Canadian Male Farm Residents, Pesticide Safety Handling Practices, Exposure to Animals and Non-Hodgkin s Lymphoma (NHL)

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1 AMERICAN JOURNAL OF INDUSTRIAL MEDICINE SUPPLEMENT 2:54 61 (2002) Canadian Male Farm Residents, Pesticide Safety Handling Practices, Exposure to Animals and Non-Hodgkin s Lymphoma (NHL) H.H. McDuffie, PhD, 1 P. Pahwa, PhD, 1 J.J. Spinelli, PhD, 2 J.R. McLaughlin, PhD, 3 S. Fincham, PhD, 4 D. Robson, BSc, 5 J.A. Dosman, MD, FRCPC, 1 and J. Hu, MD 1 Background A majority of published studies indicate that farmers have an elevated risk of developing non-hodgkin s lymphoma (NHL) compared to other workers. Methods We evaluated accidental exposure to pesticides, the use of personal protective equipment, and exposure to animals among male farm residents in a Canadian population-based, multi-centre, NHL-control questionnaire study. Results In a multivariate model, the following variables had statistically significant adjusted odds ratios (OR) using 95% confidence intervals (95% CI) (a) higher risk: having more than 13 head of swine, raising bison, elk or ostriches, a personal history of cancer, > 4 and 15 years of farm residence and occupational exposure to diesel fuel and exhaust; (b) lower risk: raising cattle and a personal history of measles. Conclusions Future multidisciplinary studies of NHL should include a comprehensive review of exposure to animals in sufficient detail to assess etiological mechanisms to explain the putative associations between exposure to farm animals and NHL. Am. J. Ind. Med. Suppl. 2:54 61, ß 2002 Wiley-Liss, Inc KEY WORDS: non-hodgkin s lymphomas; farm animals; swine; cattle; male farm residents, Canada INTRODUCTION 1 Centre for Agricultural Medicine, Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada 2 Cancer Control Research, BC CancerAgency,Vancouver, BC, Canada 3 Division of Epidemiology and Biostatistics,Samuel Lunenfeld Research Institute,Department of Public Health Sciences, University of Toronto,Toronto, ON, Canada 4 Division of Epidemiology, Prevention and Screening, Alberta, Edmonton, AB, Canada 5 Saskatchewan CancerAgency, Regina, SK, Canada Aspects of the study were conducted in each of the institutions listed above. Contract grant sponsor: Health Canada; Contract grant number: ; Contract grant sponsor: British Columbia Health Research Foundation; Contract grant sponsor: Centre foragricultural Medicine, University of Saskatchewan. *Correspondence to: H.H. McDuffie, Geneticist, Centre foragricultural Medicine, Professor, Department of Medicine, University of Saskatchewan, 103 Hospital Drive, P.O. Box120, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada. mcduffie@sask.usask.ca Accepted17 October 2001 DOI /ajim Published online in Wiley InterScience ( Associations of non-hodgkin s lymphoma (NHL) with farmers [Cantor, 1982; Burmeister et al., 1983; Buesching and Wallstadt, 1984; Delzel and Grufferman, 1985; Pearce et al., 1985; Schumacher, 1985], certain farming practices [Blair et al., 1985; Pearce et al., 1987; Pearce and Reif, 1990; Pearce and Bethwaite, 1992; Wigle et al., 1990], agricultural exposures including animals [Pearce et al., 1987; Pearce and Reif, 1990], and specific pesticides [Hardell et al., 1981; Hoar et al., 1986; Pearce et al., 1986; Wiklund et al., 1987; Hoar-Zahm et al., 1990; Vineis et al., 1991; Blair et al., 1992; Cantor et al., 1992; Zahm and Blair, 1992; Zahm et al., 1994] have been reported from several countries with considerable diversity in types of farming. As part of a larger study investigating putative independent predictors of NHL, we collected specific information from the subgroup of cases and controls who had ever lived or worked on a farm. The variables of interest related to pesticide exposure were accidental ß2002Wiley-Liss,Inc.

2 Canadian Farm Residents and NHL 55 pulmonary or dermal exposure, industrial hygiene practices, post-exposure acute illness, source of drinking water, and exposure to a number of different types of animals. We examined these specific exposures and practices only among this high risk group in an effort to elucidate the known associations. METHODS We conducted a mail questionnaire population-based case (NHL ICD and 202; n ¼ 517)/control (n ¼ 1506) study among men aged 19 years and older resident in six Canadian provinces. Cases were males with incident diagnoses of NHL (ICD or 202) ascertained from Provincial Cancer Registries or Hospital Registries (Quebec). Controls were selected from Provincial Health Insurance records, voters lists (British Columbia), or telephone lists (Ontario). Controls were frequency matched by age 2 years to be comparable to the entire case group (NHL, Hodgkin s disease, soft tissue sarcoma and multiple myeloma) within each province. The questionnaire was previously used in a case/control study of NHL among Saskatchewan women [McDuffie et al., 1994]. We collected demographic information, lifetime occupational history and occupational exposure to selected chemicals including broad categories of pesticides. Personal medical history variables included (a) viral infections such as chickenpox, mononucleosis, mumps, shingles, (b) bacterial infections such as rheumatic fever, syphilis, tuberculosis, urinary tract infections, (c) non-infectious antigenic stimulation including allergic conditions such as asthma, hay fever, allergies, history of desensitization shots as well as autoimmune conditions such as rheumatoid arthritis and diabetes. Personal and family history of cancer was also included. Details of personal cigarette smoking history were collected. Ethical approval was received from the appropriate agencies in each province. Conditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (95% CI) adjusting for age and province of residence and subsequently for additional important covariates (measles, personal history of cancer, certain classes of pesticides, length of farm residence). Positive responders to the question: Have you ever lived or worked on a farm or ranch? were the subjects of this inquiry. RESULTS The reported frequencies of ever living or working on a farm were similar for cases (n ¼ 235, 45.5%) and controls (n ¼ 673, 44.7%). Ten percent of each of the total case and control respondents were current residents on a farm while 9.3% of cases and 7.0% of controls list farming as their current occupation [OR adj (95%CI) ¼ 1.53 (1.04, 2.25)]. Cases [( SE (years) ¼ )] and controls ( )(T ¼ 1.91, P ¼.06) were similar in the mean length of time resident on a farm and the age at which they left (cases , controls years) (T ¼ 1.03, P ¼.30). As shown in Table I, farm resident cases and controls were similar in their reported exposure to chemical compounds defined generically as pesticides. This similarity was shown for industrial hygiene practices (storage and washing TABLE I. Canadian (Quebec, Ontario, Manitoba, Saskatchewan, Alberta, British Columbia) Farm Residents: Pesticide Safety Handling Practices, and History ofaccidents/acute Illnesses Among Male NHL Cases and Population Controls NHL (235) Controls (673) n % a n % a OR b adj (95% CI) Lived on a farm where pesticides were used (0.69, 1.31) Pesticide contaminatedclotheswere storedinthehousebeforewashing (0.49, 1.18) Pesticide contaminated clothes were washed in the same washing (0.81,1.73) machine as the regular family wash Gloves or protective clothing were worn when handling pesticides (0.65, 1.44) Masks or respirators were worn when handling pesticides (0.48, 1.35) Entered newly sprayed fields or buildings? Regularly Infrequently Regularly and infrequently combined (0.61, 1.27) Accidental spill of a pesticide on skin or clothing (0.86, 1.97) Accidental inhalation of a pesticide directly into lungs (0.75, 1.88) Illness during or within 24 hr after exposure to pesticides (0.78, 2.70) a % of farm dwellers. b Adjusted for age andprovince ofresidence.

3 56 McDuffie et al. of pesticide contaminated clothing, use of protective gloves, clothing or masks while handling pesticides, and entering newly sprayed fields). Accidental pesticide inhalation or spills on skin or clothing were not infrequent events; however, cases and controls were equally likely to have experienced these events. Acute illness during or within 24 hr after exposure to a pesticide was reported by fewer than 10% of farm residents. Among farm residents, the most common source of water for drinking, washing, and bathing was a deep well. There was not an increased risk associated with obtaining drinking water from a shallow well [OR adj (95%CI) ¼ 0.95 (0.66, 1.38)]. The majority of farm residents were exposed to cattle, dogs, cats, chicken, and horses while fewer were exposed to pigs, turkeys, duck, geese, sheep, rabbits, and goats. Men with NHL were less likely to have had cattle [OR adj (95% CI) ¼ 0.68 (0.48, 0.94)], and more likely to have bison, ostriches or elk [OR adj (95% CI) ¼ 2.56 (1.60, 6.55)] on the farm where they lived and/or worked (Table II). Table II shows that raising small herds of cattle and of swine decreased risk while husbanding of exotic animals increased risks when each type of animal was studied individually with adjustment for age and province of residence. The majority of both groups personally cared for animals on the farm (Table III). A small minority of both groups (cases n ¼ 5, 2.1%, controls n ¼ 17, 2.5%) reported having had animals on the farm diagnosed with leukemia or lymphoma [OR adj (95%CI) 0.84 (0.29, 2.40)]. Univariate adjusted analyses of other selected variables with known or suspected associations with NHL are shown in Table III. These include medical history and occupational exposures. In stratified analyses, those who lived on a farm > 4 and 15 years had a higher risk compared to those whose length of farm residence was 4 years. Table IV shows that risk of NHL was statistically significantly increased after adjustment for covariates (a) by having more than 13 head of swine; (b) by raising bison, elk or ostriches; (c) by a personal history of cancer, and (d) by occupational exposure to diesel fuel and exhaust. Statistically significant adjusted OR less than one were calculated for the variables (a) raising cattle; (b) a personal history of measles. DISCUSSION There are several puzzling and unexplained aspects of the associations found between exposure to specific pesticides and NHL or other rare tumors. In most studies reported, the risk of pesticide exposed individuals relative to the comparison group is similar to that of the more generic variable current farmer. Is pesticide exposure a surrogate for other unmeasured factors on the farm? Are there farm related factors which in addition to pesticides confer an increased risk of developing these tumors? Exposure to farm and other animals [Bross and Gibson, 1970; Priester and Oleinick, 1970; Kvarnfors et al., 1975; Olson and Driscoll, 1978; Olsen et al., 1986; Pearce et al., 1987; Pearce and Bethwaite, 1992] has been investigated as a suspected risk factor for hematopoietic and lymphoid tumors. The evidence remains controversial. Etiological mechanisms which have been proposed and investigated to explain the putative association between exposure to farm animals and specific rare human tumors include (1) interspecies viral transmission [Bross and Gibson, 1970; Priester and Oleinick, 1970; Olson et al., 1972; Priester and Mason, 1974; Kvarnfors et al., 1975; Gardner, 1982; Olsen et al., 1986; Martirosov et al., 1990; Pearce and Bethwaite, 1992; Wright et al., 1992], (2) chronic antigenic stimulation [Pearce and Reif, 1990; Pearce and Bethwaite, 1992], (3) exposure to mycotoxins, endotoxins, and fungi [Zejda et al., 1994; Eduard, 1997], and (4) application of insecticides and fungicides to animals [Cantor, 1982; Baris et al., 1998]. Domesticated animals develop cancers. For example, lymphoma has been reported in both pet [Hayes et al., 1991] and working dogs [Hayes et al., 1990] as well as in cattle and cats [Priester, 1979]. Leukemia occurs in cats [Priester, 1979] and cattle [Priester and Oleinick, 1970; Kvarnfors et al., 1975] and lymphosarcoma in sheep [Olson et al., 1972]. The idea of possible viral transmission from animals to humans is supported by experimental and natural interspecies transmission. One example is the transmission of lymphosarcoma from cattle to sheep [Olson et al., 1972]. Another is the finding of genes of pig origin in influenza A virus found in turkeys [Wright et al., 1992]. However, the influenza A virus found in pigs was species specific. The potential transmission of bovine leukosis to humans has been studied using several methodologies. In a defined geographical area with high incidences of both bovine leukosis and human leukemia [Kvarnfors et al., 1975], no spatial or temporal associations were found. In an occupational study [Priester and Oleinick, 1970], no increased risk of developing leukemia or lymphoma among workers exposed to cattle diagnosed with bovine leukosis was found. Olson and Driscoll [1978] published a review article which concluded that there is no association between human cancer and bovine leukosis. People occupationally exposed to poultry do not appear to be at increased risk of developing leukemia, lymphoma, or Hodgkin s disease [Priester and Mason, 1974]. Butchers who slaughter animals have been shown to be at higher risk [OR (95% CI) ¼ 5.3 (1.0, 27)] [Metayer et al., 1998] of developing hematopoietic and lymphatic tumors. Using case/control methodology, Bross and Gibson [1970] reported that exposure to cats with leukemia doubled the risk of developing childhood leukemia. However, this type of exposure explained only a fraction of the cases. The recent outbreak of Nipah virus encephalitis

4 Canadian Farm Residents and NHL 57 TABLE II. Canadian (Quebec, Ontario, Manitoba, Saskatchewan, Alberta, British Columbia) Farm Residents: Distribution of Types and Numbers ofanimals Per Farm Among Male NHL Cases and Population Controls NHL (235) Control (673) n % n % OR adj (95% CI) b Any cattle a (0.48,0.94) 0 (reference) and (0.42, 0.91) (0.71, 1.05) Any dogs (.62, 1.20) 0 (reference) (0.63, 1.30) (0.53, 1.22) Any cats (0.67, 1.27) 0 (reference) and (0.58, 1.22) (0.70, 1.54) Any chickens (0.75, 1.44) 0 (reference) and (0.57, 1.22) (0.92, 2.03) Any horses (0.78, 1.44) 0 (reference) and (0.70, 1.56) (0.76, 1.65) Any swine (0.72,1.36) 0 (reference) and (0.43, 0.99) (0.96, 2.05) Any turkeys (0.67, 1.54) 0 (reference) and (0.58, 1.76) (0.58, 1.76) Any ducks (0.65, 1.54) 0 (reference) and (0.64, 2.00) (0.45, 1.77) Any geese (0.61, 1.57) 0 (reference) and (0.42, 1.36) (0.75, 3.23) Any sheep (0.46, 1.26) 0 (reference) and (0.28, 1.17) (0.52, 2.01) Any rabbits (0.64, 1.73) 0 (reference) and (0.50, 1.83) (0.59, 2.45)

5 58 McDuffie et al. TABLE II. (Continued ) NHL (235) Control (673) n % n % OR adj (95% CI) b Any goats (0.64, 2.44) (0.64, 2.44) Other animals c (1.00,6.55) Other than above 0 (reference) (1.00, 6.55) a The reference category is none of the specified type of animal. b The OR are adjusted forage andprovince ofresidence. c The term otheranimals includes ostriches, bison,elk. and putative transmission from pigs to pig farmers in Malaysia increased concern [Goh et al., 2000]. Chronic antigenic stimulation is considered to occur by exposure to animal hair, dander, saliva, feathers, and dusts contaminated by feed and manure. This hypothesis is supported by epidemiological studies. In addition, among children aged 5 19 years, parental chicken farming increased risk for all cancers in Norway [Kristensen et al., 1996]. Abattoir workers had significantly increased risk of NHL, a tumor type associated with antigenic stimulation [Metayer et al., 1998]. Evidence suggests that farmers and farm residents are exposed to a variety of mycotoxins (compounds secreted by microorganisms), endotoxins (present in the cell walls of Gram-negative bacteria), and fungi [Zejda et al., 1994; Eduard, 1997]. The carcinogenicity of these substances is under review [IARC, 1993; Mastrangelo et al., 1996]. Exposures within animal confinement areas, while distributing animal bedding and tending cattle enhance exposure to bacterial endotoxins and fungi [Eduard, 1997]. The respiratory health of swine workers is impaired by exposure to high levels of endotoxin [Zejda et al., 1994]. Impaired TABLE III. Canadian (Quebec, Ontario, Manitoba, Saskatchewan, Alberta, British Columbia) Farm Residents: Selected Covariates With a P-value of 0.10 or Less in Bivariate Age and Province Adjusted Analyses NHL (235) Controls (673) n % n % OR a adj (95% CI) Personally caring for animals on the farm b (0.62,1.26) Animalswitha diagnosisoflymphoma orleukemia onthefarm (0.29, 2.40) Personal history of measles (0.45, 0.87) Personal history of previous cancer (1.49, 4.14) Personal history of infectious diseases (0.47, 0.95) Exposure to diesel fuel/exhaust (1.17, 2.26) Exposure to fungicides (0.91, 5.58) Exposure to slimicides (0.02,1.18) Exposure to carbamate insecticides (1.01, 3.03) Exposure to organophosphate insecticides (1.08, 2.40) Exposure to dicamba herbicides (1.15, 2.69) Length of farm residence reference > 0and 4 years > 4and15 years (1.33, 3.27) > 15 and 25 years (0.83, 2.20) > 25 years (0.98, 2.64) Missing a Adjusted forage andprovince ofresidence. b Variables with P.10 were entered intothe model (Table IV).

6 Canadian Farm Residents and NHL 59 TABLE IV. Canadian (Quebec, Ontario, Manitoba, Saskatchewan, Alberta, British Columbia) Farm Residents: Conditional Logistic Model a Variable OR adj (95% CI) Cattle b ( 1and 30) 0.52 (0.32,0.84) Cattle ( 31) 0.68 (0.53, 0.88) Swine ( 1and 12) 0.93 (0.56, 1.54) Swine ( 13) 1.96 (1.21, 3.18) Bison, elk, ostriches 3.26 (1.20, 8.89) Measles (yes) 0.54 (0.38, 0.77) Personal history cancer (yes) 1.95 (1.14, 3.35) Exposure to dicamba herbicides (yes) 1.45 (0.84, 2.50) Exposure to organophosphorus insecticides (yes) 1.29 (0.77, 2.15) Carbamates (yes) 1.04 (0.52, 2.08) Exposure to diesel fuel or exhaust (yes) 1.52 (1.05, 2.19) Exposure to fungicides (yes) 1.86 (0.64, 5.41) Exposure to slimicides (yes) 0.12 (0.01, 1.03) Length of farm residence (>4, 15 years) 2.15 (1.34,3.45) Length of farm residence (>15, 25 years) 1.19 (0.71, 2.02) Length of farm residence (> 25 years) 1.34 (0.77, 2.34) a Adjustmentsforage,provinceofresidence,andcovariateswithaP valueof0.10orless in bivariate analyses. b The reference categories are no animals of the specified type on the farm, no personal history of the indicated medical condition, no exposure to the designated chemical and > 0and4year history ofliving/working on a farm. pulmonary function may permit carcinogens to remain in the circulation, leading to an increased risk of cancer [Cohen, 1978]. The indoor and outdoor application of insecticides and/or fungicides to animals has been associated with significantly increased risks of developing NHL. Exposures to insecticides, including chlorinated hydrocarbons, natural products and organophosphates, used on livestock increased risk of NHL in a North American study by Cantor et al. [1992]. However, Pearce et al. [1987] in New Zealand found no association of NHL and work-related exposures on sheep, dairy, or poultry farms. The statistical analysis of our data which included exposure to animals and other important covariates, including pesticides, suggests that exposure to swine and to exotic animals are independent risk factors. We did not have any direct measures of (a) interspecies viral transmission, (b) chronic antigenic stimulation due to cultivation or exposure to animals, or (c) exposure to mycotoxins, endotoxins or fungi. Similar to other studies, these possibilities are inferred. The role of childhood exposures leading to an increased risk of cancer in adulthood is difficult to explore. In this study, higher risk was associated with a relatively short period of farm residence. In a previous study of Saskatchewan women [McDuffie et al., 1994], we demonstrated that the longer the period of residence on the farm, the higher the risk of developing NHL which implies that ongoing exposure is more important than exposure as a child. The issue of childhood cancer in response to putative exposure to pesticides in utero or during the peri-natal period is controversial with well-designed and implemented studies producing opposite results [Holly et al., 1992; Bunin et al., 1994; Leiss and Savitz, 1995; Kristensen et al., 1996; Wilkins and Koutras, 1998]. This study was limited by design and methodological issues inherent in the case/control design. Women were excluded from the study for financial reasons. We reported results for a large number of agents, not all of which were specified in the hypotheses. The analyses related to these unspecified agents was exploratory. The wording of the question used to establish this farming subpopulation may have been too vague and diffuse as people who have lived the majority of their lifespan in nonfarm environments were included. By requesting certain information and conducting statistical analyses based on case-control differences only among farmers, ranchers, and farm residents, we lowered the number of eligible subjects, decreased our statistical power and may have overmatched. The study was enhanced by the number of cases (235) and controls (673) even in this subgroup analysis. Cases and controls were recruited from population-based sources similar to those used in other studies of this topic. Minimal numbers of responses from surrogates were included thereby enhancing the accuracy of the occupational exposure information collected. The questionnaire was previously used in a case-control study of NHL among Saskatchewan women [McDuffie et al., 1994]. Additional questions were used with the permission of Hoar et al. [1986]. It was validated in Saskatchewan during a pilot study to determine a suitable definition of pesticide exposure and to test the study procedures prior to implementation. The large geographical area of Canada included encompasses a diversity of farming practices which are generally not incorporated into a single case-control study. Measures of duration and intensity of exposure to various potential hazards on the farm, general measures of industrial hygiene, and customary safety habits were incorporated into a statistical model which included other important covariates. ACKNOWLEDGMENTS The authors are indebted to the members of the Advisory Committee for this project for the sharing of their experiences (Dr. G.B. Hill, A. Blair, L. Burmeister, H. Morrison, R. Gallagher, D. White); to the provincial coordinators and data managers for their meticulous attention to detail (T. Switzer, M. Gantefor, J. Welyklolowa, J. Ediger, I. Fan, M. Ferron, E. Houle, S. de Freitas, K. Baerg, L. Lockinger, E. Hagel, P. Wang, G. Dequiang) and to Dr. G. Theriault for supervising the collection of data in Quebec. We appreciate the care and dedication of S. de Freitas in the

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