Genotoxic Threshold Mechanisms and Points of Departure

In genetic toxicology, induced deoxyribonucleic acid (DNA) damage is used as a surrogate for cancer risk, as it is well known that cancer is induced by genetic aberrations. Genotoxic agents that are DNA reactive and direct acting have long been assumed to display linear dose responses. The main argument against a linear dose response for genotoxicants is the presence of natural cellular defenses, which have evolved to cope with our daily exposure to unavoidable genotoxicants. In 2009, a comprehensive analysis of the genotoxic dose responses for two alkylating agents was reported. The ability of a cell to repair its DNA following damage is a vital means for maintaining the genetic stability of the cell's genome. In order to assess the dose response of genotoxicants, it is imperative that the most sensitive tests available are employed to achieve sufficient power to calculate the point of departure.