The probable future of toxicology - probabilistic risk assessment.

ABSTRACT

Both because of the shortcomings of existing risk assessment methodologies, as well as newly available tools to predict hazard and risk with machine learning approaches, there has been an emerging emphasis on probabilistic risk assessment. Increasingly sophisticated AI models can be applied to a plethora of exposure and hazard data to obtain not only predictions for particular endpoints but also to estimate the uncertainty of the risk assessment outcome. This provides the basis for a shift from deterministic to more probabilistic approaches but comes at the cost of an increased complexity of the process as it requires more resources and human expertise. There are still challenges to overcome before a probabilistic paradigm is fully embraced by regulators. Based on an earlier white paper (Maertens et al., 2022), a workshop discussed the prospects, challenges and path forward for implementing such AI-based probabilistic hazard assessment. Moving forward, we will see the transition from categorized into probabilistic and dose-dependent hazard outcomes, the application of internal thresholds of toxicological concern for data-poor substances, the acknowledgement of user-friendly open-source software, a rise in the expertise of toxicologists required to understand and interpret artificial intelligence models, and the honest communication of uncertainty in risk assessment to the public.

Probabilistic risk assessment, initially from engineering, is applied in toxicology to understand chemical-related hazards and their consequences. In toxicology, uncertainties abound ­ unclear molecular events, varied proposed outcomes, and population-level assessments for issues like neurodevelopmental disorders. Establishing links between chemical exposures and diseases, especially rare events like birth defects, often demands extensive studies. Existing methods struggle with subtle effects or those affecting specific groups. Future risk assessments must address developmental disease origins, presenting challenges beyond current capabilities. The intricate nature of many toxicological processes, lack of consensus on mechanisms and outcomes, and the need for nuanced population-level assessments highlight the complexities in understanding and quantifying risks associated with chemical exposures in the field of toxicology.