In our daily lives, we are continuously exposed to a diverse array of chemicals, such as pesticides and food additives, in low doses and simultaneously—a phenomenon known as combined exposure. Even if the amount of each individual chemical remains well below safety thresholds, their combination can potentially trigger additive or synergistic health risks. However, conventional toxicity testing primarily evaluates single substances, failing to reflect real-world exposure scenarios. Furthermore, Japan has yet to establish definitive guidelines or methodologies for assessing the combined risks of chemical mixtures on human health.

To address this challenge, a novel framework proposed by the OECD is gaining traction: the Adverse Outcome Pathway (AOP). The AOP concept maps out how chemicals induce toxicity across biological levels—from molecules and cells to tissues and the whole organism. By identifying shared pivot points, known as Key Events (KEs), this framework enables a more efficient and predictive approach to risk assessment.

Our laboratory focuses on AOPs related to neurotoxicity, leveraging innovative in vitro cell assay systems to evaluate how multiple chemicals impact shared Key Events. For combinations predicted to exert additive or synergistic effects, we conduct in vivo animal studies to verify their impacts on higher-order brain functions, aiming to elucidate the true nature of these combined risks.

We anticipate that our findings will contribute to the development of the "Guidance for the Assessment of Combined Effects of Chemicals (Tentative Title)" currently being drafted by the Ministry of the Environment, Japan. Ultimately, this research paves the way toward establishing next-generation risk assessment methodologies that accurately reflect complex, real-world exposure scenarios.

This research is supported by the Environmental Research and Technology Development Fund (Innovative Research and Development [Early-Career Researchers]) of the Ministry of the Environment and the Environmental Restoration and Conservation Agency of Japan 【JPMEERF20245RA1】.