Pulmonary-route-dominant retention and exposure burden of biodegradable PLA microplastics: Radiotracer-based toxicokinetics and development of the TRACE exposure-response framework.

Despite the growing adoption of polylactic acid (PLA) as a biodegradable alternative to conventional plastics, its biological fate following human exposure remains poorly defined. No study has systematically compared the toxicokinetics of PLA microplastics (MPs) across inhalation and oral exposure routes within a unified experimental framework. Here, we developed a radiotracer-based platform combining 125I radiolabeling and high-resolution SPECT/CT imaging to quantify route-dependent biodistribution and clearance kinetics of PLA MPs in mice. Intratracheal administration produced greater and more persistent tissue burdens than oral administration, with prolonged pulmonary retention, systemic redistribution, and a 2.25-fold higher blood area under the curve. To systematically link organ-level exposure burden with cellular biological response, we developed the TRACE (Toxicological Response And Cellular Exposure) framework, comprising five indices (TRACE-M, -C, -E, -R, -I) spanning mitochondrial injury, oxidative stress, and exposure-linked toxicity. TRACE-based analyses revealed stronger oxidative and ultrastructural stress responses in lung-derived cellular models than in gastrointestinal systems. Human exposure contextualization via allometric scaling and time-dependent mass-balance modeling further indicated that repeated inhalation may drive progressive pulmonary PLA accumulation under environmentally plausible conditions. Together, these findings establish inhalation as the dominant hazard route for PLA MPs and demonstrate that biodegradability does not confer biological safety.