Response to the ACPA's Critique
The critique by Acquavella et al. (1) of the WRI report "Pesticides and the Immune System: The Public Health Risks" (2) represents significant progress, despite its criticisms. The pesticide industry now acknowledges that this issue is an important area for future research and evaluation. This position is very different from the pesticide industry's initial reactions to the report.
For the benefit of readers unfamiliar with this debate, we recapitulate the basic argument of the WRI report (2). It reviewed a large body of experimental research and wildlife studies, as well as the limited amount of human epidemiological research available on pesticide-induced disregulation and suppression of the immune system. It found that, despite limitations in each of these areas of research, the body of evidence raises serious concerns regarding immunotoxicological consequences of pesticide exposure.
The report pointed out that if pesticides in common use do suppress immune responses, the public health risks could be serious, particularly in developing countries. In these regions, a large fraction of the population still lives in the countryside and works on farms. Pesticide use is increasing rapidly, and compounds that have long been banned or restricted on health grounds in the United States and Europe are still used. Health and safety regulations are weak and there is widespread evidence that farmworkers, their families, and others are significantly exposed. In addition, infectious and parasitic diseases are widespread, health care is inadequate, and for many in these populations, malnutrition has already compromised immune functioning. Additional weakening of immune defenses from pesticide exposure is difficult to detect because it manifests itself in heightened morbidity and mortality from common infectious diseases that are already among the leading causes of death.
The WRI report (2) recommended that immunological screening should be strengthened as part of the pesticide registration process, that an expanded international research program should be developed with emphasis on human epidemiological studies of vulnerable populations, and that steps should be taken to limit unnecessary exposures by improving training and regulatory programs, especially in developing countries. We continue to believe that these conclusions are fully justified by the available evidence.
The WRI report (2) referenced and briefly summarized nearly 200 experimental studies of pesticide immunotoxicity. These studies varied widely in design, dose, exposure route, immunological biomarkers measured, and in presentation of results. Some studies developed dose-response relationships; others did not. Some reported measures of statistical significance for immunological deviations; others did not. However, most of those surveyed found evidence that major pesticide classes produced toxic effects on immune system organs, functioning, and competence.
Although the pesticide industry criticizes this body of evidence, many other scientists who have assessed the same literature reach similar conclusions (3). The WRI report (2) discusses, quotes from, and references these reviews. Of particular interest is the conclusion reached several years ago, on more limited evidence, by Dennis Flaherty (a co-author of the pesticide industry critique): "Pesticides should be considered presumptively immunotoxic from the limited animal and human data available and for the potential related to their widespread use" (4). We agree. Moreover, if pesticides are considered presumptively immunotoxic, doesn't it make sense to screen them more carefully, to step up research into human health impacts, and to reduce unnecessary exposures?
The WRI report (2) also examined the limited amount of human evidence available. We drew attention to ongoing Canadian research into an Inuit population exposed through diet to organochlorine compounds, including pesticide residues. The pesticide industry scientists question the relevance of this research but base their criticism on the wrong study (5). Following on that study, as the WRI report recounts, Eric Dewailly and his colleagues at the Laval University Hospital in Quebec initiated a prospective study of Inuit infants, examining chemical exposures, biomarkers of exposure, and clinical outcomes. Dewailly hypothesized that the high levels of organochlorines found in the typical Inuit diet were being passed in breast milk to infants, increasing their susceptibility to acute otitis media and other infectious diseases (6). Their study found decreased T-helper/T-suppressor cell ratios and increased incidence of acute otitis media associated with increased duration of breast-feeding and organochlorine levels in milk (5). It was also reported that exposed infants were hard to vaccinate because of insufficient antibody response to vaccines (8).
The pesticide industry critique mischaracterizes this important research, which implicates organochlorines in immune disregulation and altered host resistance in a human population. Clearly, further research is warranted to sort out the role of pesticides from that of other organichlorines and to resolve other issues (9).
The WRI report (2) refers to evidence that farmers and other groups exposed to pesticides experience higher risks of certain malignancies and suggests the possibility that reduced immune surveillance may promote these cancers. The pesticide industry critique (1) first questions whether cancer rates are affected by pesticide exposure. However, the National Cancer Institute has stated that exposure to the herbicide 2,4-dichlorophenoxyacetic acid or to certain organophosphate insecticides increases the risk of non-Hodgkin's lymphoma, particularly among farmers (10). The Institute of Medicine also states that there is sufficient evidence of an association between exposure to some herbicides and higher risks of non-Hodgkin's lymphoma, Hodgkin's disease, and soft-tissue sarcomas (11).
The pesticide industry critique (1) also questions whether pesticides increase susceptibility to cancers by weakening immune surveillance. Immune surveillance is a well-recognized component of host resistance to cancer. Exposures to such known immunosuppressive agents as cyclosporin A, a drug administered to transplant patients, results in strikingly increased risks of lymphatic tumors. Though evidence linking pesticide exposure to altered immune surveillance and cancer promotion is sparse, other experts, including an Italian Working Group on the Epidemiology of Hematolymphopoietic Malignancies, have also suggested the link (12). In a case-control study, Rothman et al. (13) found a strong dose-response relationship between polychlorinated biphenyl concentrations and risks of non-Hodgkin's lymphoma among a small sample of rural Americans, but only a nonsignificant positive association with concentrations of DDT residues. Ongoing studies in Italy should provide more evidence regarding an effect of pesticide exposure on immune surveillance (14).
The WRI study (2) identified epidemiological research literature on the immunotoxic effects of pesticide exposure on human populations extending back 20 years in the former Soviet Union. Because this literature was virtually unknown in the West, we provided references and summaries. It is appropriate that pesticide industry scientists have now examined this body of evidence. It is true that the studies would not meet currently accepted standards of epidemiological research. Most lack adequate controls on potentially confounding factors, adequate measures of exposure, or satisfactory control populations. Hence, the Soviet studies do not provide conclusive evidence of human immunotoxic or health impacts. Nonetheless, they do show a pattern of immunotoxic effects consistent with the experimental evidence. The methodological weaknesses in these studies certainly do not exonerate pesticides as potential immunotoxicants. Rather, they emphasize the need for further properly designed epidemiological research, which is the conclusion the WRI report drew from them.
The WRI report (2) recommended that an expanded epidemiological research program be designed and organized, and we are happy that the pesticide industry has agreed to participate in an international expert meeting that will consider the serious issues involved in designing such research. We hope that this meeting will stimulate and enable a program of field research in exposed and vulnerable populations.
The WRI report (2) recommended that immunotoxicity testing of pesticides, as a condition of registration, be strengthened to reflect improved immunological methods, a need with which the pesticide industry concurred. We are happy that in the United States the EPA has announced increased testing requirements. However, these requirements will not be applied to pesticides already registered or reregistered. We hope that the pesticide industry will also voluntarily carry out this expanded battery of immunotoxicity tests on products already on the market.
It is evident that the conditions for safe use and disposal of pesticides are not now being met in much of the world. In view of the serious risks this poses to vulnerable populations, including the possibility of reduced resistance to widespread and often deadly communicable diseases, we hope that the pesticide industry will also cooperate actively in reducing unnecessary exposures.
Robert Repetto
Sanjay Baliga
World Resources Institute
Washington, D.C.
References
1. Acquavella J, Burns C, Flaherty D, Holsapple M, Kimber I, Ladics G, Loveless S, Tobia A. A critique of the World Resources Institute's report "Pesticides and the Immune System: The Public Health Risks." Environ Health Perspect 106:51-54 (1998).
2. Repetto R, Baliga S. Pesticides and the Immune System: The Public Health Risks. Washington, DC:World Resources Institute, 1996.
3. Holliday SD, Luster MI. Developmental immunotoxicology. In: Developmental Toxicology (Kimmel CA, Buelke-Sam J, eds). 2nd ed. New York:Raven Press, 1994;93-118.
4. Burrell R, Flaherty DK, Sauers LJ. Agents and effects of immunotoxicity. In: Toxicology of the Immune System: A Human Approach. New York:Van Nostrand Reinhold, 1992;235-292.
5. Julien G, Baxter JD, Crago M, Ilecki HJ, Therien F. Chronic otitis media and hearing deficits among native children of Kuujjuaraapik (Northern Canada): a pilot project. Can J Public Health 78:57-61 (1987).
6. Dewailly E, Ayotte P, Bruneau S, Laliberte C, Muir DCG, Norstrom RJ. Inuit exposure to organochlorines through the aquatic food chain in arctic Quebec. Environ Health Perspect 101:618-620 (1993).
7. Dewailly E, Bruneau ES, Laliberte C, Belles-Iles M, Weber JP, Ayotte P, Roy R. Breast milk contamination by PCBs and PCDDs/PCDFs in arctic Quebec: preliminary results on the immune status of Inuit infants. In: Dioxin '93: 13th International Symposium on Chlorinated Dioxins and Related Compounds, Organohalogen Compounds, Vol 13 (Fiedler H, Frank H, Hutzinger O, Parzefall W, Riss A, Safe S, eds). Vienna:Federal Environmental Agency, 1993;403-406.
8. Lindstrom G, Hooper K, Petreas M, Stephens R, Gilman A. Workshop on Perinatal Exposure to Dioxins-Like Compounds. I. Summary. Environ Health Perspect 103(suppl 2):135-142 (1995).
9. Birnbaum LS. Workshop on Perinatal Exposure to Dioxin-Like Compounds. V. Immunologic effects. Environ Health Perspect 103(suppl 2):157-160 (1995).
10. National Cancer Institute, Cancer Information Service. Occupational risk of cancer from pesticides: farmer studies. http://cancernet.nci.nih.gov/clinpdq/ risk/ Occupational_Risk_of_Cancer_from_ Pesticides:__Farmer_Studies.html (25 June 1997).
11. Institute of Medicine, Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. In: Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (Other Health Effects). Washington DC:National Academy Press, 1994;672-720.
12. Davis DL, Blair A, Hoel DG. Agricultural exposures and cancer trends in developed countries. Environ Health Perspect 100:39-44 (1992).
13. Rothman N, Cantor K, Blair A, Bush D, Brock J, Helzisouer K, Zahm S, Needham L, Pearson G, Hoover R. A nested case-control study of non-Hodgkin's lymphoma and serum organochlorine residues. Lancet 350(9073):240-244 (1997).
14. Faustini A, Settimi L, Pacifici R, Fano V, Zuccaro P, Forastiere F. Immunological changes among farmers exposed to phenoxy herbicides: preliminary observations. Occup Environ Med 53(9):583-585 (1996).
Response
Repetto and Baliga have cast our critique, both implicitly and explicitly, as the work of vested interests and, therefore, of questionable merit. That is unfortunate. Ad hominem criticism is a barrier to the exchange of scientific views. Nonetheless, we hope readers will benefit from the time we spent to obtain, translate, and critically review the many foreign references cited in the World Resources Institute (WRI) report (1).
Our assessment of these references, contrary to the conclusion in the WRI report (1), is that we do not find credible evidence that modern, widely used pesticides are causing immune dysfunction in millions of people. The toxicologic studies cited in the WRI report have questionable relevance to real world exposure scenarios. The epidemiologic studies that were cited either have severe methodologic weaknesses or did not find an effect for pesticides. The studies of the Inuits deserve special mention. The ongoing dietary studies mentioned by Repetto and Baliga have not linked otitis media with dietary pesticide exposure (2-4). These studies have focused on dioxins and polychlorinated biphenyls. Why imply that these studies (may) implicate pesticides? We made particular note of the study by Julien et al. (5) because it offered a plausible alternative hypothesis not mentioned in the WRI report: that the high prevalence of disease was associated with the change from a nomadic existence to a sedentary one. This explanation is consistent with the lesser disease prevalence among Cree Indians who share environmental factors with the Inuits.
Our assessment of the evidence does not mean that we oppose prudence in limiting pesticide exposure, that we oppose improvements in screening pesticides for possible immunologic effects, or that we oppose appropriate epidemiologic research. The admonition by Burrell, and our coauthor Flaherty, et al. (6)--published years before the WRI report--that "Pesticides should be considered presumptively immunotoxic...." reflects appropriate caution to minimize exposures to potential toxicants. Industry has been supportive of appropriate improvements in immunotoxic screening for pesticides, as evidenced by the collaboration of government and industry scientists to update EPA's Toxic Substances Control Act immunotoxicity testing guidelines. The related Federal Register notice (7) cites the work of many industrial immunotoxicologists.
Finally, we support improved epidemiologic research on potential immunotoxic effects of pesticides, but this is a difficult area in which to conduct research. Methodologic difficulties, as evidenced in past studies, must be recognized in order to make progress. Repetto and Baliga's characterization of our criticism notwithstanding, we hope our critique is helpful to scientists interested in this area of research.
John Acquavella
Dennis Flaherty
Monsanto Company
St. Louis, Missouri
Carol Burns
Michael Holsapple
Dow Chemical Company
Midland, Michigan
Ian Kimber
Zeneca Company
Cheshire, England
Gregory Ladics
Scott Loveless
E.I. du Pont de Nemours and Company
Newark, Deleware
Abraham Tobia
BASF Company
Research Triangle Park, North Carolina
References
1. Repetto R, Baliga S. Pesticides and the Immune System: The Public Health Risks. Washington, DC:World Resources Institute, 1996.
2. Dewailly E, Bruneau S, Laliberte C, Belles-Iles M, Weber J, Ayotte P, Roy R. Breast milk contamination by PCBs and PCDDs/PCDFs in artic Quebec: preliminary results on the immune status of Inuit infants. In: Dioxin 93: 13th International Symposium on Chlorinated Dioxins and Related Compounds, Organohalogen Compounds, Vol 13 (Fiedler H, Frank H, Hutzinger O, Parzefall W, Riss A, Safe S, eds). Vienna:Federal Environmental Agency, 1993; 403-406.
3. Birnbaum L. Workshop on Perinatal Exposure to Dioxin-like Compounds. V. Immunologic effects. Environ Health Perspect 103(suppl 2):157-160 (1995).
4. Lindstrom G, Hooper K, Petreas M, Stephens R, Gilman A. Workshop on Perinatal Exposure to Dioxin-like Compounds. I. Summary. Environ Health Perspect 103(suppl 2):135-142 (1995).
5. Julien G, Baxter JD, Crago M, Ilecki HJ, Therien F. Chronic otitis media and hearing deficit among native children of Kuujjuaraapik (Northern Quebec): a pilot project. Canadian J Public Health 78:57-61 (1987).
6. Burrell R, Flaherty DK, Sauers LJ. Agents and effects of immunotoxicity. In: Toxicology of the Immune System: A Human Approach. New York:Van Nostrand Reinhold, 1992;235-292.
7. Toxic Substances Control Act Test Guidelines; Final Rule. Fed Reg 62:43819-43864 (1997).
Repetto's Response to Acquavella
Contrary to John Acquavella's assertion, my coauthor and I have responded directly to the substance of points made by the pesticide industry scientists in print and in person. We agree that ad hominem attacks restrict scientific discourse. Therefore, we think it regrettable that when our report was first published, the chief spokesman for the American Crop Protection Association, which organized this scientific critique, publicly impugned our motives and qualifications for undertaking the study. We also regret that senior officials of some of the pesticide manufacturing companies saw fit to address letters of complaint to members of the WRI's board of directors about the study, seeking to influence our organizational policies and financing.
The report in question, Pesticides and the Immune System: The Public Health Risks, has been reviewed repeatedly by scientists and scientific organizations not linked to the pesticide industry, including the U.S. EPA, the World Health Organization, and the Netherlands Institute for Public Health and Environment. Their judgments differed dramatically from those expressed in the industry's critique. Most recently, while this exchange has been under way, our report received an award in the British Medical Association's 1997 Medical Book Competi-tion after a peer-reviewed selection process. The report received High Commendation (2nd prize) in the public health category. The citation from the judges read as follows:
An excellent review of the literature on the immunotoxic effects of pesticides with informed speculative comment on the potential effects of biocidal agents in combination. Essential reading for policymakers, it is well presented and should be of interest to many health professionals.
Why, we wonder, does the judgment of the medical profession of Great Britain differ so markedly from that of Aquavella and his colleagues? Our hope is that this exchange will stimulate readers of Environmental Health Perspectives to read the report for themselves and form their own conclusions. Copies of the report can be obtained through the WRI website (http://www.wri.org).
Robert Repetto
World Resources Institute
Washington, D.C.
Last Update: February 4, 1998