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.

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Acknowledgments

The research on the topic of hormesis has been supported by awards from the US Air Force and ExxonMobil Foundation over a number of years. Sponsors had no involvement in study design, collection, analysis, interpretation, writing and decision to submit.

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Calabrese, E.J. Origin of the linearity no threshold (LNT) dose–response concept. Arch Toxicol 87, 1621–1633 (2013). https://doi.org/10.1007/s00204-013-1104-7

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Keywords

  • Ionizing radiation
  • Linearity
  • Dose response
  • Risk assessment
  • Threshold dose response
  • Target theory
  • Eugenics
  • LNT