Comments on Extrapolation of Cancer Response from High Dose to Low Dose

In making judgments as to the cancer risk from low level exposure to carcinogens it is generally necessary to base these judgments on high dose or high incidence data from laboratory or epidemiological studies. The biological considerations involved in making such extrapolations are discussed, as well as some of the mathematical procedures. The difficulties presented by moving from species to species, or from differently acting carcinogenic agents is considered. Prediction from high cancer incidence in humans or laboratory animals to the lower levels possibly associated with community air pollution is difficult. At the present time, it seems that projections from human epidemiological data are more reliable, un-certain though they may be, than are projections from laboratory animals. The art of quantitative evaluation of car-cinogenicity in laboratory animals has progressed immensely in the past twenty years. It seems reasonably reliable in simple situations, but uncer-tain in more complex circumstances. If one makes the assumption that intrinsic tissue sensitivity is reasonably uniform from species to species (there are exceptions), dosage can be com-puted on a rational basis moving between species, and from higher and lower doses, especially where the tumors are produced in the exposed tissue by direct-acting carcinogens. With high dose, direct-acting agents, e.g., ioniz-ing radiation or alkylating chemicals, confidence in quantitative inferences is highest. Thus in the direct production of skin cancer from ionizing radiation (1), or from inhaled alkylating agents, e.g., bis(chloromethyl)ether (2), one is dealing with di-rect dosage of the responsive tissue. Also, promot-ing or cocarcinogenic factors are probably of less importance in the high dose-response range. On the other hand, it is perfectly clear that even with ioniz-ing radiation, coacting factors can be of decisiv