History of dose response.

An abbreviated history of the dose-response curve or chemical concentration-effect relationship is presented in this article. No attempt has been made to include all references on the subject. Just an outline, overview, and discussion of the most important eras are presented. The history of dose response may be divided roughly into three Eras, Preclassical, Classical, and Current. Paracelsus, who lived from 1493 to 1541, must be recognized as the first one to realize that dose was the most important issue to deal with in determining whether a chemical was toxic or not. However, that issue seems to have been forgotten and is still ignored by some. The Classical Era began about 1900 and ended about t; he time of the death of Gaddum in 1965, during which almost all of the progress had been made in solving the parameters to use in analyzing data. The Current Era began with the acceptance of the linearized multistage model in the mid-1970's. In this author's opinion, the biggest mistake in all of toxicology occurred with the acceptance and use of the linearized multistage for DNA-reactive carcinogens with dose on a linear scale. It had been clearly established in the Classical Era that dose should be plotted on a logarithmic scale. Plotting dose on a linear scale distorts the curve for low doses so that any attempt to detect the relationship of dose of carcinogen to carcinogenesis is impossible.