Community air-quality standards are set to reflect the costs and benefits of air pollution control measures. The costs of air pollution are both intrinsic (effects) and extrinsic (prices). Biomedical scientists are concerned with evaluating the intrinsic costs of pollution, but the standards are set by representatives of society, who evaluate the extrinsic costs. Biomedical science is limited in meeting the expectations of the lay public, since "causality" cannot be proven by epidemiological methods, the range of human experimentation is highly restricted, and results of animal experimentation may be misleading when applied to man. Furthermore, not all the effects of air pollution have yet been discovered; consequently, focusing onthe quantification of known effects alone will result in inadequate assessment. Current methods for studying effects of pollutants include biochemical, cellular, pathophysiological, pathogenetic, and epidemiological techniques. Mechanisms are studied in the fundamental molecular and cellular systems, whereas societal costs can be determined best by epidemiology and pathophysiology.

 Community ambient air quality standards can be defined functionally as the levels of air pollution that are acceptable to society. In the setting of these standards, it is hoped that they represent a balance between the costs and benefits of air pollution control measures. Evaluation and integration of the health costs of air pollution tends to make the standards more stringent, but consideration of the costs of abatement produces less stringent standards. The minimum abatement costs—in dollars—are fairly easy to compute, but evaluation of the health costs is not as easy. Health costs rank among the most important costs of air pollution, but all of the possible health effects have not yet been discovered, let alone quantified. Therefore, accurate assessment of these costs for setting future air quality standards depends on a major investment in biomedical research. This paper examines current biomedical research capabilities in relation to the current strategy for air pollution control. It also reveals some popular but unrealistic expectations of biomedical science.

 There are many independent facets to the cost-benefit analysis leading to the setting of standards, involving many levels of activity—from the basic scientific to the political. It is not easy to describe the standards-setting process because some of these contributing factors are incongruous with others. Nevertheless, the attempt must be made to synthesize them before standards-setting can make any sense at all. This paper is one such attempt. It seems logical to begin by describing the functional roles of both scientists and the representatives of society who set standards, in terms of the cost-benefit analysis involved.

 Intrinsic and Extrinsic Values

 The distinction between "effects" and "costs," as the terms are used herein, is fundamental. "Effects" are the "intrinsic" biological responses to pollution, whereas "costs" are the "extrinsic" values that society ascribes to those effects.¹ As an illustration of these qualities of value, consider a particular painting by Rembrandt; it may have an extrinsic value (market price) of hundreds of thousands of dollars, whereas its intrinsic biological value is virtually zero, since it is too indigestible to be eaten, and too friable to serve as shelter or clothing. Esthetic appeal accounts for only part of the great disparity between the intrinsic and extrinsic values of the painting—a larger part arises from its uniqueness. On the other hand, the market value of air is zero, despite its great intrinsic biological value.

 This distinction between intrinsic and extrinsic values clearly distinguishes the scientist's role in the standards-setting process from that of society's representative; the scientist concerns himself with evaluating the intrinsic effects, whereas society' s representative tries to put an acceptable price tag on those effects. The former is concerned with "correctness" and "incorrectness;" the latter with the moral questions of "rightness" and tlwrongness." In short, the former develops knowledge, but the latter cultivates wisdom.

 It would be ideal, of course, if extrinsic values were established based on knowledge of intrinsic effects. Similarly, it would be useful if scientific research were to reflect society's values. Although these two sets of values are not expressed in the same dimensional units, it is still possible—and in my opinion, highly desirable—to create interfaces for communication between the scientific and societal subcultures. In this way, reconciliation between the intrinsic and the extrinsic values could be facilitated.

 The Role of the "Standards-Setter"

 The prime motivation for establishing air quality standards, or for initiating any abatement procedure, is political. That is, the general public, through its formal institutions, defines the goals and promulgates the rules for air quality control. Society's political institutions give the authority and responsibility for establishing acceptable standards to the standards-setter. To carry out this responsibility, he must evaluate the costs of air pollution and balance them against the costs of abatement. He is the one who must make the final integration of much information including, but not limited to, biological information. In short, he translates biological "effects" into societal "costs."

 A commentary on the inherent advantages and disadvantages of this system is tangential to the theme of this paper. However, since the validity of any cost-benefit analysis depends on the judgment of the analysts as well as the scope of the analysis, it is appropriate to list those traits that I believe characterize an "idealized" standardssetter:

 First, he is concerned with the realistic goal of adopting "acceptable" standards rather than visionary "perfect" standards. He recognizes that "acceptable to society" does not mean "unanimous acceptability. He can evaluate esthetic and intangible variables that have value to society but may not have obvious prices. Finally, he is fully capable of making decisions without insisting on guaranteed results; he lives by the admonition—paraphrased from Harry Truman—"If you can't stand uncertainty, then stay out of the kitchen." Briefly, he is the practitioner of an "art, which I have previously defined as "a field in which it is more important to be right than to be rigorous."²

 The Contribution of Biomedical Science

 The role of the biomedical scientist in the process of setting standards is discussed below, but the interaction between the scientist and society's representative can be illustrated by an example: A scientist might demonstrate that a given ambient level of sulfur dioxide is associated with a measurable increase in mortality, and that most of the excess deaths occur in persons who are either over 65 years or under 5 days of age. Furthermore, he might calculate the increment in actual dollar costs that is caused by those deaths. But, society puts its own value on those deaths; and that extrinsic value—the price society is willing to pay—is the only one that counts in the social assessment of air pollution damage.

 Currently, it is believed that society places a fairly high value on the protection of the most sensitive definable subpopulation within the population. " Consequently, that criterion has been established as the threshold "health effect" in setting ambient standards. This public policy is reflected in the directions of traditional epidemiological and medical health effects research. For example, patients with asthma and acute myocardial infarction have been evaluated for response to ambient air pollution levels.

 Apparently, society also places a quite high value on the esthetic consideration of "visibility." In fact, in the case of particulate pollution, this "esthetic cost-factor" probably outweighs the intrinsic health effects of aerosols; consequently, esthetic values and not health effects, are the limiting factors in setting particulate standards.

 Amelioration of health costs is an important benefit of air pollution control programs, but the abatement costs are substantial, too. In addition, costs of the abatement are much better known than its health benefits. Consequently, standards-setting agencies such as the Environmental Protection Agency and the California Air Resources Board have developed "shopping lists" of questions they would like biomedical scientists to answer. Biologists are asked to produce licritical data" and "definitive studies" in order to provide defendable bases for air quality standards. Of course, "critical" and "definitive" mean quite different things to different people, and those words can have very expensive implications. Furthermore, in a world of no absolutes, the defendability of standards depends largely on who is being asked to judge them. Therefore, it is appropriate to examine thevalidity of these requests to discover (a) whether they are scientifically realistic, and (b) whether the "interested parties" are interested enough to pay for the answers they are asking for. Only the former is discussed in this paper; the latter issue is raised here only as a sobering thought.

 The Limited Validity of the Strategy

 The current strategy for air pollution research and control was initiated by social pressures, and it is administered by social institutions. Nevertheless, it is embodied in engineering diagrams and flow charts. In the development of the strategy, it was assumed that a rational course for controlling air quality would be to develop documents, "Air Quality Criteria," detailing the available data about the health effects of each of the pollutants. Then, by a process of interpretation, air quality standards for each of the pollutants could be developed. Finally, by this plan, source emission standards could be set for each pollutant to allow a technologically feasible implementation of the standards.

 Unfortunately, though, it has not been established that this strategy conforms with Nature. On the contrary, in order for the grand strategy to work, the biological effects of the individual pollutants must be superposable when the pollutants are mixed; however, most biologists would expect nonlinear interactive effects. In other words, based on their experience with biological systems, their a priori prediction would be that the presence of any one Pollutant would modify the biological response to any other pollutant. In biological terms then, "smog" does not equal nitrogen dioxide plus oxidant plus particulate plus carbon monoxide, and so forth.

 Consequences of the Strategy—"Implied Research"

 Whether or not it is valid, we must recognize the existence of the grand strategy. Furthermore, since it does exist, certain other social phenomena have become inevitable. Prominent among them is the belief among politicians and other public officials that all they must do is to ask questions in order to have their regulations and standards justified. That fantasy is complemented—and in fact strengthened—by some scientific administrators who are in search of funds. They get funds by promising that their people will provide the answers to the questions—regardless of whether or not the questions are answerable.

 The experimental biologist must continuously be aware that his chance of success depends entirely on whether he has asked the right question. He must be able to exercise educated judgment to determine which questions are within the limits of research capabilities. Inevitably, realistic research will sometimes fail to conform with the expectations or hopes of the lay public. When that happens, good sense dictates that the scientists should provide answerable questions and testable hypotheses; otherwise, we can expect to throw more and more money into the bottomless pit of "implied research." This kind of research is usually justified by implying that it will solve immediate problems by the application of scientific principles and knowledge, even though those principles and that knowledge do not exist.

 As a third consequence of the air pollution control strategy, practically every layman has developed his own system for interpreting and evaluating "health effects" data. Professional scientists and other technical people are not immune from this disorder; they are sometimes found promoting unsubstantiated speculation as fact, demanding "proof" for untestable hypotheses, or in general, recklessly scattering invalid criticisms of biomedical research—even though they may understand that their own specialized training and supervised experience were designed to help them avoid these pitfalls in their work.

 As indicated above, limits on experimental methodology determine whether or not questions or hypotheses are realistic. Some of the very broad limits are discussed here in general terms. Expectations and questions commonly associated with biological research can be tested against reality with these facts.

 Nonlinear Interactive Effects

 The problem of nonlinear interactions among the pollutants has already been discussed. This phenomenon is the source of much discussion in the process of setting standards, because even if the effects on a given biological system were known for each pollutant, its behavior when mixed with other pollutants would not be predictable. Thus, it appears unreasonableto set a standard for each pollutant that is independent of all the others. That is one reason deleterious effects are generally overestimated when the evidence is inadequate, and standards are set conservatively.

 "Proof of Causality"

 A very common, but naive expectation of biological research involves the "proof of causality." Some critics of air quality standards, citing epidemiological studies, blithely assert that standards should not be set until there is "proof" that air pollution causes mortality or morbidity. In response, defenders of the standards often naively call upon scientists to provide such proof. "Causality" is a red herring in these conflicts, though; broadly speaking the experimental determination of causality would not be directly applicable to setting standards, anyway. In fact, experimental methods are in use that measure very fundamental physicochemical properties of biological systems. As a rule though, results of these studies are only remotely related to the kind of data needed to set standards based on integrated biological effects. On the other hand, the "medical" and epidemiological methods closest to the "practical" ideal, are removed by many levels of complexity from questions of mechanism.

 To an experimentalist, the hoped-for panacea of "proven causality" is never more than a temporarily useful working model that is a stepping stone toward the development of more fundamental mechanistic hypotheses. So, science can never be expected to provide a deterministic basis for setting standards; human judgment cannot be circumvented by appealing to a mythical scientific oracle.

 Human vs Animal Experimentation

 Some of the limitations that inevitably face experimental biologists are social rather than scientific. These relate to the use of humans as experimental subjects and to the problems resulting from interpretation of experiments using experimental animals. Ethical considerations make it highly risky—legally, as well as medically—to subject a person to experimental situations that might be unduly hazardous. It would obviously be criminal, for example, to conduct a gas chamber experiment to determine the lethal dose of the pollutants to humans; consequently, these values will never be known to a high degree of accuracy. Accordingly, when standards are set, they are set in the absence of such information.

 In contrast to the unacceptability of high-dose experiments, it is apparently acceptable to "subject" persons to clean air; consequently, some experiments have been designed in which clean air is the variable, and smoggy ambient air the "normal" control. The rationale is that the subjects can be put to no more arduous test than they would ordinarily be exposed to. In a gentle stretch of that principle, it is apparently also thought to be acceptable to use what might euphemistically be called "partially clean blir"; that is, air having up to ambient levels of a single pollutant, say CO, but none of the other components of smog. Nevertheless, even with such ingenious experimental or semantic designs, the range of information that can be achieved with such experiments is fairly restricted.

 The use of experimental animals to determine physiological and pathological effects of pollutants is the only available method for consistently obtaining reproducible and reliable quantitative data. Yet, theoretically, each extrapolation to man of results in lower animals must be justified by analogous experiments in man. In actual practice though, the extrapolation step can usually be circumvented satisfactorily by the experimenter's use of good judgment based on his own experience and training.

 Quantification vs Discovery of Effects

 Finally, it is important to realize that, despite the often-repeated calls for quantification of health effects, it is generally overlooked that the known effects—the quantifiable ones—are undoubtedly far outnumbered by the unrecognized effects. In other words, at this stage in history, the ability to evaluate the total impact of pollution on biological or human systems still depends much more on the process of discovery than on the process of measurement. Unfortunately, though, since a proposal to measure a known effect looks potentially more productive than a proposal to look for unknown effects, funding agencies may give low priority to the important research needed to discover effects—agencies anxious to produce immediate results have probably not fully considered the necessity of funding current basic research as an investment in future applications.

 This paper is concluded by describing several research systems that are being used for the evaluation of intrinsic pollution effects. The examples below are not necessarily the most sensitive or the most widely applicable; they have been chosen because they illustrate their respective principles well, and because they represent current work. Examples are given for systems at five levels of biological complexity and organization: biochemical, cellular, pathophysiologic, pathogenetic, and epidemiological.

 Biochemical Systems

 The study of biochemical reactions is a discipline very close to the determination of mechanisms of action in living organisms. Conversely, this discipline is also quite far from the study of integrated animal behavior and function. Biochemistry, however, provides many predictive models for the evaluation of toxicity in the whole animal. This is important because carrying out long-term experiments on large populations of animals is very expensive; to be efficient, experimenters would like to have a very good idea of their expected results before they design their experiments.

 An examination of the effect of ozone on protein function is provided in a set of experiments with amino acids.³ Amino acids—the "building blocks" of proteins—can conveniently be studied in vitro. Several distinct patterns of damage have been described for individual amino acids exposed to ozone. Tryptophan, an aromatic compound, is broken down stoichiometrically. Methionine, a sulfurcontaining amino acid, is oxidized to methionine sulfoxide, and histidine is degraded into several products, including ammonia. Glycine and alanine are unaffected by ozone.

 Logically, one would predict that if amino acids were capable of being broken down by ozone, proteins containing them might also be susceptible to damage. The experiment to test this prediction was carried out on pancreatic ribonuclease. This protein was chosen, not because it is suspected as an air pollution casualty, but for technical experimental reasons: its structure and amino acid sequence are well known, it is an enzyme whose activity depends on the integrity of histidine, it contains no reduced sulfhydryl groups, and it contains no tryptophan. Experimentally, ozone reduces the activity of this enzyme, thus supporting the mechanistic prediction.

 Other biochemical systems that can be studied in the test tube include the oxidation and peroxidation of lipids by ozone. These studies may be related fairly closely to pollution effects, since it is believed that the peroxidation of the unsaturated fatty acids is one contributing factor to the overall aging process. In this regard, vitamin E, an antioxidant agent, is becoming a popular research object—there is evidence that lipid peroxidation of cell membranes in the lung can be retarded by antioxidants such as vitamin E.

 Cellular Systems

 Pollution effects that depend on cellular integrity can be studied in free-living protozoans, cell cultures, or organ cultures. Nucleic acid synthesis, protein building, and reproduction are important processes that can be evaluated by addition of small amounts of pollutants. In the case of a one-celled animal called Tetrahymena, addition of methyl mercury causes a linear increase in the time between generations.⁴ It has been shown that protein metabolism is not affected in that system but DNA synthesis is inhibited.⁵

 The metabolism of the environmental carcinogen benzo(a)pyrene (BaP) is being studied in organ culture, cell culture, and isolated enzyme preparations.⁶ it is relevant to the question of species differences that rodent, monkey, and human tissues metabolize BaP in the same way. This is significant because BaP is carcinogenic only after it is metabolized. Exposures to airborne BaP in city dwellers in this country are equivalent to the doses received by light smokers.⁷

 Pathophysiological Methods

 The effects of pollutants on individual organ systems such as the pulmonary and cardiovascular systems can be evaluated by modified classical physiological methods. Some of these methods have the advantage of being adaptable for use with human subjects. Under well-controlled laboratory conditions, physiological responses to stress, such as running on a treadmill to exhaustion, can be evaluated before, during, and after exposure to controlled concentrations of gaseous pollutants.

 In studies more difficult to control—but more realistic—patients with angina pectoris have been exposed to ambient air in Los Angeles.⁸ The time required to produce chest pain by mild exercise was reduced after the exposure to ambient air containing high CO compared with low CO in the controls. Also, electrocardiographic abnormalities were more pronounced after such exposures.

 A physiological response in animals that closely resembles asthma in humans is the reaction to methacholine, a drug that causes respiratory distress by constricting bronchioles. The threshold for the methacholine effect can then be related to pollution concentration. In another asthma-like condition in animals that is produced by inhalation of sensitizing antigens, a high degree of susceptibility to ozone and nitrogen dioxide has been demonstrated.⁹

 Pathogenesis

 Some effects of pollutants are severe enough to cause identifiable structural damage. Controlled production of pulmonary lesions has been accomplished consistently in mice exposed to ambient Los Angeles air.¹⁰ Major chronic pathologic changes are produced in the alveolar wall. This effect is irreversible in older animals, whereas younger animals are more resistant to the chronic changes. The pathogenetic sequence is very reproducible: first, the endothelial cells forming the walls of capillaries undergo degeneration and cell death. Following that, the epithelial cells that are the wall of the alveolus itself undergo fragmentation. The most resistant structure in the alveolar subunit is the basement membrane.

 The resistance of animals to bacterial invasion is dependent on several protective mechanisms in the lung. Important among these is the macrophage system; a set of cells capable of ingesting foreign particles, including bacteria. Ozone and nitrogen dioxide both reduce the efficiency of the lung's protective mechanisms.¹¹ It is interesting that determination of the response to chronic exposures in these experiments was limited by the fact that rats were unable to inhale enough of their bacterial test burden after they had been exposed to ozone for a few hours.

 Epidemiological Studies

 Health effects inferred from epidemiological studies have been predominant in evaluating air quality standards up to the present. While this type of experiment theoretically could indicate the actual health costs to a population exposed to pollution, the results are measures of the degrees of association among variables, and do not directly address questions of mechanism. Nevertheless, in human studies, the "experiment in nature" is a noncontroversial form of human experimentation. Also, by carefully selecting target populations in advance, fairly high levels of control can be achieved. Such studies are being initiated among school children in three areas of the Los Angeles basin, and among asthmatics in urban areas.¹²

 Community air quality standards are set to reflect a balance between the costs and benefits of abatement measures. The costs of air pollution are evaluated in terms of both the "intrinsic" biological responses and the "extrinsic" value that society places on the effects. These qualities of value clearly distinguish the separate roles of "science" and "society" in the standards-setting process: Scientists are responsible for investigating and measuring intrinsic costs, whereas representatives of society evaluate extrinsic costs. The skills and knowledge required for these roles are distinct; nevertheless, there is an increasing tendency for the lay public to judge scientific merit according to the needs of technology or society.

 Poor understanding of the capabilities of biomedical science by funding agencies leads to unnecessary expenditures of funds for "implied research." This wasteful practice of pursuing unrealistic goals inevitably results from aiming at desirable applications without regard to the need for developing knowledge to apply.

 Maximal productivity in research depends on asking realistic questions and designing realistic experiments. Therefore, research can be expected to be much more productive when it is directed from the field by working scientists, rather than from the "top" by a funding bureaucracy.

 The systems and methods developed by scientists for determining the intrinsic effects of pollutants represent several levels of biological organization and complexity. They include biochemical, cellular, pathophysiological, pathogenetic and epidemiological techniques. The epidemiological methods are closely related to the evaluation of total human health costs of pollution, but these studies cannot provide "proof of causality." On the other hand, the basic physicochl-mical studies of mechanism are not useful for estimating the overall costs'. The entire spectrum of research is needed for an adequate assessment of the intrinsic biological costs of pollution.

 This report was prepared under the auspices of the U.S. Atomic Energy Commission. The author thanks the many people—scientists and laymen, public officials and private citizens—who have contributed to this project.

 2. D.E. Watson, "Comparative Environmental Costs of Various Energy Sources; a Perspective," in Proc. Health Phys. Soc. Sixth Ann. Topical Symp., Radiation Protection Standards: Quo Vadis, Vol. 2, pp. 366-376 (1971).

 3. J.B. Mudd, R. Leavitt, A. Ongun, and T. T. McManus, "Reaction of Ozone with Amino Acids and Proteins," Atmos. Environ. 3, 669-682 (1971).

 4. J.D. Thrasher, "Effects of Mercuric Compounds on Dividing Cells," in Effects of Drugs on the Cell Cycle, 1. F. Cameron and G. Padilla, Eds., in press, Academic Press (1972).

 5. J.D. Thrasher and J. Adams, "The Effects of Mercuric Compounds on the Generation Time in Tetrahymena pyriformis WH-14," Environ. Res. in press (1972).

 6. T.T. Crocker and L. L. Nunes, "The Effect of Cigarette Smoke Condensate, Air Pollution Composite, and Benzo(a)pyrene on Monkey Respiratory Mucosa in Organ Culture," unpublished document. (1972).

 7. D.E. Watson, The Risk of Carcinogenesis from Long-Term Low-Dose Exposure to Pollution Emitted by Fossil-Fueled Power Plants, University of California, Lawrence Livermore Laboratory, Rept. UCRL-50937 (1970).

 8. W. Aronow, C. Harris, and S. Rokaw, "The Effect of Freeway Travel on Angina," Ann. Intern. Med. in press (1972).

 9. Y. Matsumura, "The Effects of Ozone, Nitrogen Dioxide and Sulfur Dioxide on the Experimentally Induced Allergic Respiratory Disorder in Guinea Pigs: III. The Effect on the Occurrence of Dyspneic Attacks," Am. Rev. Resp. Dis. 102, 444-447 (1970).

 10. R.F. Bils, "Ultrastructural Effect of Air Pollution on Lung Cells," J. Air Pollut. Contr. Ass. 18, 313-314 (1968).

 11. E. Goldstein, W. S. Tyler, P. D. Hoeprich, and C. Eagle, "Ozone and the Antibacterial Defense Mechanisms of the Murine Lung," Arch. Intern. Med. 127, 1099-1102 (1971).

 12. S. Rokaw, Tuberculosis and Respiratory Disease Association of Los Angeles. California, personal communication (April 1972).