Assessing Causal Evidence Beyond Correlation: Linking Cadmium Exposure to Disease, Using Bradford Hill Framework

Exposure to cadmium (Cd) is a significant public health concern owing to its widespread presence in the environment and its harmful effects on human health. However, the causal relationship between dietary Cd exposure and cancer and non-cancer defects remains unclear. This study systematically applied a quantitative scoring scheme based on the nine aspects of causal assessment proposed by Sir Austin Bradford Hill, namely strength of association, consistency, specificity, temporality, dose-response relationship, plausibility, coherence, experiment and analogy to evaluate causal relationships between dietary Cd exposure and both cancer and non-cancer health risks. Among non-carcinogenic effects, the strongest evidence was observed for bone effects, with odds ratios (ORs) for osteoporosis reported between 1.3 and 9.2 across studies using urinary Cd to reflect cumulative body burden. Renal outcomes ranked second, with ORs for chronic kidney disease generally ranging from 1.5 to 4.1. Notably, our findings also indicated that reproductive effects and cardiovascular diseases represented additional endpoints of concern. Regarding cancer effects, reproductive cancers including prostate, breast and endometrial cancers, ranked the highest in terms of association with Cd exposure, with ORs for breast cancer typically ranging from 1.6 to 6.1 in urinary Cd studies. Collectively, the current study suggested that bone and kidney endpoints should be prioritized when assessing the risks of dietary Cd exposure. These results underscore the value of integrating epidemiological, mechanistic, and toxicological evidence under Bradford Hill Criteria to guide food safety standards and inform global Cd policy.