Statement of CropLife America on pesticide testing involving human subjects.

As the regulatory policy leader of CropLife America, the national trade association representing the crop protection industry, I would like to respond to the letter from Sass and Needleman, which criticizes human testing of pesticides.

On 14 December 2001, the U.S. Environmental Protection Agency (EPA) commissioned the National Academy of Sciences (NAS) to examine the "scientific and ethical issues" posed by the U.S. EPA's use of human tests in registering pesticides and evaluating environmental contaminants and other chemicals in order to set safe levels of exposure. The NAS position is important because the U.S. EPA has conducted human studies on environmental contaminants and other compounds for many years and requires pesticide registrants to conduct and submit human testing data such as worker exposure, biomonitoring, and pharmacokinetic studies. The U.S. EPA has a long history of requesting and accepting industry-sponsored "third-party" human testing and using these data in its risk assessment process (U.S. EPA 1998).

Following an intense media campaign and political pressure by activist groups the U.S. EPA reversed its policy relative to industry-sponsored human testing of pesticides in December 2001, without following applicable legal requirements. In June 2003, the U.S. Court of Appeals overruled the U.S. EPA on this matter (CropLife America et al. v. U.S. EPA 2003), reinstating the U.S. EPA's previous practice of

   considering third-party human studies on a case-by-case
   basis, applying statutory requirements,
   the Common Rule, and high ethical standards as
   a guide ... until it is replaced by a lawfully promulgated
   regulation.

In considering the scientific merits and ethical acceptability of human studies with any chemical, medicine, cosmetic, or household product, it is necessary to consider the comparative risks and benefits. Crop protection and other pest control products provide enormous societal benefits in the form of plentiful food of high nutritional quality; reduction in exposure to foodborne allergens, mycotoxins, and other natural toxins; control of human disease vectors; reduced need for agricultural land; and reduced need for manual labor.

The crop protection industry is legally and ethically bound to provide to government regulators the information they need to judge the safety of products and to set guidelines for their proper use. Likewise, the U.S. EPA is bound by law to consider all "available data" in evaluating the safety of pesticide use (Food Quality Protection Act of 1996). The vast majority of the toxicity tests conducted by industry under government guidelines use laboratory animals or in vitro procedures. When appropriate, human studies are conducted to confirm the relevance of animal data for humans, thus increasing confidence that the products are safe.

Human volunteer studies with pesticides are conducted under scientific and ethical guidelines equivalent to those followed in phase 1 clinical trials of potential pharmaceutical products. Phase 1 trials are also carried out in healthy volunteers who receive no direct benefit. Results of phase 1 trials are used to provide assurance that patients can be treated with safety in subsequent clinical trials for pharmaceutical efficacy. In both types of trials, pharmaceutical and pesticide, and under the required safeguards, the individual volunteers accept a small personal risk for a large societal benefit. An extensive toxicology database is available for pesticides before any human studies are even considered. This allows the use of pesticide doses that can be predicted not to cause adverse effects, thereby minimizing the risk to volunteers. These scientific points have been clearly articulated to the NAS committee examining this issue.

The Joint Meeting on Pesticide Residues (JMPR) of the World Health Organization (WHO) and the Food and Agriculture Organization (FAO) of the United Nations (FAO 2002) has stated that

   Human data on a pesticide, whether from volunteer
   studies or from other investigations of
   human exposures in the workplace or environment,
   can be extremely valuable in placing the
   animal data in context and, when available,
   should always be evaluated even when they are
   not used to derive a reference dose. However,
   when performing a risk assessment on a pesticide,
   the entire database should be considered and the
   most appropriate studies and safety Factors used
   to derive reference values.

The JMPR also emphasized the need to look at the scientific merit of human studies and clearly pointed out that human studies must conform to accepted international standards.

The "Common Rule" (U.S. EPA 1991) is a well-established, rigorous set of legal, regulatory, scientific, and ethical guidelines that regulates research involving human studies conducted or sponsored by federal government agencies and incorporates the principles set forth by the U.S. Food and Drug Administration, the WHO, and the World Medical Association Declaration of Helsinki (World Medical Association 2002).

The crop protection industry supports application of the Common Rule to regulate third-party human clinical trials conducted and submitted to support pesticide registrations. A thorough review shows that past studies conducted by industry met the conditions of the Common Rule, although not specifically required by regulation to do so (Charnley and Patterson 2003).

Human testing of pesticides is not intended to determine levels of exposure that cause adverse effects but rather to confirm the adequacy of established safe levels of exposure. This can be achieved in different ways, depending on the needs of the risk assessment process. For example, biochemical markers, such as enzyme inhibition in blood, might be measured instead of the effects themselves in other organs such as the brain. Such data are of immense value in establishing whether humans are more or less sensitive than animal species and help to reduce uncertainty in applying laboratory data to human exposure.

We believe that abandoning human testing, as proposed by some groups who are generally opposed to the use of pesticides and chemicals, would jeopardize public health and make it more difficult for regulators to set safe exposure levels for workers and consumers. Regulators would be faced with greater uncertainty in assessing potential risks. Using human data, we can confirm the adequacy and appropriateness of the margin of safety. Lack of appropriate data would limit the availability of a wholesome and safe food supply, as well as reduce protection from dangerous disease vectors. Above all, decades of well-considered legal, regulatory, and scientific protocols requiring human volunteers to assure the safe development of medicines should not be ignored in the safe development of pesticides.

Moreover, it would be unethical to ignore existing human data per se. The scientific validity of a study and its conformance with ethical standards applicable at the time it is conducted must be determined by objective evaluation, not by the identity of the study's sponsor, the potential uses of the material being tested, or the author's affiliation. When the weight-of-evidence approach is used, and it includes data from studies in humans, allowable levels of exposure may be either increased of decreased (Dourson et al. 2001).

The author declares he has a competing financial interest because he is employed by CropLife America, the national trade association representing the industry that manufactures and sells agricultural pesticide products. CropLife America's member companies conduct and submit to the US EPA the research that supports registration of pesticide products, including the human clinical trials in question.

REFERENCES

Charnley G, Patterson J. 2003. Review of procedures for protecting human subjects in recent clinical studies of pesticides. Regul Toxicol Pharmacol 38:210-223.

CropLife America, et al. v. U.S. EPA. 2003. Case No 02-1057, United States Court of Appeals for the District of Columbia Circuit, Washington, DC.

Dourson ML, Andersen ME, Erdreich LS, MacGregor JA. 2001. Using human data to protect the public's health. Regul Toxicol Pharmacol 33:234-256.

FAO. 2002. Pesticide Residues in Food--2002. FAO Plant Production and Protection Paper No 172. Rome:United Nations Food and Agriculture Organization.

Food Quality Protection Act of 1996. 1996. Public Law 104-170.

U.S EPA. 1991. Protection of Human Subjects. 56FR28012, 28022, 29756. [40 CFR Part 26]. Washington, DC:U.S. Environmental Protection Agency. Available: http://www.access.gpo.gov/nara/cfr/waisidx_03/40cfr26_03.html [accessed 12 February 2004].

--. 1998. Guidelines for neurotoxicity risk assessment, Fed Reg 63:26925-26954. Available: http://www.epa.gov/fedrgstr/EPA-TOX/1998/May/Day-14/t12303.htm [accessed 12 February 2004].

World Medical Association. 2002. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. Available: http://www.wma.net/e/policy/b3.htm [accessed 1 July 2003].

Ray S. McAllister

CropLife America

Washington, DC

E-mail: [e-mail]