Feb. 20, 2004 WASHINGTON – When regulating chemicals to protect public health, the U.S. Environmental Protection Agency should consider information from studies that involve intentional dosing of humans with toxic chemicals only if such experiments meet the most stringent scientific and ethical standards, ensuring that research participants are protected and that the studies are scientifically necessary and valid, says a new report from the National Academies' National Research Council. At the same time, EPA should establish a Human Studies Review Board (HSRB) to evaluate all human dosing studies – both at the beginning and upon completion of the experiments – if they are carried out with the intent of affecting the agency's policy-making. Human testing of chemicals must be approached with the utmost caution and care, warned the committee that wrote the report.
"Human studies involving pesticides, air pollutants, or other toxicants – as opposed to therapeutic agents – are particularly controversial, and because of this, EPA should subject these studies to the highest level of scientific and ethical scrutiny," said committee co-chair James F. Childress, a professor of ethics and medical education, and director, Institute for Practical Ethics, University of Virginia, Charlottesville. "Our report proposes a framework for EPA's oversight of this research. And the recommended framework should apply to studies that are sponsored by so-called 'third parties' – private companies or other sources outside the agency – as well as by EPA."
The issue of whether – and if so, how – EPA should use information from such studies when formulating regulations has long been highly controversial. In 1996 Congress passed the Food Quality and Protection Act, which tightened safety standards on pesticides. Some chemical manufacturers asserted that the new standards and "reference doses" were not based on a solid scientific foundation. In support of this assertion, several companies sponsored or conducted clinical trials to assess human risk from exposure to pesticides and submitted the results to the agency for consideration. Some public health advocates and others, questioning the industry's research findings, urged the agency to reject the results.
In response to the controversy, EPA announced in 1998 that it would not use the studies to inform its policy-making until many ethical and scientific issues had been resolved. Later, a majority of a joint subcommittee of EPA's Science Advisory Board and the Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel concluded that human dosing studies could be ethically and scientifically justified under certain circumstances, subject to stringent conditions and oversight. EPA sought a broader scientific review from the National Academies evaluating key issues of third-party human dosing studies of pesticides and of some chemical regulatory programs within the agency. EPA itself has sponsored human dosing studies of air pollutants and other potentially hazardous chemicals when it considered the studies necessary to set health-related regulations. But typically, EPA assesses human risk from exposure to toxic substances by determining the lowest level that is harmful to laboratory animals and then reducing that amount by a series of extrapolating factors.
Setting a High Bar
As part of its comprehensive review of the science base, the Research Council committee evaluated intentional human dosing studies that were voluntarily submitted by a number of pesticide companies which had previously submitted their results to EPA. It also reviewed information about human dosing studies that had been sent to the agency's Office of Pesticide Programs. And it held a public forum last year to receive input from various groups and individuals.
The committee recommended that intentional dosing studies in humans be conducted and used for EPA regulatory purposes only if all of the following conditions are met:
* Studies must be necessary and scientifically valid, addressing important regulatory questions that cannot be answered with animal studies or other studies that do not involve human testing. They must be designed, conducted, and reported in a scientifically rigorous manner to ensure that they answer a specific research question.
* The possible benefits to society from such studies must outweigh any anticipated risks to participants.
* Studies whose results would be used for the sole purpose of improving the scientific accuracy of EPA's established reference doses for humans, and that would not provide health benefits otherwise, would be justified only if there were no identifiable risks to participants, or if investigators could show with reasonable certainty that participants would not be harmed.
* All of the recognized ethical standards and procedures for protecting the interests of study participants must be observed, including equitable selection and recruitment of human subjects, the obtaining of informed consent, and independent review of the scientific and ethical merits of a given study by an institutional review board (IRB) or its equivalent.
Extra safety measures mandated by the 1996 Food Quality and Protection Act (FQPA) to protect children would not be affected by the use of data from intentional dosing studies in humans, the report adds; dosing studies in children generally would be unethical. Also, information directly relevant to children cannot be obtained from these types of dosing studies in adults.
The committee concluded that EPA should use data from third-party human dosing experiments to establish reference doses for organophosphates and carbamates only if the agency thoroughly reviews the studies and finds that they meet the conditions listed above – the same process EPA should employ when weighing all studies that involve intentional human dosing with toxins. These classes of pesticides were among the most hotly disputed during the debate over the FQPA. They can interfere with proper functioning of the nervous systems of not only insects, but also humans and other vertebrates.
On the whole, oversight in this area is crucial, the committee said. A careful risk assessment is a prerequisite from the outset. EPA should require that all human research conducted for regulatory purposes be approved in advance by IRBs or by acceptable equivalents in other countries. To supplement IRB oversight, the proposed Human Studies Review Board also should evaluate in advance all intentional human dosing studies being proposed for use in formulating regulations, to ensure that the studies meet high scientific and ethical standards – whether the research is sponsored or carried out by the agency. Private entities should be strongly encouraged to voluntarily submit their research plans to the HSRB before beginning a study. This board's conclusions would be advisory only. Its functions and track record should be assessed after five years by a group of EPA staff and external reviewers.
"The committee purposely set a very high bar when it comes to intentional human dosing studies, especially for those that do not promise health or environmental benefits," said committee co-chair Michael R. Taylor, senior fellow and director of the risk, resource, and environmental management division, Resources for the Future, Washington, D.C. "Improving the quality of the science used for regulatory purposes is itself a worthy social goal, but it could never justify harming human research participants."
Protecting Research Participants
The relevant benefits that might be associated with any ethically sound and scientifically valid and necessary dosing studies would be societal. For example, a human study of an air pollutant could provide essential data to establish or strengthen environmental standards, aiding the public at large. Studies that could possibly cause adverse effects must have a very high likelihood of producing significant health or environmental benefits if they are to be undertaken. But even those studies could not be ethically justified if they might cause long-term harm to participants.
Research participants should be representative of the target population, and scientific investigators should take steps to avoid exploitation of any particular social group, the report says. All parties involved in designing and evaluating a research protocol should consider whether the proposed level of remuneration given to participants would constitute exploitation or offer an undue incentive to take part.
Voluntary, informed consent by research participants is another principal requirement, the report says. In this area, EPA should develop and disseminate to relevant IRBs, investigators, and research sponsors a list of "best practices" regarding informed consent in intentional human dosing studies. It also should encourage stakeholders to implement the measures and require their adoption in studies that the agency itself sponsors or carries out. Sponsors of or institutions conducting human dosing studies also should ensure that participants receive necessary medical care, free of charge, for any injuries they might incur from their involvement in research.
The study was sponsored by the U.S. Environmental Protection Agency. The National Research Council is the principal operating agency of the National Academy of Sciences and the National Academy of Engineering. It is a private, nonprofit institution that provides science advice under a congressional charter. A committee roster follows.
Copies of Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues are available from the National Academies Press; tel. 202-334-3313 or 1-800-624-6242 or on the Internet at http://www.nap.edu.
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