title: Origin of the linearity no threshold (LNT) dose-response concept.
abstract: This paper identifies the origin of the linearity at low-dose concept [i.e., linear no threshold (LNT)] for ionizing radiation-induced mutation. After the discovery of X-ray-induced mutations, Olson and Lewis (Nature 121(3052):673-674, 1928) proposed that cosmic/terrestrial radiation-induced mutations provide the principal mechanism for the induction of heritable traits, providing the driving force for evolution. For this concept to be general, a LNT dose relationship was assumed, with genetic damage proportional to the energy absorbed. Subsequent studies suggested a linear dose response for ionizing radiation-induced mutations (Hanson and Heys in Am Nat 63(686):201-213, 1929; Oliver in Science 71:44-46, 1930), supporting the evolutionary hypothesis. Based on an evaluation of spontaneous and ionizing radiation-induced mutation with Drosophila, Muller argued that background radiation had a negligible impact on spontaneous mutation, discrediting the ionizing radiation-based evolutionary hypothesis. Nonetheless, an expanded set of mutation dose-response observations provided a basis for collaboration between theoretical physicists (Max Delbruck and Gunter Zimmer) and the radiation geneticist Nicolai Timoféeff-Ressovsky. They developed interrelated physical science-based genetics perspectives including a biophysical model of the gene, a radiation-induced gene mutation target theory and the single-hit hypothesis of radiation-induced mutation, which, when integrated, provided the theoretical mechanism and mathematical basis for the LNT model. The LNT concept became accepted by radiation geneticists and recommended by national/international advisory committees for risk assessment of ionizing radiation-induced mutational damage/cancer from the mid-1950s to the present. The LNT concept was later generalized to chemical carcinogen risk assessment and used by public health and regulatory agencies worldwide.
authors.affiliation: Department of Public Health, Environmental Health Sciences, University of Massachusetts, Morrill I, N344, Amherst, MA, 01003, USA. edwardc@schoolph.umass.edu
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Calabrese
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000528:radiation effects*; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D018876:Environmental Illness / Q000517:prevention & control; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D016014:Linear Models; D016296:Mutagenesis / Q000187:drug effects / Q000528:radiation effects*; D009153:Mutagens / Q000008:administration & dosage / Q000633:toxicity; D060051:Occupational Injuries / Q000517:prevention & control; D011832:Radiation Injuries / Q000517:prevention & control*; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D018570:Risk Assessment / Q000266:history / Q000331:legislation & jurisprudence / Q000379:methods; D020711:Threshold Limit Values; D014116:Toxicology / Q000266:history* / Q000331:legislation & jurisprudence; D014481:United States
chemical_list: D002273:Carcinogens; D009153:Mutagens