Historical population lead exposure shows strong association with Motor Neurone Disease mortality in Australia

STRUCTURED ABSTRACTO_ST_ABSBackgroundC_ST_ABSAustralian age-standardized Motor Neurone Disease (MND) mortality increased steadily from 1959 and peaked around 2010-2012 and then declined steadily to 2022. The environmental drivers of this trend remain poorly understood. Historical exposure to leaded petrol, reflected in long-term population blood-lead levels, has been proposed as a potential contributor to contemporary MND risk due to the neurotoxicity and long latency associated with lead exposure. MethodsWe examined national age-standardised MND mortality in Australia from 1996-2022 in relation to reconstructed cumulative population blood-lead levels derived from digitised Kristensen (2015) data, forward-shifted by 20 years to account for exposure-disease latency. Annual insecticide use per capita was included as a secondary exposure, and calendar year was used to adjust for secular trends. A generalized additive model (GAM) was fitted using a 4-degree-of-freedom spline for cumulative blood-lead levels and linear terms for insecticides and year. Model fit was evaluated using coefficient estimates, joint significance testing for the spline term, and visual inspection of partial-dependence smooths. ResultsThe GAM R2 explained approximately 58.9% (adjusted R2 = 49.1%) of year-to-year variation in Australian age-standardised MND mortality rates. The spline for cumulative blood-lead levels was highly significant (p = 0.00024), indicating a strong non-linear association between long-term lead exposure and MND mortality. In contrast, insecticide use showed no statistically meaningful independent effect after adjustment (p = 0.39). Year demonstrated a borderline significant positive association (p = 0.072). Partial-dependence plots revealed substantial curvature in the lead-MND exposure-response relationship, with different historical lead burdens corresponding to distinct changes in predicted MND mortality. ConclusionsThese findings support a robust, non-linear association between historical population lead exposure and contemporary MND mortality in Australia, independent of secular trends and insecticide use. The results strengthen the hypothesis that past leaded petrol emissions may contribute to current MND risk, consistent with the long biological persistence and delayed neurotoxic effects of lead. Further work integrating individual-level data, biomarker validation, and mechanistic studies is warranted to clarify causality and quantify population-attributable risk. SUMMARY BOX [Table 1]