral exposure to DEHP based on a NOAEL of 5.8 mg/kg/day for testicular pathology in male rats that were exposed to DEHP in the diet for up to 104 weeks in a chronic toxicity study (David et al. 2000a). The LOAEL in this study was 29 mg/kg/day for bilateral aspermatogenesis. The chronic MRL was derived by dividing the 5.8 mg/kg/day NOAEL by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). 

Objectives of the chronic toxicity study are to characterize the profile of a chemical in any mammalian species, following prolonged and repeated exposures, through oral, dermal, or inhalation route. In this respect, the chemical toxicity should be interpreted broadly to include any change from the normal. The duration of a chronic toxicity study for effects other than neoplasia is still widely debated. Chronic toxicity testing in animals requires exposure to the test chemical by appropriate route and at an appropriate dosage for much of the test animal s lifespan, if not for the entire life. Chronic toxicity tests assess potential toxicity from long-term exposures at low levels. 

Effects in Adult Animals in Chronic Toxicity Studies Doses Tested in EFD Study (NOAEL or highest dose tested) Effects on Fertility, Pregnancy and Development Clinical Dose Pregnancy Category... 

In all of the reproductive toxicity studies mentioned above, mammalian species are used as these are the most relevant model for risk evaluation in humans. It is recommended to use laboratory animals of the same species, strain and quality also used in acute and chronic toxicity studies as this enables the kinetics,... 

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