National Food Institute, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.
Center for Biomedical Research (CIBM), University of Granada, Spain; Instituto de Investigación Biosanitaria Ibs Granada, Spain.
Environ Int. 2023 Mar;173:107815. doi: 10.1016/j.envint.2023.107815. Epub 2023 Feb 11.
Scientific evidence for underestimated toxicity from unintentional exposure to chemical mixtures is mounting. Yet, harmonized approaches on how to assess the actual risk of mixtures is lacking. As part of the European Joint programme 'Human Biomonitoring for Europe' we explored a novel methodology for mixture risk assessment of chemicals affecting male reproductive function.
We explored a methodology for chemical mixture risk assessment based on human in vitro data combined with human exposure data, thereby circumventing the drawbacks of using hazard data from rodents and estimated exposure intake levels. Human androgen receptor (hAR) antagonism was selected as the most important molecular initiating event linked to adverse outcomes on male reproductive health.
Our work identified 231 chemicals able to interfere with hAR activity. Among these were 61 finally identified as having both reliable hAR antagonist and human biomonitoring data. Calculation of risk quotients indicated that PCBs (118, 138, 157), phthalates (BBP, DBP, DIBP), benzophenone-3, PFOS, methylparaben, triclosan, some pesticides (i.e cypermethrin, β-endosulfan, methylparathion, p,p-DDE), and a PAH metabolite (1-hydroxypyrene) contributed to the mixture effect. The major chemical mixture drivers were PCB 118, BBP, PFOS, DBP, and the UV filter benzophenone-3, together contributing with 75% of the total mixture effect that was primarily driven by high exposure values.
This viable way forward for mixture risk assessment of chemicals has the advantages of (1) being a more comprehensive mixture risk assessment also covering data-poor chemicals, and (2) including human data only. However, the approach is subjected to uncertainties in terms of in vitro to in vivo extrapolation, it is not ready for decision making, and needs further development. Still, the results indicate a concern for adverse effects on reproductive function in highly exposed boys, especially when considering additional exposure to data-poor chemicals and chemicals acting by other mechanisms of action.
越来越多的科学证据表明，人们在无意中接触到化学混合物时，其毒性被低估了。然而，对于如何评估混合物的实际风险，缺乏协调一致的方法。作为欧洲联合计划“欧洲人体生物监测”的一部分，我们探索了一种新的化学混合物风险评估方法，用于评估影响男性生殖功能的化学物质。
我们探索了一种基于人体体外数据结合人体暴露数据的化学混合物风险评估方法，从而避免了使用啮齿动物危害数据和估计的暴露摄入量水平的缺点。人体雄激素受体（hAR）拮抗作用被选为与男性生殖健康不良结局相关的最重要的分子起始事件。
我们的工作确定了 231 种能够干扰 hAR 活性的化学物质。其中，有 61 种最终被确定为具有可靠的 hAR 拮抗剂和人体生物监测数据。风险比的计算表明，多氯联苯（PCB 118、138、157）、邻苯二甲酸酯（BBP、DBP、DIBP）、二苯甲酮-3、全氟辛烷磺酸、甲基对羟基苯甲酸酯、三氯生、一些农药（如氯菊酯、β-硫丹、甲基对硫磷、p,p-DDE）和一种多环芳烃代谢物（1-羟基芘）对混合物的作用有贡献。主要的化学混合物驱动因素是 PCB 118、BBP、PFOS、DBP 和紫外线过滤器二苯甲酮-3，它们共同贡献了总混合物效应的 75%，主要是由高暴露值驱动的。
这种可行的化学混合物风险评估方法具有以下优点：（1）是一种更全面的混合物风险评估方法，也涵盖了数据匮乏的化学物质；（2）仅包括人体数据。然而，该方法存在从体外到体内外推的不确定性，还不适合决策，需要进一步发展。尽管如此，结果表明，高暴露的男孩的生殖功能可能会受到不良影响，特别是当考虑到对数据匮乏的化学物质和其他作用机制的化学物质的额外暴露时。
