Biology Based Lung Cancer Model for ChronicLow Radon Exposures

摘要

Low dose effects of alpha particles at the tissue level are characterized by theinteraction of single alpha particles, affecting only a small fraction of the cells within that tissue.Alpha particle intersections of bronchial target cells during a given exposure period weresimulated by an initiation-promotion model, formulated in terms of cellular hits within the cycletime of the cell (dose-rate) and then integrated over the whole exposure period (dose). For a givenaverage number of cellular hits during the lifetime of bronchial cells, the actual number of singleand multiple hits was selected from a Poisson distribution. While oncogenic transformation isinterpreted as the primary initiation step, stimulated mitosis by killing adjacent cells is assumed tobe the primary radiological promotion event. Analytical initiation and promotion functions werederived from experimental in vitro data on oncogenic transformation and cellular survival.To investigate the shape of the lung cancer risk function at chronic, low level exposures inmore detail, additional biological factors describing the tissue response and operating specificallyat low doses were incorporated into the initiation-promotion model. These mechanisms modifyingthe initial response at the cellular level were: adaptive response, genomic instability, induction ofapoptosis by surrounding cells, and detrimental as well as protective bystander mechanisms. Toquantify the effects of these mechanisms as functions of dose, analytical functions were derivedfrom the experimental evidence presently available. Predictions of lung cancer risk, includingthese mechanisms, exhibit a distinct sublinear dose-response relationship at low exposures,particularly for very low exposure rates.