Aldicarb study misrepresented in human testing debate.

The pesticide industry is legally and ethically bound to provide government regulators with the studies needed to determine that our products do not cause "unreasonable adverse effects." The scientific tests we conduct under government guidelines use laboratory animals almost exclusively. In fact, human studies are not conducted until we have a good understanding of sale levels of human exposure based on animal testing. When appropriate, human studies are conducted to confirm the relevance of animal data and ultimately increase confidence in the overall safety assessment. When performed ethically and scientifically, there is no substitute for the knowledge gained from these studies.

In their letter, Sass and Needleman state that human volunteer studies conducted with pesticides are scientifically misleading and are foisted on the U.S. Environmental Protection Agency (EPA) in order to weaken regulatory standards. They cite the aldicarb human studies as one of the examples supporting their position. Bayer CropScience takes issue with their misrepresentation of the extensive aldicarb database.

It is known that aldicarb can cause inhibition of cholinesterase, a well-known biomarker of exposure. In fact, all of the animal and human cholinesterase data generated over the last 40 years support a no observed effect level (NOEL) of 0.01-0.025 mg/kg body weight (bw). The U.S. EPA has relied on this data to set the reference dose (RfD) and to assess risk to humans.

Between 1985 and 1988, three separate incidents of alleged human foodborne poisoning from illegal applications of aldicarb to watermelons and cucumbers occurred in California (California EPA 1989) and were reported by Goldman et al. (1990a, 1990b). The authors attempted to derive exposure estimates for these alleged aldicarb incidents flora average body weights, self-reports of symptoms and consumption, and average aldicarb residues from those watermelons and cucumbers that were available for analysis. Specifically, the authors' questionable derivation of high consumption levels deliberately biased toxicity estimates. The description of cases used for estimates was very limited in terms of onset, duration, and severity. Many of the symptoms of cholinesterase inhibition were nonspecific and difficult to diagnose in the onset of illness.

In 1991, the U.S. EPA considered that the incident data were not consistent with results from a human study conducted in 1971 and that they indicated that the animal studies might not be predictive of the human response. Thus the agency revised the RfD from 0.001 to 0.0002 mg/kg bw/day.

Following the U.S. EPA's decision to revise the RfD, the New England Epidemiology Institute (Rothman et al. 1991) reviewed the articles by Goldman et al. (1990a, 1990b) and concluded that they "... form an inappropriate foundation for establishing a reference dose."

Taking into account these events, Bayer CropScience concluded that reliable human data would be necessary to refine the dose response and time course of cholinesterase inhibition following exposure to aldicarb and to further investigate the relative sensitivity of humans compared to animals.

The 1992 aldicarb human volunteer (double blind) study was conducted at Inveresk Clinical Laboratories in Edinburgh, Scotland (Wyld et al. 1992) according to all of the recommended scientific and ethical guidelines that were in place at the time of the study. Inveresk is a well known experimental laboratory experienced in conducting both human and animal studies. Before the study was initiated, the Ethics Review Board of Inveresk Clinical Laboratories approved the study design and objectives. The candidates were all prescreened and given physical examinations. Their personal physicians were also consulted for any medical reasons that might preclude an individual's participation in the study. Information sheets on the profile of aldicarb were given and explained to the candidates. Informed consent forms were then given to and signed by all study participants.

No serious adverse effects occurred in this study. One male subject (0.075 mg/kg bw group) developed profuse sweating, which was reported to be related to aldicarb. Of the remaining 23 symptoms reported, almost half were noted in the placebo group (22 individuals), whereas the others were either not related to the expected time course of symptoms, not consistent with symptoms associated with cholinesterase inhibition, or were noted among the remaining 35 individuals. Thus, the NOEL for clinical symptoms was 0.05 mg/kg bw and the NOEL based on inhibition of RBC was 0.025 mg/kg bw (Figure 1).

[FIGURE 1 OMITTED]

In 1992, Bayer CropScience submitted the human volunteer study (Wyld et al. 1992) to the U.S. EPA. The agency reviewed the aldicarb human study and determined that it was acceptable and that it was a key study to set the RfD (U.S. EPA 1992). The U.S. EPA determined the overall NOEL in this study to be 0.01 mg/kg bw/day, confirming the NOEL established in multiple animal studies. The RfD was reestablished at 0.001 mg/kg bw/day. The U.S. EPA has used this RfD to assess risk since 1992. In addition, the agency also had the study reviewed by a Joint Science Advisory Panel/Science Advisory Board in 1992 (U.S. EPA 1992) and they also determined the study to be acceptable and appropriate for use in the risk assessment process. The 1998 U.S. EPA panel reaffirmed the use of the data in the risk assessment process. Also, the panel addressed additional questions of other matters concerning aldicarb. These critical facts have been omitted by Sass and Needleman and lead the reader to draw conclusions that the human study was never reviewed and accepted by the U.S. EPA and its joint advisory panels.

In conclusion, good science and the law (Federal Food, Drug, and Cosmetic Act 1997; Federal Inssecticide, Fungicide and Rodenticide Act 1972; Food Quality protections Act of 1996) require the U.S. EPA to consider all credible data when making regulatory decisions. The aldicarb human study conducted in 1992 (Wyld et al. 1992) was essential in confirming the relevance of the existing animal database and refining the risk assessment. The weight given to any particular study or data set (human or animal) can vary depending on its scientific merit, but no valid study or data set should be discounted from the evaluation process on the basis of personal and emotional arguments.

The authors declare a competing financial interest because they are employed by Bayer CropScience.

REFERENCES

California EPA. 1989. Summary of ToxicoLogy Data: Aldicarb (Temik). Chemical Cede 000575. Sacramento, CA:California Environmental Protection Agency, Department of Pesticide Regulation, Medical Toxicology Branch. Available: http://www.cdpr.ca.gov/docs/toxsums/pdfs/575.pdf [accessed 11 February 2004]

Federal Focal, Drug, and Cosmetic Act. 1997. 21USC346a. Available: http://www.fda.gov/opacom/laws/fdcact/fdctoc.htm [accessed 10 February 2004]

Federal Insecticide, Fungicide and Rodenticide Act. 1972. 7USC136

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

Goldman LR, Beller M, Jackson RJ. 1990a. Aldicarb food poisonings in California, 1985-1988: toxicity estimates for humans. Arch Environ Health 45(3):141-147.

Goldman LR, Smith DF, Neutra RR, Saunders LD, Pond EM, Stratton J, et al. 1990b. Pesticide food poisoning from watermelons in California Environ Health 45(3):229-235.

Rothman KH, Pastides H, Cole P. 1991. Letter from KH Rothman (Harvard School of Public Health), H Pastides (University of South Carolina), P Cole (University of Alabama at Birmingham), to the U.S. EPA. Epidemiological Review of Golman et al. Paper. Washington, DC:U.S. Environmental Protection Agency.

U.S. EPA. 2000 Comments on the Use of Data from Testing of Human Subjects. EOA-SAB-EC-00-0017. Washington, DC:U.S. Environmental Protection Agency. Available: http://www.epa.gov/sab/pdf/ec0017.pdf [accessed 10 February 2004].

Wyld PJ, Watson CE, Nimmo WS, Watson N. 1992. A Safety and Tolerability Study of Aldicarb at Various Dose Levels in Healthy Male and Female Volunteers. Rhone-Poulenc, Lyon, France. ICR Project No. 003237. Inveresk Clinical Research Report No. 7786. MRID No. 42373-01. HED Document No. 0010459. Washington, DC:U.S. Environmental Protection Agency.

Abraham Tobia

Alan Ayers

Ann Blacker

Larry Hodges

Bayer CropScience

Research Triangle Park, North Carolina

Email: [e-mail]

Neil Carmichael

Bayer CropScience

Sophia-Antipolis, France