Document OEM25NypBmwDo3LQamq6V9ZKL

Agricultural Exposures and Cancer Aaron Blair and Shelia Hoar Zahrn Occupational Studies Section, National Cancer Institute, Bethesda, Maryland The purpose of this report ISto review the literature on cancer among persons employed in agriculture, to characterize the value of this line of research, and to recommend future directions. Farmers, despite a generally favorablemortality, appear to experience elevated rates for several cancers, including leukemia, non-Hodgkin's lymphoma, multiple myeloma, soft-tissue sarcoma, and cancers of the skin. lip, stomach, brain, and prostate. The rates for several of these tumors he., non-Hodgkin's lymphoma, multiple myeloma, skin, brain. and prostate) appear to be increasing in the general population. No set of established etiologic factors explains all the cancer excesses observed among farmers, although several are associated with naturally occurring or medically induced immunodeficiencies. This suggests that there may be factors% the agricultural environment that introduce immune system deficiencies. Farmers are exposed to a variety of substances that could operate through this mechanism, including pesticides, engine exhausts, solvents, dusts, and zoonotic microbes. Studies to further characterize the cancer risk among farmers, their dependents and farm laborers. and to identify the exposures that may be involved would not only be useful in providing a safe work environment in agriculture but may furnish considerable insight into the causes for a number of tumors that are rising in incidence in the general -population. Environ Health Perspect 103(Suppl8):205-208(1995) Key words: agriculture, farmers, farmworkers. cancer, pesticides, review. exposures Introduction The agricultural population is large, with an estimated 2 million farmers, 2.7 million farm laborers, and perhaps 6 million family members (I). Agriculture is an important component of the national economy, and the population has some unique characteristics and exposures. Farm populations may come into contact with a variety of potentially hazardous substances. including pesticides, fertilizers. fuels and oils, engine exhausts. paints, solvents. welding fumes, dusts, and zoonotic microbes. Epidemiologic studies of agricultural populations are desirable because a ) farmer ownerloperators, farm laborers, and dependents of farmers have not been as intensely studied as many other occupational groups, and such research is necessary to ensure a safe workplace; and 6 ) many exposures rradirionally associated with farming are becoming more commonplace in the urban environment. Thus, investigations among farmers may provide important clues to the etiology of cancer in the general population. In this paper, we provide a brief overview This paper was presented at t h e Presldent's cancer Panel Conference on Avoidable Causes of cancer held 7-8 April 1994 In Bethesda. Maqland Manuscript received 9 March 1995, manuscript accepted24 March 1995 Address correspondence to Dr Aaron Blair. National Cancer Institute. Occuparional Studies k t l o n . Executwe Plaza NoRh. Room 418. Rockville. MD 20892-7364 Telephone I301I 496-9093 Fax (301)402-1819 Email Blairaaepndcenamh gov Abbreviations used DDT, dichlorodlphenyl- trichloroethane. DHHS. Depanment of Health and Human Services.NCI, National Cancer Institute of cancer risks among farmers and suggest directions for future research. Cancer among Farmers In the mid-1970s, the National Cancer Institute (NCI) developed a series of maps displaying mortality parterns for specific cancers in the United States by county or state economic area (2).T h e map for leukemia showed a string of high-rate counties through the center of che United States, ranging from the Dakotas to Texas. This pattern suggested a role for some factors associated with agriculture because these high-rate areas generally did nor include cities. A series ot research projects was initiated to clarify cancer risks among farmers and to identify factors that might be involved. Occupational surveys available from many developed countries were used to evaluate the overall cancer pattern among farmers. These data indicate that farmers have a more favorable experience than the general population for many causes of death, including all causes combined, heart disease, all cancers combined, as well as cancers of the lung, bladder, liver, colon, esophagus, rectum, and kidney (3)(Table 1). Despite their overall excellent mortality, farmers from many countries tend to experience higher rates than the general population for cancers of the lymphatic and hematopoietic system, skin (melanotic and nonmelanotic), softtissue sarcoma, lip, prostate, brain, and stomach (3).Although the excesses for these cancers are not large in absolute terms, they are striking because they occur in an occupational group that has a low mortality for most other causes. A review of cohort and case-control studies that provide information on cancer risk among farmers noted a similar pattern to the general surveys; ix., lower risk from major causes of death and from many cancers than other groups but higher risks for the cancers noted above (4). Why are these particular cancers excessive among farmers? What ties them together? Although there are no clear explanations, three findings stand out. First, these tumors are not smoking related. In fact, the smoking-related cancers tend to have lower rates among farmers than among other occupational groups. This is consistent with the lower prevalence of smoking among farmers than among the general population and many other occupational groups (5).Second, several of the cancers that are excessive among farmers show rising rates among the general population of many developed countries. These Table 1. Causes of death showingdeficits and excesses among farmers. Deficits All causes Heart disease All cancer Cancers of the: Lung Bladder Liver Colon Esophagus Rectum Kidnev Excesses Accidents Leukemia Non-Hodgkin's lymphoma Multiple myeloma Skin (melanomaand other) Soft-tissue sarcoma Cancers of the: Lip Prostate Brain Stomach Data from Blair et al. (3). Environmental Health Perspectwes 205 - BLAIRANDZAHM tumors include multiple myeloma, nonHodgkin's lymphoma, and cancers of the prostate, brain, and skin (6).Finally, several of the cancers that are excessive among Farmen appear to be associated with genetic or therapeutically induced i m m u n o deficiencies (7-12).Tumors linked to immunodeficiencies include non-Hodglun's lymphoma. leukemia, melanoma, softtissue sarcoma, and cancers of the stomach, brain, and lip. The overlap of cancers occurring excessively among farmers, cancers showing rising rates in the general population, and cancers occurring among individuals with immunodeficiencies suggests char investigations of agricultural populations m a y be useful to identify new factors involved in the etiology of cancer, to help explain rising rates for some tumors, and to provide leads regarding mechanisms of environmental carcinogens. Although farmers may come into contact with a number of potentially hazardous subsmnces. epidemiologic srudies have only recently attempted to focus on specific exposures. Early investigations looked at hrmers as a group or at broad subgroups of farmers defined by agricultural commodities produced. Because individuals with dif- ferent farming operations can have quite diverse exposures, this approach has a limited capability to identify specific factors that may contribute to the cancer burden. More targeted investigations have focused primarily on pesticides, but other agriculrural exposures such as fuels, oils, engine exhausts, organic solvents, dusts, and microbes need study. In epidemiologic investigations focusing o n pesticides, the strongest association has been between non-Hodgkin's lymphoma and phenoxyacetic acid herbicides (13-16), but leukemia has been linked with several insecticides ( 17),soft-rissue sarcoma with phenoxyacetic acid herbicides (18) and animal insecticides (19),ovarian cancer with triazine harbicides (lo),prostate cancer with herbicides (21),and D D T with cancers of the lung (22)and pancreas (23) (Table 2). Mosr srudies have included only men, but invesrigarions including women have reporred associations between several pesticides and nomHodgkin's lymphoma (24) and multiple myeloma (25). Studies of women in the general population have reported an association between D D T and breast cancer (26-28). Investigations of this association among women in agriculture are needed and some are under way. High-priority research efforts for the future table 2. Pesticide classes associated with cancer in epidemiologic studies. Pesticidesclass Cancer Phenoxyacetic acid herbicides Organochlorine insecticides Organophosphate insecticides Arsenical insecticides Triazine herbicides Non-Hodgkin's lymphoma. soft-tissuesarcoma, prostate leukemia. nonHodgkin`s lymphoma,soft-tissue sarcoma. pancreas, lung, breast Non-Hodgkin's lymphoma. leukemia Lung, skin Ovary Data from f 13-28) include a concentration on methodologic issues in exposure assessment as well as etiologic concerns. ExposureAssessment T h e major limitation to date in investigations of cancer among agricultural populations is the lack ofdetail regarding exposure. Often, no specific exposure assessment is undertaken and analyses are based simply on the job tide farmer. This does not allow identification of specific factors that may be related to the development of cancer and tends to introduce confusion because disease risks are ofien compared between farmers with radically differenr exposure patterns. Since different firming operations may yield quite diverse exposures, simply comparing farmers overall, or broad subgroups of farmers, introduces exposure. misclassification, which decreases study power and tends to bias risk estimates toward the null, rhus diminishing opportunities ro identi$ etiologic facrors. More detailed assessment of exposures is needed in the hture. Assessment of historical exposures is always difficult in epidemiologic studies. At first glance, it may appear that reconstructing agricultural exposures would be paniculady problematic. However, exposure assessment in agriculture may be no more difficult to assess than many lifestyle or other occupational ficrors. In facr. srudies of farmers probably offer special advanrages, parricularly when exposures are based o n inrerview data. Farmers are very knowledgeable about chemicals they use. In many industrial siruarions. management makes decisions regarding the selection and purchase of materials, while labor actually uses them. In such situations, nei~hermanagement n o r labor is familiar with all aspecrs of the operation. O n many family farms. unlike in mosr industries, the farmer represents both labor and management and is engaged in the selection, purchase, and use of farm chemicals. For pesticides, the farm owner/operaror decides if there is a pest problem, determines when to treat the problem, selects the pesticide, applies the chemical, checks the results of the treatment, and records the purchases (this is a tax-deductible expense). These activities reinforce memory, which enhances the reliabiliry and validity of informarion obcained by interview. There is also an impression that farmers use so many pesticides and change chemicals so frquendy that recall must be poor. This is not the case for many farmers. In several NCI surveys, rhe total number of pesticides used over a farmer's lifetime averaged less than 10 and, typically, the same ones were used year afcer year (29). Thus, the number of chemicals used seems amenable to recall. This is not to say, however, that improvements in assessment of pesticide exposures are not needed. It may be more difficult to reconstruct pesticide exposure histories for agricultural workers who are not farm ownedopcraton. For example, migrant and seasonal workers are unlikely to know which pesticides have been applied to the fields where they work. It is clear that different approaches must be developed to assess exposures in this group (30). The experimental and epidemiologic evidence suggests that potentially carcinogenic pesticides are not likely to be limited to any particular chemical class (31).To date, too few epidemiologic investigations have attempted to obrain information on individual pesricides. This must be the focus in rhe future. Exposure assessment can be improved by collecring information from several sources (e.g., interviews with farmers and suppliers), reviewing records (farmers are now required to keep records of pesticide purchases), conducting exposure monitoring during application, and obtaining blood or urine specimens for assessment of dose. Interviews should probe for information on specific pesticides and amounts used, mixing and application procedures, and types of prorective equipment and actions used. No one parricular exposure assessment approach is likely to be universally success- ful in all situations. IL may nor be possible ro achieve rhe desired degree of quantification of exposure simply from interviews and records. Environmental and biologic monitoring provides such quantification but only for a very short period (usually days). Farming activiries resulting in exposures are often limited to relatively brief 206 Environmental Health Perspectives AGRICULTURAL EXPOSURES AND C A N C M time periods during the year; thus, when the monitoring occurs is critical. T h e use of detailed questionnaires supplemented with monitoring and other informarion together would allow a more accurate classification of relative exposure. Pesticides understandably have been suspected of causing cancer in agricultural populations because a number of these chemicals are carcinogenic in laboratory bioassays. The mechanism of action of pesticides, however, is not well understood. Although some pesticides have genotoxic effects (32),others may cause immune sys- tem defects (33).For example, it has been proposed that organophosphate insecticides may play a role in oncogenesis through their inhibition of serine esterases, which are necessary for Functioning of T-lymphocytes and natural killer cells (34).Engine exhausts may also affect the immune system because polycyclic aromatic hydrocarbons have been associated with depression of serum IgG and IgA levels (35).Stimulation of the immune system through exposure to mycotoxins also appears worthy of study (36).Investigations of agricultural exposures that incorporate biologic marker components are needed to characterize potential environmental hazards faced by the agricultural and general population. Efforts must also be undertaken to obtain information on exposure to potential agricultural hazards other than pesticides. The epidemiologic research to date has focused on pesticides, but it is time to pay attention to engine exhausts, fuels and oils, dusts, ferrilizers, and zoonotic viruses. EfFom to betrer characterize exposures from drinking water are also needed, as contamination of drinking water by agricultural fertilizers and pesticides represents a growing problem in many areas of the country, particularly in agricultural areas (37). Epidemiologic Investigations Most epidemiologic investigations to dare have focused on farm owner/operators and have mainly included men. Additional work on this population is warranted because few studies so far have attempted to assess cancer risks from specific agricultural exposures. Long-term prospective studies should be considered in addirion to case-control designs. Future efforts, however, must also be expanded to include evaluation of cancer risks among other groups in the agricultural setting, i.e., spouses, children, and laborers. The role ofspouses in the farming operation varies. Some wives are fully engaged in all activities and may perform the same tasks as their husbands. Investigation of cancer risks among this population is imporcant to assess risks for female-related tumors from agricultural exposures. A study of women farmers is also important to determine whether cancer risks from agricultural exposures vary by gender. Such diffcrences could occur because of anaromid and physiologic differences between the sexes (38)or because different approaches to job tasks result in disparate exposures. Some spouses do not actually engage in farm activities that require direct contact with farm chemicals, but because they live on the farm (which is like living at the factory in other industries), indirect exposure is possible. For example, the potential for contamination of vehicles, furniture, and clothing may provide exposure opportunities to pesticides used on the farm to Family members not directly engaged in application. This level of exposure, although it may be considerably less than that of farm operators, may equal or exceed exposure levels experienced by the general public. Studies of farm spouses could provide vduable information regarding cancer risks to the general population from such indirect exposures. Farm children may also experience direct and indirect exposures at ages when they may be especially susceptible. Farm laborers such as seasonal and migrant workers may also experience unique exposure scenarios that put them at special risk (30).Exposures may occur at a young age because children work in the / / fields or must accompany their parents to the fields because of the lack of child care facilities. Lack of protective equipment and prompt access to showers and laundry facilities (33)may exacerbate hazards by prolonging the time during which pesticides are in contact with the skin. There is growing concern over contamination of food and drinking water with agricultural chemicals. Studies of agricultural populations may offer special advantages to address this issue. For example, the level of contamination of drinking water is greater in private wells than in public water systems, and farms often use private wells as their water source. This, plus the residential stability of farm families, offers distinct advantages over urban areas for the study of cancer risks from chemical contamination of drinking water. It is imporrant to remain d e n for unusual exposure situations that may provide unique opportunities to evaluate cancer risks from specific agricultural chemicals. For example, studies of cancer risks among persons engaged in fruit and vegetable production have nor been conducted. T h e intense use of pesticides, particularly fungicides, on these commodities underscores the need for evaluation. Studies of workers in hothouses producing flowers and vegetables could be informative because of heavy exposures from the use of chemicals within a confined space. Special opportunities may exist in other countries where pesticides are used more heavily and exposures may be considerably higher than in the United States. Conclusion Studies of cancer risk among agricultural populations will improve health and safety among chis important segment of the population. These investigations may also alert us to possible hazards to the general population, identify factors contributing to the rising incidence of some cancers, and provide clues to carcinogenic mechanisms. REFERENCES 1. Merchant JA. Research for agricultural safety and health. In: Papers and Proceedings of the Surgeon General's Conference on Agricultural Safety and Health (Myers ML, Herrick RF. Olenchock SA, Myers JR, Parker JE, Hard DL, Wilson K. cds). NIOSH Pub1 No 92-105. Washington:Narional Instirute for Occupational Safety and Health, 179273-85. 2. Mason TJ, McKay FW, Hoover R. Blot WJ. Fraumeni J F Jr. Atlas of cancer mortaliry for U.S.counties: 1950-1969. DHEW Pub1 No (NIH) 75-780. Washington:U.S. Department of Health, Education and Wclhre, 1975. 3. Blair A, Zahm SH, Pearce NE, Heineman EF, Fraumeni JF Jr. Clues to cancer etiology from studies of farmers. Scand J Work Environ Health 18:209-215 (1992). 4. Blair A, Zahm SH. Cancer among farmers. In: Health Hazards of Farmin Vol 6 (Cordes DH, Rea DF, eds). Philadelphia: Hanky anj'Belfus, I99 1:335-354. Volume lU3. Supplement8, November 1995 207 r' Id B U R AND LqHM 5. Brackbill R, Frazier T, Shillin S. Smoking characteristics of U.S.workers, 1978-1980. Am YInd Med 13:541 (1988). 6. Davis DL, Hoe1 D, Fox J, Lopcz A. International trends in cancer morraliry in France. West Germany, Italy, Japan, England and Wales, and the USA. Lancet 336:474-48 1 (1990). 7. Hoover R, Fraumeni JF Jr. Risk of cancer in renal transplanr recipicnrs. Lancet 2:55-57 (1973). P8. Filipovich AH, S ector BD, Kersey J. Immunodeficiency in humans as a risk acror in the development of malignancy. Prev Med 9:252-259 (1980). 9. Blohme I, Brynger H. Malignanr disease in renal rransplanr parients. Transplancarion 39:23-25 (1985). 10. Penn I. Immunosuppression and skin cancer. Clin Plasr Surg 7:361 (1980). 11. Kinlen L. Doll R. Pero J. The incidence of tumors in human transplant recipienrs. Transplant Proc 15: 1039-1042 ( I 983). 12. Kolb HJ, Bender-Corn C. Late complicarions after allogeneic bone marrow transplanration for leukemia. Bone Marrow Transplanr 6:6 1-72 ( 1 990). 13. Hardell L. Eriksson M, Lenner P, Lundgrcn E. Malignant lymphoma and exposure to chemicals, especially organic solvents, chlorophenols, and phenoxy acids: a case-conrrol studv. . Br JCance; 43: 169-176 (198I).' 14. Hoar SK. Blair A. Holmes FF. Bovsen CD. Robel R1. Hoover R, Fraumcni JF Jr. Agricultural hirbicide use and risk of lym- !ihoma and soft tissue sarcoma. JAMA 256:1141-1147 (1986). 15. ahm SH, Weisenburger DD, Babbirr PA. Saal RC. Vaughr JB, Cantor KP. Blair A. A case- control study of non- Hodgkin's lymphoma and the herbicide 2,4-dichlorophenoxy- acetic acid ( 2 . 4 - D ) in eastern Nebraska. Epidemiology 1:349-356 (1990). 16. Wigle DT, Semenciw RM, Wilkins K. Riedel D, Rittcr L. Morrison HI, Mao Y. Mortalirv study of Canadian male farm operators: non-Hodgkin's lymphoma mortality and agricultural practices in Saskatchewan. J Natl Cancer Insr 82575-582 ( 1990). 17. Brown LiM, Blair A. Gibson R, Everett G D , Cantor KP. Schuman LAM.Burmcister LF. Van Lier SF, Dick F. Pesticide exposures and orher agriculrural risk factors for leukemia among men in Iowa and iMinnesota. Cancer Res 50:6585-659 1 (1990). 18. Hardell L, Sansrrom A. Case-control srudy: soft-tissue sarcoma and exposure ro phenoxyaceric acids and chlorophcnols. Br J Cancer 39:7 1 1-717 ( 1979). 19. Zahm SH. Blair A. Holmes FF. Bovsen CD. Robel RJ. A casereferent study of soft-tissue sarcoma and Hodgkin's disease. Farming and insecticide use. Scand J Work Environ Hcalrh I4:214-230 ( 1988). 20. Donna A. Crosignani P, Boburti F. Bctra PG. Bocca R. Marinai N. Ferrario F. Fissi R. Berrino F. Triazine herbicides and ovarian epirhelial neoplasms. Scand J Work Environ Health i 5:47-53 (1989). 21. .Morrison H. Savirz D, Scmcnciw R. Hulka B. Mao Y. Morrison D. Wiglc D. Farming and prosratc cancer rnorraliry. .imJ Epidcmiol 137270-280 (1993). 22. Austin H, Keil JE, Cole P. A prospecrive follow-up srudv of cancer mortality in relarion ro serum D D T . Am J Public Health 79:43-46 ( I 989). 23. Garabranr DH. Held J , Langholz B. Peters JIM. !&ck TM. DDT and related compounds and risk of pancreatic cancer. J Natl Cancer Inst 84:764-771 (1992). 24. Zahm SH, Weisenburger DD, Saal RC, Vaughr JB, Babbitt PA, Blair A. The role of agricultural pesticide use in the dcvclopment of non-Hodgkin's lvmphoma in women. Arch Environ Health 48:353-358 [1993).' ' 25. Zahm SH, Blair A, Weisenburger DD. Sex differences in the risk of mulriole mveloma associated with aericulture. Br I Ind Y <~ Med 49:8151816 (1992). 26. Falck F, Ricci A, Wolff IMS. Godbold J, Deckers P. Pesticides and polychlorinated bi henyl residues in human breast lipids and their relation to !,east cancer. Arch Environ Health 47:143-146 (1992). 27. Wolff MS, Toniolo PG, Lee E, Rivera M,Dubin N. Blood Icv- els of organochlorine residues and risk of breast cancer. J Narl sCancer Insr 85:648-652 (1993). 28. Krieger N , Wolff MS, Hiatt M,Rivera M, Vo elman J, Orentreich N. Breast cancer and serum organoch orines: a prospecrive study among white. black. and Asian women. J Natl Cancer Inst 86:589-599 (1994). 29. Blair A, Zahm SH. Parterns of pesticide use among farmers: implications for epidemiologic research. Epidemiology 4:55-62 (1993). 30. Zahm SH, Blair A. Cancer among mi rant and seasonal farm- workers: an epidemiologic review a n 8 research agenda. Am J Ind Med 24:753-766 (1993). 31. Blair A. An overview of porential health hazards among farmers from use of pesticides. In: Papers and Proceedings of rhe Sur eon General's Conference on Agricultural Safety and Hea!rh (Myers ML, Herrick RF, Olenchock SA, Myers JR, Parker ]E, Hard DL, Wilson K, eds). NIOSH Pub1 No 92-105. Washingron:Narional Insrirute for Occupational Safety and Hcalrh, 1992229-242. 32. Garrett NE, Stack HF, Waren MD. Evaluarion of the genetic activiy profiles of65 pcsticida. Murat R a 168:301-325 (1986). 33. Thomas PT. Busse WE, Kerfvliet NI,Luster MI, Munson AE, Murray M, Roberts D. Robinson hi,Silkworrh J, Sjoblad R, Smialowicz R. Immunologic effects of pesticides. In: The Effects of Pesticides on Human Health (Baker SR. Wilkinson CR. eds). Princeton, NJ:Princeton Scienrific Publishing, 1990:261-295. 34. Ncwcombe DS. Immune suneillance. organophosphorus exposure and lymphomagcnesis. Lncer 339:539-54 1 i1992). 35. Szczeklik A, Szczeklik J , Galuszka Z, .Musial J , Kolarzvk E. Targosz D. Humoral immunosuppression in men exposed ro polycyclic xomaric hydrocarbons and related carcinogens in pollurcd environmcnrs. Environ Health Pcrspcct 102:302-304 ( 1994). 36. Abramson D. Mycotoxins in grains and dust. In: Principles of Healrh and Safety in Agriculrurc (Dasman JA. Cockcroft DW. cds). Boca Raron. FL:CRC Press. 1989:125-127. 37. Power JF, Schepers JS. Nitrarc contamination of groundwater in Norrh America. Agric Ecosysr Environ 26: 165-187 (1987). 38, Silvaggio T. iMarrison DR. Setring occuparional health srandards: toxicokinetic differences among and bcnvecn m e n m d women. J Occup bled 363849-854 (1994). 39. Slcsinger DP. Ofstead C. Economic and health needs of Wisconsin migranr farm workers. J Rural Health 9:138-148 (1993). I -. . . . - -