Ying Tao, Liu Xin, Zhang Lei, Cao Wencheng, Wen Sheng, Wu Yongning, He Gengsheng, Li Jingguang
School of Public Health, Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China.
NHC Key Laboratory of Food Safety Risk Assessment, Chinese Academy of Medical Science Research Unit (No. 2019RU014), China National Center for Food Safety Risk Assessment, Beijing 100021, China.
Environ Health (Wash). 2024 Jun 14;2(9):661-671. doi: 10.1021/envhealth.4c00017. eCollection 2024 Sep 20.
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--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 (benchmark dose corresponding to a 10% extra risk) and BMDL (lower bound on the BMD) 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 bw week 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.
二噁英是普遍存在的内分泌干扰物质，但确定共同暴露情况下的影响和基准剂量极具挑战性。本研究的目的是评估二噁英与妊娠期糖尿病（GDM）之间的关系，计算共同暴露情况下二噁英的基准剂量（BMD），并使用优化的基于生理的毒代动力学（PBTK）模型得出每日暴露阈值。基于一项巢式病例对照研究，该研究包括77例GDM病例和154例对照，在妊娠9至16周时测量了29种二噁英类化合物（DLCs）以及10种全氟烷基酸（PFAAs）、7种多溴二苯醚（PBDEs）和5种非二噁英类多氯联苯（ndl - PCBs）的血清水平。采用贝叶斯机器核回归（BKMR）来识别重要化学物质，并使用概率单位和逻辑模型计算针对重要化学物质调整后的BMD。通过贝叶斯 - 蒙特卡罗马尔可夫链方法，利用多氟二苯并 - 对 - 二噁英和二苯并呋喃（PFDD/Fs）数据对基于生理的毒代动力学（PBTK）模型进行了优化，并用于确定每日膳食暴露阈值。总二噁英毒性当量（TEQ）的血清中位数水平为7.72 pg TEQ/g脂肪。逻辑回归分析显示，总TEQ水平处于第五分位数的个体患GDM的几率显著高于处于第一分位数者（比值比，8.87；95%置信区间3.19，27.58）。BKMR分析确定二噁英TEQ和BDE - 153为影响最大的化合物。二元逻辑和概率单位模型表明，在考虑高达80%水平的BDE - 153共同暴露时，BMD（对应10%额外风险的基准剂量）和BMDL（BMD的下限）分别为3.71和3.46 pg TEQ/g脂肪。使用优化的PBTK模型和修正因子估计，为了不达到对GDM有害的血清浓度，每日暴露应低于4.34 pg TEQ kg bw/周。进一步的研究应在参考剂量计算中采用共同暴露统计方法和基于生理的药代动力学（PBTK）模型。
