Regulatory Toxicology

C H A P T E R

50 Regulatory Toxicology A R P A D SOMOGYI,* GIO B. GORI, * KLAUS E. APPEL* 9Federal Institute for Health Protection of Consumers and Veterinary Medicine, Berlin, Germany tThe Health Policy Center, Bethesda, Maryland

ollary arguments have raised additional questions about the potential conflicts of interest in the delegation of regulatory autonomy to unelected officials who--ostensibly free of most checks and balances-are expected at once to define hazards and risks, to produce the related normative writ, and to enforce the same with power of police, imposing fines, and even detention. At the same time, it is undisputable that the essence of government is regulation and that elected legislators generally lack technical expertise and cannot be expected to shoulder the volume and detail of work required to fulfill the regulatory needs and expectations of complex societies. These requirements have been universally construed to justify regulatory administrations with the authority to formulate and execute policies, usually restrained by the continuing oversight of elected representatives and the allowance of legal actions by citizens and organizations for or against specific regulation. Necessary as it is, the legitimacy and the bounds of the regulatory apparatus continue to raise philosophical questions and debate in modern societies. A detailed survey of such questions is beyond the scope of the present analysis, which will focus rather on the technical issues of regulation, although selected aspects of these questions will surface from time to time in the following pages. Getting closer to more practical aspects of regulation, our ideal social model would recognize that risks posed by hazards are inevitable attributes of living, that the attainment of a risk-free society is Utopian and could not be the goal of regulation, and that risk taking usually has a utilitarian counterpart. At the

INTRODUCTION

Toxicology--the science of poisons--meets real life when asked to help regulate and restrict the attending risks in a social context through appropriate norms. The framework of regulatory toxicology will depend as much on the philosophical premises and the cultural and ethical values of the society it is to serve as on the scientific objectivity and experimental verifications that define poison hazards. It follows that regulatory toxicology is interpreted differently in different countries, even when they profess to share the common social model of a liberal democracy. The differences account for often subtle nuances in what is considered the permissible reach of government's paternalism and on historically diverse levels of autonomy that public officials are granted in different societies. In seeking some common ground, we shall here assume a somewhat ideal social model generally protective of the rights to self-determination of citizens, who in turn accept mutual limitations on their liberties as social norms. What could be the philosophical and ethical underpinnings for regulatory toxicology in this model? The model's philosophy is fundamentally libertarian, although it allows a limited authority of regulatory intervention to the state. In practice, the bounds of these limitations are not fixed by general consensus but are modulated by continuing arguments pitting statist and libertarian views around such pristine questions as what could justify a coercive government interest in fostering longevity per se, in restricting voluntary risk taking, and in preventing risks whose existence often appear to be merely hypothetical. Cor-

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same time, a distinction is drawn between risks and costs that are voluntarily accepted and risks or costs that are suffered involuntarily, the latter being either naturally occurring or caused by the hazardous activities of other members of society. Because of utilitarian implications, the model recognizes the implicit value m however idiosyncraticmof voluntary risk taking to individuals (e.g., rock climbing), as well as the value to individuals and to society of certain hazardous activities that may subject members of society to involuntary risks or costs (e.g., pesticide uses). The understanding of regulatory toxicology would be incomplete without a clear vision of the different interests of toxicology as a science and of regulatory agencies as political constructs. While toxicologists should be interested in the experiment-driven truthseeking of science, regulators are under pressure to accommodate a variety of demands and expectations, which include the often idealistic intransigence of statutes under which they operate, their own institutional interests, the insistence of assorted advocates, the reactions of the regulated, and the inadequacy of toxicology and epidemiology in providing reliably objective input. In this regard, uncertainties frequently give regulators no alternative but to extend the meaning of tentative toxicological evaluations in order to justify the often exacting demands of legislation and the pressures of public anxieties. All things considered, it should not be surprising that attempts to accommodate various tensions have resulted in a regulatory practice based on contrasting and even contradictory principles and guidelines, the upshot of which has deeply affected toxicology. Regulatory agencies have developed their own toxicological laboratories and are a major source of funding for academic toxicology, a situation that has put increasing pressures on the profession to comply with the requirements of the agencies. The same agencies have provided guidelines for toxicological research to suit their needs and prescribe how toxicological investigations should be conducted, while the research supported by the agencies focuses on the solutions to problems and directions that the agencies perceive as useful to their goals and needs. The regulated industries develop toxicology usually in compliance with regulatory guidelines but also with confrontational aims, in a manner that also exerts a profound influence on research methods and priorities. Thus, in the end, it is inevitable that the administrative imposition of technical and scientific standards in the service of regulation eventually should affect the professional and intellectual Weltanschauung of toxicologists, many of whom are actually employed by regulatory agencies and the regu-

lated industries. This becomes especially evident when considering that regulators must act in a real time framework and cannot postpone until some distant research might (perhaps) provide better answers. They have to make decisions "here and now" on the basis of actually available knowledge. In principle and by necessity, regulators focus on moving targets and remain flexible and open to emerging new evidence, but at any given time they must seek definite and even particular answers, even though the scientific reality may permit only a range of more or less plausible conjectures.

THE SCOPE OF REGULATORY TOXICOLOGY Over the years, the scope of regulation and toxicology has expanded parallel to the development of global industries, which has multiplied the potential hazards to the environment, to health, and safety. In the United States, the European Union, and most other developed areas, regulatory toxicology covers most aspects of manufacturing, trade, and the environment. The following are some of the main areas of interest.

Foods The model for most food regulation in the world has been the 1906 Food and Drug Act of the United States, the basic language of which is unchanged today; it bars the marketing of food that contains added substances that may render it injurious to health, or that contains natural agricultural commodities that may be ordinarily injurious to health (FDCA, 1938). Regulations are usually applied to functional additives (e.g., colorants, sweeteners, tenderizers, emulsifiers, and bulking agents), and nonfunctional or indirect additives (e.g., residues of drugs used in animals, pesticide residues, and contaminants) that migrate to foods from contact with manufacturing tools and packaging.

Medicinal Substances Medicines for human use are the most stringently regulated substances in most countries. Unlike other substances, medicines are generally required to pass safety and efficacy tests in human clinical trials, usually after extensive preclinical experimentation in animals. For most medicines, approval depends on how favorable the ratio is between therapeutic efficacy and undesirable side effects, and their dispensation and use are regulated under strict medical super-

Regulatory Toxicology vision. Equally stringent requirements are applied to medical devices and veterinary medicines, particularly when the latter result in residues in foods for human consumption.

Toxic Substances Many countries regulate the production, storage, packaging, distribution, disposal, and use of substances that could pose hazards to health and safety. Agricultural and environmental pesticides are a special class of toxic substances that are usually more stringently regulated because they end up in the food and drinking water supplies. Here, too, economic considerations generally require risk-benefit considerations to enter in all regulatory decisions that may limit exposures.

Work Place Safety Permissible exposures of workers to toxic substances are regulated in many countries with widely different criteria and safety standards, and usually with decisive reliance on risk-benefit considerations.

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cosmetic colorants are handled under the strict guidelines that regulate potential carcinogenic substances. In the European Union, the Directive on cosmetic products includes a list of substances whose use is prohibited as cosmetic ingredients. In addition, it lists the substances that are allowed to be used only in certain areas of application or up to a specified maxim u m quantity. Three annexes list preservatives, UV filters, and coloring agents that have obtained final or limited authorization and specify the area of application, as well as maximum concentrations.

Consumer Products Consumer products, from toys to automobiles, are regulated in certain countries by agencies that evaluate their ultimate safety at point of use. In addition to sources of mechanical injury, these agencies focus on potential toxic, radioactive, corrosive, explosive, and flammable hazards, often joining forces with agencies that regulate other substances under different statutes. Here too, regulations are heavily influenced by risk-benefit considerations.

Air and Water Pollutants

PROCEDURAL FRAMEWORKS OF REGULATION

Legislation in various countrieshas been directed at reducing toxic emissions from stationary sources (e.g., manufacturing plants, mines, agricultural activities and runoffs, aquifers, and potable waters)as well as from mobile sources, such as cars and other transport. Given that the sources of pollution derive from activities of significant economic value, most regulations in this area rely on and are profoundly affected by risk-benefit considerations. Regulations may impose limits of emission for stationary sources and motor vehicles; quality standards for urban air, drinking water, rivers, and lakes; and controls for contamination levels in hazardous waste sites.

Different statutes create different regulatory philosophies in different agencies. Fundamental differences can arise in regard to "burden of proof" issues, that is, whether the statute requires the regulating agency or the regulated parties to provide proof of the safety of a product or procedure. In the United States, for instance, the Food and Drug Administration (U.S. FDA) regulates under the former requirement, but the Occupational Safety and Health Administration (U.S. OSHA) observes the latter approach. Similar situations prevail in other countries.

Mandates for No-Risk Tolerance Substances of Abuse Psychotoxic, addictive, and other substances that can be abused are usually prohibited, although many are permitted under strict regulation when they may have significant therapeutic efficacy.

Cosmetics In the past, the regulation of cosmetics has followed a more relaxed interpretation of the general guidelines of food and medicines regulation. More recently in most countries, notably the United States,

Often, governing statutes mandate a strict no-risk approach to regulation. The notorious precedent for this approach is the Delaney clause, introduced in the United States into the Food, Drug, and Cosmetic Act (FDCA) in 1958; this clause has influenced similar concepts in other countries. The clause is found in sections 409 and 412 of the FDCA and reads in part "that no additive shall be deemed to be safe if it is found to induce cancer when ingested by man or animal, or if it is found after tests which are appropriate for evaluation of safety of food additives to induce cancer in man or animal" (FDCA, 1958). Such a no-

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risk approach has been directed specifically at potentially carcinogenic substances, based on the overpowering public emotions on the subject of cancer and the resulting urge of legislators and regulators to adopt default assumptions that negatemat least in principle and theory--the possibility of safe levels for carcinogens. Because the Delaney clause would be triggered merely by carcinogenic results in animal tests, it has the potential of forbidding many of the significant products of science and technology. This is because animal tests for carcinogenicity have been designed to maximize positive outcomes and usually succeed in doing so in more than half the tests. In fact, positive carcinogenic responses in animals can be elicited by most common foods under favorable if extreme experimental conditions. In the United States, all sorts of compromises and legal and administrative stratagems have been devised, largely on the basis of explicit or implicit risk-benefit considerations, to permit the use of countless substances, from foods to medicines to pesticides, food additives, industrial chemicals, and their consumer derivatives. In the United States again, the clause has been partially neutralized by the existence of other "flowthrough" provisions of the FDCA. Section 402, for instance, provides for the regulation of pesticides in raw agricultural commodities at tolerances specified in section 408, but also permits pesticides in processed foods if the levels do not exceed those set out in section 408 for raw commodities. This statutory equivocation has been the source of some confusion, but at the same time it has been of much practical use as a counter to an absolute no-risk Delaney clause with the potential of causing impossible hardship to the overall food supply.

Substances in Traditional Use Regulation in the United States and other countries recognizes the implicit safety of substances that have been in traditional human use for long time, especially foods and common dietary components. In the United States, these are listed in the class of substances generally recognized as safe (GRAS). The regulatory recognition and approval of safety is specific for traditional uses but not for uncommon ones, so that a GRAS substance could be used freely in foods but not for medicinal or other uses (U.S. FDA, 1997).

A p p r o v e d Tolerances In theory, approved tolerances are issued for hazards that are not carcinogenic, although--as discussed m carcinogens too could be approved within

certain limits of use. For noncarcinogens, approved tolerances are defined by first determining a no observable adverse effect level (NOAEL), initially measured by animal tests and then transformed into human equivalents by suitable formulas. A further reduction of NOAEL values is obtained by the application of safety factors that cover a discretionary range from 10 to 10,000, depending on the uncertainties, cost benefit considerations, and the judgment of regulators. For instance, safety factors may be higher in the case of items for child use, or lower for occupational situations. Approved tolerances have different denominations in different regulatory settings. For foods, they are usually expressed as "acceptable daily intake" (ADI) levels; for occupational situations they could be "threshold limit values" (TLV) and "permissible exposure limits" (PEL) for peak exposures, or "short-term exposure limit" (STEL) and "timeweighted averages" (TWA) for prolonged exposures. Also used in occupational settings are acute warning levels, such as the IDLH, "immediately dangerous to life or health."

9 Threshold or De Minimis Regulation The concept that regulation should focus only on significant hazards has been around for a long time under the legal maxim that de m i n i m i s non curat lex. It has often surfaced in various regulatory settings as the concept of tolerable risk, variously defined as a 10 -6 risk or similar definition. Although discussed and proposed for decades the concept has been adopted only in 1995 by the U.S. FDA with the promulgation of threshold of regulation guidelines (U.S. FDA, 1995a). The guidelines exempt from regulation certain indirect contact food additives that could migrate from packaging or processing equipment, if their concentration does not exceed 0.5 ppb in the total daily diet. The effectiveness of this procedure continues to be tested, but it holds a promise of relieving much of the delay in regulatory decisions due to the administrative gridlock that trivial issues are known to cause.

R i s k - B e n e f i t Considerations In considering approval, regulators are usually required by law or compelled by circumstances to relax or restrict evaluation criteria based on cost-benefit tradeoffs. In the United States, for instance, the U.S. OSHA may only consider a standard that "most adequately assures, to the extent f e a s i b l e . . , that no employee will suffer material impairment . . . (U.S. OSHA, 1970). U.S. OSHA's test of feasibility depends

Regulatory Toxicology on whether risk-reducing technology may be available, and whether it can be economically provided. The U.S. Environmental Protection Agency (U.S. EPA) is required to conduct extensive risk and benefit balances before acting under the U.S. Toxic Substances Control Act (TSCA, 1976). Similarly the control of pesticides by the U.S. EPA under the U.S. Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA, 1972) is limited by the obvious advantages of their use in producing adequate food supplies, so that restrictions are applied only if the pesticide use may cause "unreasonable adverse effects on health or the environment." Risk-benefit considerations usually command the last word in actual regulation and could prevail over any other concern. A clear example is that of drinking water, where chlorine has been used to control bacterial contamination. The practice results in vanishing but measurable traces of chloroform, which is carcinogenic in animals under certain conditions and could trigger a strict regulatory ban under Delaney criteria. The benefits of an otherwise safe drinking water override this last injunction in favor of a threshold approach. In the United States, for instance, the U.S. EPA issues a "maximum contaminant level goal" (MCLG) for potable water as a nonenforceable ideal objective, coupled with an enforceable "maximum contamination level" (MCL) that is higher than the goal and is periodically revised to reflect what is technologically attainable.

REGULATORY INFLUENCES IN T O X I C O L O G Y Because of their legal authority, regulatory agencies have exerted a profound influence on the practice of toxicology, both with the imposition of testing protocols, and with the design and funding of research to discover novel toxicological hazards and the methods for their detection and evaluation. In general, agencies that require approval before a substance is produced and marketed (premarketing approval) have had the most profound influence and in many countries this has resulted in the promulgation of standard test guidelines. Because of different statutory objectives and language, different regulatory agencies may produce somewhat conflicting guidelines, even within the same country. National coordination committees have been instituted in many countries to mitigate the problem, usually with modest success. At the international level, various attempts at harmonization have been in place for many years through such organizations as the OECD, FAO, and others.

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Although the globalization of trade continues to be a force for international harmonization of regulatory policy, a strong reason behind the reluctance of major players to adopt uniformity is that differing regulatory prerogatives and incentives have been traditionally used to secure advantages in trade. For the moment, the only widely shared protocols are those of good laboratory practices (GLP), which refer to generic standards of experimentation, i.e., cleanliness, environmental variables, and animal care and handling (GLP, 1989). A major contribution of GLP standards is the requirement of impeccable record-keeping to safeguard technical integrity and to prevent misconduct and abuses. Still, toxicologists in different countries may use similar GLP standards, but will design and evaluate experiments by often quite different methods and purposes, usually as prescribed by their own regulatory laws, policies, and agencies. In certain countries much of toxicology research in and out of academia is funded directly by regulatory agencies, or by the regulated industries that anticipate or respond to regulatory requirements. As a consequence, toxicology research is constrained by practical necessities more often than not. In general, such pressures emphasize the development of testing methods over the study of more fundamental mechanistic processes of toxicity, and the search for novel hazards that may expand the reach of regulatory agencies. It should be emphasized that health and safety regulations are influenced equally by animal tests and by clinical and epidemiological studies in humans. For ethical reasons, studies in humans cannot be proactive but seek answers about potential hazards that are already in use, except for clinical trials of new medicines. Strict guidelines have been accepted and practiced only for clinical trials, whereas the rest of epidemiology operates generally without standards of conduct and practice for study design, conduct, and interpretation. Such laxity and other incurable uncertainties have not prevented epidemiology from having a strong regulatory influence, a situation that could considerably improve if guidelines of good epidemiologic practice were to be issued and enforced. It would be most desirable that efforts in this direction-pioneered by the Association of French Speaking Epidemiologists--should be rapidly considered and adopted worldwide (ADELF, 1997). Guidelines for animal tests as surrogates of human risk detection have been issued by many countries and international agencies, and all share common features. The most stringent and controversial guidelines are those for the testing of potential carcinogenic agents, which theoretically aim at maximizing the chance of obtaining positive results. With this in

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mind, those tests require maximum tolerated doses, ostensibly to make up for the statistical disparity between a few hundred test animals and the much larger human populations they are supposed to represent. Still, high doses have no rational justification as surrogates of statistical power, while the toxicity they inevitably produce is known to induce secondary effects that can induce cancer responses not specifically linked to the agent tested. It is known that susceptibility varies from species to species. Hence results can be further skewed by requirements that the most susceptible animals be used. For instance, there is a wide disparity of response from rats to mice, the latter being especially prone to develop hepatomas, and especially under marginal liver toxicity. Further complications arise when guidelines give priority to positive reports or require the pooling of benign and malignant lesions: problematic issues in view of the often contrasting judgments of different pathologists. Other dilemmas arise when agents appear to protect animals against certain tumors while enhancing others. Overall, the conclusion seems inescapable that guidelines result in tests that are unreliable predictors of cancer risks in humans and perhaps in animals. Nevertheless, lacking better means, animal tests are universally required under the standard default assumptions of conservative prudence.

RISK ASSESSMENT, CHARACTERIZATION, AND MANAGEMENT The inputs of both toxicology and epidemiology are the initial considerations of the regulatory process, which then proceeds with the evaluation of potential risks, and finally with the regulations that are intended to manage those risks. Although data might be fairly well documented and reliable for most toxicological endpoints, they become much less so in the case of carcinogens, a situation that results in the most contentious policies and regulatory outcomes. Here, inescapable difficulties are encountered at the initial stages because direct human toxicological data are seldom available and because epidemiologic studies are seldom verified according to the standard scientific criteria of verification--namely through experiments that account for biases and confounders, that compare groups that are the same except for the variable being measured, and that are repeated and repeatable under controlled conditions to yield the same or equivalent results.

In epidemiology, for instance, most studies of diseases of multifactorial origins (such as cancer, cardiovascular, and other chronic diseases) compare nonrandomized groups that differ in many more than the variables being studied, which generally excludes the possibility of an adequate control for confounding variables. As a norm, such studies are observational surveys which are not replicable under controlled conditions and which often yield contrasting outcomes. Sir Richard Doll, a prominent epidemiologist, noted that "epidemiological o b s e r v a t i o n s . . , have serious disadvantages . . . . They can seldom be made according to the strict requirements of experimental science and therefore may be open to a variety of interpretations . . . . These disadvantages limit the value of observations in humans . . . . " Randomization of the epidemiologic studies might improve the situation, but prospective experimental studies of cancer causation in human subjects are clearly unethical, which leaves animal experiments as the only surrogates for the testing of potential carcinogens. Unfortunately, reliably objective ways of translating carcinogen bioassay results in terms of human risk are not available, and regulators have had no other option but to adopt certain assumptions (default assumptions) even though they may be conjectural or may conflict with the available evidence. The main assumptions are that humans are as susceptible or more susceptible than the test animals to the agents tested; that physiological, immunological, repair, metabolic, and clearance patterns are similar in test animals and humans; that kinetics of response are independent of dose and follow identical (linear) kinetics in test animals and humans; that human routes of exposure can be reproduced in test animals; and that maximum tolerated doses are necessary to evaluate the carcinogenic risks of chemicals, although they do not reflect the potential exposures in humans. As a consequence, carcinogenicity bioassays and their interpretation may use sophisticated protocols and technologies, but in the end their interpretations inevitably reflect value judgments. Just as with epidemiology, this unhappy situation has led to the admission that " . . . a correlation between carcinogenicity in animals and possible human risk cannot be made on a scientific basis." The absence of objective evidence is not unique to carcinogens but extends to a variety of pathologic and hazard endpoints that do not depend on single causes--as in the case of infectious diseases--but on complex multifactorial mechanisms that prevent pinpointing the individual responsibility of associated risk factors. Some of these endpoints include teratogenicity, reproductive toxicity, genotoxicity, immu-

Regulatory Toxicology notoxicity, neurotoxicity, and other complex outcomes that may target specific tissues, organs, and systems. The specific case of carcinogens is simply the most discussed, probably on account of the visceral fears that cancer evokes in public perceptions and, by reflection, in legislative concerns and regulatory statutes around the world. Uncertainties notwithstanding, it is an axiom of health and safety regulation that the worst is to be assumed unless demonstrated otherwise. In this context, the lack of reliable toxicological and epidemiological evidence has had the effect of imposing judgmental approaches to regulation, which in time have given rise to ever more complex methodologies, with the intent of compensating for the absence of objective data and the straightforward regulatory decisions they would enable. Despite their apparent complexity and numerical sophistication, there is wide recognition among experts--but not necessarily in the public opinion--that current approaches to the regulation of most agents remain judgmental. Indeed, the regulatory process can be relatively straightforward when risks can be identified with a degree of certainty that compels all parties--the regulated, advocacy groups, and the l a w - - t o face reality and to accept suitable regulatory standards. Yet, in the case of potential carcinogens and other hazards that are not objectively definable, regulators are facing potential risks that might or might not exist. Here, the regulatory intent can only be prudential, and addresses not realities but "what if" questions. The inevitable arbitrary nature of such decisions has been uncomfortable, and has persuaded different regulators to adopt different regulatory approaches, here summarized as two extremes. Some countries have adopted closed and strictly administrative regulatory procedures that at most admit the confidential participation of outside experts, as was the case in Europe at one time, and which still is the case in Japan, Canada, and other countries. Elsewhere, and notably in the United States, the potential for controversial decisions has persuaded regulators to adopt the open process of a political dialog with the participation of experts and other interested parties m a move intent on easing the responsibilities of regulators and securing public acceptance, but often ending up in heightened tensions. This approach usually culminates in a public hearing, known in the United States as a "rule-making" hearing. In any event, both the closed and open regulatory models advance through the progressive phases of hazard identification, usually by animal bioassay and doseresponse and exposure assessment; characterization of population risk; risk-benefit considerations; and fi-

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nally risk management leading to regulatory standards.

Hazard Identification The first step is to define the toxic mode(s) of a particular agent, generally by experimentation that may supply information on cytotoxicity, mutagenicity, developmental toxicity, neurotoxicity, other specific organ and biochemical effects, carcinogenicity, and mortality. The data usually derive from exploratory animal experimentation, at times motivated by clinical or epidemiological observations. Participants in this phase are technical experts alone.

Dose-Response Assessment Information about the intensity of an effect in relation to dose and duration of exposure is seldom obtained by direct human observations in clinical or epidemiological settings. This information is usually extrapolated from animal experiments, which require maximum tolerated doses in the contentious case of carcinogens. Even in animals, response effects at low exposures cannot be experimentally detected and are unknown, which has prompted regulators to use a variety of mathematical models to extrapolate from a few high-dose observations to unobservable low-dose projections. Regulation usually admits threshold models and extrapolations when thresholds are observed, but in the case of carcinogens the prevailing official policies usually disregard thresholds, even if experimentally observed, and require nonthreshold extrapolation models. For carcinogens, various mechanistic assumptions have been used, The single hit (one mutation = one cancer cell) and multi-hit (multiple mutations = one cancer cell) assumptions result in nonthreshold Poisson distribution models that in time have been superseded by linearized multistage (LMS) models, which assume multiple hits and transformation stages before a cell becomes cancerous. Although LMS models are the most commonly used, other models that are still employed are the Probit and Logit distributions, and the time-to-tumor variants of the Weibull and Cox models. Both cancer and noncancer models extrapolate to presumed low-dose effects, and require a further step for scaling from animals to humans, most often using empirical formulas, such as KW2/3

100S, where K is a constant peculiar to the animal

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species, W is the weight in kg, and S is the body surface in m 2. Another widely used scaling formula is simply W 3/4 (U.S~EPA, 1992). In estimating potential cancer risks to humans from animal data, additional uncertainties often occur when a compound may be carcinogenic in one species but not in another, or when the tumors observed may be peculiar to the animals in the test, as is often the case for hepatomas in mice. Much has been made of the possible use of mechanistic data, but until reliable knowledge about cancer causation and development is available, such an approach remains largely speculative. More often, the mechanistic approach is limited to physiologically based pharmacokinetic considerations (PBPK) regarding the absorption, distribution, metabolism, and excretion (ADME) of a substance, but those considerations also may have unknown relevance to the final objective of human risk determinations. Conversely, some use of certain physiological and pathological peculiarities have been used to disregard the regulatory significance of certain animal effects, as in the cases of d-limonene and isophorone and kidney tumors mediated by ~2~-globulin in male rats; red No.3, ethylenethiourea, sulfametazine and rat thyroid tumors induced by imbalances in thyroid hormones; glass beads, melanine, or oxalate crystals and bladder tumors in rodents, possibly induced by mechanical injury; and butylhydroxytoluene and propionic acid and forestomach tumors in rodents mediated by epithelial irritation. In the end, and despite the vast amount of mathematical expertise and ingenuity that these models have inspired, it is widely understood and conceded that such exercises cannot claim the verifiable superiority of one over the others, all being structured around conjectural assumptions with no verifiable links to actual human conditions.

Risk Characterization Technical experts have exclusive competence in the preceding phases of risk assessment and, despite scientific and rational injunctions against human risk inferences from most animal data, they provide such inferences routinely on the basis of policies and procedures that have the effective weight of law. Reflecting fundamental uncertainties, in general such procedures lack well-defined rules and rely heavily on judgmental criteria, such as the strength and specificity of endpoint measures, consistency among different animal tests, and biological plausibility in humans. When the available information is epidemiological, equivocal, and short of exposure-responses data, often other considerations have resulted in the much-

used weight-of-evidence approach, theoretically aimed at consolidating in a final judgment all available evidence. Here, too, the potential for elastic and selective interpretations of available reports has prompted the exploration of analytical methodologies, the most notable of which is the statistical procedure of meta-analysis. This method combines endpoints from different studies into single estimates, usually by combining the mean of relative risks or odds ratios of different studies, each weighted by the inverse of their variance. The procedure has been especially popular and useful in summarizing the results from randomized clinical trials, but it has been extended in epidemiology to the synthesis of results from disparate observational studies, with less than satisfactory outcomes. The obstacle is that the combined studies must be homogeneous--usually a salient feature of clinical trials that share common protocols--whereas observational studies in epidemiology are inevitably heterogeneous because of the lack of randomization and differences in biases and confounders in the study design and protocols and in the ways data are collected. Further difficulties can be introduced by a bias favoring the publication of data that sustain popular hypotheses, or by the intentional selection or exclusion of available reports in ways that could be dangerously close to scientific fraud. Risk determinations resulting from animal or epidemiological sources are often introduced uncritically in the risk characterization phase, where an additional initial step is also left to the sole competence of technical experts. This step involves estimating what fractions of a population might be exposed to a hazard, at what concentrations, and for how long. The procedure is inherently problematic because it lacks empirical inputs, given that it usually deals with exposures that are new or whose distributions are poorly understood. Various approaches to these estimates have been proposed, the most recent one by the U.S. EPA, which favors a Monte Carlo probabilistic elaboration of demographic assumptions and market and distribution inferences. Regardless of their numerical sophistication, these methodologies are open to criticism, as they are likely to compound the uncertainties derived from dose-response inferences.

Risk-Benefit Considerations Procedures for risk-benefit analysis have been widely discussed as providing useful generic guidance, but they generally recommend approaches that are tailor-made to the specific issues at hand. Regulators or specialized advisors execute the necessary

Regulatory Toxicology analyses at least in a preliminary mode, to be further refined and stabilized in policy hearings and debates.

Rule-Making Hearings Especially in the United States, regulators have felt the necessity to open up the rule-making process and to share responsibilities through a formal open hearing that invites public dialog. Usually, this phase extends the evaluation of a problem under "what if" assumptions, introducing a crossover of ethical and risk-benefit considerations to decide what level of protection the regulation should target. The tolerance of a one in one million adverse event has often been mentioned as a standard objective, but considerable departures have applied if the target population are children, or workers, or expectant mothers, or the elderly, and so on. Thus, risk characterization in open hearings ends up being a deliberative and often confrontational process.

Risk Management Risk management is the last phase of regulation and entails the promulgation of regulations that reflect risk characterization decisions and, subsequently, their policing and enforcement.

Regulation and the Courts Often regulators are challenged by court actions that either demand specific regulatory attentions or that challenge regulatory outcomes. Seldom have regulators been forced to initiate regulatory proceedings as a result of court injunctions, but it has not been unusual for the courts to deny, reverse, or to require modification of issued regulations, especially in the United States.

Postregulatory Surveillance Many regulations are the product of over-conservative assumptions and defaults that t e n d - - a t least in principle--to ensure the virtual absence of risks. Still, when cost-benefit considerations or other reasons of need have been the major determinants of regulations that cannot cancel residual risks, the necessity of monitoring the effectiveness of those regulations becomes obvious. Programs to assess post-regulatory effectiveness are routinely established, especially in occupational situations, for approved medicines and food additives, and for certain environmental norms likely to affect large fractions of a population, such as drinking water, air quality, and vehicle safety.

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When toxicology or epidemiology objectively identifies strong hazards, their input is unquestionably normative and directly results in regulation. However, it is apparent that hazard signals that are weak or not scientifically verifiable are handled differently. In the political context of regulation, they simply raise warning signals of different strengths, which are then considered in a "what if" context of prudence. In that context, the original toxicological or epidemiological reports that raised the warning signal are overcome by a value-laden political dialog that considers how much costly societal "prudence" could be applied. Toxicological or epidemiological inputs to the process acquire a symbolic truth in the political debate of the risk characterization process, even though they may have been obtained on the basis of assumptions and extrapolations from animal data that are not objectively interpretable in equivalent human terms, or from highly uncertain epidemiological reports. Toxicologists and epidemiologists dealing with regulatory issues need to be alert to the fact that their reports are usually taken at face value by nonscientists, so that the results of a political dialog of risk characterization often are made to appear more solid than they actually are and could result in debatable regulation. Even in countries where the regulatory procedure is strictly administrative and without public participation, the regulatory outcomes may not be better, although in such situations regulators have the discretion of discarding ex officio weak toxicological signals that are not worthy of consideration before they can arouse unjustified public anxieties. Yet, such discretionary power carries potential risks too, as the evolving BSE (bovine spongiform encephalopathy) saga has shown. It is clear that the combined pressures of scientific progress, of uncertainty, and of the political dialog will continue to make sure that health and safety regulation will not be a static paradigm of fixed rules and policies. It should also be apparent that toxicology and epidemiology have most likely already discovered the major health and safety risks that can be incontrovertibly verified on objective scientific grounds. What will continue to interest regulation are the potential risks that might derive from novel uses of human-made or naturally occurring agents whose chronic effects cannot be tested ethically in humans, leaving the usually vague epidemiological observations and animal tests as possible detectors. Advancing research in molecular biology and genetics carries the promise of mechanistic understandings of direct relevance to human risk assessment, although their practical availability is not in sight.

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Epidemiology will continue to be a source of equivocal frustrations, given that nonexperimental observational studies can be expected to continue providing hints of increasingly smaller potential risks, whose interpretation will be made extremely problematic by complex tangles of multifactorial associations that are virtually impossible to sort out. Although the potential risks flagged by animal tests and epidemiological reports will likely get smaller and more uncertain, they still will not be ignored in open societies that by design and inclination rely on the adversarial confrontation of different interests. In all probability, such realities will make life progressively harder on regulators, who already find themselves a natural target of fire from all directions and who will encounter mounting difficulties in reaching consensual solutions under the added prospect of increasing legal challenges. What are the promising directions that regulators might take to ease these pressures? Seeking consensus, regulators might seek to adopt the open U.S. model of public hearings and participation in the rulemaking process, but such a move would raise new reservations because the introduction of more dialectic and emotional issues could further distance the regulatory process from objective scientific benchmarks and could result in increased tensions rather than consensus. In a more promising direction, regulators may be compelled to face a wider problem also looming on the horizon, namely how to set regulatory priorities in a context of limited resources. Until now, and notwithstanding the requirements for risk-benefit considerations, a philosophy of safety at all costs has been the implicit regulatory ideal in affluent developed societies driven by the allied interests of advocacy groups, media, public opinion, and legislators. Soon, however, this philosophy may no longer be sustainable, as advocacy and popular exigencies are likely to press for the regulation of increasingly smaller and more uncertain risks, whose hypothetical prevention would carry costlier and costlier price tags. Hence the need for priorities. Both at the national and global levels, the evidence will mount that an efficient use of scarce resources calls for setting defensible priorities among the many warning signals and the public anxieties that animal tests and epidemiological reports will continue to foster. Regulators will be increasingly challenged with the responsibility of grading potential "what if" hazards and of proposing which ones may deserve regulatory priority and the expenditures of costly measures of prudence. Credible procedures for ranking the uncertainty of risks are not available and need to be formalized: an effort also likely to demand the

attention of regulators, who while relentlessly pursuing their inalienable mission of protecting the public from harm emanating from toxic chemicals, must increase their level of alertness to the consequences of their actions on overall economic and cultural values. This would be a new, unfamiliar, and as yet untested role for toxicologists and epidemiologists who may participate in setting regulatory priorities. Both professions could gain much from a chance to represent themselves forthrightly as the purveyors not of absolute evidence but of credible prudent choices about possible risks. The affirmation of Paracelsus that the dose makes the poison is still fundamental, and it matches the common observation that life endures against all but the most extraordinary odds. Thus, in time, toxicologists, epidemiologists, and regulators might come to find it desirable to adopt changed attitudes and a new role in public educat i o n m t h a t of persuading a well-informed public to demand regulatory policies that are always solidly based on the best available science and grounded in realities, and to resist both economically motivated pressure and conjectural anxieties leading to unwarranted excesses of hypothetical prudence.

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