Genotoxicity threshold for methyl methacrylate in Chinese workers: a novel multi-endpoint genotoxicity assessment incorporating biological aging.

Methyl methacrylate (MMA) is a widely used foundational monomer in industrial and medical manufacturing. Current occupational exposure limits (OELs) for MMA are established based on its irritant and sensitizing effects, which may not fully prevent its genotoxicity. Here, we conducted an occupational biomonitoring study, including 45 MMA-exposed workers, 26 MMA-toluene/xylene-exposed (MMA-TX) workers, and 31 concurrent controls from a machinery manufacturing plant. Genetic damage in peripheral blood was assessed using the novel PIG-A mutation assay and cytokinesis-block micronucleus test. MMA-exposed workers showed significantly higher PIG-A mutant frequencies (10.49 ± 7.84 vs. 5.00 ± 2.70 × 10-6), and frequencies of micronuclei (6.28 ± 2.97 vs. 3.40 ± 1.67‰), nucleoplasmic bridges (0.80 ± 0.67 vs. 0.32 ± 0.49‰), and nuclear buds (1.68 ± 1.02 vs. 0.48 ± 0.58‰) than the controls. MMA-TX-exposed workers had significantly higher PIG-A mutant frequencies (15.15 ± 11.37 × 10-6) than MMA-exposed workers, and exhibited a slightly higher but non-significant biological age acceleration, as estimated using the Klemera-Doubal method from clinical biomarkers. Quantitative benchmark dose analysis yielded a point of departure of 0.03 mg/m3-year for MMA-induced genetic damage, indicating a lower exposure threshold than the current OELs. In MMA-treated TK6 cells, a slight increase in C > T mutations was observed using high-accuracy error-corrected sequencing, resembling the mutational signature of formaldehyde, a metabolite of MMA. The findings demonstrate that MMA below the current OELs may induce cumulative genetic damage in MMA-exposed workers, providing a quantitative basis for revising OELs to better protect worker health.