The Three Clocks of Tobacco Harm: Exposure Misclassification, Molecular Persistence and Disease Risk

Smoking status, pack-years and time since cessation remain essential to tobacco epidemiology, yet they do not measure the same temporal construct as biochemical exposure markers, persistent somatic alterations or future disease risk. This Perspective proposes the ‘three clocks of tobacco harm’: an exposure clock describing the timing and sources of inhaled agents; a molecular clock describing the acquisition, persistence and regression of detectable alterations; and a clinical clock describing outcome-specific risk over a defined horizon. These are conceptual measurement timescales, not newly discovered biological timers. Their proposed contribution is an explicit evidentiary rule: exposure verification, biological association, causal mediation, risk prediction and clinical usefulness require separate tests. Evidence from bronchial mutational studies, methylation-based risk models, clonal haematopoiesis and proteomics demonstrates both the promise and the limits of molecular characterisation. Recent epigenetic findings link internal nicotine dose with later outcomes but do not establish that molecular measurements improve clinical decisions. We propose falsifiable studies incorporating repeated source-specific exposure histories, serial molecular sampling, robust conventional comparators, appropriate causal inference, external validation and decision-analytic assessment. Molecular tests should enter clinical or public-health practice only when they demonstrably improve an actionable decision without disproportionate cost or harm. Accurate exposure histories, smoking cessation and established tobacco-control measures remain indispensable. The relevant question is not whether tobacco leaves a molecular imprint, but whether measuring it changes what clinicians and public-health systems should do.