Time after a peak-pesticide use period and neurobehavior among ecuadorian children and adolescents: The ESPINA study.

BACKGROUND: Limited evidence exists regarding transient neurobehavioral alterations associated with episodic pesticide exposures or agricultural pesticide spray periods. We previously observed that children examined soon after a pesticide spray period (the Mother's Day flower harvest [MDH]) had lower neurobehavioral performance than children examined later. The present study builds on our previous work by incorporating longitudinal analyses from childhood through adolescence. METHODS: We examined participants in agricultural communities in Ecuador (ESPINA study) during three periods: July-August 2008 (N = 313, 4-9-year-olds); April 2016 (N = 330, 11-17-year-olds); July-October 2016 (N = 535, 11-17-year-olds). Participants were examined primarily during a period of low floricultural production. Neurobehavior was assessed using the NEPSY-II (domains: Attention/Inhibitory Control, Language, Memory/Learning, Visuospatial Processing, and Social Perception). Linear regression and generalized linear mixed models were used to examine cross-sectional and longitudinal associations between examination date (days) after the MDH and neurobehavioral outcomes, adjusting for demographic, anthropometric, and socio-economic variables. RESULTS: Participants were examined between 63 and 171 days after the MDH. Mean neurobehavioral domain scores ranged from 1.0 to 17.0 (SDrange = 2.1-3.1) in 2008 and 1.0 to 15.5 (SDrange = 2.0-2.3) in 2016. In cross-sectional analyses (2016 only; N = 523), we found significant or borderline positive associations between time after the MDH and Attention/Inhibitory Control (difference/10 days [ß] = 0.22 points [95% CI = 0.03, 0.41]) and Language (ß = 0.16 points [95% CI = -0.03, 0.34]). We also observed positive, longitudinal associations (2008-2016) with Attention/Inhibitory Control (ß = 0.19 points [95% CI = 0.04, 0.34]) through 112 days after the harvest and Visuospatial Processing (ß = 3.56, ß-quadratic = -0.19 [95% CI: -0.29, -0.09]) through 92 days. CONCLUSIONS: Children examined sooner after the harvest had lower neurobehavioral performance compared to children examined later, suggesting that peak pesticide spray seasons may transiently affect neurobehavior followed by recovery during low pesticide-use periods. Reduction of pesticide exposure potential for children during peak pesticide-use periods is advised.

Possible pro-carcinogenic association of endotoxin on lung cancer among Shanghai women textile workers.

BACKGROUND: Endotoxin (lipopolysaccharide) is a widespread contaminant in many environmental settings. Since the 1970s, there has been generally consistent evidence indicating reduced risks for lung cancer associated with occupational endotoxin exposure. METHODS: We updated a case-cohort study nested within a cohort of 267,400 female textile workers in Shanghai, China. We compared exposure histories of 1456 incident lung cancers cases diagnosed during 1989-2006 with those of a reference subcohort of 3022 workers who were free of lung cancer at the end of follow-up. We applied Cox proportional hazards modelling to estimate exposure-response trends, adjusted for age and smoking, for cumulative exposures lagged by 0, 10, and 20 years, and separately for time windows of ⩽15 and >15 years since first exposure. RESULTS: We observed no associations between cumulative exposure and lung cancer, irrespective of lag interval. In contrast, analyses by exposure time windows revealed modestly elevated, but not statistically significant relative risks (∼1.27) at the highest three exposure quintiles for exposures that occurred >15 years since first exposure. CONCLUSIONS: The findings do not support a protective effect of endotoxin, but are suggestive of possible lung cancer promotion with increasing time since first exposure.

Lung cancer and occupational exposures other than cotton dust and endotoxin among women textile workers in Shanghai, China.

OBJECTIVES: Numerous epidemiological studies of lung cancer among textile workers worldwide consistently indicate reduced risks related to cotton dust exposure, presumably due to endotoxin contamination. Our objective was to investigate associations with other exposures potentially related to lung cancer, including wool and synthetic fibre dusts, formaldehyde, silica, dyes and metals, that have only been studied to a limited extent in the textile industry. METHODS: We conducted a case-cohort study nested within a cohort of 267,400 women textile workers in Shanghai, China. We compared work assignments and exposure histories of 628 incident lung cancer cases, diagnosed during 1989-1998, with those of a reference subcohort of 3188 workers. We reconstructed exposures with a job-exposure matrix developed specifically for textile factories. Cox proportional hazards modelling was applied to estimate age/smoking-adjusted relative risks (hazard ratios) and risk gradients associated with job assignments and specific agents other than cotton dust and endotoxin. RESULTS: No associations were observed for lung cancer with wool, silk or synthetic fibre dusts, or with most other agents. However, increased risks, although statistically imprecise, were noted for ≥ 10 years' exposures to silica (adjusted HR 3.5, 95% CI 1.0 to 13) and ≥ 10 years' exposures to formaldehyde (adjusted HR 2.1, 95% CI 0.4 to 11). CONCLUSIONS: Exposures to silica and formaldehyde, although not widespread among the cohort, may have increased lung cancer risk. Silica is an established human lung carcinogen, whereas there is only weak prior evidence supporting an association with formaldehyde. Both exposures warrant consideration as potential lung carcinogens in textile manufacturing.

Post hoc Parkinson's disease: identifying an uncommon disease in the Cardiovascular Health Study.

BACKGROUND: Although ongoing cohort studies offer a unique opportunity to apply existing information collected prospectively to further the scientific understanding of Parkinson's disease (PD), they typically have limited information for clinical diagnosis. METHODS: We used combinations of self-report, International Classification of Diseases - 9th edition codes and antiparkinsonian medications to identify PD in the Cardiovascular Health Study. To determine whether the expected inverse association between smoking and PD is evident using our outcome definitions, we assessed baseline smoking characteristics for various definitions of PD. RESULTS: We identified 60 cases with prevalent PD (1.0%; 95% confidence interval, CI = 0.8-1.3%) and 154 with incident PD by year 14. Clear associations were observed for current smokers (odds ratio, OR = 0.50; 95% CI = 0.26-0.95) and for those who smoked ≥50 pack-years (OR = 0.53; 95% CI = 0.29-0.96). Estimates for smoking were similar when ≥2 data sources were required. Estimates for self-report alone were attenuated towards null. CONCLUSIONS: Using multiple data sources to identify PD represents an alternative method of outcome identification in a cohort that would otherwise not be possible for PD research. Ongoing cohort studies can provide settings in which rapid replication and explorations of new hypotheses for PD are possible.

Human PON1, a biomarker of risk of disease and exposure.

Human paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated serum enzyme that exhibits a broad substrate specificity. In addition to protecting against exposure to some organophosphorus (OP) pesticides by hydrolyzing their toxic oxon metabolites, PON1 is important in protecting against vascular disease by metabolizing oxidized lipids. Recently, PON1 has also been shown to play a role in inactivating the quorum sensing factor N-(3-oxododecanoyl)-l-homoserine lactone (3OC12-HSL) of Pseudomonas aeruginosa. Native, untagged engineered recombinant human PON1 (rHuPON1) expressed in Escherichia coli and purified by conventional column chromatographic purification is stable, active, and capable of protecting PON1 knockout mice (PON1(-/-)) from exposure to high levels of the OP compound diazoxon. The bacterially derived rHuPON1 can be produced in large quantities and lacks the glycosylation of eukaryotic systems that can produce immunogenic complications when inappropriately glycosylated recombinant proteins are used as therapeutics. Previous studies have shown that the determination of PON1 status, which reveals both PON1(192) functional genotype and serum enzyme activity level, is required for a meaningful evaluation of PON1's role in risk of disease or exposure. We have developed a new two-substrate assay/analysis protocol that provides PON1 status without use of toxic OP substrates, allowing for use of this protocol in non-specialized laboratories. Factors were also determined for inter-converting rates of hydrolysis of different substrates. PON1 status also plays an important role in revealing changes in HDL-associated PON1 activities in male patients with Parkinson disease (PD). Immunolocalization studies of PONs 1, 2 and 3 in nearly all mouse tissues suggest that the functions of PONs 1 and 3 extend beyond the plasma and the HDL particle.

Occupational exposure to bisphenol-A (BPA) and the risk of self-reported male sexual dysfunction.

BACKGROUND: Animal studies have suggested that bisphenol-A (BPA) is a potential human endocrine disrupter; but evidence from human studies is needed. METHODS: We conducted an occupational cohort study to examine the effect of occupational exposure to BPA on the risk of male sexual dysfunction. Current workers from BPA-exposed and control factories were recruited. The exposed workers were exposed to very high BPA levels in their workplace. Male sexual function was ascertained through in-person interviews using a standard male sexual function inventory. RESULTS: BPA-exposed workers had consistently higher risk of male sexual dysfunction across all domains of male sexual function than the unexposed workers. After controlling for matching variables and potential confounders, exposed workers had a significantly increased risk of reduced sexual desire [odds ratios (OR) = 3.9, 95% confidence interval: 1.8-8.6), erectile difficulty (OR = 4.5, 95% CI 2.1-9.8), ejaculation difficulty (OR = 7.1, 95% CI 2.9-17.6), and reduced satisfaction with sex life (OR = 3.9, 95% CI 2.3-6.6). A dose-response relationship was observed with an increasing level of cumulative BPA exposure associated with a higher risk of sexual dysfunction. Furthermore, compared with the unexposed workers, BPA-exposed workers reported significantly higher frequencies of reduced sexual function within 1 year of employment in the BPA-exposed factories. CONCLUSIONS: Our findings provide the first evidence that exposure to BPA in the workplace could have an adverse effect on male sexual dysfunction.

Future needs of occupational epidemiology of extremely low frequency electric and magnetic fields: review and recommendations.

The occupational epidemiological literature on extremely low frequency electric and magnetic fields (EMF) and health encompasses a large number of studies of varying design and quality that have addressed many health outcomes, including various cancers, cardiovascular disease, depression and suicide, and neurodegenerative diseases, such as Alzheimer disease and amyotrophic lateral sclerosis (ALS). At a 2006 workshop we reviewed studies of occupational EMF exposure with an emphasis on methodological weaknesses, and proposed analytical ways to address some of these. We also developed research priorities that we hope will address remaining uncertainties. Broadly speaking, extensive epidemiological research conducted during the past 20 years on occupational EMF exposure does not indicate strong or consistent associations with cancer or any other health outcomes. Inconsistent results for many of the outcomes may be attributable to numerous shortcomings in the studies, most notably in exposure assessment. There is, however, no obvious correlation between exposure assessment quality and observed associations. Nevertheless, for future research, the highest priorities emerge in both the areas of exposure assessment and investigation of ALS. To better assess exposure, we call for the development of a more complete job-exposure matrix that combines job title, work environment and task, and an index of exposure to electric fields, magnetic fields, spark discharge, contact current, and other chemical and physical agents. For ALS, we propose an international collaborative study capable of illuminating a reported association with electrical occupations by disentangling the potential roles of electric shocks, magnetic fields and bias. Such a study will potentially lead to evidence-based measures to protect public health.

Dust and chemical exposures, and miscarriage risk among women textile workers in Shanghai, China.

INTRODUCTION: To investigate possible associations between miscarriage and occupational exposures in the Shanghai textile industry. METHODS: A retrospective cohort study of miscarriages among 1752 women in the Shanghai textile industry was conducted. Reproductive history was self-reported by women and occupational work histories were collected from factory personnel records. Occupational exposures were assigned by linking work history information to an industry-specific job-exposure matrix informed by factory-specific textile process information and industrial hygiene assessments. Estimates of cotton dust and endotoxin exposure were also assigned. Odds ratios (OR) and 95% CI were estimated by multivariate logistic regression, with adjustment for age at pregnancy, educational level, smoking status of the woman and her spouse, use of alcohol, and woman's year of birth. RESULTS: An elevation in risk of a spontaneously aborted first pregnancy was associated with exposure to synthetic fibres (OR 1.89, 95% CI 1.20 to 3.00) and mixed synthetic and natural fibres (OR 3.31, 95% CI 1.30 to 8.42). No increased risks were observed for women working with solvents, nor were significant associations observed with quantitative cotton dust or endotoxin exposures. Associations were robust and similar when all pregnancies in a woman's reproductive history were considered. CONCLUSIONS: Occupational exposure to synthetic fibres may cause miscarriages, and this possibility should be the subject of further investigation.

Alpha-synuclein, pesticides, and Parkinson disease: a case-control study.

BACKGROUND: Aggregation and fibrillization of the alpha-synuclein protein (encoded by the SNCA gene) may represent key events in the pathogenesis of Parkinson disease (PD). Variability in the length of a dinucleotide repeat sequence (REP1) within the SNCA promoter confers susceptibility to sporadic PD. Pesticide exposures may also confer susceptibility to PD. Our objective was to test possible joint effects of SNCA REP1 genotypes and pesticide exposures on the risk of PD. METHODS: This was a case-control study. Cases were recruited prospectively from the Department of Neurology of the Mayo Clinic, Rochester, MN, after June 1, 1996. The control subjects included unaffected siblings of cases and unrelated population control subjects. We assessed pesticide exposures by telephone interview and genotyped SNCA REP1. Odds ratios (ORs) and 95% CIs were determined using conditional logistic regression models. RESULTS: There were 833 case-control pairs. We observed an increased risk of PD with increasing SNCA REP1 bp length (OR, 1.18 for each score unit; 95% CI, 1.02-1.37; p = 0.03). Pesticide exposures were associated with PD in younger subjects only (lowest quartile of age at study,

Work area measurements as predictors of personal exposure to endotoxin and cotton dust in the cotton textile industry.

OBJECTIVES: To determine if work area measurements of endotoxin and/or cotton dust obtained from the vertical elutriator (VE) can be used to predict levels of personal endotoxin exposure as measured by the Institute of Occupational Medicine (IOM) inhalable dust sampler in the cotton textile industry. METHODS: Fifty-six work area cotton dust samples were collected from 14 areas and 82 personal cotton dust samples were collected from 41 workers in three textile mills (Mills A, B and C) in Shanghai, China. Cotton dust concentrations were determined gravimetrically from sample filters, of which endotoxin concentrations were determined using a kinetic chromogenic modification of the limulus amoebocyte lysate assay. Linear regression models were used to determine the association between log IOM personal endotoxin concentration and log VE area endotoxin concentration. RESULTS: Median cotton dust and endotoxin concentrations measured from VE area samples in the three mills were 0.36 mg m(-3) and 1280.76 endotoxin units per cubic meter (EU m(-3)), respectively, compared to 1.74 mg m(-3) and 2226.83 EU m(-3) from IOM personal samples. Excluding samples from weaving processes, we observed linear associations between VE area measures of endotoxin and IOM personal endotoxin concentrations; VE area concentration of endotoxin explained 83 and 89% of the total variation in IOM personal endotoxin concentration for Mills A and B, respectively (Mill A: R2 = 0.83, P < 0.0001; Mill B: R2 = 0.89, P < 0.0001). Although area measures of cotton dust was also a significant predictor of person endotoxin, the model explained less of the variance in personal endotoxin measurements. CONCLUSIONS: Specific to the conditions of the textile mills investigated in this study, work area measurements of endotoxin, but not cotton dust, may be reasonable proxies for personal levels, at least for rank-ordering exposures.

Cell markers, cytokines, and immune parameters in cement mason apprentices.

OBJECTIVE: Cement masons are known to have significant silica exposure, and silica exposure and silicosis are thought to increase risk of autoimmune disease. Because the mechanisms remain obscure, with inconclusive reports of systemic immune effects following silica exposure, our goal was to identify potential early markers of silica-related immunologic and respiratory effects. METHODS: We conducted a cross-sectional study of cement mason apprentices and electrician (control) apprentices. Demographics, dust exposure history, symptoms, spirometry, exhaled nitric oxide, and blood (for immunoglobulins, cytokines, cell counts, and surface markers) were obtained from 11 cement mason apprentices and a comparison group of 21 electrician apprentices. RESULTS: Masons had significantly higher (P < 0.05) masonry dust exposure (42 versus 9 dust-hour-years), serum interleukin-1beta (IL-1beta; 12 versus 9 pg/ml), IL-2 (20 versus 8 pg/ml), IL-4 (193 versus 67 pg/ml), IL-10 (44 versus 21 pg/ml), and interferon-gamma (139 versus 65 pg/ml) compared with electricians. In contrast, masons had significantly lower percentages of CD25+ (12% versus 20%) and CD69+ (4% versus 9%) lymphocytes. CONCLUSION: Mason apprentices had higher levels of serum proinflammatory cytokines and lower percentages of CD25+ and CD69+ lymphocytes than did electrician apprentices. These preliminary findings suggest that mason apprentices may be at greater risk of a systemic proinflammatory state that is potentially linked to immune dysregulation. Although distinct limitations of this preliminary data are recognized, this is consistent with early biologic effects leading to increased incidence of autoimmune disease among silica-exposed workers. Prospective studies are needed to validate these initial findings and clarify the temporal sequence of observed relationships.

Prioritizing future resources for epidemiologic research on old and newly emerging occupational hazards.

BACKGROUND: Inevitably, occupational epidemiologists must decide when and how to shift research attention and resources from investigations of old, established health hazards to a focus on newly emerging potential risk factors. As yet unknown occupational health consequences of burgeoning worldwide technologies, such as the microelectronics industry, and increasing recognition of the importance of common, yet non-traditional occupationally-related health effects, such as musculoskeletal disorders in office workers, give strong impetus for embarking in new directions. However, there remains much to be learned from continued investigation of well-established occupational hazards, such as asbestos, benzene, and lead. OBJECTIVES: A rational strategy for planning future research will need to consider optimizing resources. CONCLUSIONS: The following suggestions are offered. 1) First and foremost, occupational risk factors are most directly, and arguably most validly, identified by studying workers in well-defined cohorts, ideally when exposures are adequately characterized. To this end, industry-based cohort studies should be given priority, at least for older hazards, over population-based case-control and surveillance designs. 2) Defined cohorts with extensive exposure and health outcome data should continue to be followed, as resources permit; 3) Launching cohort studies for potential new hazards should incorporate extensive exposure assessments at the outset, and should preferentially select inception cohorts of newly hired workers. Valid biomarkers of pre-clinical disease will be especially valuable in this regard. 4) Capitalizing on new technological advances in exposure assessment, clinical medicine, molecular genetics should be encouraged

Occupational risk factors for pancreatic cancer among female textile workers in Shanghai, China.

OBJECTIVES: To investigate whether occupational exposures to dusts and chemicals in the Shanghai textile industry are associated with risk of pancreatic cancer. METHODS: A case cohort study nested in a cohort of 267,400 female textile workers in Shanghai, China was conducted among 180 incident pancreatic cancer cases and an age stratified randomly selected comparison subcohort (n = 3188). A complete occupational history of work in the textile industry was obtained for each woman, and was linked to a job exposure matrix developed for the textile industry to estimate exposures to specific dusts and chemicals. Cumulative exposures to cotton dust and endotoxin were reconstructed from historical and contemporaneous measurements. RESULTS: After adjusting for smoking status, a trend of decreasing risk of pancreatic cancer was observed for increasing cumulative exposures to cotton dust and endotoxin with a lag of 20 years. The hazard ratios for women cumulatively exposed to >143.4 mg/m3 x years of cotton dust and >3530.6 EU/m3 x years of endotoxin were 0.6 (95% CI 0.3 to 0.9) and 0.5 (95% CI 0.3 to 0.9), respectively, compared to unexposed women. There was little evidence that exposures to other textile dusts and chemicals were associated with risk of pancreatic cancer. CONCLUSIONS: Occupational exposure to cotton dust and endotoxin in the textile industry may have reduced risks of pancreatic cancer in this cohort. These associations should be replicated by others before making a firm conclusion of their possible effects on pancreatic cancer.

Reproductive history, occupational exposures, and thyroid cancer risk among women textile workers in Shanghai, China.

OBJECTIVES: Thyroid cancer risk has been previously associated with increased age at first pregnancy and history of miscarriage. Occupational risk factors for thyroid cancer, with the exception of radioactive iodine, have not been well investigated. We conducted a case-cohort study nested in a cohort of 267,400 female textile workers in Shanghai, China, who had been followed for cancer incidence during 1989-1998. METHODS: The analysis included 130 incident thyroid cases and 3,187 subcohort non-cases. Reproductive history was determined by questionnaire at baseline. Historical exposures were reconstructed from work history and information on factory processes and exposures. Cox proportional hazards analysis was performed to estimate hazard ratios (HR) for reproductive factors and occupational exposures. RESULTS: Associations were observed between thyroid cancer and employment in jobs with 10 or more years of benzene exposure (HR 6.43, 95% CI: 1.08, 38) and formaldehyde exposure (HR 8.33, 95% CI: 1.16, 60). Administration workers also had an increased risk (HR 1.56, 95% CI: 1.08, 2.25). No associations between examined reproductive factors and thyroid cancer were observed in this study. CONCLUSIONS: Despite statistically imprecise risk estimates, the findings suggest potential associations with some occupational chemical exposures in this cohort of textile workers.

Occupational risk factors for nasopharyngeal cancer among female textile workers in Shanghai, China.

AIMS: To investigate whether occupational exposure to dusts and chemicals in the Chinese textile industry are associated with risk of nasopharyngeal cancer. METHODS: Sixty seven nasopharyngeal carcinoma (NPC) cases identified during 1989-98 and a random sample (n = 3188) of women were included in a case cohort study nested in a cohort of 267,400 women textile workers in Shanghai, China. A complete occupational history of work in the textile industry was obtained for each woman. A job exposure matrix developed by experienced industrial hygienists was used to assess exposures to specific dusts and chemicals. RESULTS: Risk of NPC is associated with cumulative exposure to cotton dust. The hazard ratio for women cumulatively exposed to >143.4 mg/m3 x years of cotton dust was 3.6 (95% CI 1.8 to 7.2) compared with unexposed women. Trends of increasing risk were also found with increasing duration of exposure to acids and caustics (p = 0.05), and with years worked in dyeing processes (p = 0.06). Women who worked at least 10 years in dyeing processes had a 3.6-fold excess risk of NPC (95% CI 1.0 to 12.1). CONCLUSIONS: Occupational exposure to cotton dust, acids, and caustics, and work in dyeing and printing jobs in the textile industry may have increased risk of NPC in this cohort.

Colorectal cancer incidence among female textile workers in Shanghai, China: a case-cohort analysis of occupational exposures.

Previous studies have suggested increased risks of colorectal cancers among textile industry workers, potentially related to synthetic fibers. To investigate risks of colon and rectum cancers in relation to these and other textile industry exposures, we conducted a case-cohort study nested within a cohort study of female employees from the Shanghai Textile Industry Bureau (STIB). Cox proportional hazard regression modeling was used to estimate hazard ratios (HR) for colon and rectum cancers associated with duration of employment (e.g., 0, >0 to <10, 10 to <20 years, > or =20 years) in various jobs classified according to process type and exposures to specific agents. Our findings indicate that certain long term exposures may pose increased risk of colorectal cancers, especially dyes and dye intermediates with colon cancer (> or =20 years exposure versus never, HR=3.9; 95% CI: 1.4-10.6), and maintenance occupation (HR = 2.3; 95% CI: 1.0-5.7) and metals exposure (HR = 2.0; 95% CI: 1.1-3.6) with rectum cancer. A decreased risk of rectum cancer was associated with exposure to natural fibers such as cotton (HR = 0.7; 95% CI: 0.5-0.9), and a trend of decreasing rectum cancer incidence was observed by category of cumulative quantitative cotton dust or endotoxin exposures, when exposures were lagged by 20 years.

Risk of lymphatic or haematopoietic cancer mortality with occupational exposure to animals or the public.

BACKGROUND: Occupational exposure to animals or the public could result in exposure to infectious agents, which may play a role in the aetiology of lymphohaematopoietic (LH) cancers. AIMS: To conduct a population based, case-control study of death certificate data from 1984 to 1998 in 24 US states in order to evaluate the risk of mortality from LH neoplasms associated with occupational exposure to animals or the public. METHODS: Cases were selected as those with an underlying cause of death of non-Hodgkin's lymphoma (NHL, n = 72,589), Hodgkin's disease (HD, n = 5479), multiple myeloma (n = 35,857), or leukaemia (n = 68,598); 912 615 controls were randomly selected from all remaining deaths, frequency matched on age, sex, race, and geographic region. RESULTS: Occupational exposure to animals was associated with modest increased risks of mortality from all four LH cancers; these associations varied by region. Occupational exposure to the public was associated with only negligible increased risk with LH cancer outcomes. Occupations involving animal exposure were predominantly agricultural, and the risks associated with employment in the livestock industry exceeded the corresponding risks associated with the crop industry for all outcomes except HD. CONCLUSIONS: Increased risks of NHL, HD, multiple myeloma, and leukaemia were associated with occupations that involved animal exposure. Regional differences in risk imply that the risks may be associated with exposure to specific livestock or farming practices. However, these associations may be confounded by other farming related exposures, such as pesticides. Because the use of death certificates to classify occupation may result in misclassification during aetiologically relevant time periods, these hypotheses should be further explored in studies with detailed information on lifetime occupation.