Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
Crit Rev Toxicol. 2024 Aug;54(7):476-484. doi: 10.1080/10408444.2024.2377203. Epub 2024 Jul 23.
The European Union (EU) Chemicals Strategy for Sustainability regards chemicals that affect the immune system among the most harmful ones. The Extended One-Generation Reproductive Toxicity study (EOGRTS; Organisation for Economic Co-Operation and Development (OECD) Test Guideline (TG) 443), addresses, among others, potential effects of chemicals on development. In specific cases, the EOGRTS is performed with addition of a so-called cohort 3, that addresses potential effects on the developing immune system, by means of a central assay measuring the T-cell dependent antibody response (TDAR). This assay is based on an interplay of antigen presentation, T-cell help and antibody production by B-cells, and together comprises a functional immune response. In the context of the EOGRTS review project of the European Chemicals Agency (ECHA), we evaluated 15 available TDARs for compliance with conduct and reporting requirements. Collectively, the majority of the TDAR studies were considered to be adequately conducted. We however observed: (i) the protocols differed by the antigen used (sheep red blood cells (SRBC) or KLH), the route of administration (intravenous, intraperitoneal, or subcutaneous), prime or prime/boost immunizations, and whether IgG was measured. (ii) There was major variation in the effects of the positive control for immunosuppression, cyclophosphamide. (iii) Proficiency was not always shown. (iv) Statistical analysis was not always done or reported. (v) Results of effects on lymphocyte populations or other immunotoxicity observations obtained in cohort 1 (or 2) of the EOGRTS were not always discussed together with results of the TDAR. Taken together, next to an improved quality of reporting, this may suggest a need to better define the conduct of the TDAR in OECD TG 443 and OECD Guidance Document (GD) 151, at least for certain aspects.
欧盟化学品可持续发展战略认为，影响免疫系统的化学品是最有害的化学品之一。扩展一代生殖毒性研究（EOGRTS；经济合作与发展组织（OECD）测试指南（TG）443）除其他外，还涉及化学品对发育的潜在影响。在特定情况下，EOGRTS 通过添加所谓的第 3 队列来进行，该队列通过测量 T 细胞依赖性抗体反应（TDAR）的中心测定法来解决对正在发育的免疫系统的潜在影响。该测定法基于抗原呈递、T 细胞辅助和 B 细胞产生抗体的相互作用，共同构成了功能性免疫反应。在欧洲化学品管理局（ECHA）的 EOGRTS 审查项目中，我们评估了 15 种可用的 TDAR 是否符合行为和报告要求。总体而言，大多数 TDAR 研究被认为是充分进行的。然而，我们观察到：（i） 所用的抗原（绵羊红细胞（SRBC）或 KLH）、给药途径（静脉内、腹腔内或皮下）、初次免疫或初次免疫/加强免疫以及是否测量 IgG 不同，导致协议存在差异。（ii）免疫抑制阳性对照物环磷酰胺的效果存在很大差异。（iii）并非总是显示出熟练程度。（iv）并非总是进行或报告统计分析。（v）在 EOGRTS 的第 1 队列（或 2 队列）中获得的淋巴细胞群或其他免疫毒性观察结果的影响的结果，并非总是与 TDAR 的结果一起讨论。总之，除了提高报告质量外，这可能表明需要更好地定义 OECD TG 443 和 OECD 指南文件（GD）151 中 TDAR 的进行，至少在某些方面如此。
