Toxicity studies, conventional rodent

Conventional rodent toxicity studies characterize adverse effects of a chemical primarily on apical endpoints such as clinical signs or pathological states. Evidence of organ toxicity in the form of an apical endpoint does not always provide mechanistic understanding of the toxicity involved (see Chapter 13). The exposure of rodents in a cancer bioassay model can result in species-specific responses that are not relevant to humans (e.g., alpha2u-globulin-induced rat renal tumors) (see Chapter 18) (EPA 1991). Rodents may also have increased sensitivity to a particular toxicity pathway relative to humans (e.g., disruption of thyroid homeostasis and thyroid follicular tumors in rodents) (EPA 1998 I ARC 2001). There are rodent responses to chemical treatment in tissues where there is a high spontaneous incidence to develop... 

The toxicologist usually moves from studies of a single exposure to ones in which animals are exposed on each of 90 consecutive days. The 90-day subchronic study has become a convention in the field. Rodents usually live 2-3 years in the laboratory, so 90 days is about 10% of a lifetime. An enormous amount of 90-day rodent toxicity data have been collected over the past several decades and have played key roles in judging the risks of environmental chemicals. 

Where functional cross-reactivity to at least one of the usual toxicology species is present, and appropriate assays for PK and PD have been developed, the clinical candidate can be used in a relatively conventional developmental toxicity program with that species (preferably the rat, for which the most background data will be available). Following early sub-chronic repeat-dose toxicity testing in the rodent (usually up to 1 month s duration), with accompanying PK/PD data, the reproductive study program can be planned as appropriate to the circumstances. 

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... 

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