A unifying concept for carcinogenic risk assessments

Carcinogens influence both the initiation of abnormal cells and the subsequent promotion of such cells into neoplasia. Certain other insults seem limited to the stimulation of cellular proliferation and of carcinogenic potentiation. Common examples include surgical, mechanical, chemical, and temperature wounding of tissue followed by healing. In addition, certain hyperplastic growth induced by some chemicals may also enhance tumorigenesis. We propose that the quantification of carcinogenic potentiation may derive from a common-index-quantity estimated according to enhanced cell proliferation resulting from cytotoxicity or toxic hyperplasia induced by a specific exposure. At this time, it is not possible to define, in a restrictive sense, the molecular events which are critical to potentiation but the processes of cell proliferation resulting from cytotoxicity/hyperplasia seem to serve as indices which contain the necessary (and perhaps several secondary) biological responses. The unique advantage is that cell-culture, animal, and human-level studies can be used to evaluate certain parameters of the mathematical model for an untested treatment protocol or chemical insult suspected to be a cofactor in tumorigenesis. The main thrust of this paper is to propose that tumorigenesis should be studied in terms of cellular-population kinetics in response to a biological challenge rather than according to chemical or energetic parameters of that challenge.This approach leads to mathematical equations which can serve as a unifying concept for carcinogenic risk assessments. Sample results, to illustrate the utility of this model, are given for polynuclear aromatic hydrocarbons, trace metals, ionizing radiations, CO, NO, SO₂, O₃, and NO₂. Treatment, here, is for acute exposure conditions, but because the model is mechanistic, other exposure protocols can be addressed by simply adjusting some of the mathematical parameters according to factors estimated from a relative potency comparison of in vitro and in vivo studies best suited to the particular application of interest.