REGULATORY

TOXICOLOGY

AND

Adjudicating

PHARMACOLOGY

13,309-325 (199 i)

Cancer Causation: Scientific, Political, and Legal Conflicts GIO BATTA

The Health

Policy

Center,

GORI

6704 Barr Road,

Received

December

Bethesda,

Maryland

20816

19, 1990

Lawsuits concerning cancer causation resort to scientific argumentation. Yet, the apparent ambiguities of science confuse the courts, the juries, and the public. This is especially so with regard to official regulatory definitions of cancer causation that carry the weight of law. At the heart of this problem is a prevailing misunderstanding of science and the scientific method, and of the limits of current scientific knowledge about cancer. Moreover, current regulatory policies encourage the public to perceive official cancer risk assessments as if they were scientifically derived and accepted, even though official fine print readily admits they are not. Some recent court decisions have begun to recognize these difficulties with a body of precedent, and this may result in future rulings influenced more by objective appraisals than by reliance upon official but contingent assumptions. 0 1991 Academic PRSS. 1~.

INTRODUCTION In advanced societies, infectious diseases gradually decreased during this century in the wake of economic and public health advances. The resulting longevity gains shifted prevailing causes of morbidity and mortality to chronic diseases linked to age, of which cancer is arguably the most dramatic example. Although cancer research has been endowed with massive funding, there is a persistent frustration in defining cancer causation. Here, science is still a sophisticated guessing game dominated by several intriguing hypotheses, whose prominence is more a function of trendy technologies than of conclusive experimental evidence. At the same time, empirical tests have found that many man-made chemicals can induce cancer in animals, usually after unrealistic high dose challenges for lifetime. The reasons for these outcomes remain elusive, nor is there objective evidence as to their relevance to natural exposures at low doses in man or animals. Such “positive” findings seem to have no counterpart in the real world, where an increase in overall cancer incidence in advanced industrial societies is not apparent (1, 2), despite a massive increase in the production of man-made chemicals and their pervasive intrusion into the environment. Nevertheless, a public impression of a cancer epidemic caused by man-made chemicals has emerged from animal studies and from a few epidemiologic correlations with 309 0273-2300/91 $3.00 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form resewed.

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excess cancer for some high exposure occupations. Consequently, federal and local legislatures were motivated to establish new regulatory agencies, which were empowered by statutes that presume a factual scientific understanding of cancer causation. Since this in reality is not available, the classification and regulation of substances that may cause cancer are unable to meet rational standards of scientific objectivity. Prodded by their statutory mandates and by the activism of legislative oversight committees and advocacy groups, regulatory agencies found they could operate only by adopting “default assumptions” or “principles” of cancer causality, which they codified as official mandates for prudent action. Some of the most important of these assumptions are that epidemiologic correlations are sufficient proof of causality, that results in mice and rats treated with maximum tolerated doses for lifetime are valid predictors of human risk, that negative epidemiologic or animal results cannot prove safety, that thresholds of exposure do not exist, or, conversely, that there is an effect in response to a single suspected molecule. As could be expected, often these default assumptions have been challenged in legal regulatory disputes and have not survived tests of rationality and even reasonableness when closely analyzed (3). On the other hand, the same assumptions have been allowed to be perceived by the public as the final answers to questions of cancer causation, as if in fact they were scientifically founded. In this guise they have encouraged and supported many lawsuits seeking compensation for alleged damages or even fear of damages. Recently, however, regulatory agencies have been increasingly open about the political rather than scientific nature of their procedures for cancer risk assessment. This, and a better appreciation that not all of science is factual knowledge, have begun to influence judicial outcomes more deferential to traditional standards of objective evidence. The arguments for such changes become apparent from a more detailed analysis of the science involved and of the limitations of epidemiology and animal experiments. SCIENCE

AND THE

SCIENTIFIC

METHOD

Science is the rational art of understanding reality. It proceeds according to the scientific method, of which the fundamentals are: * Science measures only what is observable. * Physical observations and their measures are uncertain to varying degrees because of the relativistic nature of matter, the inevitable approximations of measurements and measurement tools, and the limitations of human senses in using these tools. * In addition to the systematic indexing of natural events, science produces mechanistic cause/effect hypotheses. Because of uncertainties in observation and measurement, hypotheses are provisional to a degree that varies from virtually undetermined to virtually certain. Validation progresses from consistency of measurements to experimental reproducibility of cause/effect sequences, to logic and mathematical consistency, to the elimination of competing hypotheses of causation, and ultimately to the experimental proof of cause/effect predictions, with the disappearance of effects once the presumed cause is removed. Besides knowledge regarded as factual, science includes theories and hypotheses in various phases of verification. Ultimately, science has predictive ambitions: in its practical applications only virtually certain scientific knowledge is suitable for objective

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decision making, where inevitable residues of uncertainty and approximation can be ignored. Virtual certainty, in turn, derives from rational standards of causality. THE CONCEPT

OF CAUSALITY

Causality recognizes mechanistic sequences of events, which in the physical world are defined by observation. Earlier philosophers were impressed with the logical rigor afforded by rational abstractions and were openly suspicious of physical observations. This mistrust was formalized by Hume who affirmed that no amount of repeated observation could establish absolute proof of causality, because the possibility of a spurious association could never be ruled out. A long chain of thinkers ending with Karl Popper and his followers have not resolved this apparent problem (4), and yet observation-based science has progressed beyond anyone’s dreams. One can argue that the issue raised by Hume is incomplete because logical symmetry demands the mirror argument of equal validity, namely the possibility that a string of repeated associations may not be spurious. The two arguments appear mutually destructive and irrelevant, while objective observations endure. Today we accept that physical reality is not precisely definable as abstract concepts and that only hypotheses can be formulated, with a probability of proof that varies from slightly less than one to slightly more than zero. However, the utilitarian application of science and the semantics of daily language and human behavior recognize a discontinuous nature of decision making. Existential choices, exemplified by yesno, here-and-not-there, these-and-not-others dilemmas, lead to nonambiguous quanta1 decisions with a confidence that depends on the predictability of the situation. In common language, causes that are sufficient to produce a given outcome are accorded the highest predictability, such as for gravity and falling bodies. Next are causes that are not always sufficient to produce a set outcome, but that are necessarily present for the outcome to happen, for instance, the pathogens of infectious diseases. With the understanding that the same outcomes could have more than one sufficient or necessary cause, such concepts of causality and predictivity are the only ones that allow rational people to reach decisions with virtually absolute confidence. Sufficient and necessary causes relate one-to-one to individual outcomes. However, other events may associate with given outcomes with statistically variable frequencies, being present only at times. This implies that such outcomes have multiple determinants that appear neither sufficient nor necessary, but each raising intriguing questions about possible involvement. Examples are the associations of air pollutants and climatic factors with global warming, market determinants and stock price trends, socioeconomic factors and birth rates, and the multifactorial determinants or cancers and cardiovascular and other chronic diseases. In general these associations are open to many interpretations and vary from being perceived as near truths to being hints, guesses, feelings, and superstitions. The degree of their credibility is determined by our accuracy in excluding the role of other factors that associate with a given outcome and in defining mechanistically the partial causal roles of the remaining factors. In fact the difficulties of science lie not with conundrums such as Hume’s argument, but rather with the difficulty of identifying true causes, given a very complex reality and the continuous danger of mistaking for causes what simply correlates without any causal function.

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In the difficult relationship of science and regulatory policy, much that is uncertain derives from the immaturity of certain multivariate scientific hypotheses and from their inability to generate causal statements that are universally acceptable. This uncertainty is especially noticeable with cancer, but also with ailments such as cardiovascular diseases, emphysema, allergies, late neurological or immunological deficiencies, and others, all construed as being influenced by low-level long-term exposures to many potential hazards. So far as is known, such disorders correlate with multiple suspected determinants that individually seem neither necessary nor sufficient; indeed, a persistent lack of mechanistic understanding frustrates even an objective definition of the presumable partial responsibility of any one of these factors. This conclusion is sustained by a closer examination of the fundamental constraints of the epidemiology of multifactorial diseases, and of the limitations of animal tests as predictors of human risk. EPIDEMIOLOGY

AND CAUSATION

As a discipline concerned with statistical generalizations, epidemiology deals with the lives of many people and understandably becomes an exercise of political significance and the instrument of public health policies and social intervention. Early in this century, the need and ability to control infectious diseases gave impetus to modern epidemiology. Infections are relatively simple to study because they have well definable causes, not always sufficient but always necessary. Here, inferences of causality can be made in a rational framework and to a level of detail that includes persuasive mechanistic observations and/or the elimination of diseases, thus confirming beyond reasonable doubt the attributions of causality. Although we have made impressive advances in the pathogenesis of cancer and cardiovascular, chronic respiratory, and neurological diseases, no one has succeeded in solving their proximate causes or their biological mechanics, nor have we learned to control or prevent them beyond a few limited exceptions (5, 6). The reasons for this impasse are many. The formation of cancers, for instance, is strongly dependent on physiologic determinants linked to the inevitable deteriorations of aging. Also, the insults which seem to induce, promote, or precipitate the onset of clinical cancers are many and likely to operate through a variety of biologic pathways (5,6). This implies the probable existence of multiple causal components in any causative cascade of events and for any single disease the probability of many causative cascades, each with a different chain of causal components. Is there a hope to identify definitive causes-sufficient or necessary-in a situation like this? The answer is probably yes, but not likely through epidemiologic investigations that study multifactorial diseases in a simplistic, end-result, black-box approach without the benefit of biologic mechanistic information. With these limitations current epidemiology can be expected at best to identify factors associated with a given disease, but whose causality remains hypothetical. Future biologic research may discover prime molecular mechanisms that trigger cancer, the factors necessary for its progression, and the pathogenic potential of various internal and external insults, including man-made substances. Until then, epidemiology could have only a modest role. By any rational analysis, current epidemiologic definitions of cancer causes remain as clues derived from associations and elevated to the status of causes by acknowledged policy demands. Various allusive terminologies-

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besides causes-have been used in epidemiology for these items, such as risk factors, contributing factors, and cofactors. However, these definitions are presented with an implication of causality that rationally and factually is not warranted. The term “causoids” has been suggested as a more accurate descriptor of their uncertainty (7). In fact, epidemiologists found it necessary to create a new set of special criteria to deftne causation for cancer and other diseases of multifactorial origin. These criteria have required a departure from the lexical and rational ways of accepting inductive causal inferences, on the basis of arguments succinctly summarized by Rothman as he writes (8, p. 17) Despite philosophic injunctions concerning inductive inference, criteria have commonly been used to make such inferences. The justification offered has been that the exigencies of public health problems demand action and that despite imperfect knowledge causal inferences must be made.

This statement says that political imperatives shall override logical and scientific consideration when policy so requires. By this admission-widely shared-modern epidemiology appears to have become subservient to policy in its readiness to relax rational scientific standards. The criteria used by epidemiologists to extract causal meaning from causoids originated with the 1964 Surgeon General’s report on the effects of smoking and were later formalized by Hill (9) and elaborated on by Rothman (8), Susser (lo), and others. The first criterion refers to the numerical strength of the association, including doseresponse gradients, although a number of strong but spurious associations may be identified in most instances. The second is the consistency of the association in different studies, although consistent bias would produce consistently biased results. The third is specificity of a cause resulting in a single effect, an unlikely happening for multifactorial diseases. The fourth, temporal sequence, means that a cause must precede the effect and is obviously a prerequisite but not a guarantee of causation. The fifth, coherence, refers to biological plausibility, which appears difficult to define in the absence of acceptable mechanistic understanding of the diseases involved. Coherence with a mechanistic hypothesis is not persuasive of causality until the hypothesis is clarified. The sixth is experimental evidence, which for most chronic diseases of man is apparently not yet available. Other criteria such as plausibility and analogy are intuitively much weaker. Susser added predictive performance as perhaps the most important criterion (lo), but so far attempts at predictive verification have generally failed with multifactorial diseases ( 11, 12). Many flaws have been suggested to affect the causal claims advanced today for chronic diseases. Critics have classified numerous sources of methodological bias: systematic bias and random bias; standardization, diagnostic, and classification bias; exposure assessment bias; case-control versus cohort studies; questionnaire bias; data processing bias; publication bias; and others (13). However, a principal source of error seems to be the propensity to make studies more manageable by formulating simple experimental hypotheses despite the obvious complexity of the corresponding reality, It appears intuitive that the epidemiology of multifactorial diseases is bound to be naive until we formulate realistically complex hypotheses and test at least those that appear more plausible. Today it is understood that potential carcinogenic agents are naturally ubiquitous and probably more numerous than manmade entities. Even greater amounts of potential carcinogens seem to be produced continuously inside our bodies as by-products of our own metabolism or by our intestinal bacteria (14-20). Substantial amounts of

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natural radioactive isotopes are found in our bodies. Our environment and food are naturally radioactive and contain significant amounts of substances that are carcinogenic in animals (14-19, 21). We truly live-and man has always lived-in a sea of potential carcinogens. That most of us endure to ripe old age testifies to the efficient natural defenses that evolution has provided. According to global estimates most cancers appear to be associated with dietary and other lifestyle factors and natural radiation, with only l-4% being possibly associated with exposures to man-made entities (22-24). However, other studies indicate that most foods and many drugs and chemicals suspected as carcinogens are also essential elements of life processes and ultimately of disease prevention and of survival. Thus it is not surprising that besides saying that food is probably the most important source of cancer determinants, it has been so far nearly impossible to sort out specific causal elements in the diet with any objective satisfaction. When we attempt to do so, seemingly insurmountable contradictions and competing hypotheses become apparent and frustrate the process. What causes lung cancer? Published studies have identified over two dozen independent risk factors for lung cancer. However, the U.S. Environmental Protection Agency assures us that natural radon exposure accounts for up to 25% of annual cases in the United States (25). Others assert, on the basis of epidemiologic studies, that as much as 10% of annual cases are caused by asbestos exposure (26). A few years ago, a panel of senior epidemiologists and scientists from the National Cancer Institute and other federal agencies stated that as much as 40% of lung cancer is caused by occupational exposures, a conclusion supported by the International Agency for Research on Cancer (27-29). The U.S. Surgeon General states that 90% of annual cases are caused by cigarette smoking (30). Several other independent risk factors for lung cancer have been reported (3 1). While many understand the political motivations behind these claims, a commonsense observer can see only that there are not enough lung cancer cases in the United States to account for these competing claims and would be understandably puzzled, more so when hearing that the many causes of a disease may account for more than 100% of its attribution. Rothman again writes (8, p. 14) There is in fact no upper limit to the sum . being constructed; of disease attributable to various causes is not 100 percent but infinity.

the total of the proportion

Theoretically this statement could be belabored if all the so called causes of a given cancer were in fact necessary parts of each possible set of distinct causative chains, but observation shows that people develop a given cancer even in the apparent absence of one or many of the putative causal factors identified. While this statement could not mean that more than 100% of any disease can be prevented, some epidemiologists often advance a complementary argument. This sustains that if, for instance, statistical correlation attributes a certain percentage of a cancer’s incidence to an apparent risk factor, then such a factor has the same percentage of causal responsibility when that cancer occurs in a single exposed individual (32). In reality this is not a permissible inference, because statistical conclusions are valid for groups and not for individual members of any group. As a pertinent analogy, a patient can draw little comfort from knowing that a forthcoming operation has an 80% rate of success: there is no objective way to know in advance from such a statistic alone whether that patient will meet with success or failure. Moreover, the cancer present in an individual can have any

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one or many independent causes, in multifactorial combinations that are impossible to unravel and ascertain epidemiologically. In this atmosphere of ambiguity most epidemiologists have become pessimistic. For instance, it seems plausible that while yet unknown multifactorial complications prevent ascertaining the causal meaning of positive associations, negative findings should give confidence that the exposures under study are not invariably significant causal operants. If they were, no negative effects could be expected from well-conducted studies (33). To say that-because of limited sensitivity-negative results do not rule out possible causality seems to paraphrase Hume’s metaphysical argument, one that could not be proved or disproved in factual terms. Pragmatically it appears a sophistry of no concern in decision making. If well-run epidemiologic studies of adequate statistical power fail to detect risk, they should be sufficient evidence for all practical purposes. Failure to accept it as such would seem to turn the clock back to those dark ages when irresolvable arguments and irrational fears wasted individual lives and the better energies of mankind. Today epidemiology speaks at best of putative risk factors or causoids of most chronic diseases. Even in occupational studies, where the overall variables may be considerably fewer, inferences of causality appear stronger, but are confirmed only in those situations where removal of the presumed cause leads to eliminating or reducing the disease. At the opposite end of the reliability spectrum are the dubious associations that occasionally emerge from the statistical sifting of generic data bases (13). Here, culturally and politically driven suspicions, not science, seem the real motivators of both value judgments and public and private decisions. What legitimate roles causoids should have in public health can be argued, but it is undeniable that they are official determinants of public policies. When using imperfect epidemiologic data, health officials and regulators claim statutory prerogative on two assumptions. One is that no other information is available: the other is that the public has nothing to lose and perhaps much to gain from decisions taken in the name of prudence (34, 35). With the former it is apparent that unreliable information may not endorse action. The latter would be tenable if we had a reliable understanding of the network of multifactorial determinants of health and disease, but we do not. It is also necessary to face the failure to consistently reduce mortality in the numerous intervention experiments involving hundreds of thousands of subjects in the United States and Europe, whose lifestyles had been experimentally modified, based on superficial epidemiologic inferences ( 11, 12, 36-39). With perhaps two dozen exceptions, the same is valid for environmental or occupational exposures to the vast majority of man-made substances, for which epidemiologic studies of massive proportions seldom have uncovered discernible evidence of risk. Against all this, the historical scenario of a spectacular expansion of industrialization speaks of overall falling cancer rates (1, 2), and increasing longevities. In fact epidemiology appears so inadequate in providing reliable evidence of cancer causation for specific agents that regulators were forced to seek answers from animal studies. EXPERIMENTAL

ANIMAL

DATA

AS PREDICTORS

OF HUMAN

RISK

Our culture deems it unethical to utilize prospective epidemiologic studies for testing agents or situations that could possibly cause harm to humans. Such cases call for animal tests.

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We distinguish short-term or acute from long-term or chronic animal tests. The former lasts from minutes to several days, the latter from months to the lifespan of the animals. Short-term tests identify immediate effects on cells, tissues, organs, or the whole animal, and usually test agents at restricted sites-e.g., the eye, nose, skin, etc.-or at relatively high systemic doses that would not be tolerated or permit survival in the long term. Despite recognized diversities, immediate responses are qualitatively analogous in different organisms, and short-term tests give reasonable trans-species approximations of acute effects. On the other hand, the dosing of test agents in long-term assays by definition must not produce short-term effects and must be tolerated at least marginally for lifetime. Tolerance levels and the long-term reactions of different animals to subtoxic doses are quite different, given often gross differences in genetic, somatic, metabolic, immunologic, physiologic, pathologic, experimental, and environmental conditions. Such differences increase and mutually amplify each other over time. This causes chronic test outcomes that are quite divergent among species at the end of lifespans and that essentially prevent trans-species comparability. Indeed, the prediction of human cancer risk from rat and mice data has required the official imposition of statutory, nonscientific assumptions-“default assumptions” in the jargon-much as it has been happening for epidemiology. The current official definition of carcinogens is also a black-box/end-result one, for lack of mechanistic understanding. It defines carcinogens as agents that increase the natural incidence of cancer in animals or that shorten the time usually necessary for their appearance (40). The problems with this definition are many. On one hand, animals experience erratic rates of natural cancer incidence from unknown natural causes; on the other, tested agents do not exist in isolation but act on organisms while interacting with a number of simultaneous conditions that are largely uncontrollable, such as genetic differences, diet, environment, experimental handling, diseases, stress, and so on (41). Although the specific mechanisms of cancer causation are still unknown to science, clinical cancers appear to be the outcome of a cascade of events over time, rather than the result of a sudden or single fatal injury from any single agent (5, 6). Observation shows that cancers occur spontaneously in nature, their frequency modulated by innumerable operants and not by single identifiable causes. Even when agents are tested in animals, the results are inevitably influenced by many uncontrollable confounding factors, most of them unknown and undetectable. The Occupational Safety and Health Administration of the United States listed in 1980 some three dozen thorny issues raised by animal tests (42). Ten years later these questions have not found scientifically objective answers that would justify animal testing, while much contrary evidence has been accumulating. On the question of why animal tests are nonetheless prescribed by official regulatory policies, the reply is that there is nothing else available as a means of testing and therefore animals must do, which means that political expediency has imposed this as a surrogate of scientific legitimacy in human cancer risk assessment (34, 35). Unfortunately, science cannot be instructed by statutory pronouncements. According to recent studies, the reproducibility of some animal tests is apparently the result of the mandated use of maximum tolerated doses (14-17, 43, 44), a condition that is both nearly lethal and rarely encountered in natural settings. Toxicity is likely to be a good predictor of carcinogenicity, because its persistent insults generate conditions that favor and enhance the expression of cancer determinants naturally present in all animals

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(14-17, 44). In this regard, the analogy of a person forced to drink 1500 cans of diet soda a day for lifetime has been a popular and sobering stereotype. Official statements also justify maximum tolerated doses as a means to make up for the numerical disparity between a few hundred experimental animals and the much larger human population they are said to represent (34, 35). High doses, however, lack scientific qualification as surrogates of statistical power. Animal experiments seem to be further biased by the requirement that the most susceptible animals should be employed (34,35,43-45) and that positive results should take precedence (35, p. 33,999). In reality, susceptibility appears to be different among animal species and in man, challenging the meaning of animal data in estimating human risk. Results of numerous tests conducted by the National Toxicology Program over the last 15 years have been tabulated and show that animal tests provide data of dubious human relevance (43, 46-49). For instance, one review indicates that only about 20% of results were positive in both sexes of rats and mice, 3 1% were concordant for species only, and 46% were not concordant either for sex or for species (47). In a more familiar metaphor, this would correspond to trying turning right in a car that turns right only one out of five attempts, other times not turning at all or actually turning left. Such lack of consistency between sexes of the same species and between closely related mice and rats would seem to invalidate the free transcription of rat data into mouse equivalents and to cast even greater doubts on the significance of rodent data to human risk assessment. Man is not a big rat, and the obvious physical and metabolic differences are well known (50-55). Yet, official policy dictates that a single carcinogenic response in any species is sufficient for the universally valid classification of a carcinogen (35, pp. 33, 995, 33, 997). Defenders of animal assayscontend that species differences in carcinogenic response may be quantitative but not qualitative, suggesting that proper dose/duration regimens would cancel out sensitivity differences among species. This argument, however, seems to ignore that carcinogenesis in certain animals is known to depend on metabolic peculiarities specific to those animals and not to others (consider for instance melamine, saccharin, BHT, formaldehyde, d-limonene, and others) and that negative results in one species but not another dispose of the sensitivity argument, after testing at MTD levels for lifetime. Of special interest is the controversial meaning of mouse liver tumors (hepatomas), easily induced by a variety of compounds. The inherent uncertainty on this issue is magnified by the inability of different pathologists to consistently classify and interpret benign or malignant, neoplastic, hyperplastic, metaplastic, or metastatic lesions of the mouse liver (56, 57). An extensive review has shown that laboratory mice have an extremely high incidence of liver tumors under natural conditions and without any apparent challenge (58). This natural incidence can fluctuate from year to year in the same strain, and widely different results can be obtained after testing the same compound in different experimental settings. Liver lesions peculiar to mice usually are associated with local liver toxicity, by now a well-recognized factor in experimental carcinogenesis (43) but with no demonstrable counterpart in human risk. Complications also derive from the official practice of pooling benign and malignant lesions as if they were all malignant (35, p. 33, 997). A further dilemma often arises when a test agent protects the animals against certain tumors while enhancing others, suggesting it may be also an anticancer substance. This paradox is apparent in numerous

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studies, but is uncomfortable and ignored in regulatory decisions (59). It seems inescapable that the standard mouse and rat tests are unreliable as predictive models and may provide no better credibility than tossing a coin in assessing putative human risk. This disconcerting state of affairs is best summarized in a report of the International Agency for Research on Cancer, a branch of the World Health Organization of the United Nations and traditionally an advocate of animal testing. The Agency felt obliged tostate that “. . . at the present time a correlation between carcinogenicity in animals and possible human risk cannot be made on a scientific basis. .” (60). If so, it would seem reasonable to ask on which basis is the correlation made. A few years back the Director of the National Toxicology Program testified in Congress that the interpretation of animal data is not a scientific enterprise, but rather a mystical experience that requires-in his word-faith (61, p. 52). Without faith, and only on the basis of objective scientific reasoning, he testified that very few substances could be qualified as human carcinogens and regulated accordingly (6 1, p. 57). The dialectic of official default assumptions has been further extended to the manipulation and interpretation of animal data, as they are fed to mathematical models developed around simulated risk dimensions and assumptions, but incapable of curing the biologic deficiencies of animal data. Ideally models should provide factual information which could then become the object of reasoned prudence; yet current models appear unable to even verify prudence. The intrinsic uncertainty of the data is stretched by the compounding concatenation of “conservative” assumptions imposed on the models, which are forced to produce seemingly sophisticated numerical results that the public is asked to accept at face value. For instance, official models for cancer risk assessment are based on dose/response functions justified by the “multistage” hypothesis of carcinogenesis. Mathematical renditions of this hypothesis-and its derived linear multistage models-have filled numerous publications with increasing complexities of numerical elegance, however strange they must appear to observers aware of the virtual absence of verifiable experimental support. The usual statement that the data fit a given function would seem lame, since a number of functions could fit the three or four high dose data points that most experiments yield. Indeed there is no objective evidence to predict what the response might be at realistic low-level exposures in man or animals for virtually all substances tested. Official pronouncements imply that there is a consensus about the validity of modeling and of using animals in carcinogenicity testing, but apparently no consensus exists even among modeling experts (34, 61-68). A few years back, the U.S. Occupational Safety and Health Administration (OSHA) published examples of risk assessment estimates using different models, which for the same substance and based on the same animal data project estimates that vary over a 10,000,000-fold range (68). This is because all models are open to the most disparate and arbitrary assumptions and produce results that are not scientific, but rather the apparent reflection of the social, political, or institutional agendas of their originators. Federal testing guidelines for carcinogens, issued by the Office of Science and Technology Policy of the White House, acknowledge that the entire official framework of animal testing for carcinogens and its interpretation are based on a set of default assumptions dictated perhaps by prudence, but that cannot be scientifically justified (34). OSHA also recognized these currently insurmountable difficulties to objective scientific verification (69) and several scientists have warned repeatedly about the

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unscientific use of animal data of undeterminable significance 70a, 71). Yet, these guidelines have continued to impose the overriding positive outcomes in animal tests must be related to corresponding that negative results cannot prove safety. A substance is hazardous while no proof of safety is admissible (34, 35).

(14-17,

41, 70,

assumptions that human risks and until proven safe,

CONCLUSION Scientific uncertainty about cancer causation and cancer risk in man, either with epidemiology or with animal testing, lingers, rare exceptions notwithstanding. This is because the pertaining scientific hypotheses are still in the early steps of verification and much closer to the uncertain than to the virtually certain in the range of causal inference. Consequently, they seem powerless in providing rationally defensible guidance in decision making. Yet they are the basis of far-reaching official regulatory actions and many argue that if government authority finds reason to regulate, then risk must exist. Unfortunately few are in a position to understand and distinguish between the objective limitations of science and the autonomies allowed regulatory agencies. Because of statutory obligations and prerogatives, regulators elect to appear prudent and concerned when facing uncertainty. Prudence is in fact the overriding criterion when assessing future putative probabilities of cancer risk in man, an exercise that in rational scientific terms seems to remain illusory, with a handful of exceptions. Regulators run cost/benefit estimates and eventually arrive at judgmental decisions in carcinogen regulation on the presumption of saving lives efficiently (24, 34, 35,62, 72). In this proce 7, they must find ways to set in action legislative mandates that both reflect and ignite public concerns and fears. They must be alert to the shifting congressional currents vying for voter attention, to the prodding of advocates and the media, to the reactions of regulated interests, and to their own survival in a political minefield. Safety regulation and public health policies on cancer have made liberal use of intellectual authority borrowed from the spectacular success associated with the control of infectious diseases, where clearly definable causes have led to control measures whose rationality is universally obvious. However, regulatory decisions are not easily accepted even in the presence of more obvious evidence, as with motorcycle helmets, car seat belts, industrial accident prevention, and acute exposures to hazards. They become much more difficult and controversial when regulators are unable to offer rationally defensible causative hypotheses. Yet regulate they must. No one could deny that public health policies could be formulated even in the absence of firm evidence of causality, but it would seem equitable also to define some bounds to the use of uncertainty. Before suspicions of causality are officially stated and policies imposed on grounds of prudence, it may be reasonable to ask that at least the most obvious competing hypotheses should be adequately scrutinized, rejected, or factored into provisional verdicts. Foremost, this would imply the rejection of regulatory proposals based solely on hypothetical conjectures that something might happen. Such should be the intuitive minimum standards of rational, fair, and sustainable policies, because their absence inevitably opens attractive incentives to officious posturings of prudence, which the record shows to have been seldom resistible. In today’s

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regulatory context prudence is no longer some abstract ethical concept but a commodity of vast economic implications. It should be of concern that its administration may have been left virtually unsupervised in the hands of vested bureaucratic and advocacy interests, creating what seems to be an independent regulatory economy prone to use prudence as much for its institutional survival as for a presumption of public safety (62). To be operational, agencies have been persuaded to develop ritualistic procedures embedded in official “guidelines” that have acquired the value of law for all practical purposes. These guidelines are reluctantly modified, with an eye to preserving credibility and to avoiding legal repercussions. It is illuminating to recall the closing words of the initial draft report of a review committee (45) that suggested substantial modifications of the operating procedures of the National Toxicology Program (NTP): NTP should assessthe effectsof modifications and enhancements in the bioassay process on the validity of the results obtained with previously tested agents. In any case, where a comprehensive audit raises serious questions about the results or interpretation of the study, the need for retesting should be considered.

Such words, which did not appear in the final report of the Committee, open chilling legal prospects and arguments that run against substantive procedural changes. Innumerable conferences and discussions have been held to analyze and explain the anguished philosophy of regulating putative human carcinogens. In over 20 years the issues have changed little, because scientific uncertainty has not improved. What has changed with time is a still-guarded willingness to acknowledge the political essence of human cancer risk assessment and the persisting want of objective scientific endorsement. One of the latest examples of a candid dialogue in the sunshine took place at a symposium organized by The Rockefeller University in May 1989 (73). Participants represented government, Congress, regulators, industry, academia, advocates, and the media. The report of this symposium is perhaps the most clear admission to date of the continuing frustration in providing credible answers. The report reveals why regulators have no choice but to fall back on “default assumptions,” such as that mice and rats are human proxies, that maximum tolerated doses surrogate for statistical power, and that no thresholds exist. An insistent preoccupation of the participants was how to make cancer risk assessments credible to the public, to Congress, andas it appears-to themselves as well. In the end there were and there are no solutions in sight, not even “consensus” solutions. Different agencies appear to have different constituencies, different agendas, different standards and default assumptions, and different perceptions of prudence, and could not even agree on what research to pursue. Here, as in many court proceedings, the limitations of most experts in cancer causation are fully exposed, as they merely succeed in defining uncertainty at finer levels of detail before being forced to admit an unresolved dearth of evidence or the untenable pretense of personal opinion. Today, regulators concede openly that their decisions are based on judgmental prudence and faith and have only a meaning of hope (34,6 l), because it is impossible credibly to predict whose lives might be saved and how many, or whether in fact lives will be saved or lost (72). Faith, hope, and prudence may be suitable political motivators, but they seem hardly acceptable in determining factual responsibilities in court proceedings that rely on principles of fault by a “more probable than not” standard. Under the Administrative Procedures Act of 1946 and its later interpretations (74)

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proposed agency rulings have been repeatedly challenged on legal, administrative, and scientific grounds, as in the cases of benzene (75), urea-formaldehyde foam (76), ethylene dibromide, Alar (77), and others. Similarly, several courts in tort lawsuits have been persuaded to distinguish between policies based on faith and hope, and more objective requirements of evidence. During the last few years such courts have understood the artificiality of introducing inadequate epidemiologic or animal data in human cancer risk assessment. They have ruled such evidence inadmissable, because it is so unreliable that a jury could not find reasonable grounds for determining causality (78-90). In essence, these courts have discovered that not all science is factual knowledge and have understood that official cancer policies are construed by expert consensus not from scientific fact but from untested hypotheses, and under pressures of dubious objectivity (3,34,35). While these policies may be tried in support of politically and conceptually elastic public health programs, they cannot qualify as scientifically endorsed. The emerging perception of these inadequacies is likely to keep influencing a judicial trend toward restoring objective tests of evidence. Eventually this may begin to contain the flood of lawsuits that have relied on official doctrine to support allegations of cancer causality, as if they needed no further proof and against which no objective rebuttal could be conceived. Note added in proof: The author previously expressed some concepts and excerpts of this assay in Reference I.

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Cl0

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ROSE. G.. TUNSDALL-PEDOE, J. D., AND HELLER. R. F. (1983). UK heart disease prevention project: Incidence and mortality results. Lancet 1, 1062-1065. 40. Interdisciplinary Panel on Carcinogenicity (1984). Science 225, 682-687. 4 1. GORI. G. B. (1980). The regulation of carcinogenic hazards. Science 208, 256-26 1. 42. Occupational Safety and Health Administration (1980). Identification, classification and regulation of potential occupational carcinogens. Fed. Regist. 45 (15), 5002-5003. The actual questions are: 39.

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-Can strains with a high spontaneous incidence of tumors be used in carcinogenicity testing? -Does the presence of tumor viruses invalidate results obtained in mouse tests? --Is the spontaneous incidence of tumors in certain mouse strains unstable, and if so, does this invalidate positive results obtained in them? -Can liver tumors in mice be diagnosed reliably and consistently? --Is the induction of tumors in mice predictive of carcinogenicity in other species? -Can reliable results be obtained in inbred strains of rodents? -Are there other characteristics of rodents which would invalidate their use in carcinogenicity testing? -Should non-positive results in human studies outweigh positive results in animal experiments? -Should non-positive results in animal experiments outweigh positive results in other animal experiments? -What precautions should be taken to avoid placing weight on false-positive results? -How should OSHA deal with data of varying quality? -Do biological reasons make testing of EMTDs (estimated maximum tolerated doses) inappropriate? -How much weight should be placed upon the induction of benign tumors in animals as an indication of potential carcinogenic hazards in humans? -How much weight should be placed on the induction of a type of tumor which occurs spontaneously in untreated animals? -Are most routes of administration appropriate? -How much confirmation of positive results is necessary? -Can safe or no-effect levels be set for exposure to carcinogens? -Do bionutrients necessarily display thresholds? -Are there theoretical reasons to expect that a threshold exists at the cellular level? -Have thresholds in fact been demonstrated for specific carcinogens? -1s there a consistent relationship between dose and latent period that would result in a practical threshold at low doses? -Would the interaction among carcinogens invalidate the concept of threshold? -Should criteria or protocols be established for the conduct and interpretation of carcinogenesis bioassays? -Does OSHA need to review protocols of animal bioassays which yield evidence that a substance is carcinogenic? -Should OSHA prescribe protocols for design and execution of carcinogenesis bioassays? -Should OSHA prescribe standards for the interpretation of bioassay data? -Which factors need to be taken into account by OSHA in the interpretation and evaluation of animal carcinogenicity experiments? -How should OSHA determine whether positive bioassay reports meet scientific criteria for acceptability? -Should tumor promoters be distinguished from tumor initiators and regulated differently? -Should metabolic and pharmacokinetic information be used in the identification or regulation of potential carcinogens? -In what circumstances would metabolic and pharmacokinetic information serveto rebut a qualitative presumption of risk? --Is our present knowledge of metabolism and pharmacokinetics sufficient to be useful in practice? -Can specific procedures or criteria for the use of metabolic or pharmacokinetic information be laid down on the basis of our present knowledge? 43. BERNSTEIN. L., et al. (1985). Some tautologous aspects of the comparison of carcinogenic potency in rats and mice. Fundram. Appl. Toxicol. 5, 79-88. 44. ZEISE, L., et al. ( 1984). Use of acute toxicity to estimate carcinogenic risk. Risk Anal. 4, 187- 199. 45. Ad hoc Panel on Chemical Carcinogenesis Testing and Evaluation (1984). Draft Report P 121. National Toxicology Program, U.S. Department of Health and Human Services, Research Triangle Park, NC (February 15). 46. LAVE, B. L., ENNEVER, F. K., ROSENKRANZ, H. S., AND OMENN, G. S. (1988). Information value of the rodent bioassay. Nature 336, 631-633. 47. DI CARLO, F. J. (1984). Carcinogenesis bioassay data: Correlation by species and sex. Drug Metab. Rev. l&409-413. 48. HASEMAN, J. K., AND CRAWFORD,D. D. (1984). Results for 86 two-year carcinogenicity studies conducted by the National Toxicology Program. J. Toxicol. Environ. Health 14, 621-639.

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49. PURCHASE,I. F. H. (1980). Inter-species comparison of carcinogenicity. Br. J. Cancer 41, 454-468. 50. ALTMAN, P. L.. AND KATZ, D. D. (1979). Irnbred and Genetica& Dehned Strains of Laboratov Animals. FASEB, Bethesda, MD. Comparative Data for Young Males of Rats and Humans

Body weight (g) Surface (m’) Life expectancy (days) Basal metabolism kcal/kg/day kcal/day Food consumption (dry) g/kg/day kg/2-year lifespan kg/50-year lifespan

51. 52. 53. 54. 55. 56. 57. 58. 59.

Rat

Man

Ratio

400 0.048

1000

70,000 1.88 26,000

175 39 26

109 43.6

25.6 1,792

0.23 41

50

10

0.25

12.775

875

14.6

The rat has several pairs of mammary glands. has no gall bladder, does not menstruate, is multiparous, has profound metabolic differences and nutritional requirements, and has different protein degradation rates,enzymatic activity levels,and blood composition, The rat, unlike man, can synthesize ascorbic acid, is naturally coprophagous. eats its young, is nocturnal, and has evolved to thrive in ground-level natural environments quite different from ours. The relative weights of internal organs are usually smaller in the rat with the exception of the liver, and its gestation period is over twice as long in relation to lifespan. when compared with man (5 l-55). Equally strong differences exist for mice. TRIEB. G., et al. (1976). Toxicol. Appl. Pharmacol. 35, 531-542. BRODY, S. (1964). Bioenergetics and Growth. Haffner, New York. MITRUKA. G. M., AND RAWNSLEY, A. M. (1969). Clinical Biochemical and Hematological Reference l,hlues in Normal Experimental Animals. Masson, New York. MUNRO. H. N. (I 969). Mammalian Protein Metabolism, Vol. 3. Academic Press, New York. National Research Council (1978). Nutrient Requirements of‘ Laboratory .4nimals. 3rd ed. National Academy of Sciences, Washington, DC. National Academy of Sciences( 1977). Pesticide Information Review Evaluation Committee: An Evaluation ofthe Carcinogenicity of Chlordane and Heptachlor, pp. 7 and 15. National Academy of Sciences, Washington, DC (October 25). TAKAYAMA, S. (1975). Variation of histological diagnosis of mouse liver tumors by pathologists. In Mouse Hepatic Neoplasia (W. H. Butler and P. M. Newberne, Eds.). Elsevier, New York. BANNASH,P. (1983). Strain and speciesdifferencesin susceptibility to liver tumor induction. In Modulators of Experimental Curcinogenesis (V. Turusov and R. Montesano, Eds.). IARC scientific publication No. 5 I International Agency for Research on Cancer, World Health Organization. Lyons, France. WEINBERG, R. A. M., AND STOER.J. B. (1985). Ambiguous carcinogens and their regulation. Risk .4nal. 5,151-156.

60.

6 I. 62. 63. 64. 65. 66. 67.

IARC Working Group (1980). An evaluation of chemicals and industrial processes associated with cancer in humans based on human and animal data. Cancer Res. 43, l-52. RALL, D. P. (198 I). Hearing before the Subcommittee on Investigations and Oversight. Committee on Science and Technology, U.S. House OfRepresentatives,July 15, 1981. pp. 52, 53, 57. U.S. Government Printing Office, Washington, DC. U.S. Office of Management and Budget (1990). Regulatory Program of the United States Government. .4prill. I990-March 31, 1991. Government Printing Office. Washington, DC. World Health Organization (1974). Assessment of the Carcinogenicity and Mutagenicity of Chemicals, p. 13. Technical Report Series No. 546. World Health Organization, Geneva. Office of Science and Technology (1979). Identification, Characterization. und Control of Potential Human Carcinogens: A Framework for Federal Decision Making. p. 14. Office of Science and Technology Policy, Executive Office of the President, Washington, DC (February I ). CORNFIELD, J. (1977). Carcinogenic risk assessment.Science 198, 695. International Agency for Research on Cancer (1978). IARCMonographs on the Evaluation ofthe Carcinogenic Risk of Chemicals to Humans, Vol. 17, p. 20. IARC, Lyons, France. Occupational Safety and Health Administration (1980). Fed. Regist. 45 (15), 5200.

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68. Occupational Safety and Health Administration (1980). Methods for extrapolating dose-response data to low-dose levels. Fed. Regist. 45 (1 S), 5 184. 69. Occupational Safety and Health Administration (1980). Identification, classification and regulation of potential occupational carcinogens. Fed. Regist. 45 (15), 5061. ‘I. . OSHA recognizes that lhere may be no data which provide absolutely definitive evidence-one way or another [sic]-as to whether cancer is caused in humans by a substance that has been shown to be carcinogenic in test animals. OSHA states, however, that the failure to assume that such a substance does pose some level of carcinogenic threat to humans seems imprudent .” (emphasis added). 70. MILLER, J. (1983). Preface. In Orgun and Species Specificity in Chemical Curcinogenesis (Langenbach et al. Eds.). Plenum, New York, 1983. 70a.RUBIN. H. (1983). Letter to the Editor. ,Qiencc 219, 1170. 7 1. SHUBIK, P. (1983). Letter to the Editor. Science 220, I 126. 72. MORRALL. J. F. (1986). A review of the record. Regulation (November/December), pp 25-34. 73. The Rockefeller University (1990). Regulatory Management of Carcinogenic Chemical Risks: Report of a May 2-5, 1989, Svmposium, Wrightsville Beach, NC. Life Sciences and Public Policy Program, The Rockefeller University, New York. 74. 5 U.S.C. $55 1 I, 706(2)(A), 707(2)(E). 75. AFL-CIO v. API, 448 US 607 (1980). 76. GRAHAM. J.. ROBERTS, M., AND GREEN, L. (1988). Seeking Safety: Science, Public Policy and Cancer Risk. Harvard Univ. Press, Cambridge, MA. 77. JASANOFF,S. (1987). EPA’s regulation of daminozide: Unscrambling the messageon risk. Science Technology and Human Values 12, 1 Iti- 124. 78. Bernhardt v. Richardson-Merreli, Inc.. 723 F. Supp. 1188 (D. Miss. 1988). 79. Lynch v. MerreN-National Laboratories, 830 F. 2d 1190 (1st Cir. 1987). 80. Richardson v. Richardson-Merrell, Inc., 857 F. 2d 823 (D.C. Cir. 1988). 8 1. Viterbo v. Dow Chemical Co., 826 F. 2d 420, 424 (5th Cir. 1987). 82. In re “Agent Orange” Product Liability Litigation, 611 F. Suppl. 1223, 1241 (E.D. N.Y. 1985) affd, 818 F. 2d 1987 (2d Cir. 1987) cert. denied sub nom. Lombardi v. Dow Chemical Co., 108 S. Ct. 2898 (1988). 83. Lynch v. Merreil-National Laboratories, 830 F. 2d 1190. 1194 (1st Cir. 1987). 84. In re Paoli Railroad PCB Litigation, 706 F. Suppl. 358 (E.D. Pa. 1988). 85. Brock v. Merrell-Dow Chemical Corp., 874 F. 2d 307, 313 (5th Cir.), reh’g denied, 884 F. 2d 167 (5th Cir. 1989) (“animal studies of questionable applicability to humans”; “quite speculative”). 86. Rubanick v. Witco Chemical Corp.. 542 A. 2d 975, 984-4 (N.J. Super. L. 1988). 87. Ealy et al. v. Richardson-Merrell, Inc., Nos. 87-7214 and 87-7219, slip op. at 3 (D.C. Cir. March 9. 1990). 88. Dauber? et al. v. Merrell-Dow Pharmaceuticals, Inc., 727 F. Suppl. 750, 575-76 (S.D. Cal. 1989). 89. Ambrosini ef al. v. Richardson-Merrell Inc. et al.. No. 86-278. 1989 U.S. Dist. LEXIS 7568 (D.C. Cir. June 9, 1989). (“This Circuit has found, as a matter of law, that expert opinion testimony, which relies upon chemical structure analysis, in vivo. in vitro studies, or reformulated epidemiologic data, is not admissible.“) 90. Ambrosini et al. v. Richardson-Merrell Inc., et al., No. 84-3483, 1989 U.S. Dist. LEXIS 8036 (D.C. Cir. July 12. 1989). (Note. This opinion is exactly as above.)