Toxicity test designs study duration

Many of the procedures used in conventional toxicity testing with animals have arisen by an apparently empirical process (e.g., period of exposure and selection of dose levels). Safety studies are performed with a variety of experimental animals, including rodents, rabbits, nonhuman primates, and farm animals, before progressing to studies with human volunteers, and other animals in the case of veterinary medicines. The individual study designs vary with the chosen animal species, route of administration, duration (dependent on the proposed or estimated exposure in... 

Data adequacy The key study was well designed and conducted and documented a lack of effects on heart and lung parameters as well as clinical chemistry. Pharmacokinetic data were also collected. The compound was without adverse effects when tested as a component of metered-dose inhalers on patients with COPD. Animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The values are supported by a study with rats in which no effects were observed during a 4-h exposure to 81,000 ppm. Adjustment of the 81,000 ppm concentration by an interspecies and intraspecies uncertainty factors of 3 each, for a total of 10, results in essentially the same value (8,100 ppm) as that from the human study. ... 

The duration of repeat-dose studies should be at least as long as the proposed clinical study. These studies are designed to establish a dose-response relationship, define target organ(s) of toxicity, and determine whether observed toxicities are reversible. Evaluation parameters should include not only those routinely performed in the acute studies, but those performed in the additional studies as well. Special tests, such as ophthalmoscopic, electrocardiograph, body temperature, and blood... 

Is there sufficient systematic toxicity data available at levels that demonstrate adequate exposure If a study was designed such that there was insufficient exposure or duration of exposure to potential lymphoid target tissues, the test protocol may not be adequate to demonstrate an adverse effect. 

The reproductive/developmental toxicity screening test can provide initial information on possible effects on reproduction and/or development and may make it possible to identify a substance as being toxic to reproduction, i.e., the test gives a clear positive result. However, this test offers only limited means of detecting postnatal manifestations of prenatal exposure or effects that may be induced during postnatal exposure. In addition, because of the study design (e.g., relatively small numbers of animals per dose level, relatively short smdy duration), the test will not provide evidence for definite claims of no effects. 

Chronic-Duration Exposure and Cancer. Kidney toxicity (Franchini et al. 1983 Mutti et al. 1992 Price et al. 1995) and symptoms of chronic encephalopathy (Gregersen 1988) were reported in studies of humans occupationally exposed to tetrachloroethylene. Other occupational exposure studies have not identified kidney (Lauwerys et al. 1983 Solet and Robins 1991) or irreversible central nervous system effects (Cai et al. 1991 Coler and Rossmiller 1953 Lauwerys et al. 1983). Deficits in behavioral tests that measured short-term memory for visual designs (Echeverria et al. 1995) have also been noted in humans occupationally C5q)osed to tetrachloroethylene. There are conflicting reports on the effect of tetrachloroethylene on color vision in persons occupationally exposed to tetrachloroethylene. Cavalleri et al. (1994) reported an effect on color vision at an average concentration of 7.3 ppm, while Nakatsukaet al. 

---