Lawrence Berkeley National Laboratory

Thirdhand smoke (THS) is a reservoir of toxic compounds that persist in indoor environments and on surfaces long after active smoking has ceased. Major THS chemicals, including nicotine, tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, and heavy metals, can induce DNA damage, epigenetic alterations, oxidative stress, and chronic inflammation. These biological changes contribute to one or more canonical hallmarks of cancer. In this minireview, we propose an integrated mechanistic framework that incorporates the hallmarks of cancer into environmental exposure risk assessment. This framework offers a system-level approach to carcinogenicity assessment that transcends the limitations of conventional single-endpoint toxicological assays. As a case application, we systematically analyze how THS chemicals disrupt specific cancer hallmarks and delineate the molecular and cellular mechanisms through which persistent tobacco smoke residues promote carcinogenesis. These insights establish a mechanistically grounded framework for assessing the environmental cancer hazard associated with THS.