Science
17 January 2003

Academy Panel Mulls Ethics of Human Pesticide Experiments
Jocelyn Kaiser

Over the past 6 years, a number of companies have been deliberately exposing human volunteers to pesticides to see how much is needed to trigger a metabolic response or even make subjects sick. Such "dosing" experiments offer the best safety data, industry officials assert. Yet despite their admitted utility, these tests have posed a quandary for the U.S. Environmental Projection Agency (EPA). If it accepts these data in its safety reviews, is the agency condoning practices that many consider unethical?

Such information "is valuable," says EPA office of risk assessment director William Farland, and the agency "would like to find a way to bring human data into the process." But, he adds, "whether it's ethical is the question we're all struggling with."

In late 2001, the agency turned to the National Academy of Sciences (NAS) for advice. Last week, the new NAS panel heard from both advocates and opponents of dosing experiments. Their vehement debate underlines the difficulty the panel faces in trying to untangle the scientific and ethical questions.

The panel's recommendation, due in December, could be far reaching. In addition to pesticides, EPA has recently received data on humans deliberately exposed to groundwater contaminants, and the agency hopes to continue to use outside human studies testing the toxicity of air pollutants.

The trigger for this recent spate of testing was the 1996 Food Quality Protection Act, which mandated that EPA reduce acceptable levels of pesticides in foods to protect children. Up to that point, EPA had set a limit several orders of magnitude smaller than the minimum dose that causes effects in animals. Faced with the new law, pesticide companies began supplementing animal studies with human data in an effort to avoid a 10-fold safety factor built in to account for possible higher sensitivity in people; this could offset the tighter limits for children. Since the new law was enacted, companies have submitted about two dozen human toxicity studies to EPA (see table).

Selected Human Pesticide Dose-Response Studies

In 1998, the Environmental Working Group (EWG) in Washington, D.C., questioned the ethics of these studies, in which volunteers (mostly in the United Kingdom) were paid $600 or more. EPA officials had become concerned as well and had shelved the studies until an advisory committee weighed in (Science, 1 January 1999, p. 18). That committee issued a report in 2000 saying that some human tests, such as metabolism studies, were acceptable under strict conditions--but most dosing experiments were not. Switching gears, EPA under the Bush Administration indicated that it would consider the tests but, facing heavy criticism, it held off and requested the academy study.

Much of the ethics debate hinges on what are perceived to be industry's motives. Pesticide-dosing tests are unethical because they are done expressly for the benefit of industry and offer no conceivable advantage to society, asserted EWG's Richard Wiles. But Ray McAllister of CropLife America, an industry group, argued that dosing tests of pesticides are in fact no different from phase I clinical trials of drugs, which test toxicity and don't directly benefit the subject.

Some of the toxicologists on the panel suggested that if the tests were well designed ethically and scientifically, the public might benefit from the data. John Doull of the University of Kansas Medical Center in Kansas City pointed out that some human studies have shown that people are more sensitive than animals to certain substances, such as lead, so human dosing experiments might sometimes result in more protective standards. But Jennifer Sass, a toxicologist at the Natural Resources Defense Council, argued that the dosing studies are often too small to be scientifically meaningful.

Lynn Goldman, a pediatrician at Johns Hopkins University who headed the EPA pesticides office from 1993 to 1998, argued that EPA should ban dosing tests with well-studied organophosphate pesticides because they don't add much new information. But EPA should permit human-dosing studies of environmental pollutants such as ozone to which people are "exposed daily anyway," she suggested. Goldman added that mechanistic studies involving human subjects might sometimes be justified, for example, with new pesticides.

The overarching problem with all human data used by EPA, said Goldman, is that unlike the Food and Drug Administration, EPA has no protocols for human studies and lacks a stringent policy for ethics reviews of human data. The agency "needs strong and enforceable standards," she says, an issue the panel will likely consider.