Highlight
– Direct personal use of organochlorine and select organophosphate insecticides is associated with increased risk of incident rheumatoid arthritis (RA) in female spouses of pesticide applicators.
– Indirect exposure through the applicator’s use of specific pesticides, such as metribuzin, also increases RA risk among women who do not personally use these chemicals.
– The use of any fungicide and engagement in several farming tasks (e.g., cleaning with solvents, driving gas tractors) further elevate RA risk.
– These findings underscore occupational and household environmental exposures as important, modifiable risk factors for RA in women living in agricultural settings.
Background
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease marked by symmetric polyarthritis and progressive joint destruction, affecting 0.5–1% of adults worldwide. Women are disproportionately affected, with peak incidence in midlife. While genetic predisposition (e.g., HLA-DRB1 alleles) and lifestyle factors (e.g., smoking) are established contributors, environmental exposures—particularly in agricultural communities—remain underexplored. With agricultural workers and their families facing routine contact with pesticides, clarifying the links between pesticide exposure and RA is critical for prevention and public health.
Study Overview and Methodological Design
This study is a prospective cohort analysis nested within the Agricultural Health Study, focusing on female spouses of licensed pesticide applicators in North Carolina and Iowa (1993-1997). The cohort included 32,126 women, with detailed baseline data on direct pesticide use, indirect exposure (via spouse’s use), farming activities, and sociodemographic and lifestyle factors. Incident RA cases were rigorously ascertained through follow-up surveys, medical record review, medication usage, and Medicare claims, resulting in 410 probable cases (median age at diagnosis: 51 years) and 21,850 non-RA controls (median age: 45 years).
Exposure assessment covered 32 specific pesticides (herbicides, insecticides, fungicides), with analysis stratified by personal versus spousal use. Logistic regression models adjusted for confounders (age, smoking, education, state, and other exposures) estimated adjusted odds ratios (aORs) for incident RA.
Key Findings
– Nearly half of participants never personally used agricultural pesticides. Of those who did, most reported low annual (≤20 days/year) and cumulative (≤20 years) use, yet even short-term exposure increased RA odds (aOR 1.26, 95% CI 1.01–1.57).
– Personal use of organochlorine insecticides significantly increased RA risk (aOR 1.54, 95% CI 1.14–2.07), with dichlorodiphenyltrichloroethane (DDT) (aOR 1.89, 95% CI 1.30–2.75) and lindane (aOR 1.97, 95% CI 1.12–3.47) showing the strongest associations.
– Among organophosphate insecticides, coumaphos use was notably associated with increased RA risk (aOR 2.32, 95% CI 1.29–4.19).
– Among women who never personally used specific pesticides, their spouse’s use of metribuzin (a triazinone herbicide) was linked to higher RA odds (aOR 1.66, 95% CI 1.10–2.52).
– Fungicide use (any) was also associated with RA (aOR 1.72, 95% CI 1.24–2.38).
– Several farming tasks (e.g., cleaning with solvents, driving gas tractors, grinding feed, painting, applying chemical fertilizers, planting) were each independently associated with higher RA risk.
Mechanistic Insights and Pathophysiological Context
The biological plausibility of these associations is supported by the known immunotoxic effects of certain pesticides. Organochlorines and organophosphates have been shown in experimental models to disrupt immune regulation, promote autoantibody production, and modulate cytokine release—all key features in RA pathogenesis. Chronic exposure to these chemicals may trigger systemic inflammation, breach immune tolerance, and initiate autoimmune cascades in genetically susceptible individuals. Additionally, some pesticides act as endocrine disruptors, which may further influence immune responses and joint inflammation.
Clinical Implications
These findings have immediate relevance for clinicians caring for women in agricultural settings. A detailed occupational and household exposure history should be part of the RA risk assessment, especially in rural practice. Preventive counseling regarding personal protective equipment, safe pesticide handling, and minimizing household contamination (e.g., removing work clothing before entering living spaces) is warranted. As RA is associated with significant morbidity, early recognition of at-risk populations enables timely intervention and potentially modifiable risk reduction.
Limitations and Controversies
Several limitations merit consideration:
– Exposure misclassification is possible despite detailed questionnaires, as recall bias may affect self-reported pesticide use.
– The observational design precludes definitive causal inference, though prospective data and robust case ascertainment strengthen the findings.
– The study population (predominantly White women from two US states) may limit generalizability to other ethnicities or geographies.
– Unmeasured confounding (e.g., other environmental toxins, genetic factors) cannot be fully excluded.
– Some pesticide exposures are historical and may not reflect current regulatory standards or usage patterns.
Expert Commentary or Guideline Positioning
The authors emphasize the importance of weighing the agricultural benefits of pesticides against the growing evidence of health risks. As stated: “While insecticides are an important tool in controlling threats to crops and human health, our results provide evidence of potential risks.” Current rheumatology guidelines do not specifically address occupational pesticide exposure, but these findings may prompt future revisions and enhanced risk stratification in clinical practice.
Conclusion
This large, prospective study provides robust evidence that both personal and indirect exposure to certain agricultural pesticides—particularly organochlorine and organophosphate insecticides—heighten the risk of incident rheumatoid arthritis in women living on farms. The results underscore the need for targeted preventive strategies, occupational health vigilance, and further mechanistic research into environmental triggers of autoimmunity. Given the rising prevalence of RA and the persistence of pesticide use in agriculture, these insights have significant implications for both individual patient care and public health policy.
This study was led by Christine G. Parks, PhD, Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
References
1. Parks CG, Leyzarovich D, Hamra GB, Costenbader KH, Chen D, Hofmann JN, Beane Freeman LE, Sandler DP. Associations of specific pesticides and incident rheumatoid arthritis among female spouses in the Agricultural Health Study. Arthritis Rheumatol. 2025 Jul 16. doi:10.1002/art.43318 IF: 10.9 Q1 . Epub ahead of print. PMID: 40665754 IF: 10.9 Q1 .2. De Roos AJ, et al. Pesticide exposures and the risk of rheumatoid arthritis: Results from the Agricultural Health Study. Environ Health Perspect. 2005;113(5):721-726.3. Costenbader KH, et al. Environmental and occupational exposures and risk of systemic rheumatic diseases. Curr Opin Rheumatol. 2016;28(2):127-133.
