Benchmark Dose for Dioxin Based on Gestational Diabetes Mellitus Using Coexposure Statistical Methods and an Optimized Physiologically Based Toxicokinetic Model

Dioxins are ubiquitous endocrine-disrupting substances, but determining the effects and benchmark doses in situations of coexposure is highly challenging. The objective of this study was to assess the relationship between dioxin andgestational diabetes mellitus (GDM), calculate the benchmark dose (BMD) of dioxin in coexposure scenarios, and derive a daily exposure threshold using an optimized physiologically based toxicokinetic (PBTK) model. Based on a nested case-control study including 77 cases with GDM and 154 controls, serum levels of 29 dioxin-like compounds (DLCs) along with 10 perfluoroalkyl acids (PFAAs), seven polybrominated diphenyl ethers (PBDEs), and five non-dioxin-like polychlorinated biphenyls (ndl-PCBs) were measured at 9-16 weeks of gestation. Bayesian machine kernel regression (BKMR) was employed to identify significant chemicals, and probit and logistic models were used to calculate BMD adjusted for significant chemicals. A physiologically based toxicokinetic (PBTK) model was optimized using polyfluorinated dibenzo-