gies of both types to detect adverse health effects of a given chemical with some level of certainty. First, screening tests identify which organs and/or physiological functions are most sensitive to the effects of the chemical. Then more specialized investigations assess the precise effects on physiological functions and seek to establish dose-response relationships. Conducted rigorously, such testing yields information that can be accurately extrapolated to humans.

In general, in vivo testing is the most effective screening method because mammals possess all the physiological systems that can be affected by a chemical in humans, and gross effects can be readily identified. In vitro investigations usually seek to evaluate the mechanism of a chemical's impact rather than its actual effects or, more recently, to provide direct sensitivity comparisons of human cells relative to those of the animals in which prior screening work has been done. Usually such information must be related back to the whole animal or human to determine how much active metabolite of a chemical reaches the receptor site at a given dose. Ideally, dose-response relationships are then developed to compare the internal concentration of the chemical resulting from external exposure of humans and experimental animals.

In vivo testing provides the best screening data but requires considerable investment. For example, experiments designed to detect the carcinogenic properties of a chemical generally involve treatments over a significant fraction of a test animal's life span. Reproductive or developmental effects require specific assessments of reproductive competence of sexually mature animals or observations of development in pregnant animals, which in turn requires observations over more than one generation.

Because of the expense involved in live animal testing, many in vitro tests have been developed for screening purposes with the hope that they would be predictive of carcinogenic and reproductive effects. These in vitro screening tests are not intended as a substitute for in vivo testing, but merely to identify chemicals needing further testing.

In the 1970s, a series of inexpensive in vitro tests was introduced into common use in safety testing. The most widely used was the Salmonella/ microsome assay, commonly known as the Ames test. Its purpose was to test for mutagenic activity, because mutation plays an important role in the development of cancer. This test was subsequently applied to a wide variety of environmental problems, including drinking water and reclaimed water, in the hopes that it would provide a cost-effective method for evaluating carcinogenic hazards in the environment. The apparent success of the test spawned an interest in developing in vitro techniques to detect other toxicological end points.

As illustrated in Table 4-6, a safety testing strategy emerged that in-



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