Abstract
INTRODUCTION: Opium and cigarette smoking have been identified as significant cancer risk factors. Recently, the International Agency for Research on Cancer (IARC) classified opium as a Group 1 carcinogen in 2020. METHOD: Using data from a multicenter case-control study in Iran called IROPICAN, involving 717 cases of bladder cancer and 3477 controls, we assessed the interactions on the causal additive scale between opium use and cigarette smoking and their attributing effects to evaluate public health relevance and test for different mechanistic interaction forms to provide new insights for developing of bladder cancer. A minimally sufficient set of confounders was identified using a causal directed acyclic graph, and the data were analysed employing multiple logistic regression and the inverse probability-of-treatment weighting estimator of the marginal structural linear odds model. RESULTS: Our findings indicated a significant increase in the risk of bladder cancer associated with concurrent opium use and cigarette smoking (adjusted OR = 6.34, 95 % CI 5.02-7.99; p < 0.001), demonstrating a super-additive interaction between these exposures (Weighted RERI(OR) = 2.02, 95 % CI 0.47-3.58; p = 0.005). The presence of a super-additive interaction suggests that interventions targeting opium users who smoke cigarettes would yield greater benefits compared to non-opium users. Furthermore, there was a mechanistic interaction between two exposures (P-value = 0.005) if we assumed two of the exposures have positive monotonic effects, i.e., there must be a sufficient-component cause for developing bladder cancer, which has both opium use and cigarette smoking as components. CONCLUSION: There is a causal additive interaction between opium use and cigarette smoking. We observed a super-additive interaction, suggesting the need to focus interventions on specific subgroups. Furthermore, the presence of mechanistic interactions offers profound insights into the mechanisms of cancer induction.