Abstract
This article assesses the historical foundations of how linearity at low dose became accepted by the scientific/regulatory communities. While the threshold model was used in the 1920s/1930s in establishing radiation health standards, its foundations were challenged by the genetics community who argued that radiation induced mutations in reproductive cells followed a linear response, were cumulative and deleterious. Scientific foundations of linearity for gonadal mutations were based on non-conclusive evidence as well as not being conducted at low doses. Following years of debate, leaders in the genetics community participated in the U.S. National Academy of Sciences (NAS) (1956) Biological Effects of Atomic Radiation (BEAR) BEAR I Committee, getting their perspectives accepted, incorporating linearity for radiation-induced mutational effects in risk assessment. Overtime the concept of linearity was generalized to include somatic effects induced by radiation based on a protectionist philosophy. This affected the course of radiation-induced and later chemically-induced carcinogen risk assessment. Acceptance of linearity at low dose from chemical carcinogens was strongly influenced by the NAS Safe Drinking Water Committee report of 1977 which provided the critical guidance to the U.S. EPA to adopt linear at low dose modeling for risk assessment for chemical carcinogens with little supportive data, much of which has been either discredited or seriously weakened over the past 3 decades. Nonetheless, there has been little practical change of regulatory policy concerning carcinogen risk assessment. These observations suggest that while scientific disciplines are self correcting, that regulatory ‘science’ fails to display the same self-correcting mechanism despite contradictory data.
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References
Ames BN (1973) Carcinogens are mutagens: their detection and classification. Environ Health Perspect 6:115–118. doi:10.2307/3428066
Ames BN, Lee FD, Durston WE (1973a) An improved bacterial test system for the detection and classification of mutagens and carcinogens. Proc Natl Acad Sci USA 70:782–786. doi:10.1073/pnas.70.3.782
Ames BN, Durston WE, Yamasaki E, Lee FD (1973b) Carcinogens are mutagens—simple test system combining liver homogenates for activation and bacteria for detection. Proc Natl Acad Sci USA 70:2281–2285. doi:10.1073/pnas.70.8.2281
Ames BN, Durston WE, Yamasaki E, Lee FD (1973c) Carcinogens are mutagens—simple test system. Mutat Res 21:209–210
Atomic Energy Commission (1950) Thirteenth Semiannual Report, July 1930, Control of Radiation Hazards in the Atomic Energy Program. Government Printing Office, Washington
Auerbach C (1939–1940) Tests of carcinogenic substances in relation to the production of mutations in Drosophila melanogaster. Proc Roy Soc Edin 60:164–173
Auerbach C, Robson JM (1946) Chemical production of mutations. Nature 157:302. doi:10.1038/157302a0
Avery OT, MacLeod CM, McCarty M (1944) Studies on chemical natures of substance inducing transformation by desoxyribonucleic acid fraction isolated from pneumococcus type III. J Exp Med 79:137–158. doi:10.1084/jem.79.2.137
Barclay AE, Cox S (1928) Radiation risks of the roentgenologist. Am J Roentgenol Rad Ther 19:551–561
Barendsen GW (1975) The effectiveness of small doses of ionizing radiations for the induction of cell reproductive death, chromosomal change and malignant transformation. In: Presented at 5th symposium on microdosimetry, Verbania Pallanza, Italy, September 22
Beadle G (1957) Biology division, C., Biology 1957 at the California Institute of Technology: a report for the year 1956–1957 on the research and other activities of the Division of Biology, pp 126
Berenblum I, Shubik P (1949) An experimental study of the initiating stage of carcinogenesis, and a re-examination of the somatic cell mutation theory of cancer. Br J Cancer 3:109–117
Bhattacharya S (1949) A study of the inability of methylcholanthrene to produce mutations in Drosophila melanogaster. Proc Zool Sox Bengal 2:187–193
Blum HF (1953) Regarding the somatic mutation hypothesis of cancer. Science 118:197–198. doi:10.1126/science.118.3059.197
Brooks P, Lawley PD (1964) Evidence for the binding of polynuclear aromatic hydrocarbons to the nucleic acids of mouse skin. Relation between carcinogenic power of hydrocarbons and their binding to deoxyribonucleic acid. Nature 202:781–784. doi:10.1038/202781a0
Brown JM (1976) Linearity versus nonlinearity of dose-response for radiation carcinogenesis. Health Phys 31:231–245
Bruce RD, Carlton WW, Ferber KH, Hughes DH, Quast JF, Salsburg DS, Smith JM, (Members of the Society of Toxicology ED01 Task Force), Brown WR, Cranmer MF, Sielken JR, Van Ryzin J, Barnard RC (1981) Re-examination of the ED01 study why the society of toxicology became involved. Fundam Appl Toxicol 1:26–128
Brues AM (1958) Critique of linear theory of carcinogenesis. Science 128:693–699. doi:10.1126/science.128.3326.693
Burdette WJ (1950) Lethal mutation rate in Drosophila treated with methylcholanthrene. Science 112:303–306. doi:10.1126/science.112.2907.303
Burdette WJ (1951a) Administration of diethylstilbestrol to the tu-36a strain of Drosophila melanogaster. Rec Genet Soc Am 20:93–94
Burdette WJ (1951b) Tumor incidence and lethal mutation rate in a tumor strain of Drosophila treated with formaldehyde. Cancer Res 11:555–558
Burdette WJ (1952a) Tumor incidence and lethal mutation rate in Drosophila treated with 20-methylcholanthrene. Cancer Res 12:201–205
Burdette WJ (1952b) Effect of nitrogen mustard on tumor incidence and lethal mutation rate in Drosophila. Cancer Res 12:366–368
Burdette WJ (1953) The somatic mutation hypothesis of cancer genesis. Science 118:196–197. doi:10.1126/science.118.3059.196
Burdette WJ (1955) The significance of mutation in relation to the origin of tumors: a review. Cancer Res 15:201–226
Calabrese EJ (2004) Hormesis: from marginalization to mainstream. A case for hormesis as the default dose-response model in risk assessment. Toxicol Appl Pharmacol 197:125–136. doi:10.1016/j.taap.2004.02.007
Calabrese EJ (2005a) Toxicological awakenings: the rebirth of hormesis as a central pillar of toxicology. Toxicol Appl Pharmacol 204:1–8. doi:10.1016/j.taap.2004.11.015
Calabrese EJ (2005b) Historical blunders: how toxicology got the dose-response relationship half right. Cell Mol Biol 51:643–654
Calabrese EJ (2008) Hormesis: why it is important to toxicology and toxicologists. Environ Toxicol Chem 27:1451–1474. doi:10.1897/07-541.1
Calabrese EJ, Baldwin LA (2000a) Chemical hormesis: its historical foundations as a biological hypothesis. Hum Exp Toxicol 19:2–31. doi:10.1191/096032700678815585
Calabrese EJ, Baldwin LA (2000b) The marginalization of hormesis. Hum Exp Toxicol 19:32–40. doi:10.1191/096032700678815594
Calabrese EJ, Baldwin LA (2000c) Radiation hormesis: its historical foundations as a biological hypothesis. Hum Exp Toxicol 19:41–75. doi:10.1191/096032700678815602
Calabrese EJ, Baldwin LA (2000d) Radiation hormesis: the demise of a legitimate hypothesis. Hum Exp Toxicol 19:76–84. doi:10.1191/096032700678815611
Calabrese EJ, Baldwin LA (2000e) Tales of two similar hypotheses: the rise and fall of chemical and radiation hormesis. Hum Exp Toxicol 19:85–97. doi:10.1191/096032700678815620
Carlson EA (1981) Genes, radiation and society: the life and work of H.J. Muller. Cornell University Press, Ithaca
Caron J (2003) Edward Lewis and radioactive fallout—the impact of Caltech biologists on the debate over nuclear weapons testing in the 1950s and 1960s. Thesis, Bachelor of Science. California Institute of Technology, Pasadena
Catcheside DG (1946) Genetic effects of radiations. Br Med Bull 4:18–24
Catcheside DG (1948) Genetic effects of radiations. Adv Genet Incorp Mol Genet Med 2:271–358
Court-Brown WM (1958a) Nuclear and allied radiations and the incidence of leukaemia in man. Br Med Bull 14:168–173
Court-Brown WM (1958b) Radiation-inducted leukemia in man, with particular references to the dose-response relationship. J Chronic Dis 8:113–122
Cowie DB, Scheele LA (1941) A survey of radiation protection in hospitals. J Natl Cancer Inst 1:767
Demerec M (1948) Induction of mutations in Drosophila by dibenzanthracene. Genetics 33:337–348
Drake JW (1978) Some guidelines for determining maximum permissible levels of chemical mutagens. In: Flamm WG, Mehlman MA (eds) Advances in modern toxicology, Volume 5-Mutagenesis. Hemisphere Publishing Corporation, New York, p 926
Drake JW, Abrahamson S, Crow JF, Hollaender A, Lederberg S, Legator MS, Neel JV, Shaw MW, Sutton EE, von Borstel RC, Zimmering S, de Serres FJ (1975) Environmental mutagenic hazards. Science 187:503–514. doi:10.1126/science.163482
Driver HE, White INH, Butler WH (1987) Dose-response relationships in chemical carcinogenesis: Renal mesenchymal tumors induced in the rat by single dose dimethylnitrosamine. Br J Exp Pathol 68:133–143
DuShane G (1957) Loaded dice. Science 125:964
Environmental Protection Agency (EPA) (1976) Health risk and economic impact assessments of suspected carcinogens. Fed Regist 41:21402–21405
Environmental Protection Agency (EPA) (1979) Water quality criteria. Fed Regist 44:15926–15931
Environmental Protection Agency (EPA) (1980) Water quality criteria documents; availability. Fed Regist 45:79318–79356
Evans RD (1949) Quantitative inferences concerning the genetic effects of radiation on human beings. Science 109:299–304. doi:10.1126/science.109.2830.299
Federal Radiation Council (FRC) (1960) Background material for the development of radiation protection standards. Report No. 1. Federal Radiation Council, Washington, DC
Finkel MP (1958) Mice, men, and fallout. Science 128:637–641. doi:10.1126/science.128.3325.637
Foulds L (1969) Neoplastic development, vol I. Academic Press, New York
Freese E (1973) Thresholds in toxic, teratogenic, mutagenic, and carcinogenic effects. Environ Health Perspect. doi:10.2307/3428074
Furth J (1957) Hearings on the nature of radioactive fallout and its effects on man, in joint committee on atomic energy. United States Government Printing Office, Washington, DC, p 2000
Glucksmann A, Lamerton LF, Maynford WV (1957) Cancer, Chapter 12. In: Raven RW (ed), Butterworths, London
Hanson FB (1928) The effect of X-rays in producing return gene mutations. Science LXVII:562–563. doi:10.1126/science.67.1744.562
Hanson FB, Heys F (1929) An analysis of the effect of the different rays of radium in producing lethal mutations in Drosophila. Am Nat 63:201–213. doi:10.1086/280254
Hanson FB, Heys F (1932) Radium and lethal mutations in Drosophila further evidence of the proportionality rule from a study of the effects of equivalent doses differently applied. Am Nat 66:335–345. doi:10.1086/280441
Hanson FB, Heys F, Stanton E (1931) The effect of increasing X-ray voltages on the production of lethal mutations in Drosphila melanogaster. Am Nat 65:134–143. doi:10.1086/280355
Henschen F (1968) Yamagiwas tar cancer and its historical significance—from Percival Pott to Katsusaburo Yamagiwa. Gann 59:447–451
Henshaw PS (1941) The biological significance of the tolerance dose in X-ray and radium protection. J Natl Cancer Inst 1:789–805
Houle CD, Ton TT, Clayton C, Huff J, Hong HL, Sills RC (2006) Frequent p53 and H-ras mutations in benzene- and ethylene oxide-induced mammary gland carcinomas from B6C3F1 mice. Toxicol Pathol 34:752–762. doi:10.1080/01926230600935912
International Commission on Radiological Protection (ICRP) (1966) The evaluation of risks from radiation, ICRP Publication 8. Pergamon Press, Oxford
Joint Committee on Atomic Energy (JCAE) of the Congress of the United States (1957) Hearings on the nature of radioactive fallout and its effects on man. 2 vols. plus summary. Government Printing Office, Washington
Joint Committee on Atomic Energy (JCAE) of the Congress of the United States (1959) Hearings on fallout from nuclear weapons tests. 3 vols. plus summary. Government Printing Office, Washington
Joint Committee on Atomic Energy (JCAE) of the Congress of the United States (1960a) Selected materials on radiation protection criteria and standards: Their basis and use. Government Printing Office, Washington
Joint Committee on Atomic Energy (JCAE) of the Congress of the United States (1960b) Statement of Dr. E.B. Lewis, Division of Biology, California Institute of Technology. Radiation protection and somatic effects. In: Selected materials on radiation protection criteria and standards: their basis and use. Government Printing Office, Washington, pp 404–407
Joint Committee on Atomic Energy (JCAE) of the Congress of the United States (1960c) Statement of Dr. Austin M. Brues, Director, Division of Biological and Medical Research, Argonne National Laboratory, Argonne, IL. Radiation protection and somatic effects. In: Selected materials on radiation protection criteria and standards: their basis and use. Government Printing Office, Washington, pp 408–437
Jolly JC (2003) Thresholds of uncertainty: radiation and responsibility in the fallout controversy. Dissertation, Oregon State University, p 591
Kathren RL (1996) Pathway to a paradigm: the linear nonthreshold dose-response model in historical context: the American Academy of Health Physics 1995 radiology centennial Hartman oration. Health Phys 70:621–635. doi:10.1097/00004032-199605000-00002
Kennaway EL (1955) The identification of a carcinogenic compound in coal-tar. BMJ 2:749–752
Kimball AW (1958) Evaluation of data relating human leukemia and ionizing radiation. J Natl Cancer Inst 21:383–391
Lamerton LF (1958) An examination of the clinical and experimental data relating to the possible hazard to the individual of small doses of radiation. Br J Radiol 31:229–239
Lamerton LF (1964) Radiation carcinogenesis. Br Med Bull 20:134
Larson CD (1989) Historical development of the national primary drinking water regulations. In: safe drinking water act: amendments, regulations and standards. Lewis Publishers, Chelsa, pp 3–15
Latarject R (1948) Production dune mutation bacterienne par des substances cancerigenes ou non. Comp Ren Des Seances Soc Biol Filiales 142:453–455
Lawley PD (1994) Historical origins of current concepts of carcinogenesis. Adv Cancer Res 65:18–111
Lewis EB (1957) Leukemia and ionizing radiation. Science 125:965–972. doi:10.1126/science.125.3255.965
Lipshitz HD (2005) From fruit flies to fallout: Ed Lewis and his science. Dev Dyn 232:529–546. doi:10.1002/dvdy.20332
Loechler EL (1996) The role of adduct site-specific mutagenesis in understanding how carcinogen-DNA adducts cause mutations: perspective, prospects and problems. Carcinogenesis 17:895–902. doi:10.1093/carcin/17.5.895
Loveless A, Hampton CL (1969) Inactivation and mutation of coliphage T2 by N-methyl-N-nitrosourea and N-ethyl-N-nitrosourea. Mutat Res 7:1–12. doi:10.1016/0027-5107(69)90043-8
Malling HV (2004a) Incorporation of mammalian metabolism into mutagenicity testing. Mutat Res 566:183–189. doi:10.1016/j.mrrev.2003.11.003
Malling HV (2004b) History of the science of mutagenesis from a personal perspective. Environ Health Perspect 44:372–386
Mole RH (1958) The dose-response relationship in radiation carcinogenesis. Br Med Bull 14:184–189
Muller HJ (1927) Artificial transmutation of the gene. Science 66:84–87. doi:10.1126/science.66.1699.84
Muller HJ (1928) The problem of genic modification. Verhandlungen des V. Internationalen Kongresses fur Vererbungswissenschaft (Berlin, 1927) in Zeitschrift fur inductive abstammungs- und Vererbungslehre. Suppl Band 1:234–260
Muller HJ (1930) Radiation and Genetics. Am Nat 64:220–257. doi:10.1086/280313
Muller HJ (1951) In: Baitsell GA (ed) Science in progress, 7th series. Yale University Press, New Haven, pp 95–165
Mustacchi PO, Shimkin MB (1956) Radiation cancer and Clunet. J Cancer 9:1073–1074. doi:10.1002/1097-0142(195611/12)9:6<1073::AID-CNCR2820090602>3.0.CO;2-9
Mutscheller A (1925) Physical standards of protection against roentgen ray dangers. Am J Roentgenol Rad Ther 13:65–70
Mutscheller A (1928) Safety standards of protection against X-ray dangers. Radiology 10:468–476
National Academy of Sciences (NAS)/National Research Council (NRC) (1956) The biological effects of atomic radiation: a report to the public. NAS/NRC, Washington
National Academy of Sciences (NAS)/National Research Council (NRC) (1959) A commentary on the report of the United Nations scientific committee on the effect of atomic radiation. NAS Publication 647. NAS/NRC, Washington
National Academy of Sciences (NAS)/National Research Council (NRC) (1972) The effects on populations of exposure to low levels of ionizing radiation. National Academy, Washington
National Committee on Radiation Protection, Measurements (NCRPM) (1960) Somatic radiation dose for the general population. Science 131:482–486. doi:10.1126/science.131.3399.482
Nordling CO (1952) Theories and statistics of cancer. Nord Med 47:817–820
Nordling CO (1953) A new theory of the cancer-inducing mechanism. Br J Cancer 7:68–72
Oliver CP (1930) The effect of varying the duration of X-ray treatment upon the frequency of mutation. Science 71:44–46. doi:10.1126/science.71.1828.44
Oliver CP (1931) An analysis of the effect of varying the duration of x-ray treatment upon the frequency of mutations. Doctor of Philosophy Thesis, University of Texas, Austin
Olivieri G, Bodycote J, Wolff S (1984) Adaptive response of human-lymphocytes to low concentrations of radioactive thymidine. Science 223:594–597. doi:10.1126/science.6695170
Pochin EE (1958) Radiation and leukaemia. Lancet 1:51–52
Richter A, Singleton WR (1955) The effects of chronic gamma radiation on the production of somatic mutations in carnations. Genetics 41:295–300
Rous P (1910) A transmissible avian neoplasm (Sarcoma of the common fowl). J Exp Med 12:696–705. doi:10.1084/jem.12.5.696
Rous P (1959) Surmise and fact on the nature of cancer. Nature 183:1357–1361. doi:10.1038/1831357a0
Safe Drinking Water Committee (1977) Drinking water and health. National Academy of Sciences, Washington
Samson L, Cairns J (1977) New pathway for DNA-repair in Escherichia coli. Nature 267:281–283. doi:10.1038/267281a0
Serebrovsky AS, Dubinin NP (1930) X-ray experiments with Drosophila. J Hered 21:259–265
Setlow JK (1964) Effects of UV on DNA-correlations among biological changes, physical changes and repair mechanisms. Photochem Photobiol 3:405–413. doi:10.1111/j.1751-1097.1964.tb08163.x
Sievert R (1925) Einige untersuchungen uber vorricht ungen zum schutz gegen roentgenstrahlen. Acta Radiol 4:61. doi:10.3109/00016922509133488
Singleton WR (1954a) The effect of chronic gamma radiation on endosperm mutations in maize. Genetics 39:587–603
Singleton WR (1954b) Radiation effects on living systems. J Heredity 45:58–64
Solomon MS, Morgenthaler P-ML, Turesky RJ, Essigmann JM (1996) Mutational and DNA binding specificity of the carcinogen 2-amino-3, 8-dimethylimidazo[4, 5-f]quinoxaline. J Biol Chem 271:18368–18374. doi:10.1074/jbc.271.41.25240
Stadler LJ (1930) Some genetic effects of X-rays in plants. J Hered 21:3–19
Sturtevant AH (1954) Social implications of the genetics of man. Science 120:405–407. doi:10.1126/science.120.3115.405
Sturtevant AH (1965) A history of genetics. Harper and Row Publishers, New York, pp 71–72
Taylor LS (1971) Radiation protection standards. CRC monotopics series. Chemical Rubber Company Press, Cleveland
Timofeeff-Ressovsky NW, Zimmer KG, Delbruck M (1935) Nachrichten von der gesellschaft der wissenschaften zu Gottingen. Uber die nature der genmutation und der genstruktur Biologie Band 1, Nr. 13
Trosko JE, Upham BL (2005) The emperor wears no clothes in the field of carcinogen risk assessment: ignored concepts in cancer risk assessment. Mutagenesis 20:81–92. doi:10.1093/mutage/gei017
United Nations Scientific Committee on the effects of atomic radiation (1958) Report of the United Nations Scientific Committee on the effects of atomic radiation. New York, United Nations. General Assembly Official Records, Thirteenth Session, Supplement No. 17 (A/3838)
United Nations Scientific Committee on the effects of atomic radiation (1962) Report of the United Nations Scientific Committee on the effects of atomic radiation. New York, United Nations. General Assembly Official Records, Seventeenth Session, Supplement No. 16 (A/5216)
United Nations Scientific Committee on the effects of atomic radiation (1964) Report of the United Nations Scientific Committee on the effects of atomic radiation. New York, United Nations. General Assembly Official Records, Nineteenth Session, Supplement No. 14 (A/5814)
Uphoff DE, Stern C (1949) The genetic effects of low intensity irradiation. Science 109:609–610. doi:10.1126/science.109.2842.609
Valadez JG, Guengerich FP (2004) S-(2-Chloroethyl)glutathione-generated p53 mutation spectra are influenced by differential repair rates more than sites of initial DNA damage. J Biol Chem 279:13435–13446. doi:10.1074/jbc.M312358200
Watson JD, Crick FHC (1953) Molecular structure of nucleic acids—a structure for deoxyribose nucleic acid. Nature 171:737–738. doi:10.1038/171737a0
Weil CS (1972) Statistics vs. safety factors and scientific judgment in the evaluation of safety for man. Toxicol Appl Pharmacol 21:454-463
Weinstein A (1928) The production of mutations and rearrangements of genes by X-rays. Science LXVII:376–377. doi:10.1126/science.67.1736.376
Whittemore GF Jr (1986) The National Committee on Radiation Protection, 1928–1960: from professional guidelines to government regulation. Thesis. Department of History of Science. Harvard University, Cambridge
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Effort sponsored by the Air Force Office of Scientific Research, Air Force Material Command, USAF, under grant number FA9550-07-1-0248. The U.S. Government is authorized to reproduce and distribute for governmental purposes notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsement, either expressed or implied, of the Air Force Office of Scientific Research or the U.S. Government. Even though their work is copiously cited in this paper, I wanted to highlight the important contributions of Whittemore (1986) and Jolly (2003) in their dissertations on critical assessment of the history of the dose response as seen through the eyes of historians of science.
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Calabrese, E.J. The road to linearity: why linearity at low doses became the basis for carcinogen risk assessment. Arch Toxicol 83, 203–225 (2009). https://doi.org/10.1007/s00204-009-0412-4
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DOI: https://doi.org/10.1007/s00204-009-0412-4