Section of Biostatistics, Department of Public Health, University of Copenhagen, Øster Farimagsgade 5, DK-1014, Copenhagen, Denmark.
Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark.
Environ Health. 2023 May 6;22(1):40. doi: 10.1186/s12940-023-00985-w.
Exposure to perfluorinated alkylate substances (PFAS) is associated with harmful effects on human health, including developmental immunotoxicity. This outcome was chosen as the critical effect by the European Food Safety Authority (EFSA), which calculated a new joint reference dose for four PFAS using a Benchmark Dose (BMD) analysis of a study of 1-year old children. However, the U.S. Environmental Protection Agency (EPA) recently proposed much lower exposure limits.
We explored the BMD methodology for summary and individual data and compared the results with and without grouping for two data sets available. We compared the performance of different dose-response models including a hockey-stick model and a piecewise linear model. We considered different ways of testing the assumption of equal weight-based toxicity of the four PFAS and evaluated more flexible models with exposure indices allowing for differences in toxicity.
Results relying on full and decile-based data were in good accordance. However, BMD results for the larger study were lower than observed by EFSA for the smaller study. EFSA derived a lower confidence limit for the BMD of 17.5 ng/mL for the sum of serum-PFAS concentration, while similar calculations in the larger cohort yielded values of about 1.5 ng/mL. As the assumption of equal weight-based toxicity of the four PFAS seems questionable, we confirmed dose-dependencies that allowed potency differences between PFAS. We also found that models linear in the parameters for the BMD analysis showed superior coverage probabilities. In particular, we found the piecewise linear model to be useful for Benchmark analysis.
Both data sets considered could be analyzed on a decile basis without important bias or loss of power. The larger study showed substantially lower BMD results, both for individual PFAS and for joint exposures. Overall, EFSA's proposed tolerable exposure limit appears too high, while the EPA proposal is in better accordance with the results.
接触全氟烷基物质（PFAS）与人类健康的有害影响有关，包括发育免疫毒性。这一结果被欧洲食品安全局（EFSA）选为关键效应，EFSA 使用 1 岁儿童研究的基准剂量（BMD）分析为四种 PFAS 计算了新的联合参考剂量。然而，美国环境保护署（EPA）最近提出了低得多的暴露限值。
我们探讨了汇总和个体数据的 BMD 方法学，并比较了两个可用数据集分组和不分组的结果。我们比较了不同剂量-反应模型的性能，包括 hockey-stick 模型和分段线性模型。我们考虑了不同的方法来检验四种 PFAS 基于毒性权重相等的假设，并评估了具有允许毒性差异的暴露指数的更灵活模型。
依赖于全数据和十分位数数据的结果非常一致。然而，较大研究的 BMD 结果低于 EFSA 对较小研究的结果。EFSA 得出了血清-PFAS 浓度总和的 BMD 的较低置信下限为 17.5ng/mL，而在较大队列中的类似计算得出的值约为 1.5ng/mL。由于四种 PFAS 基于毒性权重相等的假设似乎值得怀疑，我们证实了允许 PFAS 之间效力差异的剂量依赖性。我们还发现 BMD 分析参数线性的模型显示出优越的覆盖率概率。特别是，我们发现分段线性模型对于基准分析很有用。
考虑的两个数据集都可以基于十分位数进行分析，而不会产生重要的偏差或效力损失。较大的研究显示，无论是对个别 PFAS 还是对联合暴露，BMD 结果都要低得多。总体而言，EFSA 提出的可耐受暴露限值似乎过高，而 EPA 的提案更符合结果。
