Inflammation-Mediated Hepatotoxicity of the Emerging Lithium-Ion Battery Additive TFEP: Environmental Occurrence, Human Internal Exposure, and Mechanistic Evidence

Tris(2,2,2-trifluoroethyl) phosphate (TFEP), a flame-retardant additive indispensable for lithium-ion battery (LIB) safety, is an emerging organophosphate contaminant whose mammalian toxicity remains uncharacterized. Here, we identify TFEP as a systemic hepatotoxicant and pro-inflammatory pathway activation as its central mechanism. Environmental monitoring in Taizhou, China, detected TFEP in 64% of urban indoor dust (mean 7.7 ng/g DW), 41% of rural dust, and 83% of tap water (mean 15 ng/L), with human internal exposure in 72% of male serum (mean 2.6 ng/mL) and 87% of female serum (mean 1.4 ng/mL). Subchronic oral exposure in male mice induced dose-dependent hepatotoxicity, including hepatomegaly, elevated ALT/AST, and histopathological injury with bridging necrosis and leukocyte infiltration. Mechanistic investigation revealed activation of TNFα, IL-6, and CCL2 in serum and liver, recapitulated in TFEP-exposed human and murine hepatocytes, where cytokine upregulation coincided with concentration-dependent cytotoxicity. This concordance between in vivo and in vitro inflammatory signatures supports cytokine-mediated inflammation as a key pathogenic mechanism of TFEP hepatotoxicity. Our findings show that LIB-derived organophosphate additives constitute an unrecognized human health hazard, underscoring the urgent need for lifecycle-based management of TFEP emissions from battery manufacturing, recycling, and disposal.