Iulini Martina, Russo Giulia, Crispino Elena, Paini Alicia, Fragki Styliani, Corsini Emanuela, Pappalardo Francesco
Università degli Studi di Milano, Department of Pharmacology and Biomolecular Sciences 'Rodolfo Paoletti', Milan, Italy.
University of Catania, Department of Drug and Health Sciences, Italy.
Comput Struct Biotechnol J. 2024 Jul 1;23:2763-2778. doi: 10.1016/j.csbj.2024.06.036. eCollection 2024 Dec.
Per- and polyfluoroalkyl substances (PFAS), ubiquitous in a myriad of consumer and industrial products, and depending on the doses of exposure represent a hazard to both environmental and public health, owing to their persistent, mobile, and bio accumulative properties. These substances exhibit long half-lives in humans and can induce potential immunotoxic effects at low exposure levels, sparking growing concerns. While the European Food Safety Authority (EFSA) has assessed the risk to human health related to the presence of PFAS in food, in which a reduced antibody response to vaccination in infants was considered as the most critical human health effect, a comprehensive grasp of the molecular mechanisms spearheading PFAS-induced immunotoxicity is yet to be attained. Leveraging modern computational tools, including the Agent-Based Model (ABM) Universal Immune System Simulator (UISS) and Physiologically Based Kinetic (PBK) models, a deeper insight into the complex mechanisms of PFAS was sought. The adapted UISS serves as a vital tool in chemical risk assessments, simulating the host immune system's reactions to diverse stimuli and monitoring biological entities within specific adverse health contexts. In tandem, PBK models unravelling PFAS' biokinetics within the body i.e. absorption, distribution, metabolism, and elimination, facilitating the development of time-concentration profiles from birth to 75 years at varied dosage levels, thereby enhancing UISS-TOX's predictive abilities. The integrated use of these computational frameworks shows promises in leveraging new scientific evidence to support risk assessments of PFAS. This innovative approach not only allowed to bridge existing data gaps but also unveiled complex mechanisms and the identification of unanticipated dynamics, potentially guiding more informed risk assessments, regulatory decisions, and associated risk mitigations measures for the future.
全氟和多氟烷基物质（PFAS）广泛存在于无数消费品和工业产品中，根据接触剂量的不同，因其具有持久性、流动性和生物累积性，对环境和公众健康均构成危害。这些物质在人体内半衰期很长，在低暴露水平下即可诱发潜在的免疫毒性效应，引发了越来越多的关注。虽然欧洲食品安全局（EFSA）已评估了食品中PFAS存在对人类健康的风险，其中婴儿对疫苗接种的抗体反应降低被视为最关键的人类健康影响，但尚未全面掌握引发PFAS诱导免疫毒性的分子机制。利用包括基于主体模型（ABM）通用免疫系统模拟器（UISS）和生理药代动力学（PBK）模型在内的现代计算工具，旨在更深入地了解PFAS的复杂机制。经过改进的UISS在化学风险评估中是一个重要工具，可模拟宿主免疫系统对各种刺激的反应，并监测特定不良健康背景下的生物实体。与此同时，PBK模型揭示了PFAS在体内的生物动力学，即吸收、分布、代谢和消除，有助于绘制不同剂量水平下从出生到75岁的时间-浓度曲线，从而提高UISS-TOX的预测能力。这些计算框架的综合使用有望利用新的科学证据来支持PFAS的风险评估。这种创新方法不仅能够弥补现有数据缺口，还揭示了复杂机制并识别出意外动态，可能为未来更明智的风险评估、监管决策及相关风险缓解措施提供指导。
