Background/Objectives Occupational exposure to neurotoxicants such as pesticides, metals, and solvents has long been implicated in Parkinson’s disease (PD) and Parkinsonism, yet the cumulative impact of multiple occupational exposure families over the working life remains insufficiently characterized. This study evaluated whether long-term cumulative occupational exposures, derived from the ALOHA+ Job-Exposure Matrix (ALOHA+-JEM), were associated with PD and Parkinsonism.

Methods A hospital-based matched case–control study was conducted in the province of Brescia, Italy, including 668 participants (334 PD/Parkinsonism cases and 334 matched controls). Cases and controls were 1:1 matched based on sex, age, and lifetime occupational duration. Lifetime occupational histories were coded using ISCO-08 and harmonized to ISCO-88 for linkage with ALOHA+-JEM. Conditional logistic regression estimated associations between cumulative exposures (none/low/high) and disease status, adjusting for smoking, parental history of PD/tremor, and SNCA rs356219 genotype. Multi-agent occupational exposure burden indexes were evaluated using positively constrained repeated-holdout Weighted Quantile Sum (WQS) regression (100 bootstraps, 100 holdouts)

Results In conditional logistic regression, parental history of PD or tremor (OR = 4.55, 95% CI: 2.44–8.48; q < 0.001) and the SNCA rs356219 CC genotype (OR = 2.17, 95% CI: 1.33–3.52; q = 0.013) were significantly associated with disease. High cumulative all pesticide exposure showed positive associations with combined PD + Parkinsonism (OR = 2.98, 95% CI: 1.23–7.25) and PD alone (OR = 3.56, 95% CI: 1.25–10.15). In WQS analyses, the composite occupational exposure burden index was positively associated with disease (combined PD + Parkinsonism: OR = 1.15, 95% CI: 1.00–1.30). All pesticides received the highest mean weight in all models (w = 0.434 for combined PD + Parkinsonism), followed by metals (w = 0.210), identifying them as contributing most strongly to the composite exposure index.

Conclusions Long-term cumulative occupational exposures were associated with increased odds of PD and Parkinsonism. All pesticides and metals were most strongly associated with PD and Parkinsonism, consistent with established neurotoxic mechanisms attributable to occupational environments. These findings underscore the importance of occupational exposure prevention and risk-reduction strategies in occupational settings and highlight workplace exposures as preventable contributors to Parkinsonian disorders.

The authors have declared no competing interest.

This research was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health under award numbers R01ES019222 and T32ES033955. Additional support was provided by the Italian National Institute for Insurance against Accidents at Work (INAIL) (grant number 60002.02/07/2012) and by the European Union Sixth Framework Programme (grant number FOODCT-2006-016253). The funders had no role in the study design, data collection, data analysis, interpretation of results, manuscript preparation, or the decision to submit the manuscript for publication. The authors and their institutions did not receive payment or services from any third party for any aspect of the submitted work beyond the funding sources listed above.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Civil Hospital in Brescia, Italy (PARKGENEAMB protocol, approval granted 4 September 2012), and by the Institutional Review Board of Florida International University (protocol code IRB-22-0246, approval granted 27 May 2022). Written informed consent was obtained from all participants prior to enrollment.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

flewi017fiu.edu; ngoul003fiu.edu; sazmounfiu.edu; vsund005fiu.edu; mali092fiu.edu; lpittafiu.edu; rlucchinfiu.edu, stefano.renzettiunipr.it, d.shoiebstudenti.unibs.it; margherita.cacigmail.com; stefano.borghesiasst-mantova.it; loredana.covolounibs.it; manuela.oppinigmail.com; umberto.gelattiunibs.it; donatella.placidiunibs.it; alessandro.padovaniunibs.it; pilottoandreaegmail.com; fulvio.pepepoliambulanza.it, marinellaturlagmail.com, patrizia.crippaancelle.it, lpanimiami.edu, lucapaniunimore.it, r.c.h.vermeulenuu.nl; h.kromhoutuu.nl, luca.lambertinimssm.edu, elena.colicinomssm.edu, rlucchinfiu.edu

All data produced in the present study are available upon reasonable request to the authors.