Executive Summary and Recommendations

EXECUTIVE SUMMARY

The regulation of chemicals to protect human health and the environment is one of the Environmental Protection Agency’s (EPA’s) most important and controversial tasks. Chemicals play a central role in our modern industrial society and are pervasive in the environment and food supply. All chemicals have the potential to harm human health, depending on the conditions under which people are exposed. This makes it critically important from a public health perspective to understand the hazards and to control human exposures to chemicals so that risk of harm can be minimized or eliminated—the widely accepted purpose of chemical regulation. In practice, however, the regulation of the use of chemicals is controversial because it involves competing interests and values.

EPA administers a series of congressional enactments that establish basic standards and procedures for assessing and balancing the risks and benefits of chemicals through the regulatory process. Some of the most important issues with which EPA must grapple on a continuing basis involve the nature of the scientific evidence that will be acceptable and that will suffice as the basis for regulatory decision making.

EPA commissioned The National Academies to provide advice on the vexing question of whether and, if so, under what circumstances EPA should accept and consider intentional human dosing studies conducted by companies or other sources outside the agency (so-called third parties) to gather evidence relating to the risks of a chemical or the conditions



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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues Executive Summary and Recommendations EXECUTIVE SUMMARY The regulation of chemicals to protect human health and the environment is one of the Environmental Protection Agency’s (EPA’s) most important and controversial tasks. Chemicals play a central role in our modern industrial society and are pervasive in the environment and food supply. All chemicals have the potential to harm human health, depending on the conditions under which people are exposed. This makes it critically important from a public health perspective to understand the hazards and to control human exposures to chemicals so that risk of harm can be minimized or eliminated—the widely accepted purpose of chemical regulation. In practice, however, the regulation of the use of chemicals is controversial because it involves competing interests and values. EPA administers a series of congressional enactments that establish basic standards and procedures for assessing and balancing the risks and benefits of chemicals through the regulatory process. Some of the most important issues with which EPA must grapple on a continuing basis involve the nature of the scientific evidence that will be acceptable and that will suffice as the basis for regulatory decision making. EPA commissioned The National Academies to provide advice on the vexing question of whether and, if so, under what circumstances EPA should accept and consider intentional human dosing studies conducted by companies or other sources outside the agency (so-called third parties) to gather evidence relating to the risks of a chemical or the conditions

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues under which exposure to it could be judged safe. EPA asked the committee to consider: (1) the conditions for which EPA should accept, consider, or rely on third-party, human toxicity studies (see Chapters 3-7); (2) 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 (see Chapter 7); (3) the applicability of existing standards (e.g., the Common Rule, the Declaration of Helsinki) for evaluating the design and the conduct of this type of research (see Chapters 2 and 5); (4) whether and if so how the requirements of the Common Rule should be extended to the conduct of third-party human studies intended for submission to EPA in support of a regulatory decision (see Chapters 4-6); and (5) the extent to which, and how, the submitter of research with human subjects should be required to document or otherwise demonstrate compliance with appropriate standards for the protection of human research participants (see Chapters 3, 5, and 6).1 The organization of this report has been a challenge because the issues and analysis are so intertwined. An effort has been made to provide a coherent narrative, but it has been necessary to make numerous cross-references among chapters. The primary impetus for EPA’s request was a series of events involving agricultural pesticides and EPA’s implementation of the 1996 Food Quality and Protection Act (FQPA). This law modernized the safety standards applicable to pesticide residues in food, adding an extra measure of protection for children and placing strict deadlines on EPA’s congressionally mandated program to ensure that all agricultural pesticides currently on the market satisfy the updated safety standards. The enactment and anticipated implementation of FQPA brought into question whether current uses of certain categories of long-used pesticides—the organophosphates (OPs) and carbamates—could be maintained under the new standards. As a general rule, EPA sets safe levels of exposure to pesticide residue in food on the basis of extensive testing in animals to determine its toxic properties and to derive a Reference Dose (RfD). It then divides the highest dose at which the most sensitive indicator of human risk did not occur (the no observed adverse effect level or NOAEL) by two or more uncertainty factors to yield the relevant RfD. One uncertainty factor accounts for the possibility that the average human could be more sensitive to the chemical’s effects than the animal model from which the NOAEL was identified (the interspecies factor). A second factor accounts for the possibility of variation among humans in their sensitivity to the chemical (the 1   The complete charge to the committee is stated in Chapter 1, p. 40.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues intraspecies factor).2 EPA then makes its decision with regard to the FQPA mandate, which requires it to apply up to an additional 10-fold factor to take into account the potential for increased sensitivity for fetuses and children. The statute allows EPA to apply a factor other than 10 (i.e., lesser or greater) if reliable data are available to show that this different factor is protective of infants and children. The cumulative effect of this approach to determining safe levels of exposure to pesticides is a potential 1,000-fold margin of safety between the NOAEL in animals and allowable exposures in humans. It has long been EPA’s practice to adjust the interspecies and intraspecies uncertainty factors if justified by scientific evidence showing that a different factor would provide a more scientifically sound or “accurate” extrapolation from the animal test results. In response to FQPA, several pesticide manufacturers conducted and submitted to EPA intentional oral dosing studies involving humans for purposes of determining a NOAEL that might justify the reduction or elimination of the interspecies safety factor for certain pesticides in the widely used OP and carbamate classes. The submission of these studies has generated substantial controversy. Although it is not unusual or controversial for EPA to rely on human-derived data in its risk assessments, such data are typically derived from case reports, observational studies, or epidemiological studies that do not involve intentional dosing of humans. In part, the pesticide studies involving humans are controversial because they were conducted by economically interested third parties, whose motivation was to justify reducing the interspecies uncertainty factor, thereby increasing the acceptable or safe human exposure level and possibly permitting the continuation of certain pesticide uses that might otherwise have been precluded under FQPA’s new safety standards. Some scientists and environmental and other public interest groups challenged the ethical and scientific validity of the studies, contending among other things that people should not be put at risk for the purpose of reducing 2   Application of additional uncertainty factors in deriving the RfD may be necessary (1) to account for the lack of chronic data if deriving a traditional, chronic RfD (i.e., the subchronic-to-chronic factor), (2) to extrapolate from a LOAEL (lowest observed adverse effect level) to an estimated NOAEL, if no appropriate NOAEL can be identified in the toxicity database (the LOAEL-to-NOAEL factor), or (3) to account for the absence of key data in the toxicity database for a given chemical (the database factor). The default values for the inter- and intraspecies uncertainty factors are 10; those for the other three generally range from 3 to 10. Of course, EPA has the discretion to modify any of these default uncertainty factors if justified by the available scientific evidence.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues the stringency of regulatory standards. Pesticide manufacturers and some scientists argued that the human dosing studies were needed to ensure the scientific quality and accuracy of EPA’s safety evaluations and that they had been or could be conducted ethically. In response to this controversy, EPA declared in 1998 its intention not to use the pesticide studies until the ethical and scientific issues had been resolved and referred the matter initially to a Joint Subcommittee of EPA’s Science Advisory Board (SAB) and the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP). The majority of the SAB/SAP Subcommittee concluded that there are circumstances in which such studies could be justified ethically and scientifically, subject to stringent conditions and oversight. (A minority report was filed by two members indicating that they could not envision a situation where these types of studies could be conducted.) After receiving the subcommittee’s report, EPA decided to seek further review from the National Academy of Sciences (NAS) and to broaden the issue to encompass third-party human dosing studies related not only to pesticides but also to EPA’s other chemical regulatory programs, including those addressing toxic air pollutants and drinking water contaminants. EPA also asked the committee to consider the scientific basis that an otherwise ethically sound human study could rely on to alter the interspecies uncertainty factor. This important science policy issue lies behind much of the controversy surrounding pesticide studies. Summary of the Committee’s Response to EPA’s Questions The committee understands and respects both the intellectual difficulties and the social sensitivities involved in considering the issues surrounding human testing of chemicals. Like other groups that have addressed this subject, the committee noted that such testing should be approached with the utmost caution and care. Human studies involving pesticides, air pollutants or other toxicants, as compared to drugs or other therapeutic agents, are especially sensitive and controversial. To many, they are inherently repugnant and should never be allowed; to others, they may contribute significantly to science-based decision making. Even though the tasks EPA assigned to this committee required that members consider difficult issues, the committee was not required to invent the basic standards that govern human research in the United States. These standards are already embodied in the Federal Policy for the Protection of Human Subjects (the Common Rule), which governs human research sponsored by EPA and many other government agencies, and in other authoritative statements of principle on the ethical conduct of hu-

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues man research. The committee’s 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. In keeping with these standards, the committee recommended that intentional dosing studies in humans be conducted and used for EPA regulatory purposes only if all the following conditions are met: The study is necessary and scientifically valid—that is, it addresses an important regulatory question that cannot be answered with animal studies or nondosing human studies and has been designed, conducted, and reported in a manner that ensures the study will be adequate scientifically to answer the question. The societal benefits of the study outweigh any anticipated risks to participants. Intentional human dosing studies that are to be used only to improve the accuracy of an RfD, and that otherwise provide no health or environmental benefit, can be justified only when there is reasonable certainty that participants will experience no adverse effects. All of the recognized ethical standards and procedures for protecting the interests of study participants are observed, including equitable selection and recruitment of participants, informed consent, and independent review of the scientific and ethical merits of the study by an Institutional Review Board (IRB) or its foreign equivalent. The committee also recommended that EPA establish a high-level advisory board to conduct its own review of human dosing studies conducted for EPA regulatory purposes, whether sponsored by EPA or by a third party, both prior to and after the conduct of the study. The purpose of this review would be to ensure that the unique scientific and ethical issues associated with EPA-related studies, including whether the study is likely to be scientifically valid and otherwise beneficial for EPA regulatory purposes, have been thoroughly evaluated in advance by EPA and again prior to using the results of the study for regulatory purposes. The committee carefully considered whether the studies on pesticides that, in part, gave rise to the request for this report provide societal benefits that should be considered in assessing their ethical acceptability. The committee concluded that in order to generate societal benefits such human dosing studies must: (1) be performed in a context in which there is a clearly defined regulatory objective and a critical, unanswered question or other compelling scientific need that cannot be satisfied with animal data or nondosing human studies and (2) be designed with the requisite statistical power and other design features required to meet that regula-

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues tory objective and scientific need. These are minimum threshold requirements that any human dosing study must meet. Studies that satisfy this threshold test have the ability to improve the accuracy of EPA’s regulatory decision making. The committee concluded that improving the accuracy of the science employed in regulatory decisions, whichever direction (i.e., lower or higher) it moves the RfD, constitutes a societal benefit that can justify the conduct of a human dosing study. If the intent is to raise the RfD, however, such a study is justified only if there is no identifiable risk to participants, (as in some pharmacokinetics [PK] studies that are expected, based on very low dose levels and extensive animal testing, not to cause any biological effect in study participants), or there is a reasonable certainty, grounded in the careful review of a sufficient body of scientific evidence, that participants will experience no harm (in the sense of impairment or pain), whether lasting or transitory. Beyond the threshold benefit of improving scientific accuracy (and raising an RfD), human dosing studies can generate different kinds of societal benefits as well, such as benefits to human health or the environment, depending on the nature of the scientific question a study seeks to answer, the uses to which the study results may be put, and the consequences that may flow from those uses. In cases in which such additional benefits are present, they can be considered in determining the extent of the potential risk to which participants may justifiably be exposed, and such additional health or environmental benefits are required to justify the consideration of a human dosing study that is not in the “no identifiable risk” or “reasonable certainty of no harm” categories. Even when such additional benefits exist, a human dosing study that could be anticipated to cause lasting harm to study participants could not be ethically justified. Finally, although the committee’s charge was directed to third-party human dosing studies, the committee concludes that the ethical and scientific issues are fundamentally the same whether a human study is conducted by a third party or by EPA and that the same basic ethical framework should apply to both categories of studies. Because of the complexity of the issues considered by the committee and the need to be specific about the proposals being made, the recommendations follow. RECOMMENDATIONS The committee makes 17 recommendations to strengthen oversight and provide guidance for the use of intentional human dosing studies at

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues EPA. These recommendations are directed to EPA, IRBs, and research sponsors/investigators.3 Establishing Scientific Acceptability The scientific and ethical considerations of human participants’ research are closely related. Research that deliberately exposes humans to toxicants must be both scientifically and ethically justified. Such a study could be scientifically valid but ethically unacceptable (e.g., because the investigator failed to get informed consent or exposed participants to too much risk); however, a study cannot be ethically acceptable if it is scientifically invalid. A sound research design is the first step in developing an ethically acceptable protocol. For these reasons, scientific and ethical considerations should be integrated in the review and evaluation of all human research studies. Recommendation 3-1: Scientific Validity of Intentional Human Dosing Studies EPA should issue guidelines for determining whether intentional human dosing studies have been: justified, in advance of being conducted, as needed and as scientifically appropriate, in that they could contribute to addressing an important scientific or policy question that cannot be resolved on the basis of animal data or human observational data; designed in accordance with current scientific standards and practices to (i) address the research question, (ii) include representative study populations for the endpoint in question, and (iii) meet requirements for adequate statistical power; conducted in accordance with recognized good clinical practices, including appropriate monitoring for safety; and reported comprehensively to EPA, including the full study protocol, all data produced in the study (including adverse events), and detailed analyses of the data. Balancing Risks and Benefits Even if scientifically valid, an intentional human dosing study is not ethically acceptable unless the benefits it provides to the participants or to 3   The order of the recommendations in this executive summary does not match the order in which they appear in the full report. For clarity, in this summary, the recommendations are provided in an order more conducive to a shorter format with abbreviated discussion.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues society outweigh any risks posed to participants. Risks will vary widely depending on the inherent properties of the chemical and the particular conditions of exposure. Careful assessment of risks to participants thus is a prerequisite for conducting a human dosing study. The committee identifies three principal types of human dosing studies conducted for EPA regulatory purposes, each involving different levels of risk based on the particular information sought: (1) those seeking PK information; (2) those studying effects on a biomarker but not adverse signs or symptoms; and (3) those studying adverse but reversible effects. None of the studies the committee encountered would be expected, based generally on extensive animal data and human experience, to cause any irreversible or serious adverse effects. Low-dose PK studies that are expected based on extensive animal testing not to cause any detectable biological response commonly pose no identifiable risk to participants. For the biomarker studies in the second category, there typically are sufficient data to conclude with reasonable certainty that no harm will occur to participants from the biomarker changes. Studies in the third category, because they cause adverse effects, pose an identifiable risk the seriousness of which could vary widely. The potential benefits of an intentional human dosing study also can vary widely. Participants in human dosing studies conducted for EPA regulatory purposes are not likely to benefit personally from their participation, except to the extent they are paid for their participation. The committee concludes that financial remuneration is not a benefit that should be considered in balancing the risks and benefits of these toxicant studies, which means that the relevant benefits potentially associated with human dosing studies conducted for EPA regulatory purposes are societal. For example, a human dosing study on an air pollutant that provides essential data to establish or strengthen a health-protective standard confers on society a potentially significant health benefit. Likewise, a study that would make it possible for EPA to approve a pesticide intended to control a disease vector, such as mosquitoes or ticks, benefits society in a way that could properly be considered in balancing the risks and benefits of a study. In light of the nature and purpose of the human dosing studies that prompted this report, one of the critical questions the committee addressed was whether an intentional human dosing study anticipated to improve the scientific accuracy of EPA’s decisions—for example, by raising the RfD—but not to directly enhance health or environmental protection confers a societal benefit. The committee carefully considered the congressional judgments and intent underlying EPA’s chemical regulatory programs, including the requirement that EPA use the best available scientific evidence in making its regulatory decisions.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues The committee reviewed a number of intentional human dosing studies of the kind typically submitted to EPA or conducted by EPA for regulatory purposes, including several of the OP pesticide studies that prompted this report. Several studies reviewed by the committee measured cholinesterase inhibition, which has been widely studied in humans, as a biomarker of exposure and potential toxicity, rather than a toxic endpoint per se, and were conducted to support reduction of the interspecies uncertainty factor. Recommendation 4-1: Value of Studies That Seek to Improve the Accuracy of EPA’s Decisions But Do Not Provide a Public Health or Environmental Benefit EPA should consider a human dosing study intended to reduce the interspecies uncertainty factor (for example, a study of a biomarker such as cholinesterase inhibition) as conferring a societal benefit only if it was designed and conducted in a manner that would improve the scientific accuracy of EPA’s extrapolation from animal to human data. Because the anticipated benefit would not be as great as that conferred by studies intended to provide a public health or environmental benefit, the study could be justified ethically only if the participants’ exposure to the pesticide could reliably be anticipated to pose no identifiable risk or present a reasonable certainty of no harm to study participants. Recommendation 4-2: Value of Studies That Seek to Provide a Potential Public Health or Environmental Benefit An IRB should be properly constituted to be able to consider whether a study has the potential of providing a clear health or environmental benefit to the community. Such studies could be acceptable even if they involved a somewhat higher level of risk than that posed by studies for which there is no identifiable risk or for which there is a reasonable certainty of no harm. No study is ethically justifiable if it is expected to cause lasting harm to study participants. Ethical Considerations Many ethical considerations remain after determining that a research protocol is scientifically valid and that its probable benefits outweigh its risks to research participants. These other ethical considerations include fair selection and recruitment of potential research participants, fair pay-

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues ment for their participation, the provision of voluntary informed consent, and the provision of compensation for research-related injuries. Recommendation 5-1: Criteria for Scientific and Ethical Acceptability Studies that do not meet the highest scientific and ethical standards should not be carried out or accepted by EPA as input to the regulatory decision-making process. Necessary conditions for scientifically and ethically acceptable intentional human dosing studies include: prior animal studies and, if available, human observational studies; a demonstrated need for the knowledge to be obtained from intentional human dosing studies; justification and documentation of a research design and statistical analysis that are adequate to address an important scientific or policy question, including adequate power to detect appropriate effects; an acceptable balance of risks and benefits and minimization of risks to participants; equitable selection of participants; free and informed consent of participants; and review by an appropriately constituted IRB or its foreign equivalent. • Selection of Research Participants According to the Common Rule, IRBs should not approve a research protocol involving research participants unless “selection of subjects is equitable” (40 CFR 26.111(3)). The principle of justice directs attention to the distribution of benefits and risks—who will gain the benefits and who will bear the risks and other burdens of research—not just the overall risk-benefit ratio. Not only should the research participants be representative of the target population of interest, but the selection of participants should be inclusive in order to avoid exploitation of any particular social group. Particular concerns arise about the recruitment of persons from vulnerable populations, including persons who lack decision-making capacity and persons who may be vulnerable to coercion or undue influence. Some potential participants may be at increased risk of harm from particular research protocols. In general, individuals who would face higher risks in the experiment should not be selected for participation. An

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues exception might be warranted if their participation is necessary to answer a question of major importance in the regulatory process and perhaps one of special relevance to people with their condition. But, even then, additional protective measures would be required. Children represent a special case. They are vulnerable because they lack decision-making capacity and are greatly influenced by adults and are often more susceptible to the adverse effects of toxicants. The Department of Health and Human Services (DHHS) has addressed the tension between the need for greater knowledge about children and the need to protect them from harm and exploitation in research. Subpart D (Additional DHHS Protections for Children Involved as Subjects in Research) greatly restricts the enrollment of children in research that involves greater than minimal risk without the prospect of direct medical or health benefit. Recommendation 5-2: Participant Selection Criteria IRBs reviewing intentional human dosing studies should ensure that the following conditions are met in selecting research participants: Selection should be equitable. Selection of persons from vulnerable populations must be convincingly justified in the protocol, which also must justify the measures to be taken to protect those participants. Selection of individuals with conditions that put them at increased risk for adverse effects in such studies must be convincingly justified in the protocol, which also must justify the measures that investigators will use to decrease the risks to those participants to an acceptable level. EPA should adopt Subpart D of the Regulations for the Protection of Human Research Subjects. At a minimum, EPA should adhere to Subpart D’s requirements for research involving children. • Payment to Participants Another issue related to the principle of justice, as well as of respect for persons, involves remuneration for participation in research. Paying research participants is a common and long-standing practice in the United States. Ethically, the principles of justice, fairness, and gratitude support payment to those who bear the burdens of research on behalf of society. Nonetheless, there is little agreement in theory or in practice about what constitutes just or fair payment. Any remuneration will influence the decisions of some more than others, and the protocol must be careful

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues to protect participants, even when they misrepresent their health state and symptoms in order to participate and receive payment. All parties involved in designing and evaluating a protocol should consider whether the proposed level of remuneration would constitute exploitation or offer undue inducement. Recommendation 5-3: Payment for Participation IRBs, all relevant review boards, investigators, and research sponsors should ensure that payments to participants in intentional human dosing studies are neither so high as to constitute undue inducement nor so low as to be attractive only to individuals who are socioeconomically disadvantaged. Proposed levels of and purposes for remuneration (e.g., time, inconvenience, and risk) should be scrutinized in light of the principles of justice and respect for persons. Moreover, EPA, in conjunction with other federal agencies, should consider developing further guidance on remuneration for participation in intentional human dosing studies, including guidance regarding whether remuneration should reflect the level of risk as well as the time and inconvenience involved. • Informed Consent Voluntary, informed consent by research participants (or permission by their surrogate decision makers) is a principal requirement in the system of protections of research participants. The consent requirement expresses the principle of respect for persons, including their autonomous choices. The Common Rule stresses this requirement, as do other codes of research ethics, including the Nuremberg Code, the Declaration of Helsinki, and Food and Drug Administration’s (FDA) Good Clinical Practice (GCP) guidelines. To ensure the voluntary, informed consent of participants in toxicant studies, the committee recommends the development of a list of best practices for the consent process. These practices should be used to stimulate investigators and IRBs to consider what consent procedures would be most appropriate for a particular study. They should not be regarded as inflexible requirements that must be applied in every case. Recommendation 5-4: Best Practices in Informed Consent EPA should develop and disseminate to relevant IRBs, investigators, and sponsors a list of best practices regarding informed consent in intentional human dosing studies. EPA should encourage

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues all sponsors and investigators to adopt these practices, and it should require their adoption in studies it sponsors or conducts. • Compensation for Research-Related Injuries Debate continues in the United States about whether compensation should be provided for research-related injuries. The Common Rule requires only that when research involves more than minimal risk, information should be disclosed about whether medical treatments and other compensation will be provided for research-related injuries. Many critics of the U.S. policy believe there should be more than disclosure of information about compensation, calling for provision of medical care for research-related injuries without cost to the injured participants and, in addition, for compensation for lost wages, disabilities, and death. These claims are based on the belief that research participants, whatever their motivations, accept risk on behalf of society. When research participants are injured, justice, fairness, and gratitude mandate, at a minimum, the provision of needed medical treatment without cost to the participant. Further study is needed regarding the provision of other compensation. Recommendation 5-5: Compensation for Research-Related Injuries At a minimum, sponsors of or institutions conducting intentional human dosing studies should ensure that participants receive needed medical care for injuries incurred in the study, without cost to the participants. In addition, EPA should study whether broader compensation for research-related injuries should be required. Creation of a Comprehensive EPA Human Studies Review Process EPA is a signatory agency to the Common Rule, which requires, at a minimum, that human research protocols undergo review by an IRB and that participants provide voluntary informed consent. The Common Rule applies to human research sponsored by EPA as well as any research performed at an institution that has committed to have all research reviewed by an IRB as part of its assurance of compliance. Private sponsors of intentional human dosing studies submitted to EPA are not required by U.S. law to obtain IRB approval for studies, unless the studies are conducted at institutions that require IRB review of all research. However, it appears that all of the pesticide experiments reviewed by the committee were approved in advance by IRBs or their foreign equivalents. Even though the sponsors of those experiments acted responsibly in submitting their pro-

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues tocols for IRB review, this decision should not be left to the sponsors’ discretion. EPA itself has sponsored intentional human dosing studies involving exposure to toxicants. At least some of those experiments were approved by IRBs at the institutions that conducted the research. The committee was informed that EPA does not have an IRB, but instead has an Ethics Review Officer who typically ensures that all EPA-sponsored or conducted studies have been reviewed by an IRB. If all EPA-sponsored human research is conducted at nonfederal institutions and those institutions have appropriate IRBs operating in compliance with the Common Rule, the federal requirements might be satisfied. If EPA conducts human research in-house, it must continue to ensure that the research is reviewed by an appropriately constituted IRB. Recommendation 6-1: IRB Review of All Studies EPA should require that all human research conducted for regulatory purposes be approved in advance by an appropriately constituted IRB or an acceptable foreign equivalent. Research conducted by EPA scientists should be reviewed by an EPA-authorized IRB. As noted above, IRBs remain a crucial part of the system of protection for participants in research. However, in special situations in which research poses complicated scientific and ethical issues, as in intentional human dosing studies, IRB review requires substantial supplementation. The committee concludes that another level of review is needed for intentional human dosing studies in order to add a supplementary layer of protection and to establish a body of knowledge and expertise with regard to these studies that can then be communicated to the public and the research community. Recommendation 6-2: Human Studies Review Board To ensure that intentional human dosing studies conducted for EPA regulatory purposes meet the highest scientific and ethical standards, EPA should establish a Human Studies Review Board to address in an integrated way the scientific and ethical issues raised by such studies. To the extent possible, this board should review in a timely manner the protocols and the justification for all intentional dosing studies intended for submission to EPA, as well as study results when completed. These reviews should be conducted regardless of the sponsor or site of performance, and EPA should communicate the results of the reviews to relevant parties.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues The Human Studies Review Board should prospectively review the protocols and the justification for all studies, whether third party or EPA sponsored or conducted. While studies sponsored or conducted by EPA would be required to undergo review by the Human Studies Review Board in advance, private entities should be encouraged to voluntarily submit their protocols to the board before beginning a study. The committee notes that it would be optimal if this review of privately sponsored studies were mandatory, but because of legal and logistical concerns it recommended only that EPA consider making it mandatory. Any conclusions reached by the board should be advisory and not binding on the sponsoring companies or reviewing IRBs. The proposed board supplements but does not replace the IRB. Its principal function would be to help assure that EPA considers only intentional human dosing studies that meet the rigorous scientific and ethical standards specified in this report. Before human toxicant experiments are conducted, the board would provide advice to the sponsors proposing such research (including EPA) on how to meet these high standards. Furthermore, EPA’s awareness of all studies would help ensure that when studies unexpectedly suggest that an environmental standard must be strengthened or that a safety factor must be increased, such studies would be included in the EPA regulatory or risk-assessment processes. After the experiments are completed and the results submitted to EPA, the board would advise EPA’s relevant program offices on whether, and to what extent, the results should be considered. It would also, over time, collect and analyze information about these experiments that could enable it to suggest ways to improve such research or to assess whether EPA should continue to consider the results of these types of experiments. The post-experiment review function of the board is distinct from the kind of review that EPA undertakes for the purpose of incorporating results from particular experiments into the regulatory process. It would not replace or modify the structures and procedures for the latter kind of review. Instead, it would offer nonbinding advice to the relevant EPA units about the scientific and ethical acceptability of the completed and submitted research. Finally, the committee recommends a structure for review of these experiments that should be both rigorous and workable, but it recognizes its limits in foreseeing how well the structure might work over time and whether it will continue to be needed. Hence, timely periodic reviews will help ensure that the board plays the valuable role this committee envisions for it.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues Recommendation 6-3: Review of the Human Studies Review Board The proposed Human Studies Review Board, its functions, and its record should be assessed after 5 years by a body composed of EPA staff and external reviewers. To review data submitted from intentional dosing studies for regulatory decision-making purposes (e.g., setting standards), EPA should provide sufficient and appropriate in-house expertise, at least at the level that exists for review of animal studies. The results of scientific review of data for regulatory purposes and its use in setting standards should be communicated to the board. It is the committee’s view that the Human Studies Review Board is advisory only and is not a replacement for the scientific review EPA must perform in making regulatory decisions. EPA’s Use of Data from Studies of Cholinesterase Inhibition The committee was asked to evaluate the use of data from intentional human dosing studies in EPA’s risk-assessment process. Questions have arisen regarding the circumstances, if any, in which it would be appropriate to use such data, and the manner in which they should be used. The committee examined those questions within its task of considering whether and in what ways data from intentional dosing studies in humans could be appropriately incorporated into EPA’s general framework for risk assessment. The committee was not asked to review the framework itself and does not offer an assessment of it in this report. Recommendation 7-1: Review of Scientific Data EPA’s use of data from third-party intentional human dosing studies involving cholinesterase inhibition is advisable only if the agency undertakes a thorough review of the data (of the type typically undertaken for submitted animal studies and informed by external peer review) and finds that the studies substantially meet the scientific and ethical standards elucidated in this report. If the studies are found to be scientifically and ethically satisfactory, EPA should use the data to establish RfDs. For those cholinesterase inhibitors that have been thoroughly investigated in high-quality animal studies (including studies of developmental neurotoxicity), and for which it is clear that cholinesterase inhibition is the most sensitive indicator of toxicity, data from intentional human dosing studies may be considered for use in risk assessment. It should be recognized that these circumstances—in which the most sensitive indica-

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues tors of toxicity are the acute biological effects of chemicals and in which such effects are readily measurable in ethically acceptable human studies—are likely to be highly unusual. Indeed, at present the committee was not aware of other candidates for such studies. The committee’s recommendations regarding the cholinesterase inhibition studies are thus not expected to suggest many other cases in which intentional dosing studies in humans to establish a NOAEL will be of value and therefore justifiable. The committee’s recommendations regarding study justification (Recommendations 3-1, 4-1, and 5-1), in which proponents of intentional dosing studies in humans must document that the endpoints to be measured are the critical determinants of risk, represent a substantial hurdle. Recommendation 7-2: Use of Existing Cholinesterase Inhibition Studies The cholinesterase inhibition studies that already have been submitted to EPA, if determined to be scientifically valid and justified for EPA’s regulatory purposes, may be considered for use in risk assessment and standard setting if they were not unethically conducted (see Recommendation 5-7). As indicated in these recommendations, under stringent conditions data from intentional dosing studies in humans can be used within EPA’s risk-assessment framework. Use of such data will eliminate the need for the uncertainty factor (UFA) ordinarily used to extrapolate from animals to humans of average sensitivity. The safety factor called for under FQPA to protect children will not be affected by the use of data from intentional dosing studies in humans. Information directly relevant to children cannot be obtained from intentional dosing studies in human adults, and any such studies in children would be beyond ethical bounds. Recommendation 7-3: Eliminating or Replacing the Interspecies Uncertainty Factor In considering the use of data from the cholinesterase inhibition studies already submitted to EPA, the agency should clearly communicate to all stakeholders that information used to eliminate the interspecies uncertainty factor (UFA) will have no influence on the use of other uncertainty factors or on the use of the safety factor protecting children as required by FQPA. Several critical questions remain regarding the use of data from intentional dosing studies in humans. Studies that reveal no effects of any type at the doses used (so-called NOEL-only studies [no observed effect level])

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues may provide some data regarding safety, but they are inadequate for deriving RfDs or any other formal measure of human protection. Such data should be used only if there are no other data available and there is a compelling public health need to derive a tentative measure of public health protection because they provide no assurance that the study was capable of detecting the effect of interest. Moreover, the relationship between the presumed sensitivity of the study population and the presumed sensitivity of average humans is somewhat ambiguous and needs clarification. Thus, it is not completely clear that the people who participate in intentional dosing studies are always “individuals of average sensitivity” and that they are not, in fact, less sensitive than the “average.” Uncertainties regarding these relationships may be dealt with by a requirement for study replication in a different setting, or by use of an uncertainty factor for intraspecies extrapolation (UFH) that is somewhat greater than the usual default factor of 10. Recommendation 7-4: Data from NOEL-Only Studies and the Sensitivity of Study Populations EPA should reject data from NOEL-only studies for risk assessments if the NOEL is defined as the absence of any biological response, because such studies do not show levels that give rise to an effect (the LOEL [lowest observed effect level]). Such studies provide no assurance that they were adequate to detect the effect of interest. The agency also should consider whether the uncertainty factor used for intraspecies variability (UFH) should be increased to deal with the possibility that study participants may be of less than average sensitivity. A request for study replication also should be considered as a way to address this last issue. Use of Results from Ethically Problematic Studies A final question concerns what role, if any, ethically problematic or unethical studies should play in EPA’s regulatory decisions. The committee predicts that this question will rarely present itself after EPA formulates its new standards and procedures. However, when the question does arise in relation to such studies, it can raise difficult ethical issues. The committee concluded that, as a general rule, EPA should not use data from ethically problematic studies to inform its regulatory efforts. In an extraordinary case, when data from ethically problematic studies appear to warrant a regulatory standard that would provide better protection for public health, the Human Studies Review Board may recommend that EPA convene a special, outside panel, which should reach its judgment by considering:

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues whether the data are crucially important for protecting the public and whether the data cannot otherwise be obtained, with reasonable certainty within a reasonable period, without exposing additional research participants to the risk of harm. Unless the panel can answer both questions affirmatively, it should recommend that EPA not consider or rely on the data in question. In order to strongly deter sponsors and researchers from conducting unethical studies, data from such studies should not be used to favor the sponsor’s interests in loosening regulatory standards. Recommendation 5-6: Studies Completed After Implementation of the New Standards EPA should operate on the strong presumption that data obtained in studies conducted after implementation of the new rules1 that do not meet the ethical standards described in this report will not be considered in its regulatory decisions. Under exceptional circumstances, studies that fail to meet these ethical standards may provide valid information to support a regulatory standard that would provide greater protection for public health. Under these circumstances, EPA should convene a special, outside panel, consisting of relevant experts and members of the public, to examine the cases for and against considering data from such studies. Consideration of the use of data that were collected before the new standards are placed into effect raises particularly difficult issues. Although standards for the ethical conduct of research have been evolving, some are universal (e.g., the requirement not to intentionally harm research participants), and others have a long history. However, often it would be difficult, if not impossible, to obtain sufficient evidence to determine whether past studies, especially those in the distant past, met the ethical standards in place at that time. Recommendation 5-7: Studies Completed Before Implementation of EPA’s New Standards EPA should accept scientifically valid studies conducted before its new rules2 are implemented unless there is clear and convincing 1   The committee uses the term “rules” informally to mean guidance, guidelines, policy, protocols, rules, or regulations. 2   See footnote 1.  

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues evidence that the conduct of those studies was fundamentally unethical (e.g., the studies were intended to seriously harm participants or failed to obtain informed consent) or that the conduct was deficient relative to then-prevailing ethical standards. Exceptional cases in which the Human Studies Review Board determines that unethically conducted studies may provide valid information to support a regulatory standard that would provide greater protection for public health should be presented to a special outside panel, described in Recommendation 5-6, for consideration. This special panel should consider recommending the use of such data only with the additional requirement that the ethical concerns raised by the study are documented and made publicly available. The committee’s recommendations apply to both third-party and government-sponsored studies, and they apply to the cholinesterase inhibition studies that were central to the considerations of this committee.