Occupational lead exposure and survival with amyotrophic lateral sclerosis

Abstract

Objective: Lead exposure has been hypothesized to increase the risk of ALS, but only two studies have examined the association with ALS survival, and with inconsistent results. The use of occupational history to assess lead exposure can avoid reverse causation that may occur in epidemiologic analyses that use biomarkers of lead exposure collected after ALS onset.

Methods: We evaluated the relationship of occupational lead exposure to ALS survival among 135 cases from an international ALS cohort that included deep phenotyping, careful follow-up, and questionnaires to quantify participants’ occupation history. ALS patients were recruited in 2015–2019. We determined occupational lead exposure using a job-exposure matrix. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for survival using Cox proportional hazard analysis with adjustment for covariates.

Results: A total of 135 ALS patients completed the environmental questionnaires, among whom 38 reached a survival endpoint (death or permanent assisted ventilation). The median survival was 48.3 months (25^th–75^th percentile, 30.9–74.1). Older patients and those with initial symptom other than limb onset had shorter survival time. There were 36 ALS cases with occupational lead exposure. After adjusting for age, sex, site of onset, smoking, and military service, lead exposure was associated with an HR of 3.26 (95%CI 1.28–8.28). Results with adjustment for subsets of these covariates were similar.

Conclusions: These results suggest that lead exposure prior to onset of ALS is associated with shorter survival following onset of ALS, and this association is independent of other prognostic factors.

Keywords:

• Occupation
• lead
• amyotrophic lateral sclerosis
• survival

Acknowledgments

The authors also thank the participants in the CReATe Consortium’s Phenotype-Genotype-Biomarker (PGB) study; the CreATe project management and data management teams; Dr. Rosa Rademakers and her lab for C9orf72 testing; as well as investigators and study coordinators at each clinical site.

Declaration of interest

The authors declare there are no relevant financial or nonfinancial competing interests to report.

Data availability statement

Data are available from the corresponding author upon reasonable request.

Additional information

Funding

The Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Office of Rare Diseases Research (ORDR). CReATe is funded under grant number U54NS092091 as a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). Additional support for collection of envioronmental exposure data was provided by the Agency for Toxic Substances and Disease Registry [R01 TS000244]. Dr. Weisskopf was supported by NIH grant P30 ES000002.