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

Abstract

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 casecontrol 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-p-dioxins and dibenzofurans (PFDD/Fs) data by the Bayesian−Monte Carlo Markov chain method and was used to determine the daily dietary exposure threshold. The median serum level of total dioxin toxic equivalent (TEQ) was 7.72 pg TEQ/g fat. Logistic regression analysis revealed that individuals in the fifth quantile of total TEQ level had significantly higher odds of developing GDM compared to those in the first quantile (OR, 8.87; 95% CI 3.19, 27.58). The BKMR analysis identified dioxin TEQ and BDE-153 as the compounds with the greatest influence. The binary logistic and probit models showed that the BMD 10 (benchmark dose corresponding to a 10% extra risk) and BMDL 10 (lower bound on the BMD 10 ) were 3.71 and 3.46 pg TEQ/g fat, respectively, when accounting for coexposure to BDE-153 up to the 80% level. Using the optimized PBTK model and modifying factor, it was estimated that daily exposure should be below 4.34 pg TEQ kg −1 bw week −1 in order to not reach a harmful serum concentration for GDM. Further studies should utilize coexposure statistical methods and physiologically based pharmacokinetic (PBTK) models in reference dose calculation.