title: Could removing arsenic from tobacco smoke significantly reduce smoker risks of lung cancer?
abstract: If a specific biological mechanism could be determined by which a carcinogen increases lung cancer risk, how might this knowledge be used to improve risk assessment? To explore this issue, we assume (perhaps incorrectly) that arsenic in cigarette smoke increases lung cancer risk by hypermethylating the promoter region of gene p16INK4a, leading to a more rapid entry of altered (initiated) cells into a clonal expansion phase. The potential impact on lung cancer of removing arsenic is then quantified using a three-stage version of a multistage clonal expansion (MSCE) model. This refines the usual two-stage clonal expansion (TSCE) model of carcinogenesis by resolving its intermediate or "initiated" cell compartment into two subcompartments, representing experimentally observed "patch" and "field" cells. This refinement allows p16 methylation effects to be represented as speeding transitions of cells from the patch state to the clonally expanding field state. Given these assumptions, removing arsenic might greatly reduce the number of nonsmall cell lung cancer cells (NSCLCs) produced in smokers, by up to two-thirds, depending on the fraction (between 0 and 1) of the smoking-induced increase in the patch-to-field transition rate prevented if arsenic were removed. At present, this fraction is unknown (and could be as low as zero), but the possibility that it could be high (close to 1) cannot be ruled out without further data.
authors.affiliation: Cox Associates and University of Colorado, Denver, CO 80218, USA. tcoxdenver@aol.com
authors.forename: Louis Anthony
authors.initials: LA
authors.lastname: Cox
mesh_terms: D001151:Arsenic / Q000302:isolation & purification / Q000633:toxicity*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000517:prevention & control*; D008962:Models, Theoretical; D009154:Mutation; D011336:Probability; D011401:Promoter Regions, Genetic; D012306:Risk; D018570:Risk Assessment; D012906:Smoke; D012907:Smoking / Q000009:adverse effects*; D014026:Nicotiana
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D012906:Smoke; D001151:Arsenic