While a large body of literature has shown that microplastics (MPs) are highly likely to be accumulated in marine organisms and terrestrial animals, information about toxicity of MPs in mammal from a mechanistic point of view is more limited. Our paper fills this knowledge gap by assessing polystyrene (PS)-MPs-mice system based on toxicity-based toxicokinetic/toxicodynamic (TBTK/TD) modeling to quantify organ-bioaccumulation and biomarker responses appraised with published dataset. The key TBTK-parameters for mice liver, kidney, and gut posed by 5 or 20 μm PS-MPs could be obtained. We found that gut had the highest bioaccumulation factor (BCF) of ∼8 exposed to 5 μm PS-MPs with a mean residence time of ∼17 days. We showed that threshold concentrations of 5 and 20 μm PS-MPs among the most sensitive biomarkers were 8 ± 5 (mean ± SE) and 0.71 ± 0.14 μg g-1 bw, respectively, implicating that particle size was likely to affect TK/TD behavior in mice. The mice-based TK parameters and threshold criteria greatly assist in designing robust researches to evaluate MP consumption by humans. We establish a TBTK/TD framework for mechanistically assessing potential from mice size-specific MPs exposure that would offer a tool-kit for extrapolating to humans from health risk assessment perspective.