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Homeopathy 2015; 104(02): 69-82
DOI: 10.1016/j.homp.2015.02.007
 
Copyright © The Faculty of Homeopathy 2015

Hormesis: principles and applications

Edward J. Calabrese
Further Information

Publication History

Received22 August 2014
revised19 November 2014

accepted04 February 2015

Publication Date:
19 December 2017 (online)

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Hormesis has emerged as a central concept in biological and biomedical sciences with significant implications for clinical medicine and environmental risk assessment. This paper assesses the historical foundations of the dose–response including the threshold, linear and hormetic models, the occurrence and frequency of the hormetic dose response in the pharmacological and toxicological literature, its quantitative and temporal features, and underlying mechanistic bases. Based upon this integrative foundation the application of hormesis to the process of risk assessment for non-carcinogens and carcinogens is explored.

Keywords

Dose response - Hormesis - Biphasic - Adaptive response
 

  • References

  • 1 Calabrese E.J. The dose-response: a fundamental concept in toxicology. Hayes A.W., Kruger C.L. Principles and Methods of Toxicology. 6th edn. 2014. CRC Press; Boca Raton FL: 90-139.
    Google Scholar
  • 2 Slikker W., Andersen M.E., Bogdanffy M.S. et al. Dose-dependent transitions in mechanisms of toxicity. Toxicol Appl Pharmacol 2004; 201: 203-225.
    CrossrefPubMedGoogle Scholar
  • 3 Slikker W., Andersen M.E., Bogdanffy M.S. et al. Dose-dependent transitions in mechanisms of toxicity: case studies. Toxicol Appl Pharmacol 2004; 201: 226-294.
    CrossrefPubMedGoogle Scholar
  • 4 Clark A.J. General pharmacology. 1937. Verlag Von Julius Springer; Berlin.:
    Google Scholar
  • 5 Schakell L.F. The relation of dosage to effect. II. J Pharm Exper Ther 1925; 25: 275-288.
    PubMedGoogle Scholar
  • 6 Schakell L.F. Studies in protoplasm poisoning. I. Phenols. J Gen Physiol 1923; 5: 783-805.
    CrossrefPubMedGoogle Scholar
  • 7 Schakell L.F., Williamson W., Deitchman M.M., Katzman G.M., Kleinman B.S. The relation of dosage to effect. J Pharm Exper Ther 1925; 23/24 1924 53-65.
    PubMedGoogle Scholar
  • 8 Clark A.J. Mode of action of drugs on cells. 1933. Arnold; London.:
    Google Scholar
  • 9 Clark A.J. Applied pharmacology. 1st edn. 1926. J&A Churchill; London: 430.
    Google Scholar
  • 10 Bliss C.I. The calculation of the dosage – mortality curve. Ann Appl Biol 1935; 22: 134-167.
    CrossrefPubMedGoogle Scholar
  • 11 Bliss C.I. Estimating the dosage-morality curve. J Econom Entomol 1935; 25: 73-85.
    PubMedGoogle Scholar
  • 12 Gaddum J.H. Methods of biological assay depending on a quantal response. Med Res Counc Spec Rep Ser 1933; 183: 3-46.
    PubMedGoogle Scholar
  • 13 Bryan W.R., Shimkin M.D. Quantitative analysis of dose-response data obtained with three carcinogenic hydrocarbons in strain C3H male mice. J Nat Cancer Inst 1943; 3: 503-531.
    PubMedGoogle Scholar
  • 14 National Academy of Sciences (NAS). Drinking water and health. Washington DC 1977: 939.
    Google Scholar
  • 15 Lehman A.J., Fitzhugh O.G. 100-Fold margin of safety. Assoc Food Drug Off U S Q Bull 1953; 33: 33-35.
    PubMedGoogle Scholar
  • 16 Hays H.W. Obituary of Arnold J. Lehman. Toxicol Appl Pharmacol 1979; 51: 549-551.
    CrossrefPubMedGoogle Scholar
  • 17 Stirling D., Junod S. Profiles in toxicology, Arnold J Lehman. Toxicol Sci 2002; 70: 159-160.
    CrossrefPubMedGoogle Scholar
  • 18 National Council on Radiation Protection and Measurements (NCRPM). US National Bureau of Standards Handbook 59NCRP Rep. Permissible dose from external sources of ionizing radiation Vol 17 1954. U.S. Department of Commerce; Washington DC.:
  • 19 NAS/BEAR I Genetics Panel (W. Weaver, Chair). Genetic effects of atomic radiation. Summary Report of the Committee on Biological Effects of Atomic Radiation by the National Academy of Sciences. Science 1956; 123: 1157-1164 [Erratum, Science 124(3213):170].
    CrossrefPubMedGoogle Scholar
  • 20 Mutscheller A. Physical standards of protection against roentgen ray dangers. Am J Roentgenol 1925; 13: 65-69.
    PubMedGoogle Scholar
  • 21 Calabrese E.J. Origin of the linearity-no threshold (LNT) dose response concept. Arch Toxicol 2013; 87: 1621-1633.
    CrossrefPubMedGoogle Scholar
  • 22 Calabrese E.J. How the US National Academy of Sciences misled the world community on cancer risk assessment: new findings challenge historical foundations of the linear dose response. Arch Toxicol 2013; 87: 2063-2081.
    CrossrefPubMedGoogle Scholar
  • 23 Rosenberg T. What the world needs now is DDT. NY Times Mag 2004; 38-43.
    PubMedGoogle Scholar
  • 24 Ohanian E.V. National primary drinking water regulations for additional contaminants to be regulated by 1989. Calabrese E.J., Gilbert C.E., Pastides H. Safe Drinking Water Act. Amendments, Regulation and Standards 1989. Lewis Publishers; Ann Arbor, MI: 71-82.
    Google Scholar
  • 25 National Research Council (NRC). Health risks from exposures to low levels of ionizing radiation, BEIR VII Phase 2. 2006. National Academy Press; Washington, DC.:
    Google Scholar
  • 26 Ames B.N., Gold L.S. Proceedings of the National Academy of Sciences of the United States of America. Natl Acad Sci 1990; 87: 7772-7776.
    CrossrefPubMedGoogle Scholar
  • 27 Bruce R.D., Carlton W.W., Ferber K.H. et al. (Members of the society of toxicology ED01 task force). Re-examination of the ED01 study – adjusting for time on study. Fund Appl Toxicol 1981; 1: 67-80.
    CrossrefPubMedGoogle Scholar
  • 28 Taubes G. Epidemiology faces its limits. Science 1995; 269: 164-169.
    CrossrefPubMedGoogle Scholar
  • 29 Calabrese E.J., Baldwin L.A. Defining hormesis. Hum Exper Toxicol 2002; 21: 91-97.
    CrossrefPubMedGoogle Scholar
  • 30 Calabrese E.J. Evidence that hormesis represents an “overcompensation” response to a disruption in homeostasis. Ecotoxicol Env Saf 1999; 42: 135-137.
    CrossrefPubMedGoogle Scholar
  • 31 Calabrese E.J., Blain R. The hormesis database: an overview. Toxicol Appl Pharmacol 2005; 202: 289-300.
    CrossrefPubMedGoogle Scholar
  • 32 Calabrese E.J., Blain R.B. Hormesis and plant biology. Environ Poll 2009; 157: 42-46.
    CrossrefPubMedGoogle Scholar
  • 33 Calabrese E.J., Blain R.B. The hormesis database: the occurrence of hormetic dose responses in the toxicological literature. Reg Toxicol Pharmacol 2011; 61: 73-81.
    CrossrefPubMedGoogle Scholar
  • 34 Calabrese E.J., Bachmann K.A., Bailer A.J. et al. Biological stress response terminology: integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework. Toxicol Apppl Pharmacol 2007; 222: 122-128.
    PubMedGoogle Scholar
  • 35 Calabrese E.J. Hormesis: changing view of the dose-response, a personal account of history and current status. Mut Res 2002; 511: 181-189.
    PubMedGoogle Scholar
  • 36 Calabrese E.J. Paradigm lost, paradigm found: the re-emergence of hormesis as a fundamental dose response model in the toxicological sciences. Environ Poll 2005; 138: 379-412.
    PubMedGoogle Scholar
  • 37 Calabrese E.J. Hormesis in pharmacology. Hacker M., Bachmann K., Messer W. Pharmacology Principles and Practice, Chapter 5 2009. Academic Press; Burlington, MA: 75-102.
    Google Scholar
  • 38 Schulz H. Zur Lehre von der Arzneiwirdung. Virchows Archiv fur Pathol Anat Physiol Klin Med 1887; 108: 423-445.
    PubMedGoogle Scholar
  • 39 Schulz H. Uber Hefegifte. Pflugers Archiv Gesamte Physiol Menschen Tiere 1888; 42: 517-541.
    PubMedGoogle Scholar
  • 40 Calabrese E.J. Historical blunders: how toxicology got the dose-response relationship half right. Cell Mol Biol 2005; 51: 643-654.
    PubMedGoogle Scholar
  • 41 Crump T. Contemporary medicine as presented by its practitioners themselves. Translation of Leipzig, 1923:217–250. Nonlinear Biol Toxicol Med 2003; 1: 295-318.
    PubMedGoogle Scholar
  • 42 Branham S.E. The effects of certain chemical compounds upon the course of gas production by baker's yeast. J Bacteriol 1929; 18: 247-264.
    PubMedGoogle Scholar
  • 43 Southam C.M., Ehrlich J. Effects of extracts of western red-cedar heartwood on certain wood-decaying fungi in culture. Phytopathology 1943; 33: 517-524.
    PubMedGoogle Scholar
  • 44 Southam C.M. A study of the saprogenicity, and factors influencing decay, of certain brown-rot fungi on western red-cedar heartwood test blocks. 1941. University of Idaho, School of Forestry; Undergraduate Thesis (unpublished).
    Google Scholar
  • 45 Bellavite P., Andrioli G., Lussignoli S. et al. A scientific reappraisal of the ‘principle of similarity’. Med Hypoth 1997; 49: 203-212.
    CrossrefPubMedGoogle Scholar
  • 46 Bellavite P., Lussignoli S., Semizzi M.L., Ortolani R., Signorini A. The similia principle. From cellular models to regulation of homeostasis. Brit Hom J 1997; 86: 73-85.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Calabrese E.J., Baldwin L.A. Chemical hormesis: its historical foundations as a biological hypothesis. Hum Exper Toxicol 2000; 19: 2-31.
    CrossrefPubMedGoogle Scholar
  • 48 Calabrese E.J., Baldwin L.A. The marginalization of hormesis. Hum Exper Toxicol 2000; 19: 32-40.
    CrossrefPubMedGoogle Scholar
  • 49 Calabrese E.J., Baldwin L.A. Radiation hormesis: its historical foundations as a biological hypothesis. Hum Exper Toxicol 2000; 19: 41-75.
    CrossrefPubMedGoogle Scholar
  • 50 Calabrese E.J., Baldwin L.A. Radiation hormesis: the demise of a legitimate hypothesis. Hum Exper Toxicol 2000; 19: 76-84.
    CrossrefPubMedGoogle Scholar
  • 51 Calabrese E.J., Baldwin L.A. Tales of two similar hypotheses: the risk and fall of chemical and radiation hormesis. Hum Exper Toxicol 2000; 19: 85-97.
    CrossrefPubMedGoogle Scholar
  • 52 Salle A.J. Fundamental principles of bacteriology. 1939. McGraw-Hill Book Co.; New York: 166-167.
    Google Scholar
  • 53 Clifton C.E. Introduction to bacterial physiology. 1957. McGraw-Hill Book Co., Inc.; New York: 317-338.
    Google Scholar
  • 54 Hueppe F. Principles of bacteriology. Translated from the German by EO Jordan. 1896. The Open Court Publishing Co; Chic IL.:
    Google Scholar
  • 55 Calabrese E.J. Hormesis: why it is important to toxicology and toxicologists. Environ Toxicol Chem 2008; 27: 1451-1474.
    CrossrefPubMedGoogle Scholar
  • 56 Calabrese E.J. Toxicology rewrites its history and rethinks its future: giving equal focus to both harmful and beneficial effects. Environ Toxicol Chem 2011; 30: 2658-2673.
    CrossrefPubMedGoogle Scholar
  • 57 Calabrese E.J., Baldwin L.A. The frequency of U-shaped dose responses in the toxicological literature. Toxicol Sci 2001; 62: 330-338.
    CrossrefPubMedGoogle Scholar
  • 58 Calabrese E.J., Baldwin L.A. The hormetic dose response model is more common than the threshold model in toxicology. Toxicol Sci 2003; 71: 246-250.
    CrossrefPubMedGoogle Scholar
  • 59 Calabrese E.J., Staudenmayer J.W., Stanek E.J., Hoffmann G.R. Hormesis outperforms threshold model in National Cancer Institute antitumor drug screening database. Toxicol Sci 2006; 92: 368-378.
    CrossrefPubMedGoogle Scholar
  • 60 Calabrese E.J., Stanek E.J., Nascarella M.A., Hoffmann G.R. Hormesis predicts low-dose responses better than threshold model. Intern J Toxicol 2008; 27: 369-378.
    PubMedGoogle Scholar
  • 61 Calabrese E.J. Hormetic dose-response relationships in immunology: occurrence, quantitative features of the dose response, mechanistic foundations, and clinical implications. Crit Rev Toxicol 2005; 35: 89-295.
    CrossrefPubMedGoogle Scholar
  • 62 Calabrese E.J., Baldwin L.A. (Guest Editors) Scientific foundations of hormesis. Crit Rev Toxicol 2001; 31: 351-695.
    CrossrefPubMedGoogle Scholar
  • 63 Calabrese E.J. Hormetic mechanisms. Crit Rev Toxicol 2013; 43: 580-606.
    CrossrefPubMedGoogle Scholar
  • 64 Calabrese E.J. Hormesis: from marginalization to mainstream. A case for hormesis as the default dose-response model in risk assessment. Toxicol Appl Pharmacol 2004; 197: 125-136.
    CrossrefPubMedGoogle Scholar
  • 65 Calabrese E.J., Baldwin L.A. Hormesis as a default parameter in RfD derivation. Hum Exper Toxicol 1998; 17: 444-447.
    CrossrefPubMedGoogle Scholar
  • 66 Calabrese E.J., Cook R.R. Hormesis: how it could affect the risk assessment process. Hum Exper Toxicol 2005; 24: 265-270.
    CrossrefPubMedGoogle Scholar
  • 67 Druckrey H. Quantitative aspects in chemical carcinogenesis. UICC Monogr Ser 1967; 7: 60-78.
    PubMedGoogle Scholar
  • 68 Jones H.B., Grendon A. Environmental factors in the origin of cancer and estimation of the possible hazard to man. Fd Cosmet Toxicol 1975; 13: 251-268.
    CrossrefPubMedGoogle Scholar
  • 69 Jones H. Dose-effect relationships in carcinogenesis and the matter of threshold of carcinogenesis. Environ Health Persp 1978; 22: 171-172.
    PubMedGoogle Scholar
  • 70 Scribner J.D., Süss R. Tumor initiation and promotion. Inter Rev Exper Pathol 1978; 18: 137-198.
    PubMedGoogle Scholar
  • 71 Mitchell R.E.J. Low doses of radiation reduce risk in vivo. 14th Pacific Basin Nuclear Conference. Honolulu, HI 2004. March 21–25.
    Google Scholar
  • 72 Flood J.F., Cherkin A. Memory retention – enhancement by cholinergic drug-combinations in mice. Gerontology 1982; 22: 230-231.
    PubMedGoogle Scholar
  • 73 Flood J.F., Smith G.E., Cherkin A. Memory retention – potentiation of cholinergic drug-combinations in mice. Neurobiol Aging 1983; 4: 37-43.
    CrossrefPubMedGoogle Scholar
  • 74 Flood J.F., Smith G.E., Cherkin A. Memory retention – enhancement by syntergistic oral cholinergic drug-combination in mice. Gerontology 1984; 24: 149.
    PubMedGoogle Scholar
  • 75 Flood J.F., Smith G.E., Cherkin A. Memory enhancement – supra-additive effect of subcutaneous cholinergic drug-combinations in mice. Psychopharmacology 1985; 86: 61-67.
    CrossrefPubMedGoogle Scholar
  • 76 Calabrese E.J. Hormesis: Principles and applications for pharmacology and toxicology. Amer J Pharm Toxicol 2008; 3: 59-71.
    PubMedGoogle Scholar
  • 77 Calabrese E.J., Baldwin L.A. A general classification of U-shaped dose-response relationships in toxicology and their mechanistic foundations. Hum Exper Toxicol 1998; 17: 353-364.
    CrossrefPubMedGoogle Scholar