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show that the chemical can indeed cause the disease in an animal model, or at least, that it can induce or enhance cancer development even though it may not necessarily be at the same site as in

humans.

Bioassay systems specifically designed to detect carcinogenic chemicals, therefore, serve several purposes. Such systems have a great potential for detecting possible carcinogens among new synthetic chemicals that might in the future cause cancer in humans and thereby enabling avoidance of the spread of carcinogenic risk. As an example of such prevention, it is most fortunate that the chemical N-2-fluorenylacetamide was discovered to be a powerful carcinogen prior to the possible use of the parent 2-fluorenamine as an insecticide (10). Indeed, in 1938 before DDT and other pesticides were known and when insect pests were controlled with difficulty, 2-fluorenamine was a potent and promising insecticide. If this chemical had been used widely in

the environment as a pesticide, cancer probably would have assumed epidemic proportions in populations exposed by whatever route. Unfortunately, in a number of other instances, chemicals were found to cause cancer in animals, but sadly this warning was not applied promptly and cancer later was found induced in humans (11-18). Thus, screening for carcinogenic activity of agents which will have significant human exposure is designed to reduce the cancer risk for humans.

One of the key aims of carcinogen bioassay is to assess the carcinogenic risk of chemicals early in the stage of technical development. This is a sound economic practice, for it is waste

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ful and, indeed, imprudent to conduct carcinogen bioassays on any chemical late in the development and production stages when a finding of adverse effects would make futile all of the previous work leading to possible commercial use. While this was always the case, it is even more relevant now since there are new, rapid warning signals detectable through effective tests that can predict potentially hazardous situations with reasonable accuracy. Evaluation of the carcinogenic potential of chemicals must concern itself with two types of agents: (1) synthetic chemicals that may enter or currently are in the human environment, and (2) naturally-occurring chemicals that may be responsible for the diverse types of existing human cancer. Bioassay systems should provide sensitive, reliable, and specific tools for the detection of possible carcinogenicity of chemicals. The systems should also be economical, and as rapid as possible in the case of agents where there is already human exposure. They should, if possible, mimic the human conditions of exposure. The design and conduct of chronic bioassays in laboratory rodents, while refined to some extent in recent times, are basically not much different from the pioneering procedures of decades ago. Often they are not fast, are expensive, and sometimes even misleading when not coupled with a full evaluation of the biological characteristics of the test chemical

(19-22).

Fortunately, however, much progress has been made in

the last few years in acquiring an understanding of the

mechanisms of carcinogenesis, of the complex, step-wise nature of the overall process, of the types of chemicals capable of causing

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or enhancing cancer, of the molecular events associated with each portion of the carcinogenic process, and of the relationship between carcinogenesis and mutagenesis (23-31). In turn, this clarification has given rise to rationally designed rapid bioassay tests which can, together with the animal bioassays, taking into account quantitative aspects, yield a reasonably sound approach to health risk estimates--one of the primary goals of carcinogen bioassays.

Knowledge of the possible carcinogenic properties as

revealed by a carefully selected battery of in vitro and in vivo tests is an essential component of the data base for proper health risk assessment of a given product, naturally-occurring or synthetic. The evaluation has two components: (1) qualitative yes or no answers, and (2) quantitative evaluation for substances where (1) was positive. This chapter will provide the scientific and mechanistic background and describe the test systems appropriate for systematic approaches to health risk analysis through a battery of in vitro and in vivo bioassays.

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CONCLUDING REMARKS

Since the first edition of this monograph, sizable progress has been made in the basic sciences underlying carcinogenesis. Thus, the great diversity of chemical structures capable of causing cancer eventually depend on their specific chemical structure to be either that of an electrophilic reactant as such, or to become one after metabolic activation. Also, there has been further insight into the molecular target of genotoxic electrophilic carcinogens, namely, the genetic material in the cell, DNA. It has also been discovered that DNA with covalently bound carcinogens can be repaired and that some of the observed biologic effects, including that of organotropism, depend as much on such repair processes as on the metabolic activation and interaction with DNA.

In turn,

The interaction with DNA has yielded the necessary connection to relate mutagenicity to carcinogenicity. this has provided a sound basis for utilizing the property of mutagenicity as an assessment of potential carcinogenicity for some chemicals as such, or after the chemical's metabolic activation. We have classified chemical carcinogens into genotoxic agents, as defined above, and into other agents capable of increasing cancer risk through mechanisms other than genotoxicity--through epigenetic mechanisms. As current evidence shows that most classes of agents operating through such an epigenetic mode of action do so in a reversible, highly

dose-dependent fashion, there are theoretical and also regulatory implications for treating such agents in an entirely distinct

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manner. It is expected that further research on methods to detect such agents will provide better control of all types of potentially harmful substances without a blind, blanket indictment of all agents that can cause cancer by whatever mechanism. This is important for there is excellent evidence relative to the causes of the currently prevailing main human cancers that they depend as much on the presence of agents operating via epigenetic mechanisms as on genotoxic carcinogens. Examples are that of cancer of the lung due to smoking of cigarettes; and cancer of the colon, breast, prostate, and perhaps pancreas due to certain dietary habits, especially as regards the level of fat consumed. Thus, there is hope that these major types of cancer can be controlled by modifying not only the environment with respect to genotoxic carcingens but also with respect to that of epigenetic carcinogens, thereby, lowering the complex risk factors for these diverse human cancers.

The public is much more aware of environmental cancer risks. There is legislation and regulation at the State and Federal level, and indeed in international agreements to control possible causes of environmental cancer. Nevertheless, the public, while concerned with the issues is not well informed. Problems that come to public attention through the press and media are not necessarily those that would be most relevant to the protection of the public. It is hoped that the application of the methods and principles presented here will be of value to professionals in the field of carcinogenesis and would also result in activities enabling the public to have sound and useful facts as to avoidable cancer hazards.

(Balance of document is held in the subcommittee files.)