ever, chemists tend to produce synthetic chemicals or analyze natural chemicals that are between a molecular weight of a few hundred to a few thousand. Technological advances in chemistry will continue to increase the number of synthetic chemicals. Some of these chemicals will undoubtedly be of benefit to society; however, potentially harmful chemicals need to be identified so that human exposure is controlled or prevented. For risk assessment, a key goal is to determine which exposures to chemicals may be harmful to humans before exposure occurs.

Millions of synthetic chemicals are registered with the American Chemical Society, but fewer than 100,000 are currently in commercial or industrial use and, therefore, available for introduction into the environment (EPA 1997). Most of these chemicals have not been tested for developmental toxicity. For example, EPA (1998a) conducted a study assessing data availability on close to 3,000 chemicals that the United States produces or imports at more than 1 million pounds per year and concluded that only 23% of those chemicals had been tested for reproductive and developmental toxicity. Test data were considered available if any studies relevant to reproductive and developmental toxicity were located.

The number of synthetic chemicals is likely to increase greatly in the near future. Recent advances in combinatorial chemistry have made it possible for chemists to synthesize in parallel small amounts of a large number of chemicals (a “library,” on the order of 104-106 kinds per application). Biologically active members of the library are selected by their performance in specific biological assays (usually in vitro assays rather than animal tests) based on recent insights into the workings of cellular, developmental, and pathological processes. These new synthetic and selective methods are expected to lead to the development of drugs that are more efficacious and have specific pharmacological activities. Although all but the most promising chemical candidates will be restricted to the laboratory, it will be a challenge to gain toxicity information about many of these so that not only the most efficacious but also the safest can advance to the next phase of drug development. As drug discovery and development approaches become more sophisticated, toxicity testing approaches must also become more sophisticated.

Toxins, such as chemicals from microorganisms, fungi, plants, and animals (e.g., sponges, coelenterates, and bryozoa), have not been analyzed systematically. Systematic analysis has shown that the variety of chemical constituents is known to be great in some naturally occurring substances. For example, over 400 chemicals have been identified in red wine, and over 1,000 chemicals have been found in tobacco or tobacco smoke. Naturally occurring substances sometimes have significant pharmacological and toxic properties (see, e.g., NRC 1996). Catalogs of known naturally occurring plant toxins, for example, include more than 2,000 entries, and the number with pharmacological activity is larger (Keeler and Tu 1991; Harborne and Baxter 1996).

Animals, including humans, have evolved enzymes and ligand-binding proteins to metabolize and eliminate many natural environmental chemicals. They



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