A critical review on the toxicological and epidemiological evidence integration for assessing human health risks to environmental chemical exposures

Toxicology and epidemiology are the two traditional public health scientific disciplines which can contribute to investigate harmful health effects of exposure to toxic substances. Several frameworks for integrating different lines of evidence were proposed since 2011, evolving based of the emergence of new methodologies and approaches. Through the comparison of various theoretical frameworks for evidence integration, we examined similarities, differences, strengths, and weaknesses to provide insights into potential directions for future research. We identified several key challenges of the integration approach to be applied to risk assessment. More specifically, collaboration within a multidisciplinary team of scientists, toxicologists, epidemiologists, and risk assessors, is strongly recommended to be aligned with key regulatory objectives and promote a harmonized approach. Moreover, literature search transparency and systematicity have to be ensured by following validated guidelines, developing parallel protocols for collecting epidemiological and toxicological evidence from various sources, including human, animal, and new approach methodologies (NAMs). Also, the adoption of tailored quality assessment tools is essential to grade the certainty in evidence. Lastly, we recommend the use of the Adverse Outcome Pathway framework to provide a structured understanding of toxicity mechanisms and allow the integration of human, animal, and NAMs data within a single framework.