PDF(Pubmed)
Abstract：
The rodent cancer bioassays are conducted for agrochemical safety assessment yet they often do not inform regulatory decision-making. As part of a collaborative effort, the Rethinking Carcinogenicity Assessment for Agrochemicals Project (ReCAAP) developed a reporting framework to guide a weight of evidence (WOE)-based carcinogenicity assessment that demonstrates how to fulfill the regulatory requirements for chronic risk estimation without the need to conduct lifetime rodent bioassays. The framework is the result of a multi-stakeholder collaboration that worked through an iterative process of writing case studies (in the form of waivers), technical peer reviews of waivers, and an incorporation of key learnings back into the framework to be tested in subsequent case study development. The example waivers used to develop the framework were written retrospectively for registered agrochemical active substances for which the necessary data and information could be obtained through risk assessment documents or data evaluation records from the US EPA. This exercise was critical to the development of a framework, but it lacked authenticity in that the stakeholders reviewing the waiver already knew the outcome of the rodent cancer bioassay(s). Syngenta expanded the evaluation of the ReCAAP reporting framework by writing waivers for three prospective case studies for new active substances where the data packages had not yet been submitted for registration. The prospective waivers followed the established framework considering ADME, potential exposure, subchronic toxicity, genotoxicity, immunosuppression, hormone perturbation, mode of action (MOA), and all relevant information available for read-across using a WOE assessment. The point of departure was estimated from the available data, excluding the cancer bioassay results, with a proposed use for the chronic dietary risk assessment. The read-across assessments compared data from reliable registered chemical analogues to strengthen the prediction of chronic toxicity and/or tumorigenic potential. The prospective case studies represent a range of scenarios, from a new molecule in a well-established chemical class with a known MOA to a molecule with a new pesticidal MOA (pMOA) and limited read-across to related molecules. This effort represents an important step in establishing criteria for a WOE-based carcinogenicity assessment without the rodent cancer bioassay(s) while ensuring a health protective chronic dietary risk assessment.
摘要：
进行啮齿动物癌症生物测定以进行农用化学品安全性评估，但它们通常不通知监管决策。作为合作努力的一部分,重新思考农药项目致癌性评估（ReCAAP）开发了一个报告框架，以指导基于证据权重（WOE）的致癌性评估，该评估展示了如何满足慢性风险评估的监管要求，而无需进行终生啮齿动物生物测定。该框架是多方利益相关者合作的结果，通过编写案例研究的迭代过程（以弃权的形式），豁免的技术同行评审，并将关键学习纳入框架，以在随后的案例研究开发中进行测试。用于制定框架的豁免示例是针对已注册的农业化学活性物质进行回顾性撰写的，可以通过美国EPA的风险评估文件或数据评估记录获得必要的数据和信息。这项工作对框架的发展至关重要，但它缺乏真实性，因为审查豁免的利益相关者已经知道啮齿动物癌症生物测定的结果。先正达通过对尚未提交数据包进行注册的新活性物质的三个前瞻性案例研究的豁免，扩大了对ReCAAP报告框架的评估。预期豁免遵循考虑ADME的既定框架，潜在暴露,亚慢性毒性，遗传毒性，免疫抑制,激素扰动，行动模式（MOA），以及使用WOE评估可读取的所有相关信息。出发点是根据现有数据估计的，不包括癌症生物测定结果，建议用于慢性饮食风险评估。阅读评估比较了可靠的注册化学类似物的数据，以加强对慢性毒性和/或致瘤潜力的预测。前瞻性案例研究代表了一系列情景，从具有已知MOA的已建立的化学类别中的新分子到具有新的杀虫MOA（pMOA）的分子，并且对相关分子的读取有限。这一努力代表了在没有啮齿动物癌症生物测定的情况下建立基于WOE的致癌性评估标准的重要步骤,同时确保健康保护性慢性饮食风险评估。
