Brunel University London, Centre for Pollution Research and Policy, College of Health, Medicine and Life Sciences, Kingston Lane, Uxbridge, UB8 3PH, United Kingdom.
University College London, Department of Arts and Science, Gower Street, London, WC1E 6BT, United Kingdom.
Int J Hyg Environ Health. 2024 Jan;255:114293. doi: 10.1016/j.ijheh.2023.114293. Epub 2023 Nov 15.
The downward revision of the bisphenol A (BPA) Health-based Guidance Value (HBGV) by the European Food Safety Authority (EFSA) has led to disagreements with other regulatory agencies, among them the German Federal Institute for Risk Assessment (BfR). The BfR has recently published an alternative Tolerable Daily Intake (TDI), 1000-times higher than the EFSA HBGV of 0.2 ng/kg/d. While the EFSA value is defined in relation to immunotoxicity, the BfR alternative TDI is based on declines in sperm counts resulting from exposures in adulthood. Earlier, we had used semen quality deteriorations to estimate a BPA Reference Dose (RfD) of 3 ng/kg/d for use in mixture risk assessments of male reproductive health. We derived this estimate from animal studies of gestational BPA exposures which both EFSA and BfR viewed as irrelevant for human hazard characterisations. Here, we identify factors that drive these diverging views. We find that the fragmented, endpoint-oriented study evaluation system used by EFSA and BfR, with its emphasis on data that can support dose-response analyses, has obscured the overall BPA effect pattern relevant to male reproductive effects. This has led to a disregard for the effects of gestational BPA exposures. We also identify problems with the study evaluation schemes used by EFSA and BfR which leads to the omission of entire streams of evidence from consideration. The main driver of the diverging views of EFSA and BfR is the refusal by BfR to accept immunotoxic effects as the basis for establishing an HBGV. We find that switching from immunotoxicity to declines in semen quality as the basis for deriving a BPA TDI by deterministic or probabilistic approaches produces values in the range of 2.4-6.6 ng/kg/d, closer to the present EFSA HBGV of 0.2 ng/kg/d than the BfR TDI of 200 ng/kg/d. The proposed alternative BfR value is the result of value judgements which erred on the side of disregarding evidence that could have supported a lower TDI. The choices made in terms of selecting key studies and methods for dose-response analyses produced a TDI that comes close to doses shown to produce effects on semen quality in animal studies and in human studies of adult BPA exposures.
由于欧洲食品安全局（EFSA）下调了双酚 A（BPA）的健康基准指导值（HBGV），导致其与其他监管机构产生分歧，其中包括德国联邦风险评估研究所（BfR）。BfR 最近公布了一个替代的可耐受每日摄入量（TDI），比 EFSA 的 HBGV 0.2ng/kg/d 高 1000 倍。EFSA 的数值是与免疫毒性相关的，而 BfR 的替代 TDI 则是基于成年期暴露导致的精子数量下降。早些时候，我们曾使用精液质量恶化来估计 BPA 的参考剂量（RfD）为 3ng/kg/d，用于男性生殖健康的混合物风险评估。我们从 EFSA 和 BfR 都认为与人类危害特征无关的妊娠 BPA 暴露动物研究中得出了这一估计。在这里，我们确定了导致这些不同观点的因素。我们发现，EFSA 和 BfR 使用的分散的、以终点为导向的研究评估系统，以及对支持剂量-反应分析的数据的强调，掩盖了与男性生殖效应相关的整体 BPA 效应模式。这导致了对妊娠 BPA 暴露的影响的忽视。我们还发现 EFSA 和 BfR 使用的研究评估方案存在问题，导致整个证据链被忽略。EFSA 和 BfR 观点分歧的主要原因是 BfR 拒绝将免疫毒性作为建立 HBGV 的基础。我们发现，从免疫毒性转向精液质量下降，通过确定性或概率方法来推导 BPA TDI，得到的数值在 2.4-6.6ng/kg/d 之间，更接近目前 EFSA 的 0.2ng/kg/d，而不是 BfR 的 200ng/kg/d。所提出的替代 BfR 值是基于错误判断证据的价值判断的结果，这些证据本可以支持更低的 TDI。在选择关键研究和剂量-反应分析方法方面的选择导致了一个 TDI，这个 TDI接近于在动物研究和成人 BPA 暴露的人类研究中显示出对精液质量有影响的剂量。
