Farmer's lung is associated with handling mouldy hay and grain, and has increased prevalence in northern latitudes.3
Iowa farm residents, both farmers and their wives, had greater prevalence of farmer's lung than farmers in North Carolina. This observation is consistent both with farm production patterns associated with generation of mouldy hay and northern regions. Dairy farmers represent a population at high risk for farmer's lung6,20
and our results for silage, animal feed and raising dairy cattle suggest these to be important factors among the AHS cohort. Among farmers, working with silage was associated with farmer's lung; for spouses, grinding feed and working with dairy cattle were associated with farmer's lung. Among both the farmers and the spouses, hay and grain handling activities had stronger effect estimates than animal contact activities. Because all farm exposure information was based on activities during the year of enrolment, our results suggest that individuals with farmer's lung continue farm work including tasks which may have contributed to their disease. This inference is consistent with clinical practice, which advises work practice changes to reduce the actual exposures that resulted in disease.21
Pesticide use and handling is the one exposure category for which we had lifetime exposure information. With the exception of two case reports suggesting a role of pesticides and hypersensitivity pneumonitis,22,23,24
no previous population‐based study has associated pesticides with farmer's lung. Our large sample size and heterogeneous population allowed us to assess this relationship while adjusting for traditional risk factors. For farmers, a history of a high pesticide exposure event was strongly associated with a diagnosis of farmer's lung. High pesticide exposure events were based on response to the question “have you ever had an incident or experience while using any
type of PESTICIDE
which caused you unusually high
personal exposure?” These events are relatively common and are associated with risk‐taking attitudes and behaviours.25,26
We reviewed information regarding the type of pesticide, body part exposed and decade of exposure for farmer's lung cases, and saw no clear pattern of a specific chemical or a specific body part being affected. Thus, a history of a high pesticide exposure event may be a marker of more risky behaviour—for example, less likely to use respiratory protection when working with mouldy grain, rather than a marker of an individual chemical exposure. We have no information to assess respiratory protection for grain handling.
Both organochlorine and carbamate pesticides were associated with farmer's lung after controlling for current farming activities. When we evaluated specific chemicals, only two of nine organochlorines (DDT and lindane) and one of four carbamates (aldicarb) were associated with increased risk for farmer's lung. DDT and lindane were widely used insecticides; DDT was removed from the market in the 1970s although lindane remains in use. These pesticides may have been used by dairy farmers historically and their association with farmer's lung is as a surrogate for past exposure to dairy animals, rather than risk from pesticides per se. Aldicarb, on the other hand, is a highly toxic crop insecticide and is unlikely to be a surrogate for past animal‐related activities. Given the lack of prior hypotheses, these observations may be due to chance or confounding by historic farm activities. Limited toxicology data do suggest, however, that some of these pesticides may contribute to immune responses similar to those observed in farmer's lung.8,9,10,11,12,13,14
The pathogenesis of farmer's lung involves an acute insult from a triggering antigen, generally bacteria related to mouldy hay, followed by cough, fever, chills and malaise.27,28
The immune response triggers alveolar macrophages, which increase in number and secrete large amounts of cytokines such as tumour necrosis factor α and interleukin (IL)1.27,28
Most exposed individuals make antibodies to the antigens, but only a small subset (1–15%) progress to clinical disease.28
The three pesticides positively associated with farmer's lung in this analysis, lindane, DDT and aldicarb, have been associated with immunological effects in a limited number of studies. In a study of 20 lindane‐poisoned patients and 20 controls, Seth et al14
reported elevated tumour necrosis factor α, IL2 and IL4, and decreased interferon γ levels in blood among poisoned individuals. Lindane has also been shown to stimulate macrophage activating factor without addition of mitogens in peripheral blood lymphocytes of rainbow trout.11
DDT has been shown to inhibit murine macrophage response to mycobacterium.13
o, p′‐DDT stimulated the production of nitric oxide and proinflammatory cytokines, and upregulated the expression of NFκB transactivation in mouse macrophages.12
Using human blood samples, Daniel et al9
showed that individuals with higher plasma levels of dichlorodiphenyl dichloroethene (DDE, the primary DDT metabolite) had increased TH2 immunity as indicated by plasma IL4. Some carbamates inhibit IL2‐dependent proliferation of CTLL2 cells, a mouse T cell line; however, of all the carbamates tested, aldicarb had the weakest effect on IL2.8
Aldicarb affected macrophage function in C3H mice, reducing IL1 production.10
Taken together, these models suggest that these pesticides may stimulate immune function in a manner that may enhance the effect of farmer's lung agents; however, given the paucity of whole animal models and human data, future work is needed to evaluate whether these pesticides influence the risk of farmer's lung.
Farmers are exposed to multiple respiratory toxicants during their daily activities, and many of these exposures are correlated to some degree. We used hierarchical logistic regression models to adjust for multiple exposures. The Spearman correlations among exposure variables were generally low (<0.3). The highest observed correlation for applicators was for working in swine areas and working with hogs (r
0.72); there were six other correlations among model variables that exceeded 0.5, with the maximum being 0.56 for aldrin and heptachlor. For spouses, only the correlation between organophosphates and carbamates exceeded 0.5 (r
0.53). Given these statistical methods and the observed correlations, it is unlikely that current farm activities confounded the results for pesticide exposures. Even with this analytical strategy, some individual exposures may appear important by chance. Although we have no data to evaluate whether historic farming activities may be associated with the observed results, we think that the specific pesticides identified are unlikely to be surrogates for historic farming activities related to farmer's lung. We relied on self‐reported information on pesticide use and farming activities. Farmers, in general, and AHS participants, in particular, have been demonstrated to provide reproducible and accurate recall of their personal pesticide use.29,30,31
Although individuals with farmer's lung may have over‐reported their history of pesticide use, it seems unlikely, given the number of different medical conditions contained on the questionnaire, the lack of association with most pesticides, and the absence of previous reports of associations between pesticides and farmer's lung. Farmer's lung may predispose individuals to both asthma and emphysema; asthma within a year or two of diagnosis32,33
and emphysema as a long‐term sequela.34,35,36
Our data are consistent with increased asthma and emphysema among those with farmer's lung, because individuals with farmer's lung were also more likely to report asthma and emphysema than those without farmer's lung. However, our data are also indicative of the challenge of reporting farmer's lung, both in the lay public and among clinicians, because we observed increased rates of all respiratory diseases except childhood asthma. Because disease status was self‐reported, some of our cases probably did not meet strict clinical criteria for farmer's lung. Owing to the clinical difficulties in assessing farmer's lung, incorrect ascertainment of farmer's lung is as likely owing to inconsistent diagnostic practice as faulty recall by participants.7
Although we have no medical records to confirm or refute these self‐reports, the prevalence of farmer's lung in our sample is similar to, but slightly lower than, those reported in other farming populations with clinical confirmation of disease.3
We observed the expected inverse relationship between current cigarette smoking and farmer's lung,3,37
thus supporting the likelihood that our cases are farmer's lung cases rather than chronic bronchitis and emphysema, which are positively associated with cigarette smoking. Farmer's lung has clinical similarities to organic dust toxic syndrome and some similar risk factors.5
With our questionnaire, we have limited ability to discriminate between these two conditions. However, the expected low prevalence and the expected inverse association with smoking, as well as the similar prevalence of colds and flu among cases and controls, gives us some confidence that our cases represent farmer's lung and not organic dust toxic syndrome.
Notwithstanding the potential for disease misclassification, this large cross‐sectional questionnaire‐based study allowed us to explore a broad range of occupational exposures in a heterogeneous farming population and to suggest factors previously not considered; however, we have no information on historic farm activities that may have contributed to the development of farmer's lung. The cross‐sectional nature of the analysis may underestimate the impact of some exposures because more severely affected individuals may have changed their exposures as a result of disease diagnosis.38,39,40
Additionally, in relying on cross‐sectional data, we cannot assess whether exposure occurred prior to farmer's lung diagnosis. All farming exposures, except pesticides, were based on current farm practices at the time of enrolment. Hence, if an individual had farmer's lung early in life and had changed farming practices as a result, we would underestimate the impact of that exposure. This may explain our low‐risk estimates for dairy farming, a known risk for farmer's lung.3
Additionally, individuals may leave farming as a result of severity of disease. However, it is unlikely that our cases left farming as a result of severity of disease. Bouchard et al21
showed that cognitive and behavioural motives rather than severity of disease were predictive of leaving farming; however, 55% of farmer's lung cases left farming after the diagnosis.
This analysis of farmer's lung is one of the largest to date, with over 500 cases reported in a population of almost 52
000 farm residents. Additionally, this sample represents one of the most heterogeneous samples with regard to farming practices ever studied, providing the opportunity to explore factors previously associated with farmer's lung and to identify potential factors that may influence farmer's lung risk. Even with self‐reported disease history, we observed similar results for smoking, occupational activities and regional variation, as reported in other studies. Use of pesticides and high pesticide exposure events were independently associated with farmer's lung after adjusting for current farm activities, suggesting new areas to consider with regard to farmer's lung risk.
- Pesticides may be overlooked risk factors for farmer's lung. Dichlorodiphenyl trichloroethane, lindane and aldicarb were independently associated with farmer's lung after controlling for other common risk factors. However, confounding by historic farm activities cannot be ruled out.
- A history of high pesticide exposure events may contribute to farmer's lung risk.
- Individuals with farmer's lung continue to farm decades after diagnosis.
Prospective studies of farmers are necessary to ascertain the role of pesticides in the development of farmer's lung.