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1 Introduction and Background
Pages 21-45

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From page 21...
... 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.
From page 22...
... 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.
From page 23...
... 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.
From page 24...
... 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.
From page 25...
... 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 environ ment, 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.
From page 26...
... 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.
From page 27...
... 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.
From page 28...
... 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
From page 29...
... 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.
From page 30...
... 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.
From page 31...
... 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.
From page 32...
... 2003. Presentation at Public Forum: Providing Input to the Committee on the Use of Third Party Toxicity Research with Human Research Participants, January 8, 2003, National Academy of Sciences, Washington, D.C.
From page 33...
... Inhibition and Cholinergic Signs and Symptoms of Chlorpyrifos at Three Dose Levels 2000 A Rising Dose Toxicology Study to Determine the No-Observable-Effect Levels for Erythrocyte Acetylcholinesterase (AChE) Inhibition and Cholinergic Signs and Symptoms of Chlorpyrifos at Three Dose Levels 2000 A Randomized, Double-Blind, Ascending, Acute, Oral Dose Study of Diazinon to Determine the No Effect Level for Plasma and RBC Cholinesterase Activity in Normal, Healthy, Volunteers -- Part A: Clinical Phase 2000 A Randomized, Double-Blind, Ascending, Acute, Oral Dose Study of Diazinon to Determine the No Effect Level for Plasma and RBC Cholinesterase Activity in Normal, Healthy, Volunteers -- Part B: Analysis of DETP in Urine 2000 A Randomized, Double-Blind, Ascending, Acute, Oral Dose Study of Diazinon to Determine the No Effect Level for Plasma and RBC Cholinesterase Activity in Normal, Healthy, Volunteers -- Part C: Analysis of Diazinon in Blood and G 27550 in Urine
From page 34...
... The report recommended that EPA conduct a comprehensive review of past and current human experimentation; that it impose a moratorium on human experimentation for the purposes of pesticide registration until the review was completed; and that following the review, EPA adopt a policy to apply to studies conducted for the agency's regulatory programs such as the Federal Policy for the Protection of Human Subjects (the Common Rule) , the ethical framework for human studies that many federal agencies, including EPA, apply to their own human research (see Chapter 2)
From page 35...
... The protection of public health from adverse effects of pesti cides 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)
From page 36...
... 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.
From page 37...
... 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.
From page 38...
... 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)
From page 39...
... 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
From page 40...
... . 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.
From page 41...
... 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.
From page 42...
... , if any, the availability of human data should lead EPA to consider reducing or removing the customary 10-fold interspecies uncertainty factor; 3) What existing standards (e.g., the Common Rule, the Declaration of Helsinki)
From page 43...
... The views of the committee regarding minimum standards relat ing 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; 7) 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 8)
From page 44...
... 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.
From page 45...
... 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)


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