[Toxic effects of chlorinated organophosphate flame retardants on mice via different exposure routes].

Objective: To evaluate the effects of chlorinated organophosphate flame retardants (Cl-OPFRs) via respiratory and digestive tract exposure on multiple organs in mice. Methods: A short-term repeated exposure model of tris(2-chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCIPP) and tris(1, 3-dichloro-2-propyl) phosphate (TDCIPP) in mice was established through intratracheal instillation and oral gavage administration. The exposure doses were 0.7, 1 and 2 mg·kg^-1·day^-1, respectively, with continuous administration for 14 days. The organs of the heart, liver, spleen, lung, kidney, stomach, large intestine, small intestine, bladder and testis were collected and weighed to calculate the organ coefficients. The pathological and histological changes were observed by hematoxylin-eosin staining to quantitatively assess the effects of the three Cl-OPFRs on the various organs by using the pathology score. Results: Analysis of organ coefficients in tracheal drip-treated mice showed that the organ coefficients in the testes of the TCEP, TCIPP and TDCIPP groups were lower than those in the control group (P_TCEP-testis=0.045, P_TCIPP-testis=0.012 and P_{TDCIPP-testis}<0.001). The organ coefficients were lower in the lungs and small intestines of the TCEP group (P_TCEP-lung=0.006, P_{TCEP-small intestine}=0.042). The organ coefficients for the stomach and large intestine were higher in the TDCIPP group (P_{TDCIPP-stomach}=0.014, P_{TDCIPP-large intestine}=0.049). Analyses of gavage-contaminated mice showed that the organ coefficients for liver, stomach and small intestine in the TCEP and TDCIPP groups were higher than those in the control group (P_TCEP-liver=0.007, P_TCEP-stomach=0.003, P_{TCEP-small intestine}<0.001, P_TDCIPP-liver=0.001, P_{TDCIPP-stomach}=0.004, and P_{TDCIPP-small intestine}<0.001). Histopathological analyses of the organs of tracheal drip dyed mice showed significant pathological damage in the lung tissue of the TCIPP group, mainly in the form of thickening of the interstitium, infiltration of inflammatory cells and alveolar collapse. The results of the analysis of gavage poisoned mice showed that TCIPP exposure could lead to blurring of the red and white medullary boundaries of spleen tissues, destruction of white medullary structures, etc., and induce small intestinal cryptitis. TDCIPP induced significant pathological damage to the liver tissues of mice, which mainly included cytoplasmic washout, infiltration of inflammatory cells, acute inflammation, and other injurious effects. Significant pathological damage to the intestinal tissues of mice was also observed. Conclusions: This study demonstrates that the toxic effects of Cl-OPFRs are significantly associated with exposure routes and compound specificity. Respiratory exposure predominantly induces TCIPP-mediated pulmonary injury, while digestive exposure causes TDCIPP-driven hepatointestinal toxicity. These findings provide preliminary evidence for the toxicity screening of Cl-OPFRs.