1
Introduction and Background

The regulation of the use of chemicals to protect human health and the environment is one of the most important and persistently controversial tasks assigned by Congress to the Environmental Protection Agency (EPA). EPA’s regulation of chemicals is important because of the central role they play in our modern industrial society and their potential consequences for health. Over the last 50 years, tens of thousands of chemicals have been developed and introduced into the environment in the United States. In a typical year, more than 6 billion pounds of toxic chemicals are released by industrial facilities into the environment.1 Another 1.3 billion pounds of pesticides are applied annually to agricultural fields, homes, gardens, schools, and other settings.2 In addition, chemical air pollutants are emitted from sources such as fossil fuel combustion that are involved in providing energy for transportation, power plants, and other industrial processes. All chemicals have the potential to harm human health, depending on the conditions under which people are exposed, particularly dosage. Thus, it is critically important to understand the hazards of chemicals and to control human exposure to them.

The regulation of chemicals is persistently controversial because it involves competing values and interests. Although all chemicals can pose risks, most also provide benefits or result from beneficial activities. Agri-

1  

See EPA’s 2001 Toxics Release Inventory at www.epa.gov/tri/tridata/tri01/press/executivesummarystandalone.pdf.

2  

Ibid.



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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues 1 Introduction and Background The regulation of the use of chemicals to protect human health and the environment is one of the most important and persistently controversial tasks assigned by Congress to the Environmental Protection Agency (EPA). EPA’s regulation of chemicals is important because of the central role they play in our modern industrial society and their potential consequences for health. Over the last 50 years, tens of thousands of chemicals have been developed and introduced into the environment in the United States. In a typical year, more than 6 billion pounds of toxic chemicals are released by industrial facilities into the environment.1 Another 1.3 billion pounds of pesticides are applied annually to agricultural fields, homes, gardens, schools, and other settings.2 In addition, chemical air pollutants are emitted from sources such as fossil fuel combustion that are involved in providing energy for transportation, power plants, and other industrial processes. All chemicals have the potential to harm human health, depending on the conditions under which people are exposed, particularly dosage. Thus, it is critically important to understand the hazards of chemicals and to control human exposure to them. The regulation of chemicals is persistently controversial because it involves competing values and interests. Although all chemicals can pose risks, most also provide benefits or result from beneficial activities. Agri- 1   See EPA’s 2001 Toxics Release Inventory at www.epa.gov/tri/tridata/tri01/press/executivesummarystandalone.pdf. 2   Ibid.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues cultural pesticides, for example, contribute to our abundant, safe, and relatively inexpensive food supply. Chemicals are used to produce a vast array of other consumer products from which people directly benefit. They also enter the environment as by-products of activities people value, such as the burning of gasoline and other fuels for transportation and the production of electricity for heating and lighting our homes. No one wants the chemical by-products that can pollute the air and water and contaminate food, but few are prepared to do without the relatively low-cost energy that makes life comfortable and convenient. The controversy that stems from the two-sided nature of the use of most chemicals often is intensified by disputes among commercial interests, environmental groups, and others with diverse points of view about the proper assessment, balancing, and allocation of the associated risks and benefits. EPA’s chemical regulatory programs operate at the intersection of these competing interests and values. The agency administers a series of congressional enactments that establish basic standards and procedures for assessing and balancing the risks and benefits of the use of chemicals through the regulatory process. These statutes resolve some of the broader questions about how particular categories of chemicals are to be regulated, but they leave many controversial issues unresolved. Some of the most important issues with which EPA must grapple on a continuing basis involve the nature of the scientific evidence that will serve as the basis for regulatory decision making. EPA commissioned this study to help address a particularly vexing issue concerning the acceptability and usefulness of scientific evidence. The issue is whether and under what circumstances EPA should accept from outside parties, and consider in its regulatory decision making, studies that involve the intentional dosing of research volunteers in order to gather evidence relating to the risks of using a chemical or the conditions under which exposure to it could be judged safe. This issue is one that is multifaceted and difficult. It involves the complex interplay between important ethical concerns and scientific questions regarding the validity and usefulness of human studies for EPA’s regulatory purposes. Like chemical regulation in general, the issue of human testing involves competing interests and values. And the issue has an emotional component. For many, the idea of testing pesticides and other industrial chemicals and chemical contaminants in humans is, on its face, repugnant. It is natural and appropriate to question whether and why such testing should be conducted and considered by EPA, especially when the study participants gain little or no direct benefit.3 3   This report uses the terms “participant” and “subject” to refer to persons who participate in research. The term “subject” has been widely used for decades and appears in the federal

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues This committee understands and respects both the intellectual difficulty and the social sensitivities involved when considering the issues surrounding human testing of chemicals. Like most other groups that have addressed this subject, the committee recommends that any testing of chemicals in humans be approached with the utmost caution and care. It is essential also to consider the specific circumstances in which human testing is proposed to be conducted for EPA regulatory purposes. In medicine, human testing of drugs, many of which are extremely toxic, is a well-established practice. It is regulated by the Food and Drug Administration (FDA) and governed by a set of principles and rules that are designed to respect and protect research participants, while making it possible for society to benefit from the knowledge that can be gained from such research. The initial reason for, and still the primary purpose of FDA’s oversight of human drug studies, is the protection of research volunteers. This primary purpose governed this committee’s consideration of the similar but distinct issues facing EPA. The committee can envision circumstances in which human testing of chemicals in the EPA context could satisfy ethical and scientific standards, but, as will be made clear in the following chapters of this report, such circumstances are highly circumscribed and require careful oversight. The remainder of this chapter provides brief background material on EPA’s regulation of chemicals, the potential role of intentional human dosing studies, the events in EPA’s pesticide program that prompted this report, the prior EPA advisory panel review, EPA’s policy regarding ethical oversight of human studies, EPA’s charge to the committee, the National Academy of Sciences committee process, and the organization of this report.     regulations, but the term “participant” has become more common in recent years both internationally and in the United States (NBAC, 2001). Neither term is fully satisfactory as a label for those who are enrolled in research. The argument for using one term over the other hinges on the interpretation of the relationship between investigator and the individual enrolled in research and on the relevant values, such as respect for persons. The term “subject” seems to many to suggest that the individual is subjected to the investigator’s action, is in an unequal relationship with the investigator, and is often passive. By contrast, the term “participant” appears to many to be too broad, because it could apply to the investigator as well as to the individual enrolled in research; furthermore, it does not adequately describe those who are enrolled in research by others, such as surrogate decision makers. NBAC argued for using the term “human participant” in order to be more respectful to the individuals who participate in research and to emphasize that individuals should be active, not passive, in the decision to enroll in research studies (NBAC, 2001, 32-33). This committee report uses both participant and subject but, in accord with contemporary usage, most often uses participant unless the context, such as federal regulations, dictates the use of subject.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues EPA’S REGULATION OF CHEMICALS EPA regulates chemicals under numerous legal statutes enacted over several decades for a range of purposes generally involving the protection of human health and the environment (Box 1.1 summarizes a number of the major statutes). This report focuses on the human health aspects of these laws. Each law addresses a different set of chemical regulatory problems in the manner deemed appropriate by Congress. Several require EPA to make decisions based on assessments of the health risks that the use of chemicals may pose, which necessitates the collection of the scientific data required to make the assessment. Five of these statutory schemes are particularly relevant to the issue being addressed in this report and will be described briefly here. Three of them—those involving pesticides and toxic substances generally—impose requirements on parties outside EPA (hereafter called third parties) to conduct tests and compile and submit data to EPA concerning the potential risks of chemicals. The other two—involving toxic air pollutants and drinking water contaminants—place the burden on EPA to assemble data on health risks and possibly conduct health effect studies. EPA regulates pesticides under two statutes. Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), EPA decides whether and under what circumstances a pesticide can be applied to food crops or be used for other pest control purposes without resulting in unreasonable adverse effects on human health or the environment. Under the Federal Food, Drug, and Cosmetic Act (FFDCA), EPA evaluates the safety of pesticide residues in food and establishes tolerances (maximum legally permissible levels) for specific pesticides in specific foods based on its conclusion that consumption of foods containing residues at these levels will be safe, which Congress defines as “a reasonable certainty of no harm.” Under both FIFRA and FFDCA, the sponsor of the pesticide bears the burden of proving to EPA that a pesticide satisfies the statutory standards for approval (called registration) and for the granting of a tolerance. To meet this burden, sponsors typically must conduct extensive testing of the pesticide in accordance with testing requirements and guidelines established by EPA. The other EPA-administered law that can require parties outside EPA to conduct tests on chemicals and submit the results to EPA is the Toxic Substances Control Act (TSCA), which Congress enacted in 1976 to give EPA the ability to screen new chemicals and track the 75,000 industrial chemicals produced by or imported into the United States. EPA screens these chemicals and can require testing of those that may pose an environmental or human health hazard. EPA can ban the manufacture and import of those chemicals that pose an unreasonable risk. TSCA’s

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues BOX 1.1 Legal Statutes for EPA Regulation of Chemicals The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C. §136 et seq.)a was enacted in 1964 and has been amended numerous times since, including significant amendments particularly relevant to this report in the form of the Food Quality Protection Act (FQPA) of 1996 (P.L. 104-170)b (discussed below). In its current form, FIFRA mandates that EPA regulate the use and sale of pesticides to protect human health and preserve the environment. Under FIFRA, EPA registers pesticides for use in the United States and prescribes labeling and other regulatory requirements to prevent unreasonable adverse effects on health or the environment. Under the Federal Food, Drug, and Cosmetic Act (21 U.S.C. §371),c EPA establishes tolerances (maximum legally permissible levels) for pesticide residues in food. In addition, FQPA requires EPA to reassess all pesticide and other ingredient tolerances and exemptions that were in effect as of August 3, 1996 (when FQPA was signed). This effort is designed to ensure that existing tolerances and exemptions meet the safety standard set by FQPA. The Toxic Substances Control Act (15 U.S.C. §2601 et seq.),d which Congress enacted in 1976, gives EPA the authority to screen and track chemicals produced by or imported into the United States. This currently amounts to over 75,000 chemicals. The Clean Air Act (42 U.S.C. §7401 et seq.)e provides the primary framework for protecting humans and the environment from the harmful effects of air pollution. It is the comprehensive federal law that regulates air emissions from area, stationary, and mobile sources. This law authorizes EPA to establish National Ambient Air Quality Standards for pollutants such as ozone and particulate matter to protect public health and the environment, as well as to establish other standards for hazardous air pollutants.f Under the authority of the Safe Drinking Water Act of 1974 (42 U.S.C. §300f et seq.), EPA sets standards for approximately 90 contaminants in drinking water. a   Available at www.epa.gov/region5/defs/html/fifra.htm. b   Available at www.epa.gov/oppfead1/fqpa/backgrnd.htm. c   Available at www.fda.gov/opacom/laws/fdcact/fdctoc.htm. d   Available at www.epa.gov/region5/defs/html/tsca.htm. e   Available at www.epa.gov/air/oaq_caa.html. f   Available at www.epa.gov/air/criteria.html.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues premanufacture notification program is the only mechanism available to EPA other than the pesticide programs for requiring third parties to conduct and submit studies on the risks that may be posed by the use of chemicals as a condition to entering the marketplace. Although the chemicals covered by TSCA and the pesticide laws have clearly identifiable commercial sponsors that can be required to conduct studies and submit health risk data to EPA, this is not always the case with respect to the chemicals covered by the toxic air pollutant and drinking water contaminant laws. Under the Clean Air Act, EPA regulates and seeks to minimize the harmful health and environmental effects of air pollution. A key component of the Clean Air Act is a requirement that EPA significantly reduce daily, so-called routine emissions of the most potent air pollutants: those that are known or suspected to cause serious health problems such as cancer or birth defects. The Clean Air Act refers to these pollutants as “hazardous air pollutants,” but they also are commonly known as toxic air pollutants or simply as air toxics. As amended in 1990, the Clean Air Act requires EPA to use a “technology-based” and “performance-based” approach to significantly reduce emissions of air toxics from major sources of air pollution, followed by a “risk-based” approach to address any remaining, or residual, risks. Eight years after each technology-based standard has been adopted, EPA must assess the remaining health risks and, if necessary, adopt additional standards that address any significant remaining risk. In these cases, EPA can require industry to collect data and conduct tests, but the burden is on EPA to assess risks and set standards. The Clean Air Act also contains provisions regarding the testing of new fuel additives. Under the Safe Drinking Water Act, as amended in 1996, EPA sets standards to restrict the presence of contaminants in drinking water to a level that “maximizes health risk reduction benefits at a cost that is justified by the benefits.” The process for setting these standards includes a risk-assessment step to determine the maximum level of a contaminant in drinking water at which no known or anticipated adverse effect on the health of persons would occur and that would allow an adequate margin of safety. These health-based levels are goals; the enforceable limits are set with the goals as the starting point, but they also include consideration of the costs required to achieve a given reduction in health risk. THE POTENTIAL ROLE OF HUMAN STUDIES In implementing all of these chemical regulatory statutes, EPA follows standard approaches to risk assessment of chemicals. This includes the standard model of risk assessment described by the National Research

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues Council in 1983 (NRC, 1983; see Box 1.2 for a summary of the model as applied to pesticides), and the standard approach to evaluating the safety of chemicals in food that has evolved over the past 40 plus years in the food safety programs of both FDA and EPA. In both cases, for purposes of initially determining the toxic properties of a chemical (called hazard identification in the risk-assessment model), primary reliance is placed on toxicity studies conducted in animals. As discussed more fully in other parts of the report (Chapters 3 and 7; Appendix B), a diverse battery of animal studies in rodent and nonrodent mammalian species, involving high doses, large numbers of animals, and often lifetime or even multigenerational exposure, can powerfully elucidate the potential toxicity of a chemical. Toxicologists can then apply standard methods to extrapolate the results seen at high doses in animals to the much lower doses ordinarily experienced by humans. In addition to their power to detect a chemical’s toxic properties, animal studies play a central role in chemical risk assessment and safety evaluation as a matter of necessity. It would be economically prohibitive, but more importantly, ethically unacceptable to conduct in humans the kind of large-scale, long-term, highly invasive toxicity tests that would be required to determine the full range of a chemical’s acute and chronic toxic properties, as can be done in animal studies. Human studies, therefore, can provide assessment of only some of the toxicities apparent in animals. This does not mean, however, that data from human studies have no role in chemical risk assessment and safety evaluation. Much has been learned about the toxic properties of chemicals through the study of accidental human exposures to them, such as may occur in industrial accidents or unintentional environmental releases, and through epidemiological and occupational exposure studies that do not involve the intentional dosing of people but rather the examination of the effects of chemical exposures that people experience in their daily lives. Because they do not involve the intentional dosing of people, such studies do not raise the ethical concerns associated with a conscious decision to recruit individuals into research as a means of gaining knowledge. Established scientific principles and guidance provided by EPA and other agencies favor the use of data from such studies in risk assessment and safety evaluation when the data are available and scientifically relevant (EPA, 1989: NRC, 1993).4 4   See the World Health Organization’s Human Data Initiative at www.who.int/pcs/emerg_site/hdi/hdi_descr.html.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues BOX 1.2 Four-Step Process for Human Health Risk Assessment Following is the National Research Council’s (1983) recommended four-step process for human health risk assessment, which it described as the use of the factual base to define the health effects of exposure of individuals or populations to hazardous materials and situations: Step One: Hazard Identification The first step in the risk-assessment process is to identify potential health effects that may occur from different types of pesticide exposure. EPA considers the full spectrum of a pesticide’s potential health effects. Generally, for human health risk assessments, many toxicity studies are conducted on animals by pesticide companies in independent laboratories and evaluated for acceptability by EPA scientists. In addition, epidemiologic and in vitro data can be used. EPA evaluates pesticides for a wide range of adverse effects, from eye and skin irritation to cancer and birth defects in laboratory animals. EPA also may consult the public literature or other sources of supporting information on any aspect of the chemical. Step Two: Dose-Response Assessment The amount of a substance a person is exposed to is as important as how toxic the chemical might be. Dose-response assessment involves considering the dose levels at which adverse effects were or were not observed in test animals. In some cases, such as in the evaluation of potential carcinogens, dose-response information is used to estimate possible effects at doses below those at which effects were actually observed in animal studies. There are circumstances, however, under which animal models may not be adequate to determine the potential toxicity of a chemical and epidemiological studies cannot be conducted in a way that is scientifically relevant to the exposure that is of regulatory concern to EPA. In some cases, intentional dosing of humans may be the only way to obtain the data needed to set regulatory standards or to protect public health. EPA itself conducts air chamber studies in which research participants, some with asthma or other conditions that make them vulnerable to air pollutants, are intentionally exposed to hazardous chemicals under controlled conditions designed to mimic or even exaggerate the “real world” circumstances in which the pollutants might be expected to cause symptoms. Data from such studies have played an important role in EPA’s

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues Step Three: Exposure Assessment People can be exposed to pesticides in three ways: Inhaling pesticides (inhalation exposure); Absorbing pesticides through the skin (dermal exposure); and Getting pesticides in their mouth or digestive tract (oral exposure). The first task of an exposure assessment is to determine the concentration of the chemical to which humans are exposed, either through direct measurement or by estimate. Exposure assessment in an occupational setting consists of estimating long-term airborne exposures in the workplace. In the community, ambient concentrations of chemicals can be estimated from emission rates if transport and conversion processes are known. Assessments of exposure can be complicated by variations and personal habits among the population being studied and variable susceptibility. Step Four: Risk Characterization Risk characterization is the final step in assessing human health risks from pesticides. It is the process of combining the hazard, dose-response, and exposure assessments to describe the overall risk from a pesticide. It explains the assumptions used in assessing exposure as well as the uncertainties that are built into the dose-response assessment. The strength of the overall database is considered, and broad conclusions are made. EPA’s role is to evaluate both toxicity and exposure and to determine the risk associated with use of the pesticide. Thus, the risk to human health from pesticide exposure depends on both the toxicity of the pesticide and the likelihood of people coming into contact with it. ability to set standards to protect public health. However, such studies also raise important ethical and participant protection concerns. In some cases, intentional human dosing studies can contribute to the process of extrapolating from animal results to estimate risks in humans, determine the mechanism by which a chemical affects human health, or determine the level in humans at which exposure to a chemical can be judged safe. These extrapolations ordinarily require that certain assumptions be made about the relationship between animal test results and what can be expected to occur in humans. As explained in Chapter 4, the replacement of these “default” assumptions with human data that more accurately reveal the likely human response can produce a more accurate risk assessment or safety evaluation.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues The most germane example of replacing default assumptions with human data involves the use of human data in the safety evaluation of pesticide residues in food. In most cases, EPA determines safe levels of human exposure—levels at which there is “a reasonable certainty of no harm”—through a process that relies primarily on animal toxicity data and that involves the use of “uncertainty factors” to establish a safe level of exposure or Reference Dose (RfD) for the chemical. This process is described in detail in Chapter 7. It begins by identifying in the most sensitive animal model the highest dose at which no adverse effect from exposure to the chemical can be observed. This “no observed adverse effect level” (or NOAEL) is then divided by factors to account for the inherent uncertainty in extrapolating from animals to humans. Traditionally, EPA has applied 1 factor of 10 (the “interspecies” factor) to account for the possibility that a chemical is more toxic to humans than to the most sensitive animal species tested; and a second factor of 10 (the “intraspecies” factor) is applied to account for the possibility that humans vary widely in their response to the chemical, with some individuals being significantly more sensitive than others. Thus, under this approach to safety evaluation the animal NOAEL is divided by 100 to produce the RfD, or the dose that is judged safe for human consumption. If human data were available to demonstrate that humans were either substantially more or substantially less sensitive to the chemical than assumed by the 10-fold interspecies uncertainty factor, the factor could be adjusted upward or downward and thereby produce a scientifically more accurate RfD and safety evaluation. This possibility and the pesticide industry’s response to it are what prompted this report. EVENTS IN EPA’S PESTICIDE PROGRAM THAT PROMPTED THIS STUDY In 1996, Congress passed the Food Quality Protection Act (FQPA), which substantially amended both the basic pesticide law, FIFRA, and the tolerance setting provisions of FFDCA. FQPA, which was the culmination of nearly two decades of debate over the efficiency and protectiveness of EPA’s pesticide program, brought about important change. It mandated a single, health-based standard for all pesticides in all foods; provided special protections for infants and children; expedited approval of safer pesticides; created incentives for the development and maintenance of effective crop protection tools for American farmers; and required periodic reevaluation of pesticide registrations and tolerances to ensure that the scientific data supporting pesticide registrations will remain up-to-date in the future. A significant change resulting from FQPA involved special protec-

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues tion for infants and children. The act mandated that EPA, in calculating safe levels of exposure for purposes of setting tolerances, apply an additional 10-fold safety factor for children, in addition to the interspecies and intraspecies factors ordinarily used, with the intention of taking “into account potential pre-and postnatal toxicity and completeness of the data with respect to exposure and toxicity” (FFDCA 408(b) (2) (C)). This new requirement was based on a recommendation by the National Research Council (NRC) Committee on Pesticides in the Diet of Infants and Children, which, beginning in the late 1980s, worked for five years to examine regulatory and risk-assessment practices, assess dietary intake information, evaluate pesticide residue data, identify toxicological issues of greatest concern, and develop recommendations on policy changes and research needs. The committee concluded that the science on the susceptibility of children to pesticides was not very advanced and that children could be more or less sensitive than adults, depending on the chemical and the health endpoint of concern. One of the primary concerns of the committee, however, was that the developing organ systems in infants and children (e.g., nervous, endocrine, immune) might be particularly susceptible to some pesticides. In light of the lack of studies employing sensitive measures of such developmental effects, the NRC committee recommended that a third safety factor of up to 10 be applied (NRC, 1993). This and other committee recommendations were incorporated into the 1996 FQPA. When this new FQPA safety factor is included with the interspecies and intraspecies uncertainty factors, the result is that the NOAEL typically is divided by 1,000 to yield a presumed safe level of exposure for purposes of setting tolerances. Any one of the 10-fold factors may be modified, however, on the basis of additional data demonstrating that a different safety factor is scientifically more valid—that is, more likely to produce an accurate expression of the safe dose. In the case of the FQPA 10-fold factor for children, information demonstrating that developing animals or children are not more sensitive to the pesticide being assessed than adults or that developmental toxicity is not the most sensitive endpoint could, in some cases, be used to support a safety factor of, for example, 3 or 1, instead of 10. The interspecies uncertainty factor also can be modified for several reasons. If, for example, pharmacokinetic data are available to demonstrate that a substance’s active metabolite is generated to a significantly different extent in laboratory animals than in humans, the standard 10-fold interspecies uncertainty factor could be replaced with a more specific (larger or smaller) interspecies factor. Similarly, evidence from pharmacodynamic studies showing that humans are more or less sensitive than animals to a relevant toxicity endpoint also could lead to the selection of a

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues Protection Act. The government has in place very stringent standards that apply to federally funded research to ensure the protection of human subjects. EPA will be asking its independent Science Advisory Board to apply these same standards to pesticide data submitted to EPA by companies for review. No human test data has been used by EPA for any final decisions about acceptable levels of pesticide under the new food safety law. The protection of public health from adverse effects of pesticides can be achieved through reliance on animal testing and use of the highest ethical standards.8 PRIOR EPA ADVISORY PANEL REVIEW EPA convened a Joint Subcommittee of its Science Advisory Board and the FIFRA Scientific Advisory Panel in 1998 to provide advice and comment to the agency on the scientific and ethical questions that had been raised about the use of data from intentional human dosing studies in making pesticide registration and tolerance decisions. The subcommittee was asked to address the value of such human studies and identify factors for consideration when (1) determining what constitutes an appropriate human study for use in environmental decision making; (2) making a judgment on what constitutes an ethically appropriate human study; and (3) determining if a study is appropriate (or inappropriate) for use. The agency also asked the subcommittee to discuss the risks and benefits of these studies for the research participants and for society, as well as the issues relevant to determining whether studies are in compliance with accepted ethical guidelines. All but two of the subcommittee members could envision particular circumstances under which intentional dosing of research volunteers with small amounts of pesticides could be scientifically and ethically acceptable, subject to limitations described as ranging from “rigorous” to “severe.” However, the majority also concluded that the information sought must not be available through other sources (e.g., animal studies and models or the study of incidental exposures) and that the information expected to be gained must promise reasonable health benefits to the exposed individuals or society at large. A majority of the members of the subcommittee agreed to several basic findings and recommendations. These recommendations reemphasized the importance of protecting research participants and emphasized the need to establish a very high threshold of justification for studies that intentionally expose humans to toxic substances. Moreover, the recom- 8   Available at www.epa.gov/scipoly/sap/1998/december/epastmt.htm.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues mendations reflect the subcommittee agreement that justification of the use of humans in pesticide testing cannot be based on the ability to facilitate the interests of industry or of agriculture, but only to better safeguard the public health. The EPA joint subcommittee expressed the need for scientifically rigorous protocols and stated that investigators should recognize that unintended exposures also provide valuable opportunities for research; thus, when possible, entities should take full advantage of the opportunity to gather information through careful incident follow-up rather than through intentional dosing studies. The subcommittee warned about the possible involvement in dosing studies of participants who are less than fully informed, the exposure of large numbers of participants to toxins, and the potential for skewed use of testing protocols in developing countries. It emphasized the need for EPA to adopt policies that reflect special concern for the interests of vulnerable populations, such as fetuses, children, adolescents, pregnant women, the elderly, and those with fragile health due to compromised respiratory function or other reasons. It recommended that in no case should developing humans (i.e., fetuses, infants, young children, or adolescents) be exposed to neurotoxic chemicals. At a policy level, the EPA committee recommended that (1) EPA take whatever administrative action was necessary to extend the protections of the Common Rule (40 CFR Part 26) to all human research activities resulting in data submissions to the agency, including review by an Institutional Review Board (IRB) in compliance with the Common Rule; (2) the structure, function, and activities of EPA’s IRBs as well as the external IRBs of entities submitting data should be under “active and aggressive scrutiny by EPA”; (3) EPA establish an internal ethics review organization for compliance oversight; and (4) data derived prior to the enactment of P.L. 92-516 (amendments to FIFRA) need not be rejected, even if the research was conducted unethically. In a minority report, several committee members argued that the majority report underplayed risks to humans from intentional experimental dosing and that human studies as currently designed fail to provide information about safe levels of intake of pesticides by humans, especially children. They further argued that the majority recommendations would lead to more intentional dosing studies and eventually higher levels of pesticide exposures in the U.S. population. Following the submission of these recommendations, EPA concluded that scientific and ethical questions remained and that the issues raised could be just as relevant to many of the agency’s other programs, citing EPA’s past reliance on data from intentional human dosing studies in decision making regarding particulate and ozone air pollution.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues On December 14, 2001, EPA suspended the use of data from chemical safety studies in humans pending the completion of a report by the National Academy of Sciences (NAS) on the scientific validity and ethical acceptability of human studies of pesticides and other substances conducted by clinical laboratories under contract to private companies.9 This report is the result of that decision. Before describing the charge EPA gave to this NAS committee—the Committee on the Use of Third Party Toxicity Research with Human Research Participants—it is important to clarify EPA’s current policy concerning the ethical oversight of human studies. EPA’S POLICY REGARDING ETHICAL OVERSIGHT OF HUMAN STUDIES In administering its chemical regulatory statutes, EPA conducts and sponsors a wide variety of research studies involving humans, including observational studies of everyday common exposures, epidemiological studies, and deliberate dosing studies. EPA is a signatory to Subpart A of the Federal Policy for the Protection of Human Subjects (the Common Rule), the requirements of which are described in further detail in Chapter 2 and summarized in Box 1.3. The Common Rule is codified in the regulations of the Department of Health and Human Services (DHHS) at 45 CFR 46 and adopted for EPA purposes in 40 CFR Part 26.10 Research conducted or sponsored by EPA must be in compliance with the Common Rule. 9   Following the announcement, CropLife America, AMVAC Chemical Corporation, and Aventis CropScience USA LP petitioned the U.S. Court of Appeals for the District of Columbia stating that the moratorium constitutes an unlawful de facto regulation. Moreover, the petitioners claimed that the moratorium contravenes the clear requirement of the FFDCA that EPA consider all relevant reliable data in making pesticide decisions (21 U.S.C. §346a(b)(2)(D)), and the provision of FIFRA recognizing that human clinical studies are not invalid when people “freely volunteer to participate in the test,” and when they “are fully informed of the nature and purposes of the test,” and of any reasonably foreseeable health consequences (7 U.S.C. §136j(a)(2)(P)). Oral arguments were heard March 17, 2003, and on June 3, 2003, the District of Columbia Circuit Court invalidated EPA’s directive suspending reliance on third-party human studies on the grounds that EPA had failed to follow correct procedures in suspending use of such studies. The court did not render any substantive judgment about the EPA action. 10   Each signatory to the Common Rule promulgated the same set of regulations within its statutory authority. The original regulations, as codified by the Department of Health and Human Services, are found at 45 CFR 46. EPA promulgated the regulations as 40 CFR 26. This report will refer to the regulations as codified by EPA in 40 CFR 26, which includes only Subpart A. EPA has not yet signed on to Subparts B through D, which focus on protections for vulnerable subjects, such as children, pregnant women, and prisoners.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues BOX 1.3 Common Rule Requirements for IRB Review In essence, the Common Rule has two major substantive requirements—that human research receives review by an independent body for its ethical acceptability and that the IRB determine the requirements for informed consent by potential research participants. Current regulations instruct IRBs in approving research studies as follows: In order to approve research…the IRB shall determine that all of the following requirements are satisfied: Risks to subjects are minimized: (i) by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes. Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive In July 1999, EPA issued a directive clarifying and extending its policies for application of the Common Rule, making it applicable to a broader range of human studies, including research that (1) involves the gathering of physiological measurements (e.g., monitoring a subject’s cardio-respiratory performance) or the collection of body fluids, tissue, or expired air from subjects; (2) requires subjects to perform specific tasks other than their normal activities or to manipulate their environment (i.e., to modify their exposure); or (3) gathers or records private information (as defined in 40 CFR 26.102 (f)(2)) in a manner that associates such information with an identifiable subject. Before EPA initiates research involving humans in one of its own laboratories or supports such research, such as through a contract, grant, cooperative agreement or interagency agreement, the study must be approved by the EPA Human Subjects Research Review Official (the Review Official) or be determined by the Review Official to be “exempt research,” according to the exemptions provided in the regulations at 40 CFR 26.101(b). To obtain approval by the Review Official, the agency official

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues even if not participating in the research). The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility. Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted and should be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons. Informed consent will be sought from each prospective subject or the subject’s legally authorized representative, in accordance with, and to the extent required by 40 CFR 26.116. Informed consent will be appropriately documented, in accordance with, and to the extent required by 40 CFR 26.117. When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects. When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data. When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare of these subjects (40 CFR 26.111). responsible for the research must submit to the Review Official documentation showing to the satisfaction of the Review Official that the research will be conducted in accordance with the Common Rule. The Review Official may withhold approval of any proposal that does not adequately protect the rights and welfare of the participants. If EPA-funded studies are conducted at a non-EPA site, the study must be reviewed by the research institution’s IRB, and the research site should have an assurance of compliance on file with either EPA or the Office for Human Research Protections within DHHS. If the study is conducted at an EPA facility, EPA requires that the research be reviewed by an appropriate IRB, and a Review Official, who is a member of EPA’s Office of Research and Development, ensures that IRB review has occurred. With respect to studies conducted for EPA regulatory purposes by third parties, such as the pesticide studies discussed earlier, the Common Rule does not necessarily apply, and there is no established system within

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues EPA for reviewing the conduct of such studies from an ethical and participant protection perspective. CHARGE TO THE COMMITTEE EPA asked NAS to conduct a review of the complex ethical and scientific issues posed by EPA’s possible use of third-party studies that intentionally dose humans with toxicants to identify or quantify their effects, including specifically studies to ascertain a NOAEL. The specific tasks assigned to the committee by EPA are provided in Box 1.4. Although the recent controversies about EPA’s use of human research studies have primarily involved the pesticide program, the agency’s request to NAS was not limited to such studies, but rather asked for advice about third-party studies generally. Accordingly, the committee reviewed the question of third-party studies generally, always bearing in mind that the pesticide studies have been a particular object of concern both inside and outside the agency. The tasks EPA assigned to this committee require consideration of some difficult issues, but they do not require the committee to invent the basic standards that govern human research in the United States. These standards are already embodied in the Common Rule and in other authoritative statements of principle on the ethical conduct of human research (as discussed in Chapter 2). Rather, the committee’s assigned task was to consider how those standards should be applied in the particular case of intentional human dosing studies conducted by third parties for EPA regulatory purposes. The existing ethical standards are sufficiently general, however, and the studies in question are sufficiently different from most human research conducted in the United States that applying the standards to the cases at hand requires considerable analysis. The committee carried that analysis far enough to provide guidance to EPA on how, as a general matter, the standards should be applied. This analysis includes careful review by the committee and committee staff of some of the specific human studies that have been submitted to EPA. It was not the committee’s charge, however, to make decisions or recommendations on the ultimate acceptability of any specific study for regulatory purposes. This requires a depth of analysis, both ethical and scientific, that is beyond the scope of the committee’s charge. As noted earlier, the scientific validity of a human study for a particular regulatory purpose is intertwined with the study’s ethical acceptability. The committee explored in great depth principles of both ethical and scientific validity in order to make recommendations about how accepted principles should be applied here. The committee also accepted the charge of considering the scientific basis that an otherwise ethically sound hu-

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues man study could rely on to address one particular regulatory issue: the possible alteration of the interspecies uncertainty factor (discussed in Chapter 7). This is an important and sensitive science policy issue that lies behind much of the public interest and controversy surrounding the issues considered by this committee. Finally, although the committee’s charge was directed to third-party human studies, the committee noted that the ethical and scientific issues are fundamentally the same regardless of whether a human study is conducted by a third party or by EPA and that the same basic ethical framework should apply to both third-party and non-third-party studies. The ethical issues of concern about third-party studies arise because they potentially impose health risks on human beings, and with regard to this characteristic, third-party studies and agency-sponsored studies are indistinguishable. If third-party and agency-sponsored studies should be treated differently within an ethical framework, it would have to be because they differed systematically with regard to some other characteristic, such as the benefits to be derived from the studies or the ability of subjects to provide informed consent. Such a conclusion, however, would have to emerge from the application of the basic framework to specific experiments, rather than a priori, as an operating assumption.11 For this reason, the committee’s recommendations apply to both third-party and EPA-supported studies—that is, to any research sponsor submitting human data to EPA for regulatory purposes. NATIONAL ACADEMY OF SCIENCES COMMITTEE PROCESS To conduct this study, a committee composed of members with expertise in ethics, law, pharmacology, toxicology, genetics, pediatrics, statistics/biostatistics, economics, epidemiology, risk assessment, and clinical trials was established under the auspices of the National Academies’ Science, Technology, and Law Program and in accordance with NAS procedures and policies regarding the nomination and appointment of study committees. The names and biographies of the nominated individuals were posted to the NAS website for public review and comment. Comments were considered during the committee bias and composition discussion at the first meeting on December 16, 2002. 11   The committee did find some important distinctions to be drawn between agency-sponsored and third-party studies, primarily related to the processes for ensuring compliance with ethical standards.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues BOX 1.4 Specific Statement of Task According to EPA’s charge to NAS, the scope of information gathered by the committee and the topics on which public input shall be solicited include, but are not necessarily limited to: Whether and if so to what extent EPA’s decision to accept, consider, or rely on a third-party, human toxicity study should depend on: whether the study was conducted in substantial compliance with the provisions of the Common Rule or another standard for the protection of human subjects; the type of substance tested (e.g., pharmaceutical, pesticide, environmental contaminant); whether the results of the study tend to indicate that the substance tested is more risky or less risky than is indicated by other available data; the statistical power of the study, or the ability or inability to measure the same endpoints in humans that have been observed in animal testing of the same substance or other specific characteristics of the study design; when the study was conducted in relation to the date of any statement of policy by EPA regarding the ethical conduct of such studies; whether there are alternative methods of obtaining data of comparable scientific merit that would not involve deliberate dosing of human subjects; the nature of the test sponsor’s interest in a regulatory matter that could be affected by consideration of the data; how EPA intends to use the results in its regulatory decision making (e.g., to reduce or remove the traditional 10-fold interspecies uncertainty factor, or to provide an endpoint for use in calculating a reference dose for the test substance, or for some other purpose); whether the study has been submitted in response to a regulatory requirement of EPA, or whether it was conducted in conformity with an EPA Guideline; EPA’s assessment of the actual or potential benefits, if any, to the individual human subjects of the research, or to society; Under what circumstance(s), if any, the availability of human data should lead EPA to consider reducing or removing the customary 10-fold interspecies uncertainty factor; What existing standards (e.g., the Common Rule, the Declaration of Helsinki) are available for evaluating the design and the conduct of research with human subjects, and which of these standards would be most appropriate in judging whether human toxicity studies submitted to EPA in

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues support of a regulatory decision were conducted ethically and in a way fully protective of the interests at safety of the human subjects; Whether and if so how the requirements of the Common Rule should be extended to the conduct of third-party research with human subjects intended for submission to EPA in support of a regulatory decision; and To what extent and how the submitter of research with human subjects to EPA should be required to document or otherwise demonstrate compliance with appropriate standards for the protection of human research subjects—e.g., fully informed and fully voluntary participation and independent oversight of research design and conduct by an Institutional Review Board. The committee report shall address the full range of relevant issues (including those listed above) and provide advice—including suggesting appropriate criteria and factors, and reasons for all recommendations—for EPA to consider in establishing agency policy. The committee report shall include, but is not limited to: Identification of the committee members and a description of the process by which the committee conducted its business; A description of the opportunities for the public to be informed of and to participate in the committee’s process; A description of the current legal (statutory or regulatory) requirements governing the conduct of third-party research with human subjects and consideration by a federal agency of the result of such research; A description of the current policies and practices of other federal agencies regarding acceptance, consideration, and reliance on third-party research with human subjects and a description of any requirements and enforcement practices of such agencies relating to the ethical conduct of such research; The views of the committee regarding the types of third-party human research, if any, that EPA should always refuse to accept, consider, or rely on; The views of the committee regarding minimum standards relating to the protection of human subjects which should be met in the design and conduct of a study with human subjects, in order for EPA to accept, consider, and rely on the results of the study in regulatory decision making; The views of the committee regarding the minimum scientific standards relating to the reliability and relevance of the results that should be met for a human study in order for EPA to accept, consider, and use the results of the study in regulatory decision making; and The views of the committee regarding the best way(s) in which any minimum standard for the conduct of third-party research with human subjects should be imposed, implemented, and enforced.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues The committee met 6 times over 12 months in open and closed meetings, convened numerous conference calls, and invited testimony from a number of individuals. In addition, it convened one public forum on January 8, 2003, to receive public input on the topics under consideration. The committee received and reviewed studies voluntarily submitted by a number of companies that had previously conducted intentional human dosing studies and that had submitted their results to EPA for consideration. Some of these submissions included complete files on a particular chemical, while others were partial files. All of these materials were placed in the National Academies’ public access file for this project. In addition, committee staff filed a freedom of information request with EPA for all information relevant to the intentional human dosing studies that had been submitted to the EPA Office of Pesticide Programs. Committee staff reviewed these studies and briefed the committee on their findings. In addition, EPA provided the committee with a copy of all of the public comments submitted to the agency in response to an Advance Notice of Proposed Rulemaking concerning intentional dosing studies that it published on May 7, 2003 (EPA, 2003). ORGANIZATION OF THE REPORT Determining the organization of this report has been a challenge, because the issues and analysis involved are so intertwined. Although an effort has been made to provide a coherent narrative, it has been necessary to make numerous cross-references among chapters. Chapter 2 expands upon this chapter’s discussion of the Common Rule and the general ethical and regulatory framework for the oversight of research involving humans. Chapter 3 describes the relevant types of intentional human dosing studies and recommends criteria for assessing the scientific validity of such studies for ethical purposes and for EPA regulatory decision-making purposes. This includes consideration of the scientific justification for conducting a study and issues of study design and reporting. Chapter 4 provides a framework for assessing and balancing the risks and potential benefits of intentional dosing studies in humans and provides examples of how this framework might apply to human studies of the kind that have been submitted to EPA. Chapter 5 focuses on additional ethical considerations in the conduct of human studies, such as the selection of research participants, payment for participation in research, informed consent, compensation for research-related injuries, and the use of results from ethically problematic studies. It also outlines the committee’s conclusions and recommendations to EPA regarding proce-

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues dures for the ethical review of toxicant studies, before and after they are conducted. Chapter 6 recommends a procedural framework for EPA’s implementation of the scientific and ethical principles described in earlier chapters, including the formation of a new review board within EPA. Chapter 7 provides the committee’s discussion of and recommendations for EPA’s use of human study results in risk assessment and in considering possible adjustments in the interspecies uncertainty factor. REFERENCES Environmental Protection Agency (EPA). 1989. Risk Assessment Guidance for Superfund, Vol. 1: Human Health Evaluation Manual, Interim Final. EPA/540-1-89/002, December. Available at www.epa.gov/cgi-bin/claritgw?op-display&document=clserv:OSWER:1175;&rank=4&template=epa). EPA. 2003. Human Testing; Advanced Notice of Proposed Rulemaking. Federal Register 68:24410-24416. Environmental Working Group. 1998. The English Patients: Human Experiments and Pesticide Policy. Washington, D.C.: Environmental Working Group. Available at www.ewg.org/reports/english/English.pdf. Gorovitz, S., and H. Robertson. 2000. Pesticide toxicity, human subjects, and the Environmental Protection Agency’s dilemma. Journal of Contemporary Health Law Policy 16(2):427-458. McConnell, E. 2001. The value of human testing of pesticides. Human and Ecological Risk Assessment 7(6):1575-1581. National Bioethics Advisory Commission (NBAC). 2001. Ethical and Policy Issues in Research Involving Human Participants: Vol. 1. Bethesda, MD: U.S. Government Printing Office. National Research Council (NRC). 1983. Risk Assessment in the Federal Government: Managing the Process. Washington, D.C.: National Academy Press. NRC. 1993. Pesticides in the Diets of Infants and Children. Washington, D.C.: National Academy Press.