Toxicological Susceptibility as a Complex Genetic Trait: Implications for Risk Assessment

Safety limits on exposure to hazardous chemicals are typically treated as uniform across populations, but substantial variability exists between individuals. This review argues that susceptibility to chemical exposure should be understood as a complex genetic trait shaped by polygenic architecture, environmental context, and biological modifiers such as sex. Drawing on evidence from animal models, human-relevant test systems, and comparative genomics, we show that variation in toxic response is structured, heritable, and frequently predictable. We critically evaluate the limitations of traditional toxicology, which relies on simplified models and average responses, and highlight how this deterministic approach fails to capture population-level risk. We further examine genotype × sex interactions and the contribution of rare variants to extreme sensitivity. Finally, we discuss emerging risk assessment frameworks, including population-based and probabilistic approaches, and consider their implications for regulatory decision-making. Recognizing toxicological susceptibility as a complex trait provides a more realistic and protective basis for chemical risk assessment.