DESCRIPTIVE ANIMAL TOXICITY TESTS

Acute Toxicity Testing

Generally, the first toxicity test performed on a new chemical is acute toxicity, determined from the administration of a single exposure.

effects produced by a compound in laboratory animals, when properly qualified, are applicable to humans

This premise applies to all of experimental biology and medicine. On the basis of dose per unit of body surface, toxic effects in humans are usually in the same range as those in experimental animals. On a body weight basis, humans are generally more vulnerable than are experimental animals. When one has an awareness of these quantitative differences, appropriate safety factors can be applied to calculate relatively safe doses for humans. All known chemical carcinogens in humans, with the possible exception of arsenic, are carcinogenic in some species but not in all laboratory animals. It has become increasingly increasingly evident that the converse—that all chemicals carcinogenic in animals are also carcinogenic in humans—is not true. However, for regulatory and risk assessment purposes, positive carcinogenicity tests in animals are usually interpreted as indicative of potential human carcinogenicity. If a clear understanding of the mechanism of action of the carcinogen indicates that a positive response in animals is not relevant to humans, a positive animal bioassay may be considered irrelevant for human risk assessment. This species variation in carcinogenic response appears to be due in many instances to differences in biotransformation of the procarcinogen to the ultimate carcinogen.

exposure of experimental animals to chemicals in high doses is a necessary and valid method of discovering possible hazards in humans.

This principle is based on the quantal dose-response concept that the incidence of an effect in a population is greater as the dose or exposure increases. Practical considerations in the design of experimental model systems require that the number of animals used in toxicology experiments always be small compared with the size of human populations at risk. Obtaining statistically valid results from such small groups of animals requires the use of relatively large doses so that the effect will occur frequently enough to be detected. However, the use of high doses can create problems in interpretation if the response(s) obtained at high doses does not occur at low doses. Thus, for example, it has been shown that bladder tumors observed in rats fed very high doses of saccharin will not occur at the much lower doses of saccharin encountered in the human diet. At the high concentrations fed to rats, saccharin forms an insoluble precipitate in the bladder that subsequently results in chronic irritation of bladder epithelium, enhanced cell proliferation, and ultimately bladder tumors. In vitro studies have shown that precipitation of saccharin in human urine will not occur at the concentrations that could be obtained from even extraordinary consumption of this artificial sweetener. Examples such as this illustrate the importance of considering the molecular, biochemical, and cellular mechanisms responsible for toxicological responses when extrapolating from high to low dose and across species. Toxicity tests are not designed to demonstrate that a chemical is safe but to characterize the toxic effects a chemical can produce

Typical Tiered Testing Scheme for the Toxicological Evaluation of New Chemicals

Typically, a tiered approach is used, with subsequent tests dependent on results of initial studies. A general framework for how new chemicals are evaluated for toxicity is shown in Fig. Early studies require careful chemical evaluation of the compound or mixture to assess purity, stability, solubility, and other physicochemical factors that could impact the ability of the test compound to be delivered effectively to animals. Once this information is obtained, the chemical structure of the test compound is compared with similar chemicals for which toxicological information is already available. Structure-activity relationships may be derived from a review of existing toxicological literature, and can provide additional guidance on design of acute and repeated dose experiments, and what specialized tests need to be completed. Once such basic information has been compiled and evaluated, the test compound is then administered to animals in acute and repeated dose studies.

2 main principles

effects produced by a compound in laboratory animals, when properly qualified, are applicable to humans exposure of experimental animals to chemicals in high doses is a necessary and valid method of discovering possible hazards in humans.