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Ethics Guidelines for Pesticide Testing in Humans Urged by Panel
(Beyond Pesticides, June 7, 2004)
A group of nationally recognized experts made up of ethicists, physicians, toxicologists, and policy analysts released June 4, 2004 a series of ethical and public policy recommendations regarding the testing of pesticides in humans, in a new article, Pesticide Testing in Humans: Ethics and Public Policy, published in the peer-reviewed journal Environmental Health Perspectives (EHP). These recommendations, which come on the heels of a June 2003 U.S. Court of Appeals decision which overturned a 2001 ban prohibiting testing pesticides on humans and February 2004 recommendations from the National Academy of Sciences, address any research that the U.S. Environmental Protection Agency (EPA) sponsors, conducts, and/or accepts in pesticide registration applications. Pesticide manufacturers have tested pesticides in small groups of human volunteers over the past decade and submitted the results to the U.S. EPA for consideration in standard setting. See previous Daily News story.

The expert panel gathered in February 2002 at the Mount Sinai School of Medicine and continued their dialogue for six months afterwards, resulting in today's recommendations.

The authors note that federal health agencies such as the National Institutes of Health and the U.S. Food and Drug Administration have rules governing the ethics and scientific quality of studies submitted for research purposes -- the so called Common Rule -- but that the U.S. EPA has no such guidelines.

Under the panel's 12 recommendations, any study involving the administration of pesticides to humans must be supervised by a qualified physician; studies must include a sufficient number of subjects to provide statistically valid answers to the questions under investigation; research on animals must precede research on humans; and any human study involving risks that would be unacceptable in a developed nation may not be conducted in a developing nation. Also, under no circumstances are pesticides to be administered to children.

The lead author of the study is Christopher Oleskey of the Mount Sinai School of Medicine. Other authors were Alan Fleischman, Lynn Goldman, Kurt Hirschhorn, Philip J. Landrigan, Marc Lappé, Mary Faith Marshall, Herbert Needleman, Rosamond Rhodes, and Michael McCally.

Public interest groups wrote to EPA in 2003, urging the adoption of strict guidelines for human testing. See letter.

Excerpts from the report follow:
The minority report [of the U.S. EPA-convened joint report of the Scientific Advisory Board (SAB) and Scientific Advisory Panel (SAP}] stated that the final report minimizes the risks to humans from intentional experimental dosing and deemphasizes the issue that "no limited human study will provide information about safe levels of intake of pesticides by humans, especially children" (U.S. EPA 1999b). The minority report also argued that the final report did not adequately address the need for large numbers of subjects to achieve sufficient statistical power to find a small effect, and that the overly small human studies done by pesticide manufacturers were scientifically invalid for this reason alone. It stated that to find a small effect, at least 2,500 subjects in each group were necessary and that, with the sample sizes of 7-50 subjects used in industry studies, there was a 3-4% chance of finding an effect. The minority report concluded that the "there is strong documentation that the human studies done by the pesticide manufacturers were scientifically invalid" (U.S. EPA 1999b, 2000b).

During 1999, in response to mounting criticism from environmentalists and physicians, the Clinton administration directed the U.S. EPA to stop accepting information from pesticide industry studies conducted on humans. The decision preempted the report from the U.S. EPA SAB/SAP, which had for months been deadlocked in their deliberations (Warrick 2000).

In November 2001, the Bush administration reversed the decision of the Clinton administration, indicating that it would now accept data from human tests. The new policy, which has not been formally announced or acknowledged, appears to disregard the recommendations of the U.S. EPA SAB/SAP Joint Subcommittee on Data from Human Subjects (Shogren 2001).

During 2001, the U.S. EPA evaluated three trials in which human volunteers had been subjected to doses of pesticides hundreds of times greater than levels the U.S. EPA had deemed safe. In one study conducted in Lincoln, Nebraska, by a subcontractor to the Dow Chemical Company, volunteers were paid up to $460 to ingest doses of chlorpyrifos in concentrations up to 300 times higher than the level the U.S. EPA considers safe (Vedantam 2000). One female volunteer who received the highest dose reported numbness in her upper arms, which company officials ruled "possibly" related to the pesticide. Cholinesterase levels in her blood fell by 28%, a level unlikely due to chance. Other female participants reported headaches, nausea, vomiting, and intestinal cramps. Dow scientists concluded that the pesticide did not produce any symptoms because similar symptoms were also seen in volunteers given a placebo and there was no clear dose-response pattern (Vedantam 2000).

On 14 December 2001, the U.S. EPA announced another moratorium on human tests after considering the results of testing that exposed humans to pesticides. On 5 September 2002, the U.S. EPA signed a contract with the National Academy of Sciences to create an expert committee to examine ethical issues related to human testing of pesticides (Reuters Limited 2003).
Recently, CropLife America, a pesticide manufacturers' trade group, filed suit against the U.S. EPA. The lawsuit sought to compel the agency to accept data from pesticide testing on humans. In June 2003, the U.S. Court of Appeals of the District of Columbia overturned the 2001 ban prohibiting testing pesticides on humans, opening the door for renewed debate on the practice. The court reinstated the U.S. EPA's previous practice of considering third-party human studies until the agency issues a final rule after gathering public comment and the National Academy of Sciences (NAS) issues its final report (Reuters Limited 2003). In February 2004, the NAS concluded that the U.S. EPA should be allowed to accept test data from chemical companies that pay people to eat pesticides as long as certain standards are met (Vedantam 2004).

The Common Rule applies to research conducted by federal institutions as well as nonfederal institutions that receive federal funding. According to the Common Rule, all investigators who conduct studies that receive funding from any of the 16 federal agencies bound by the Common Rule must obtain informed consent from subjects (Steinbrook 2002). Additionally, the risks of participation must be reasonable "in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result" (Steinbrook 2002). Any institution covered by the Common Rule must establish an institutional review board for oversight of human subjects research (Office of Science and Technology Policy 1991). Some federal agencies require protection of research subjects that goes beyond the Common Rule: For example, FDA regulations 21 CFR Part 50 and 21 CFR Part 56 provide additional protection to human subjects by specifying requirements for informed consent and institutional review boards for clinical investigations regulated by the FDA (1998a, 1998b). Institutions that do not accept federal funding are not bound by the Common Rule and therefore are not required to establish institutional review boards to oversee their research. Perhaps one-fourth of all clinical research conducted in the United States receives no federal oversight (Lemonic and Goldstein 2002).

Excerpts of Recommendations:
The participants agreed unanimously to the following recommendations:
Recommendation 1. The U.S. EPA must establish ethical guidelines for all research it conducts, sponsors, or accepts in registration applications.
Recommendation 2. In its regulatory proceedings, the U.S. EPA must accept only research that is consistent with Common Rule requirements. No study that violates U.S. EPA ethical guidelines can be accepted in applications to the U.S. EPA.
Recommendation 3. All research participants involved in studies that will be used in developing U.S. EPA exposure guidelines must be given adequate information for providing informed consent. To assure that participants are not subjected to undisclosed risks or harms, informed consent processes must be consistent with Common Rule requirements.
Recommendation 4. U.S. EPA applicants and grantees must be held accountable for the ethical conduct of their research. Oversight and enforcement mechanisms must be developed and implemented by the U.S. EPA to ensure compliance with ethical guidelines.
Recommendation 5. Any study involving the administration of pesticides to humans must be supervised by a qualified physician. This physician must have direct responsibility for the well-being of those participating in the study. The physician must have the authority to intervene at any time to stop a study to minimize harm and risk of harm to subjects.
A core tenet of medical ethics is that a study should not knowingly do harm to humans, unless the possibility exists that the study will convey direct benefit to the subjects. Research involving deliberate human exposure to pesticide chemicals appears to compromise this principle (Caplan and Sankar 2002; Robertson and Gorovitz 2000; Steinberg 2000). By definition, all pesticide research designed to determine NOELs carries risk of unknown consequence. These potential risks include low-level health effects, some of which may be delayed in onset and follow the conclusion of the testing period. Historically, such effects have been recorded some time after some pesticide exposures that were thought to be safe, notably after low-dose exposure to some organophosphates, including certain pesticides (Wesseling et al. 2002).
NOEL studies inherently violate various ethical guidelines. Subjects are exposed to levels of pesticides that carry significant health risks. Also, there is no system in place to verify that NOEL studies conducted by chemical corporations are performed with the informed consent of the participants. Because the U.S. EPA does not require nongovernmental institutions to abide by any ethical protocol, the procedures of the chemical companies are not transparent. Additionally, the testing of pesticides in adults bears little relevance to pediatric toxicity.
Recommendation 6. No results obtained from any NOEL studies in humans can be considered in the formulation of exposure guidelines by the U.S. EPA.
The possibility exists that manufacturers could test pesticides in children as a way to acquire data on developmental toxicity required by FQPA. Grave concern--scientific as well as ethical--surrounds this possibility. Biologically, children are more vulnerable than adults to the effects of many pesticides. They are particularly at risk of impacts on development, which may result in lifelong damage to health and function (National Research Council 1993). Ethically, it is not conceivable that a child can give informed consent to a study of pesticide administration to humans.
Recommendation 7. Under no circumstances can children serve as subjects in studies in which they are deliberately exposed to pesticides.
The quality of scientific research is an essential component of the ethical conduct of science. Research protocols that are fundamentally flawed are unjustifiable.
Recommendation 8. Any study that is not scientifically valid--for example, does not include a sufficient number of subjects to provide statistically valid answers to the questions under investigation--must not be considered in standard setting.
To minimize harm to humans and to avoid subjecting humans to unreasonable risks, it is necessary to begin studies by testing pesticides in animals. There are special considerations involved in the testing of pesticides in animals.
Recommendation 9. Research on animals must precede research on humans.
Recommendation 10. Animals must not be used in studies unless accurate and useful information can be obtained.
Biomonitoring provides important and useful information for risk assessment, particularly for determining patterns of exposure. Given the current lack of knowledge about body burdens of pesticides in humans and particularly in children, it is imperative that biomonitoring be carried out to determine the body burdens of pesticides in the general population (Oleskey and McCally 2001).
Recommendation 11. Human biomonitoring must be conducted for every pesticide that is currently in use or present in the environment and that poses human exposure risks. Special consideration must be paid to the body burdens of pesticides in children.
Research on human subjects performed in countries outside the United States for U.S. corporations or agencies is especially controversial (Angell 1997; Varmus and Satcher 1997). Guidelines must be enacted to prohibit the export to other nations of research deemed unacceptable in the United States. Of particular concern is the potential exploitation of subjects in studies carried out in developing nations.
Recommendation 12. It is not acceptable to conduct a study involving humans in a developing nation when the risks and harms involved in the study would be considered unacceptable in an industrially developed nation. It is not acceptable to submit data from such studies in regulatory decision making in the United States. The U.S. EPA must not accept studies performed in foreign countries and conducted according to protocols that would not be accepted in the United States.

Source: Environmental Media Services.

TAKE ACTION: Let the Bush Administration know that you think strict guidelines must be adopted regarding the testing of pesticides in humans, citing some or all of the recommendations above. Send an email to EPA Administrator Mike Leavitt and to [email protected] Also let your elected members of Congress know how you feel. Contact your U.S. Senators and U.S. Representative.