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Some notes on the history of Haber's law

1999; Oxford University Press; Volume: 50; Issue: 2 Linguagem: Inglês

10.1093/toxsci/50.2.164

1096-6080

Hanspeter Witschi,

Carcinogens and Genotoxicity Assessment

Haber’s law or rule, as commonly understood in inhalation toxicology, states: C 3 T 5 constant, meaning that identical products of concentration of an agent in air (C) and duration of exposure (T), the CT product, will yield an identical biological response. The formula was originally developed by the German physical chemist Fritz Haber (1868–1934) to characterize the acute toxicity of chemicals used in gas warfare (for a brief history of the life of Fritz Haber, see Witschi, 1997). Eventually, this simple equation was used as scientific basis for the setting of exposure limits (see Atherley, 1985 and Henschler, 1984 for a critical discussion of the CT concept in standard setting). Animal experiments show that the rule does not always apply. When the effects of phosgene on pulmonary gas exchange were measured within a time interval of 5 min to 8 h, it was concluded that “there was no indication that concentration contributed more than exposure time to the magnitude of change in pulmonary performance over the range of CT values studied” (Rinehart and Hatch, 1964). In this experiment, the rule was valid. On the other hand, when the effects of subchronic phosgene exposure were examined, the unequivocal conclusion was reached that phosgene concentration rather than C 3 T product appeared to drive the toxic response (Kodavanti et al. 1997). In studies with another acutely toxic agent, ozone, similar observations were made: when protein retrieved from bronchoalveolar lavage fluid was measured as the toxicological endpoint, Haber’s rule was valid (Gelzleichter et al. 1992; Highfill et al. 1992). When the identical exposure protocol was used, but a different endpoint was measured (cell renewal in the airways), the concentration of the inhalant or the dose rate at which ozone was delivered appeared to be the driving determinant of toxicity (Rajini et al. 1993). Experiments designed specifically to test the validity of the CT concept thus can either confirm it or contradict it, and often the conclusions that are drawn depend upon the toxicological endpoints that were measured. Nevertheless, it is generally agreed that the CT could not apply to an infinite time of exposure, or there would be no safe exposure limits for prolonged or repeated exposures. Concentration of an airborne agent, which eventually will determine the dose, is generally considered the most important determining factor in toxicity. The importance of dose as a variable in toxicology has been recognized since Paracelsus. The importance of time is usually less well understood, but appears to be of equally fundamental significance, and some recent experiments shed indeed some new light on the CT concept (Rozman, 1999; Rozman et al. 1998). It is therefore appropriate to go back and take a closer look at the origins of Haber’s law and at how it was interpreted by the scientists who developed the concept.