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Getting the dose–response wrong: why hormesis became marginalized and the threshold model accepted

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Abstract

The dose–response relationship is central to the biological and biomedical sciences. During the early decades of the twentieth century consensus emerged that the most fundamental dose–response relationship was the threshold model, upon which scientific, health and medical research/clinical practices have been based. This paper documents that the scientific community made a fundamental error on the nature of the dose response in accepting the threshold model and in rejecting the hormetic-biphasic model, principally due to conflicts with homeopathy. Not only does this paper detail the underlying factors leading to this dose response decision, but it reveals that the scientific community never validated the threshold model throughout the twentieth century. Recent findings indicate that the threshold model poorly predicts responses in the low dose zone whereas its dose response “rival”, the hormesis model, has performed very well. This analysis challenges a key foundation upon which biological, biomedical and clinical science rest.

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References

  • Alexander LT (1950) Radioactive materials as plant stimulants—field results. Agron J 42:252–255

    CAS  Google Scholar 

  • Ancel P, Lallemand S (1928) Sur la protection contre l’action des rayons X par une irradiation prealable (radiophylaxie). Compt Rend Soc Biol Paris 99:1588–1590

    Google Scholar 

  • Anonymous (1951) J. R. Loofbourow, Professor and Faculty Chairman, Dies. Tech LXXI:1–2

  • Anonymous (1960a) Regulating the drug industry: reports ask for reforms while the industry leaders ask for trademark protection. Science 132:1536–1537. doi:10.1126/science.132.3439.1536

  • Anonymous (1960b) A profitable sideline. Time Magazine

  • Anonymous (2002) Paid notice: deaths. The New York Times, Southam, Chester Milton

  • Baldwin IL (1985) Edwin Broun Fred 1887–1981. A biographical memoir. National Academy of Sciences, Washington, DC

    Google Scholar 

  • Bateman E (1933) The effect of concentration on the toxicity of chemicals to living organisms. Tech Bull No. 346 US Department of Agriculture, Washington, DC

  • Beck B, Calabrese EJ, Slayton TM (2008) The use of toxicology in the regulatory process. In: Hayes AW et al (eds) Principles and methods of toxicology, 5th edn. CRC Press, Taylor & Francis Group, Florida, pp 45–102

    Google Scholar 

  • Bliss CI (1935a) Estimating the dosage-mortality curve. J Econ Entomol 25:646–647

    Google Scholar 

  • Bliss CI (1935b) The calculation of the dosage-mortality curve. Ann Appl Biol 22:134–167. doi:10.1111/j.1744-7348.1935.tb07713.x

    Article  CAS  Google Scholar 

  • Bliss CI (1935c) The comparison of dosage-mortality data. Ann Appl Biol 22:307–333. doi:10.1111/j.1744-7348.1935.tb07166.x

    Article  CAS  Google Scholar 

  • Bliss CI (1939) The toxicity of poisons applied jointly. Ann Appl Biol 26:585–615. doi:10.1111/j.1744-7348.1939.tb06990.x

    Article  CAS  Google Scholar 

  • Bliss CI (1940) The relation between exposure time, concentration and toxicity in experiments on insecticides. Ann Entomol Soc Am 33:721–766

    CAS  Google Scholar 

  • Bliss CI (1941) Biometry in the service of biological assay. Ind Eng Chem 13:84–88. doi:10.1021/i560090a009

    Article  CAS  Google Scholar 

  • Bliss CI, Cattell M (1943) Biological assay. Annu Rev Physiol 5:479–539. doi:10.1146/annurev.ph.05.030143.002403

    Article  Google Scholar 

  • Bliss CI, Packard C (1941) Stability of the standard dosage-effect curve for radiation. Am J Roentgenol Rad Therap 46:400–404

    Google Scholar 

  • Bohme H (1986) (Hugo Schulz (8/6/1853–7/13/1932) his life and work. Dissertation, Berlin: Medical Department of the Freien University of Berlin. (Translated by JM Ryan). University of Massachusetts, Amherst

  • Borak J (1944) Theories on the effectiveness of roentgen therapy in inflammatory conditions. Radiology 42:249–254

    Google Scholar 

  • Branham SE (1929) The effects of certain chemical compounds upon the course of gas production by Baker’s yeast. J Bacteriol 18:247–284

    PubMed  CAS  Google Scholar 

  • Bruce RD, Carlton WW, Ferber KH et al (1981) Re-examination of the ED01 study why the society of toxicology became involved. Fundam Appl Toxicol 1:26–128

    Google Scholar 

  • Bryan WR, Shimkin MB (1943) Quantitative analysis of dose–response data obtained with carcinogenic hydrocarbons in strain C3H male mice. J Natl Cancer Inst 3:503–531

    CAS  Google Scholar 

  • Bunning E (1989) Ahead of his time: Wilhelm Pfeffer, early advances in plant biology. (Translated from the German by Helmut William Pfeffer). Carleton University Press, Ottawa

    Google Scholar 

  • Burke V, Wiley AJ (1937) Bacteria in coal. J Bacteriol 34:475–481

    Google Scholar 

  • Calabrese EJ (1978) Methodological approaches to deriving environmental and occupational health standards. John Wiley and Sons Inc., New York (Also translated into Chinese in 1984 for use in the People’s Republic of China)

    Google Scholar 

  • Calabrese EJ (2001) Overcompensation stimulation: a mechanism for hormetic effects. Crit Rev Toxicol 31:425–470. doi:10.1080/20014091111749

    Article  PubMed  CAS  Google Scholar 

  • Calabrese EJ (2005) Historical blunders: how toxicology got the dose–response relationship half right. Cell Mol Biol 51:643–654

    PubMed  CAS  Google Scholar 

  • Calabrese EJ (2007) Threshold-dose response model—RIP: 1911 to 2006. Bioessays 29:686–688

    Article  PubMed  Google Scholar 

  • Calabrese EJ (2008a) Another California milestone: the first application of hormesis in litigation and regulation. Intern’l J Toxicol 27:31–33. doi:10.1080/10915810701876554

    Article  Google Scholar 

  • Calabrese EJ (2008b) Neuroscience and hormesis: overview and general findings. Crit Rev Toxicol 38:249–252. doi:10.1080/10408440801981957

    Article  PubMed  CAS  Google Scholar 

  • Calabrese EJ (2008c) Dose–response features of neuroprotective agents: an integrative summary. Crit Rev Toxicol 38:253–348. doi:10.1080/10408440801981965

    Article  PubMed  CAS  Google Scholar 

  • Calabrese EJ (2008d) Pharmacological enhancement of neuronal survival. Crit Rev Toxicol 38:349–389. doi:10.1080/10408440801981973

    Article  PubMed  CAS  Google Scholar 

  • Calabrese EJ (2008e) Enhancing and regulating neurite outgrowth. Crit Rev Toxicol 38:391–418. doi:10.1080/10408440801981981

    Google Scholar 

  • Calabrese EJ (2008f) Alzheimer’s disease drugs: an application of the hormetic dose–response model. Crit Rev Toxicol 38:419–451. doi:10.1080/10408440802003991

    Article  PubMed  CAS  Google Scholar 

  • Calabrese EJ (2008g) Stress biology and hormesis: the Yerkes-Dodson law in psychology—a special case of the hormesis dose response. Crit Rev Toxicol 38:453–462. doi:10.1080/10408440802004007

    Article  PubMed  Google Scholar 

  • Calabrese EJ (2008h) Astrocytes: adaptive responses to low doses of neurotoxins. Crit Rev Toxicol 38:463–471. doi:10.1080/10408440802004023

    Article  PubMed  CAS  Google Scholar 

  • Calabrese EJ (2008i) P-Glycoprotein efflux transporter activity often displays biphasic dose–response relationships. Crit Rev Toxicol 38:473–487. doi:10.1080/10408440802004049

    Article  PubMed  CAS  Google Scholar 

  • Calabrese EJ (2008j) An assessment of anxiolytic drug screening tests: hormetic dose responses predominate. Crit Rev Toxicol 38:489–542. doi:10.1080/10408440802014238

    Article  PubMed  CAS  Google Scholar 

  • Calabrese EJ (2008k) Drug therapies for stroke and traumatic brain injury often display U-shaped dose responses: occurrence, mechanisms, and clinical implications. Crit Rev Toxicol 38:557–577. doi:10.1080/10408440802014287

    Article  PubMed  CAS  Google Scholar 

  • Calabrese EJ (2008l) Modulation of the epileptic seizure threshold: implications of biphasic dose responses. Crit Rev Toxicol 38:543–556. doi:10.1080/10408440802014261

    Article  PubMed  CAS  Google Scholar 

  • Calabrese EJ (2008m) U-Shaped dose–response in behavioral pharmacology: historical foundations. Crit Rev Toxicol 38:591–598

    PubMed  CAS  Google Scholar 

  • Calabrese EJ (2008n) Addiction and dose response: the psychomotor stimulant theory of addiction reveals that hormetic dose responses are dominant. Crit Rev Toxicol 38:599–618

    PubMed  CAS  Google Scholar 

  • Calabrese EJ (2008o) Pain and U-shaped dose responses: occurrence, mechanisms and clinical implications. Crit Rev Toxicol 38:579–590

    PubMed  CAS  Google Scholar 

  • Calabrese EJ (2008p) Hormesis and medicine. Br J Clin Pharmacol 66:594–617

    PubMed  CAS  Google Scholar 

  • Calabrese EJ, Baldwin L (1977) The dose determines the stimulation (and poison): development of a chemical hormesis data base. International J Toxicol 16:545–559

    Article  Google Scholar 

  • Calabrese EJ, Baldwin LA (2000a) Chemical hormesis: its historical foundations as a biological hypothesis. Hum Exper Toxicol 19:2–31

    Article  CAS  Google Scholar 

  • Calabrese EJ, Baldwin LA (2000b) The marginalization of hormesis. Hum Exper Toxicol 9:32–40

    Article  Google Scholar 

  • Calabrese EJ, Baldwin LA (2000c) Radiation hormesis: its historical foundations as a biological hypothesis. Hum Exper Toxicol 19:41–75

    Article  CAS  Google Scholar 

  • Calabrese EJ, Baldwin LA (2000d) Radiation hormesis: the demise of a legitimate hypothesis. Hum Exper Toxicol 19:76–84

    Article  CAS  Google Scholar 

  • Calabrese EJ, Baldwin LA (2000e) Tales of two similar hypotheses: the rise and fall of chemical and radiation hormesis. Hum Exper Toxicol 19:85–97

    Article  CAS  Google Scholar 

  • Calabrese EJ, Baldwin LA (2001) The frequency of U-shaped dose–responses in the toxicological literature. Tox Sci 62:330–338

    Article  CAS  Google Scholar 

  • Calabrese EJ, Baldwin LA (2002) Hormesis and high-risk groups. Reg Toxicol Pharmacol 35:414–428

    Article  CAS  Google Scholar 

  • Calabrese EJ, Baldwin LA (2003) The hormetic dose response model is more common than the threshold model in toxicology. Tox Sci 71:246–250

    Article  CAS  Google Scholar 

  • Calabrese EJ, Blain R (2005) The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview. Toxicol Appl Pharmacol 202:289–301

    Article  PubMed  CAS  Google Scholar 

  • Calabrese EJ, Baldwin LA, Holland CD (1999) Hormesis: a highly generalizable and reproducible phenomenon with important implications for risk assessment. Risk Analysis 19:261–281

    PubMed  CAS  Google Scholar 

  • Calabrese EJ, Staudenmayer JW, Stanek EJ et al (2006) Hormesis outperforms threshold model in NCI anti-tumor drug screening data. Tox Sci 94:368–378

    Article  CAS  Google Scholar 

  • Calabrese EJ, Bachmann KA, Bailer AJ et al (2008) Biological stress terminology: integrating the concepts of adaptive response and preconditioning stress within a hormetic dose–response framework. Tox Appl Pharmacol 222:122–128

    Article  CAS  Google Scholar 

  • Cantril ST, Buschke F (1944) Roentgen therapy in gas bacillus infection. Radiology 43:333–345

    Google Scholar 

  • Clark AJ (1927) The historical aspect of quackery. Brit Med J 1:589–590

    Google Scholar 

  • Clark AJ (1933) Mode of action of drugs on cells. Arnold, London

    Google Scholar 

  • Clark AJ (1937) Handbook of experimental pharmacology. Verlig Von Julius Springer, Berlin

    Google Scholar 

  • Clark DH (1985) Alfred Joseph Clark 1885–1941. A Memoir, C & J Clark Ltd Archives, Glastonbury CT

    Google Scholar 

  • Clifton CE (1957) Introduction to bacterial physiology. McGraw-Hill Book Company, New York

    Google Scholar 

  • Coggeshall M (1931) Influence of acetic, propionic, normal butyric and sulphuric acids and potassium acetate on elongation of primary roots of seedlings of white lupine. Plant Physiol 6:389–445

    Article  PubMed  CAS  Google Scholar 

  • Colley MW (1931a) Stimulation phenomena in the growth of bacteria as determined by nephelometry. Am J Bot 18:266–287

    Article  CAS  Google Scholar 

  • Colley MW (1931b) Notes on the technique of measuring the growth of bacteria with a nephelometer. Am J Bot 18:205–210

    Article  Google Scholar 

  • Copeland EB (1903) Chemical stimulation and the evolution of carbon dioxide. Bot Gaz 35:81–183

    Article  Google Scholar 

  • Copeland EB, Kahlenberg L (1899) The influence of the presence of pure metals upon plants. Wisconsin Acad Sci Art Lett 12:454–474

    Google Scholar 

  • Curtis WC (1929) Grants in support of research on the effects of radiations upon organisms. Science 69:9–10

    Article  Google Scholar 

  • Dale HH (1906) On some physiological actions of ergot. J Physiol (London) 34:163–206

    Google Scholar 

  • Davey WP (1919) Prolongation of life of tribolium confusum apparently due to small doses of X-rays. Gen Electr Rev 22:479–483

    Google Scholar 

  • Demsia G, Vlastos D, Goumenou M et al (2007) Assessment of the genotoxicity of imidacloprid and metalaxyl in cultured human lymphocytes and rat bone marrow. Mut Res 634:32–39

    CAS  Google Scholar 

  • Desjardins AU (1931) Radiotherapy for inflammatory conditions. J Amer Med Assoc 98:401–408

    Google Scholar 

  • Desjardins AU (1937) The action of roentgen rays or radium on inflammatory processes. Radiology 29:436–445

    Google Scholar 

  • Desjardins AU (1939a) Dosage and method of roentgen therapy for inflammatory conditions. Radiology 32:699–707

    Google Scholar 

  • Desjardins AU (1939b) Radiotherapy for inflammatory conditions. New Engl J Med 221:801–809

    Article  Google Scholar 

  • Desjardins AU (1942) The action of roentgen rays on inflammatory conditions. Radiology 38:274–280

    Google Scholar 

  • Dowdy AH, Sewell RL (1941) Roentgen radiation in experimental Clostridium welchii ingection (gas gangrene) in dogs: preliminary report. Radiology 37:440–442

    Google Scholar 

  • Duggar BM (1901) Physiological studies with reference to the germination of certain fungous spores. Bot Gaz 31:38–66

    Article  Google Scholar 

  • Duggar BM (1911) Plant physiology, with special reference to plant production. Macmillan, New York

    Google Scholar 

  • Duggar BM (1935) Grants in support of research on the biological effects of radiation. Science 82:125

    Article  PubMed  CAS  Google Scholar 

  • Duggar BM (1938) Grants in support of research on the biological effects of radiation. Science 87:507–508

    Article  PubMed  CAS  Google Scholar 

  • Duggar BM (1948) Aureomycin: a product of the continuing search for new antibiotics. Ann NY Acad Sci 51:177–181

    Article  PubMed  CAS  Google Scholar 

  • Duggar BM, Hollaender A (1938) The effects of sublethal doses of monochromatic ultraviolet radiation on the growth properties of bacteria. J Bacteriol 36:17–37

    PubMed  Google Scholar 

  • Duke SO, Powles SB (2008) Glyphosate: a once-in-a-century herbicide. Pest Man Sci 64:319–325

    Article  CAS  Google Scholar 

  • Dunlop EMC (1949) Gonorrhoea and sulphonamides. Brit J Ven Dis 25:81

    CAS  Google Scholar 

  • Eaton DL, Gilbert SG (2008) Principles of toxicology. In: Klaassen CD (ed) Casarett and Doull’s toxicology, the basic science of Poisons, 7th edn. McGraw Hill Medical, New York, pp 22–24

    Google Scholar 

  • Ehrlich J, Gottlieb D, Burkholder PR et al (1948) Streptomyces venezuelae, N-SP, the source of chloromycetin. J Bacteriol 56:467–477

    Google Scholar 

  • Emerson H, Atwater RM, Breed RS et al (1957) Charles-Edward Amory Wisnlow. February 4, 1877–January 8, 1957. Amer J Pub Health 47:151–167

    Article  Google Scholar 

  • Falk IS (1923) The role of certain ions in bacterial physiology. A Review. (Studies of salt action. VIII). Abstracts of Bacteriology 7:33–50; 87–105; 133–147

  • Flexner A (1910) Medical education in the United States and Canada. A report to the Carnegie Foundation for the Advancement of Teaching, New York

  • Fred EB (1912) Ueber die beschleunigung der lebenstatigkeit hoherer und niederer pflanzen durch kleine giftungen. Centralbl Bakt II(31):185–245

    Google Scholar 

  • Fred EB (1916) Relation of carbon bisulphid to soil organisms and plant growth. Agri Res 6:1–19

    CAS  Google Scholar 

  • Gaddum JH (1933) Methods of biological assay depending on the quantal response. Medical Research Council Ond Sp Rep Ser, No. 183, HM Stationery Office, London

  • Garrod LP (1951) The reactions of bacteria to chemotherapeutic agents. Brit Med J 1:205–210

    PubMed  CAS  Google Scholar 

  • Gaylor DW (1979) The ED01 study: summary and conclusions. J Environ Pathol Toxicol 3:179–183

    Google Scholar 

  • Glenn JC Jr (1946a) Studies on the effects of X-rays of phagocytic indices of healthy rabbits. J Immunol 52:65–69

    Google Scholar 

  • Glenn JC Jr (1946b) Further studies on the influence of X-rays of phagocytic indices of healthy rabbits. J Immunol 53:95–100

    Google Scholar 

  • Gordon MB (1930) The stimulative effect of roentgen rays upon the glands of internal secretion—a review of the literature. Endocrinology 14:411–437

    Article  Google Scholar 

  • Greenfield SS (1937) Responses of stock seedlings to heteroauxin applied to the soil. Amer J Bot 24:494–499

    Article  CAS  Google Scholar 

  • Hartmann A, Kiskinis E, Fjallman A et al (2001) Influence of cytotoxicity and compound precipitation on test results in the alkaline comet assay. Mut Res 497:199–212

    CAS  Google Scholar 

  • Heald FD (1896) On the toxic effect of dilute solutions of acids and salts upon plants. Bot Gaz 22:125–153

    Article  Google Scholar 

  • Heidenhain L (1926) Rontgenbestrahlung und Entzundung. Strahlentherapie 24:37–51

    Google Scholar 

  • Heitmann JA (2002) Doing “true science”: the early history of the Institutum Divi Thomae, 1935–1951. Cathol Hist Rev 88:702–722

    Article  Google Scholar 

  • Hollaender A, Emmons CW (1941) Wavelength dependence of mutation production in the ultraviolet with special emphasis on fungi. Cold Spring Harbor Symp Quant Biol 9:179–186

    Google Scholar 

  • Holmes JA, Franklin EC, Goulg RA (1915) Report of the Selby Smelter Commission. Department of the Interior, Bureau of Mines, Bulletin 98. Washington Government Printing Office

  • Hotchkiss M (1922) The influence of various salts upon the growth of bacterium communix. Doctoral dissertation. Yale University, CT

  • Hotchkiss M (1923) Studies on salt action VI. The stimulating and inhibitive effect of certain cations upon baceria growth. J Bacteriol 8:141–162

    PubMed  CAS  Google Scholar 

  • Hueppe F (1896) Principles of bacteriology. Translated from the German by EO Jordon. The Open Court Publishing Company, Chicago

    Google Scholar 

  • Hueppe F (1923) Autobiography. In: Grote LR (eds) Die Medizin der Gegenwart in Selbstdarstellungen. Verlag von Felix Meiner, Leipzig, pp 77–138

  • Humphrey CJ, Fleming RM (1915) The toxicity to fungi of various oils and salts, particularly those used in wood preservation. US Department of Agricultural Bulletin 227, Washington, DC

  • Jagetia GC, Venkatesh P, Baliga MS (2003) Evaluation of the radioprotective effect of Aegle marmelos (L.) Correa in cultured human peripheral blood lymphocytes exposed to different doses of gamma-radiation: a micronucleus study. Mutagenesis 8:387–393

    Article  Google Scholar 

  • Jensen GH (1907) Toxic limits and stimulation effects of some salts and poisons on wheat. Bot Gaz 43:11–44

    Article  CAS  Google Scholar 

  • Johnson EL (1936) Effects of X-rays upon green plants. In: Duggar BM (ed) Biological effects of raidation, 1st edn. McGraw-Hill Book Company Inc., New York, pp 961–985

    Google Scholar 

  • Kahlenberg L (1910) The American Association for the advancement of science—the past and future of the study of solution. Science 31:41–52

    Article  PubMed  CAS  Google Scholar 

  • Kahlenberg L, True RH (1896a) On the toxic action of dissolved salts and their electrolytic dissociation. J Am Med Assoc (Preliminary paper) July 18

  • Kahlenberg L, True RH (1896b) On the toxic action of dissolved salts and their electrolytic dissociation. Bot Gaz 22:81–124

    Article  Google Scholar 

  • Kellerman KF (1903) The effects of various chemical agents upon the starch-converting power of taka diastase. Bull Torrey Bot Club 30:56–70

    Article  Google Scholar 

  • Kelly JF (1936) Present status of the X-ray as an aid in treatment of gas gangrene. Radiology 26:41–44

    Google Scholar 

  • Kirkland DJ, Muller L (2000) Interpretation of the biological relevance of genotoxicity test results: the importance of thresholds. Mut Res 464:137–147

    CAS  Google Scholar 

  • Klaunig JE, Kamendulis LM (2008) Principles of toxicology. In: Klaassen CD (ed) Casarett and Doull’s toxicology, the basic science of Poisons, 7th edn. McGraw Hill Medical, New York, pp 360–362

    Google Scholar 

  • Knasmuller S, Steinkellner H, Majer B et al (2002) Search for dietary antimutagens and anticarcinogens: methodological aspects of extrapolation problems. Food Chem Toxicol 40:1051–1062

    Article  PubMed  CAS  Google Scholar 

  • Lacoste S, Castonguay A, Drouin R (2006) Formamidopyrimidine adducts are detected using the comet assay in human cells treated with reactive metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Mut Res 600:138–149

    CAS  Google Scholar 

  • Lamanna C, Mallette MF (1965) Basic bacteriology its biological and chemical background, 3rd edn. The Williams & Wilkins Company, Baltimore

  • Latham ME (1905) Stimulation of sterigmatocytis by chloroform. Bull Torrey Bot Club 32:337–351

    Article  Google Scholar 

  • Latham ME (1909) Nitrogen assimilation of Sterigmatocystis nigra and the effect of chemical stimulation. Bull Torrey Bot Club 36:285

    Article  Google Scholar 

  • LeBourg E, Rattan SIS (eds) (2008) Mild stress and healthy aging. Applying hormesis in aging research and interventions. Springer, Germany

  • Lerner BH (2004) Sins of omission—cancer research without informed consent. New Engl J Med 351:628–630

    Article  PubMed  CAS  Google Scholar 

  • Lipman CB (1931) Living microorganisms in ancient rocks. J Bact 22:183–198

    PubMed  CAS  Google Scholar 

  • Lipman CB (1932) Are there living bacteria in stony meteorites. Am Mus Novit No 588:1–19

    Google Scholar 

  • Lipman CB (1934) Further evidence of the amazing longevity of bacteria in coal. Science 79:230–231

    Article  PubMed  CAS  Google Scholar 

  • Lipman CB, Wilson FH (1913) Toxic inorganic salts and acids as affecting plant growth. Bot Gaz 55:409–420

    Article  Google Scholar 

  • Livingston BE (1905) Chemical stimulation of a green alga. Bull Torrey Bot Club 32:1–34

    Article  Google Scholar 

  • Livingston BE, Lawrence DB (1948) Some conversational autobiographical notes on intellectual experiences and development: an auto-obituary. Ecology 29:227–241

    Google Scholar 

  • Loofbourow JR, Morgan MN (1940) Investigation of the production of growth-promoting and growth-inhibiting factors by ultra-violet irradiated microorganisms. J Bact 39:437–453

    PubMed  CAS  Google Scholar 

  • Loofbourow JR, Cook ES, Stimson MM (1938) Chemical nature of proliferation-promoting factors from injured cells. Nature (London) 142:573

    Article  CAS  Google Scholar 

  • Luckey TD (1980) Ionizing radiation and hormesis. CRC Press, Boca Raton

    Google Scholar 

  • Maki-Paakkanen J, Hakulinen P (2008) Assessment of the genotoxicity of the rat carcinogen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) in rat liver epithelial cells in vitro. Toxicol In Vitro 22:535–640

    Article  PubMed  CAS  Google Scholar 

  • Marmot MG, Rose G, Shipley MJ, Thomas BJ (1981) Alcohol and mortality—a U-shaped curve. Lancet 8220:580–583

    Article  Google Scholar 

  • Marshall MS, Hrenoff AK (1937) Bacteriostasis. J Infect Dis 61:42–54

    CAS  Google Scholar 

  • Martin RE (1933) Living germs from other worlds. Popular Science Monthly, April

    Google Scholar 

  • Merrill MC (1915) Some relations of plants to distilled water and certain dilute toxic solutions. Ann Missouri Bot Garden 2:459–498, 500–506

    Google Scholar 

  • Merritt EA, Den AJ, Wilcox UV (1944) The effects of radiation therapy in Clostridium infection in sheep. Radiology 43:325–332

    Google Scholar 

  • Moore GT (1939) Daniel Trembly MacDougal pioneer plant physiologist. Plant Physiol 14:191–193

    Article  Google Scholar 

  • Muller HJ (1927) Artificial transmutation of the gene. Science 66:84–87

    Article  PubMed  CAS  Google Scholar 

  • Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136

    PubMed  CAS  Google Scholar 

  • Oldenbusch C (1922) (1922) Stimulation of plants by carbon disulphide. Bull Torrey Bot Club 49:375–389

    Article  Google Scholar 

  • Olivieri G, Bodycote J, Wolff S (1984) Adaptive response of human-lymphocytes to low concentrations of radioactive thymidine. Science 223:594–597

    Article  PubMed  CAS  Google Scholar 

  • Parkins PV (1966) Biosciences information service of biological abstracts – abstracting and indexing provide input for a dynamic computer-based information system. Science 152:889

    Article  PubMed  CAS  Google Scholar 

  • Pfeffer W (1901) The physiology of plants. A treatise upon the metabolism and sources of energy in plants, vol 1. The Clarendon Press, Gloucestershire

  • Preminger BA (2002) The case of Chester M. Southam: research ethics and the limit of professional responsibility. Pharos Alpha Omega Alpha Honor Med Soc 65:4–9

    PubMed  Google Scholar 

  • Pu X, Kamendulis LM, Klaunig JE (2006) Acrylonitrile-induced oxidative DNA damage in rat astrocytes. Environ Mol Mut 47:631–638

    Article  CAS  Google Scholar 

  • Quimby AJ, Quimby WA (1916) Unresolved pneumonia: successful treatment by roentgen ray. NY Med J 103:681–683

    Google Scholar 

  • Rammelkamp CH, Maxon T (1942) Resistance of staphylococcus aureaus to the action of penicillin. Proc Soc Exper Biol Med 51:386–389

    CAS  Google Scholar 

  • Randall WA, Price CW, Welch H (1947) Demonstration of hormesis (increase in fatality rate) by penicillin. Am J Pub Health 37:421–425

    Article  PubMed  CAS  Google Scholar 

  • Redpath JL, Short SC, Woodcock M, Johnston PJ (2003) Low-dose reduction in transformation frequency compared to unirradiated controls: the role of hyper-radiosensitivity to cell death. Rad Res 159:433–436

    Article  CAS  Google Scholar 

  • Reed HS (1907) The value of certain nutritive elements to the plant cell. Dissertation. University of Missouri, Columbia

    Google Scholar 

  • Rees JP (2008) Finding aid to the Sarah E. Branham papers, 1930–1986. US National Library of Medicine, National Institutes of Health, Collection No. MS C 528

  • Richards HM (1897) Die Beeinflussung des Wachsthums einiger Pilze durch chemische Reinze. Jahrbucher fur wissenschaftliche Bot 30:665–688

    Google Scholar 

  • Richards HM (1899) The effect of chemical irritation on the economic coefficient of sugar. Bull Torrey Bot Club 26:463–479

    Article  Google Scholar 

  • Richards HM (1910) On the nature of response to chemical stimulation. Science 31:52–62

    Article  PubMed  CAS  Google Scholar 

  • Richet C (1905) De l’action de doses minuscules de substances sur la fermentation lactique. Arch Inter de Physiol 3:203–217

    Google Scholar 

  • Richet C (1906–1907) De l’action de doses minuscules de substance sure le fermentation lactique-troisieme memoire-Periodes d’acceleration et ralentissement. Arch inter de Physiol 4:18–50

    Google Scholar 

  • Sagan LA (1989) On radiation, paradigms, and hormesis. Science 245:574–621

    Article  PubMed  CAS  Google Scholar 

  • Salle AJ (1939) Influence of environment upon bacteria. In: Fundamental principles of bacteriology with laboratory exercises. McGraw-Hill Book Company Inc., New York

    Google Scholar 

  • Samson L, Cairns J (1977) A new pathway for DNA repair in Escherichia coli. Nature 267:281–283

    Article  PubMed  CAS  Google Scholar 

  • Sasaki YF, Kawaguchi S, Kamaya A, Ohshita M, Kabasawa K, Iwama K, Taniguchi K, Tsuda S (2002) The comet assay with 8 mouse organs: results with 39 currently used food additives. Mut Res 509:103–119

    Google Scholar 

  • Schelling NJ (1925) Growth stimulation of aspergillus niger by a vitamin B preparation. Bull Torrey Bot Club 52:291–310

    Article  CAS  Google Scholar 

  • Schmitz H (1924) Studies in wood decay IV. The effect of sodium carbonate, bicarbonate, sulphate, and chloride on the rate of decay of Douglas fir sawdust induced by Lenzites saepiaria fr. with special reference to the effect of alkaline soils on the rate of decay of wood in contact with them. Amer J Bot 11:108–121

    Article  CAS  Google Scholar 

  • Schollnberger H, Mitchel REJ, Redpath JL, Crawford-Brown DJ, Hofmann W (2007) Detrimental and protective bystander effects: a model approach. Rad Res 168:614–626

    Article  CAS  Google Scholar 

  • Schramm JR (1919) Botanical abstracts. Science XLIX:195–196

    Article  Google Scholar 

  • Schreiner O, Reed HS (1907) Some factors influencing soil fertility. US Dept. Agri. Bur. Soil., Bulletin no. 40

  • Schreiner O, Reed HS (1908) The toxic action of certain organic plant constituents. Bot Gaz 45:73–102 271

    Article  CAS  Google Scholar 

  • Schulz H (1885) About the treatment of cholera nostras with veratrine. Deutsche med Wochenschr nr. 7 (Translated by JM Ryan). University of Massachusetts, Amherst

    Google Scholar 

  • Schulz H (1887) Zur Lehre von der Arzneiwirdung. Virchows Archiv fur Pathologische Anatomie und Physiologie fur Klinishce Medizin 108:423–445

    Article  Google Scholar 

  • Schulz H (1888) Uber Hefegifte. Pfluger’s Arch fur die gesemmte Physiol 42:517–541

    Article  Google Scholar 

  • Sellei J, Sellei H, Mayer A, Went FW (1942) Effects of fluorescein on plant growth. Am J Bot 29:513–522

    Article  CAS  Google Scholar 

  • Servos JW (1996) Physical chemistry from Ostwald to Pauling. The making of a Science in America. Princeton University Press, New Jersey

    Google Scholar 

  • Shackell LF (1923) Studies in protoplasm poisoning. I. Phenols. J Gen Physiol 5:783–805

    Article  CAS  PubMed  Google Scholar 

  • Shackell LF (1925) The relation of dosage to effect. II. J Pharmacol Exp Ther 25:275–288

    CAS  Google Scholar 

  • Shackell LF, Williamson W, Deitchman MM, Katzman GM, Kleinman BS (1924/1925) The relation of dosage to effect. J Pharmacol Exp Ther 23/24:53–65

    Google Scholar 

  • Shull CA (1948) Burton Edward Livingston. Obituary. Science 107:558–560

    Article  PubMed  CAS  Google Scholar 

  • Shull C, Mitchell J (1933) Stimulative effects of X-rays on plant growth. Plant Physiol 8:287–296

    Article  PubMed  CAS  Google Scholar 

  • Silberberg B (1909) Stimulation of storage tissues of higher plants by zinc sulphate. Bull Torrey Bot Club 36:489–500

    Article  Google Scholar 

  • Smith EC (1934) I. Effects of ultraviolet light and temperature on Fusarium II. Effects of radiation on fungi. Dissertation, University of Wisconsin, Madison

  • Smith EC (1935a) Effects of ultra-violet radiation and temperature on Fusarium. I. Lethal action. Bull Tor Bot Club 62:45–58

    Article  CAS  Google Scholar 

  • Smith EC (1935b) Effects of ultra-violet radiation and temperature on Fusarium. II. Stimulation. Bull Tor Bot Club 62:151–164

    Article  Google Scholar 

  • Smith EF, Townsend CO (1907) A plant tumor of bacterial origin. Science 25:671–673

    Article  PubMed  CAS  Google Scholar 

  • Southam CM (1967a) What are the possibilities for immunotherapy and immunoprophylaxis of cancer? Clin Pharmacol Ther 8:782–788

    PubMed  CAS  Google Scholar 

  • Southam CM (1967b) Evidence for cancer-specific angigens in man. Prog Exp Tumor Res 9:1–39

    PubMed  CAS  Google Scholar 

  • Southam CM, Ehrlich J (1943) Effects of extracts of western red-cedar heartwood on certain wood-decaying fungi in culture. Phytopathology 33:517–524

    Google Scholar 

  • Sperti GS, Loofbourow JR, Lane MM (1937) Effects on tissue cultures of intercellular hormones from injured cells. Science 86:611

    Article  PubMed  CAS  Google Scholar 

  • Stadler LJ (1928) Mutations in barley induced by X-rays and radium. Science LXVII:186–187

    Article  Google Scholar 

  • Stebbing ARD (1982) Hormesis—the stimulation of growth by low-levels of inhibitors. Sci Tot Environ 22:213–234

    Article  CAS  Google Scholar 

  • Stehle KB (1932) Inhibiting influence of colloidal starch, inulin, and agar on the stimulation of aspergillus niger by zinc sulphate. Bull Torrey Bot Club 59:191–217

    Article  CAS  Google Scholar 

  • Stern K, Wilhelm R (1943) The biochemistry of malignant tumors. Reference Press, Brooklyn, New York

    Google Scholar 

  • Szabadi E (1977) Model of 2 functionally antagonistic receptor populations activated by same agonist. J Theor Biol 69:101–112

    Article  PubMed  CAS  Google Scholar 

  • Thimann KV (1937) On the nature of inhibition caused by auxin. Am J Bot 24:407–412

    Article  CAS  Google Scholar 

  • Townsend CO (1899a) The effects of ether upon the germination of seeds and spores. Bot Gaz 27:458–466

    Article  Google Scholar 

  • Townsend CO (1899b) The effect of hydrocyanic acid gas upon the germination of seeds. Sci Am Suppl 48:20010–20011

    Google Scholar 

  • True RH (1900) The toxic action of a series of acids and of their sodium salts on Lupinus albus. Am J Sci IV 9:183

    CAS  Google Scholar 

  • True RH, Gies WJ (1903) On the physiological action of some of the heavy metals in mixed solutions. Bull Torrey Bot Club 30:390–402

    Article  Google Scholar 

  • True RH, Oglevee CS (1905) The effect of the presence of insoluble substances on the toxic action of poisons. Bot Gaz 39:1–21

    Article  Google Scholar 

  • Ugazio G, Koch RR, Recknage RO (1972) Mechanism of protection against carbon-tetrachloride by prior carbon-tetrachloride administration. Exper Mol Pathol 16:281–285

    Article  CAS  Google Scholar 

  • Van’t Hoff JH (1901) Osmotic pressure and chemical equilibrium. Nobel Lecture 13 December

  • Vaughn JR (1950) Old timers in Michigan “spout forth in divers ways” herin. Aurora Sporealis 26:5

    Google Scholar 

  • von Borstel RC, Steinberg CM (1996) Alexander Hollaender: myth and mensch. Genetics 145:1051–1056

    Google Scholar 

  • Wagner WH (1964) Edwin Bingham Copeland (1873–1964) and his contributions to pteridology. Am Fern J 54:177–188

    Google Scholar 

  • Warren S (1945) The histopathology of radiation lesions. Physiol Rev 25:225–238

    Google Scholar 

  • Watterson A (1904) The effect of chemical irritation on the respiration of fungi. Bull Torrey Bot Club 31:291–303

    Article  Google Scholar 

  • Welch H, Price CW, Randall WA (1946) Increase in fatality rate of E. Typhosa for white mice by streptomycin. J Am Pharm A 35:155–158

    CAS  Google Scholar 

  • Wilms LC, Kleinjans JCS, Moonen EJC, Briede JJ (2008) Discriminative protection against hydroxyl and superoxide anion radicals by quercetin in human leucocytes in vitro. Toxicol In Vitro 22:301–307

    Article  PubMed  CAS  Google Scholar 

  • Wolff S (1989) Are radiation-induced effects hormetic? Science 245:575–621

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Effort sponsored by the Air Force Office of Scientific Research, Air Force Material Command, USAF, under grant number FA9550-07-1-0248. The US 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 US Government.

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    Edward J. Calabrese

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Calabrese, E.J. Getting the dose–response wrong: why hormesis became marginalized and the threshold model accepted. Arch Toxicol 83, 227–247 (2009). https://doi.org/10.1007/s00204-009-0411-5

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