Hormesis is central to toxicology, pharmacology and risk assessment

This paper summarizes numerous conceptual and experimental advances over the past two decades in the study of hormesis. Hormesis is now generally accepted as a real and reproducible biological phenomenon, being highly generalized and independent of biological model, endpoint measured and chemical class/physical stressor. The quantitative features of the hormetic dose response are generally highly consistent, regardless of the model and mechanism, and represent a quantitative index of biological plasticity at multiple levels of biological organization. The hormetic dose-response model has been demonstrated to make far more accurate predictions of responses in low dose zones than either the threshold or linear at low dose models. Numerous therapeutic agents widely used by humans are based on the hormetic dose response and its low dose stimulatory characteristics. It is expected that as low dose responses come to dominate toxicological research that risk assessment practices will incorporate hormetic concepts in the standard setting process.

[1]  J. Dahm-Daphi,et al.  Indicators of late normal tissue response after radiotherapy for head and neck cancer: fibroblasts, lymphocytes, genetics, DNA repair, and chromosome aberrations. , 2002, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[2]  K. Fukunaga,et al.  Stimulatory effect of suramin on the proliferation of human glioma cells. , 1995, Anticancer research.

[3]  C. Mothersill,et al.  Radiation-induced Bystander Effects: Are They Good, Bad or Both? , 2005, Medicine, conflict, and survival.

[4]  E. Calabrese Astrocytes: Adaptive Responses to Low Doses of Neurotoxins , 2008, Critical reviews in toxicology.

[5]  M. Subbiah Nutrigenetics and nutraceuticals: the next wave riding on personalized medicine. , 2007, Translational research : the journal of laboratory and clinical medicine.

[6]  J. S. Sonneborn Hormetic Triggers for Intervention in Aging, Disease and Trauma , 2008 .

[7]  J. Flood,et al.  Memory enhancement: Supra-additive effect of subcutaneous cholinergic drug combinations in mice , 2004, Psychopharmacology.

[8]  Nations United sources and effects of ionizing radiation , 2000 .

[9]  A C Upton,et al.  Comments on the article ‘Defining hormesis’, by EJ Calabrese and LA Baldwin , 2002, Human & experimental toxicology.

[10]  Aditiawarman,et al.  Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia: a double-blind cluster-randomised trial , 2008, The Lancet.

[11]  E. Calabrese Pain and U-Shaped Dose Responses: Occurrence, Mechanisms, and Clinical Implications , 2008, Critical reviews in toxicology.

[12]  E. Calabrese Cancer Biology and Hormesis: Human Tumor Cell Lines Commonly Display Hormetic (Biphasic) Dose Responses , 2005, Critical reviews in toxicology.

[13]  L. Lave Hormesis: implications for public policy regarding toxicants. , 2001, Annual review of public health.

[14]  K. Hirschi,et al.  Ouabain- and Marinobufagenin-Induced Proliferation of Human Umbilical Vein Smooth Muscle Cells and a Rat Vascular Smooth Muscle Cell Line, A7r5 , 2003, Circulation.

[15]  L. Binderup,et al.  Delayed hypersensitivity to tuberculin in rats: effects of antirheumatic drugs. , 2009, Acta pharmacologica et toxicologica.

[16]  A. Stebbing,et al.  A theory for growth hormesis. , 1998, Mutation research.

[17]  H. Chen,et al.  Vitamin A for preventing acute lower respiratory tract infections in children up to seven years of age. , 2008, The Cochrane database of systematic reviews.

[18]  C. Muirhead,et al.  Moderate dose rate ionizing radiation increases longevity? , 2005, The British journal of radiology.

[19]  M. Washington,et al.  TGF-ß Signaling in Fibroblasts Modulates the Oncogenic Potential of Adjacent Epithelia , 2004, Science.

[20]  E. Calabrese Modulation of the Epileptic Seizure Threshold: Implications of Biphasic Dose Responses , 2008, Critical reviews in toxicology.

[21]  C. Mothersill,et al.  Radiation-induced bystander effects and the DNA paradigm: an "out of field" perspective. , 2006, Mutation research.

[22]  Alvin M. Weinberg,et al.  Science and trans-science , 1972, Nature.

[23]  E J Calabrese,et al.  Defining hormesis , 2002, Human & experimental toxicology.

[24]  E. Calabrese Hormesis: Principles and Applications for Pharmacology and Toxicology , 2008 .

[25]  E. Calabrese,et al.  The Dose Determines the Stimulation (and Poison): Development of A Chemical Hormesis Database , 1997 .

[26]  J. Flood,et al.  Memory retention: potentiation of cholinergic drug combinations in mice , 1983, Neurobiology of Aging.

[27]  E. Calabrese,et al.  Chemotherapeutics and Hormesis , 2003, Critical reviews in toxicology.

[28]  W. A. Randall,et al.  Demonstration of Hormesis (Increase in Fatality Rate) by Penicillin. , 1947, American journal of public health and the nation's health.

[29]  B. Scott It's Time for a New Low-Dose-Radiation Risk Assessment Paradigm—One that Acknowledges Hormesis , 2008, Dose-response : a publication of International Hormesis Society.

[30]  E. Calabrese Drug Therapies for Stroke and Traumatic Brain Injury Often Display U-Shaped Dose Responses: Occurrence, Mechanisms, and Clinical Implications , 2008, Critical reviews in toxicology.

[31]  E. Calabrese,et al.  Hormesis and high-risk groups. , 2002, Regulatory toxicology and pharmacology : RTP.

[32]  Zbigniew Jaworowski,et al.  Radiation Risk and Ethics , 1999 .

[33]  D. Carter,et al.  Characterization of U-101017 as a GABAA receptor ligand of dual functionality , 1996, Brain Research.

[34]  E. Calabrese P-Glycoprotein Efflux Transporter Activity Often Displays Biphasic Dose-Response Relationships , 2008, Critical reviews in toxicology.

[35]  J. D. Petke,et al.  Piperazine imidazo[1,5-a]quinoxaline ureas as high-affinity GABAA ligands of dual functionality. , 1999, Journal of medicinal chemistry.

[36]  R. Clarke Control of low-level radiation exposure: time for a change? , 1999, Journal of radiological protection : official journal of the Society for Radiological Protection.

[37]  J. D. Petke,et al.  High-affinity partial agonist imidazo[1,5-a]quinoxaline amides, carbamates, and ureas at the gamma-aminobutyric acid A/benzodiazepine receptor complex. , 1996, Journal of medicinal chemistry.

[38]  A. D. Sakharov Radioactive carbon from nuclear explosion and nonthreshold biological effects , 1958 .

[39]  E. Calabrese,et al.  Inorganics and Hormesis , 2003, Critical reviews in toxicology.

[40]  Edward J Calabrese,et al.  Neuroscience and Hormesis: Overview and General Findings , 2008, Critical reviews in toxicology.

[41]  Henry I. Kohn,et al.  Sources, Effects and Risks of Ionizing Radiation , 1989 .

[42]  Edward J. Calabrese,et al.  The Importance of Hormesis to Public Health , 2006, Environmental health perspectives.

[43]  E J Calabrese,et al.  Historical blunders: how toxicology got the dose-response relationship half right. , 2005, Cellular and molecular biology.

[44]  Edward J. Calabrese,et al.  Converging concepts: Adaptive response, preconditioning, and the Yerkes–Dodson Law are manifestations of hormesis , 2008, Ageing Research Reviews.

[45]  J. Bailar,et al.  Toxicity Testing in the 21st Century: A Vision and a Strategy , 2010, Journal of toxicology and environmental health. Part B, Critical reviews.

[46]  L E Feinendegen,et al.  Evidence for beneficial low level radiation effects and radiation hormesis. , 2005, The British journal of radiology.

[47]  Shu-zheng Liu,et al.  Therapeutic effect of gene-therapy in combination with local X-irradiation in a mouse malignant melanoma model. , 2005, Biochemical and biophysical research communications.

[48]  E J Calabrese,et al.  Hormesis: U-shaped dose responses and their centrality in toxicology. , 2001, Trends in pharmacological sciences.

[49]  S. Wolff Are radiation-induced effects hormetic? , 1989, Science.

[50]  E. Calabrese Dopamine: Biphasic Dose Responses , 2001, Critical reviews in toxicology.

[51]  E. Calabrese Adrenergic Receptors: Biphasic Dose Responses , 2001, Critical reviews in toxicology.

[52]  E J Calabrese,et al.  Estrogen and Related Compounds: Biphasic Dose Responses , 2001, Critical reviews in toxicology.

[53]  R. Jennings,et al.  Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. , 1986, Circulation.

[54]  E. Calabrese Pharmacological Enhancement of Neuronal Survival , 2008, Critical reviews in toxicology.

[55]  W. J. Meredith Report of the United Nations Scientific Committee on the Effects of Atomic Radiation , 1967 .

[56]  S. Molloi,et al.  Mechanisms of suppression of neoplastic transformation in vitro by low doses of low LET radiation. , 2003, Carcinogenesis.

[57]  E. Calabrese,et al.  Hormesis Predicts Low-Dose Responses Better Than Threshold Models , 2008, International journal of toxicology.

[58]  E. Calabrese,et al.  Hormesis and plant biology. , 2009, Environmental pollution.

[59]  E. Calabrese Hormesis: from marginalization to mainstream: a case for hormesis as the default dose-response model in risk assessment. , 2004, Toxicology and applied pharmacology.

[60]  P. Bossuyt,et al.  Glycine does not add to the beneficial effects of perioperative oral immune-enhancing nutrition supplements in high-risk cardiac surgery patients. , 2007, JPEN. Journal of parenteral and enteral nutrition.

[61]  E. Calabrese Enhancing and Regulating Neurite Outgrowth , 2008, Critical reviews in toxicology.

[62]  P. Selby,et al.  Description of first germinal mosaic mutation identified in dominant skeletal mutation experiments and considerations about how to deal with this kind of spontaneous mutation in analyses. , 2004, Mutation research.

[63]  F. Tortella,et al.  Neuroprotection from glutamate toxicity with ultra-low dose glutamate , 2001, Neuroreport.

[64]  C. Teng,et al.  Dual effects of ouabain on the regulation of proliferation and apoptosis in human prostatic smooth muscle cells. , 2001, The Journal of urology.

[65]  Shigeru Kobayashi,et al.  Existence of a threshold-like dose for gamma-ray induction of thymic lymphomas and no susceptibility to radiation-induced solid tumors in SCID mice. , 2007, Mutation research.

[66]  Edward J Calabrese,et al.  Drug development and hormesis: changing conceptual understanding of the dose response creates new challenges and opportunities for more effective drugs. , 2006, Current opinion in drug discovery & development.

[67]  E. Calabrese Adenosine: Biphasic Dose Responses , 2001, Critical reviews in toxicology.

[68]  Edward J Calabrese,et al.  Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework. , 2007, Toxicology and applied pharmacology.

[69]  R. van Wijk,et al.  Mild step-down heating causes increased levels of HSP68 and of HSP84 mRNA and enhances thermotolerance. , 1994, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[70]  R. Yehuda POST-TRAUMATIC STRESS DISORDER , 1985, The Lancet.

[71]  E. Calabrese 5-Hydroxytryptamine (Serotonin): Biphasic Dose Responses , 2001, Critical reviews in toxicology.

[72]  S. Rattan,et al.  Heat Stress and Hormetin-Induced Hormesis in Human Cells: Effects on Aging, Wound Healing, Angiogenesis, and Differentiation , 2009, Dose-response : a publication of International Hormesis Society.

[73]  E. Calabrese Stress Biology and Hormesis: The Yerkes–Dodson Law in Psychology—A Special Case of the Hormesis Dose Response , 2008, Critical reviews in toxicology.

[74]  L. Taylor SOME NON-SCIENTIFIC INFLUENCES ON RADIATION PROTECTION STANDARDS AND PRACTICE , 1980 .

[75]  Fiona M. Lyng,et al.  A Dose Threshold for a Medium Transfer Bystander Effect for a Human Skin Cell Line , 2006, Radiation research.

[76]  N. Zvaifler,et al.  LYMPHOCYTE ALTERATION BY PROCAINAMIDE: RELATION TO DRUG-INDUCED LUPUS ERYTHEMATOSUS SYNDROME , 1979, The Lancet.

[77]  D. Averbeck,et al.  Recent reports on the effect of low doses of ionizing radiation and its dose–effect relationship , 2006, Radiation and environmental biophysics.

[78]  A. Barabasi,et al.  Predicting synthetic rescues in metabolic networks , 2008, Molecular systems biology.

[79]  S. Molloi,et al.  Neoplastic Transformation In Vitro after Exposure to Low Doses of Mammographic-Energy X Rays: Quantitative and Mechanistic Aspects , 2004, Radiation research.

[80]  Dudley Lamming,et al.  MicroReview: Small molecules that regulate lifespan: evidence for xenohormesis , 2004, Molecular microbiology.

[81]  G. Murrell,et al.  Modulation of fibroblast proliferation by oxygen free radicals , 1990 .

[82]  E. Calabrese Getting the dose–response wrong: why hormesis became marginalized and the threshold model accepted , 2009, Archives of Toxicology.

[83]  M Tubiana,et al.  The debate on the use of linear no threshold for assessing the effects of low doses , 2006, Journal of radiological protection : official journal of the Society for Radiological Protection.

[84]  E. Calabrese U-Shaped Dose Response in Behavioral Pharmacology: Historical Foundations , 2008, Critical reviews in toxicology.

[85]  E. Calabrese Opiates: Biphasic Dose Responses , 2001, Critical reviews in toxicology.

[86]  G. Webb The 'controllable dose' debate: results of the IRPA consultation exercise. , 2000, Journal of radiological protection : official journal of the Society for Radiological Protection.

[87]  Tanya K. Day,et al.  Extremely Low Priming Doses of X Radiation Induce an Adaptive Response for Chromosomal Inversions in pKZ1 Mouse Prostate , 2006, Radiation research.

[88]  Edward J. Calabrese,et al.  Hormesis: Why it is important to toxicology and toxicologists , 2008 .

[89]  Samuel Glasstone,et al.  The Effects of Nuclear Weapons , 1952 .

[90]  E. Calabrese,et al.  Hormesis: how it could affect the risk assessment process , 2005, Human & experimental toxicology.

[91]  E. Calabrese,et al.  A general classification of U-shaped dose-response relationships in toxicology and their mechanistic foundations , 1998, Human & experimental toxicology.

[92]  E. Calabrese,et al.  The frequency of U-shaped dose responses in the toxicological literature. , 2001, Toxicological sciences : an official journal of the Society of Toxicology.

[93]  K. Linde,et al.  Systematic clinical auditing in complementary medicine: rationale, concept, and a pilot study. , 1997, Alternative therapies in health and medicine.

[94]  Thomas B. Walker,et al.  Failure of Rhodiola rosea to alter skeletal muscle phosphate kinetics in trained men. , 2007, Metabolism: clinical and experimental.

[95]  E. Calabrese Hormetic dose-response relationships in immunology: occurrence, quantitative features of the dose response, mechanistic foundations, and clinical implications. , 2005, Critical reviews in toxicology.

[96]  A. Nicolosi,et al.  Abstract 1573: Gadolinium Limits Myocardial Infarction in the Rat: Dose-Response, Temporal Relations and Mechanisms , 2007 .

[97]  Edward J. Hanna The revenge of Gaia , 2006 .

[98]  E. Calabrese Prostaglandins: biphasic dose responses. , 2001, Critical reviews in toxicology.

[99]  Unoda Treaty banning Nuclear Weapon tests in the atmosphere, in outer space and under water , 1970 .

[100]  E. Calabrese Alzheimer's Disease Drugs: An Application of the Hormetic Dose-Response Model , 2008, Critical reviews in toxicology.

[101]  G. Schlapper Hormesis with Ionizing Radiation , 1983 .

[102]  J. M. Davies,et al.  Transient adaptation to oxidative stress in yeast. , 1995, Archives of biochemistry and biophysics.

[103]  T. Koana,et al.  Reduction of Background Mutations by Low-Dose X Irradiation of Drosophila Spermatocytes at a Low Dose Rate , 2007, Radiation research.

[104]  X. Lao,et al.  Neoplastic transformation in vitro induced by low doses of 232 MeV protons , 2005, International journal of radiation biology.

[105]  C. P. Oliver THE EFFECT OF VARYING THE DURATION OF X-RAY TREATMENT UPON THE FREQUENCY OF MUTATION. , 1930, Science.

[106]  Gary F. Bennett,et al.  International basic safety standards for protection against ionizing radiation of and for the safety of radiation sources , 1996 .

[107]  T. Mäkelä,et al.  Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization , 2007, Proceedings of the National Academy of Sciences.

[108]  L. Sagan On radiation, paradigms, and hormesis. , 1989, Science.

[109]  N. Cedergreen,et al.  Hormesis in mixtures -- can it be predicted? , 2008, The Science of the total environment.

[110]  E. Calabrese Androgens: Biphasic Dose Responses , 2001, Critical reviews in toxicology.

[111]  G. Hoffmann A Perspective on the Scientific, Philosophical, and Policy Dimensions of Hormesis , 2009, Dose-response : a publication of International Hormesis Society.

[112]  Edward J Calabrese,et al.  Toxicology rethinks its central belief , 2003, Nature.

[113]  Michael Uder,et al.  In vivo formation and repair of DNA double-strand breaks after computed tomography examinations. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[114]  L. Magos,et al.  The inhibitory effect of serum from diethyldithiocarbamate treated rats on bovine adrenal dopamine‐β‐hydroxylase activity , 1981, Journal of applied toxicology : JAT.

[115]  E. Calabrese Addiction and Dose Response: The Psychomotor Stimulant Theory of Addiction Reveals That Hormetic Dose Responses Are Dominant , 2008, Critical reviews in toxicology.

[116]  E J Calabrese,et al.  The Future of Hormesis: Where Do We Go from Here? , 2001, Critical reviews in toxicology.

[117]  G. Högberg,et al.  Treatment of post-traumatic stress disorder with eye movement desensitization and reprocessing: Outcome is stable in 35-month follow-up , 2008, Psychiatry Research.

[118]  R. Doll,et al.  Lung Cancer and Other Causes of Death in Relation to Smoking , 1956, British medical journal.

[119]  E. Calabrese,et al.  Dose-Response Features of Neuroprotective Agents: An Integrative Summary , 2008, Critical reviews in toxicology.

[120]  E. Calabrese Nitric Oxide: Biphasic Dose Responses , 2001, Critical reviews in toxicology.

[121]  P. Selby Major impacts of gonadal mosaicism on hereditary risk estimation, origin of hereditary diseases, and evolution , 2004, Genetica.

[122]  Tanya K. Day,et al.  Adaptive Response for Chromosomal Inversions in pKZ1 Mouse Prostate Induced by Low Doses of X Radiation Delivered after a High Dose , 2007, Radiation research.

[123]  E. Calabrese An Assessment of Anxiolytic Drug Screening Tests: Hormetic Dose Responses Predominate , 2008, Critical reviews in toxicology.

[124]  Edward J Calabrese,et al.  Hormesis outperforms threshold model in National Cancer Institute antitumor drug screening database. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[125]  E J Calabrese,et al.  Hormesis: A Highly Generalizable and Reproducible Phenomenon With Important Implications for Risk Assessment , 1999, Risk analysis : an official publication of the Society for Risk Analysis.

[126]  E. Calabrese Hormesis and medicine. , 2008, British journal of clinical pharmacology.

[127]  Edward J. Calabrese,et al.  The road to linearity: why linearity at low doses became the basis for carcinogen risk assessment , 2009, Archives of Toxicology.

[128]  C. Dalgård,et al.  No influence of increased intake of orange and blackcurrant juices and dietary amounts of vitamin E on paraoxonase-1 activity in patients with peripheral arterial disease , 2007, European journal of nutrition.

[129]  E. Calabrese,et al.  Ethanol and Hormesis , 2003, Critical reviews in toxicology.

[130]  C. Mothersill,et al.  Genetic Factors Influencing Bystander Signaling in Murine Bladder Epithelium after Low-Dose Irradiation In Vivo , 2005, Radiation research.

[131]  E. Calabrese,et al.  Stimulation of Growth of Peppermint (Mentha piperita) by Phosfon, a Growth Retardant , 1976 .

[132]  T. Kokunai,et al.  Effect of dexamethasone on cell proliferation of neuroepithelial tumor cell lines. , 1998, Neurologia medico-chirurgica.

[133]  J. Redpath,et al.  Detrimental and Protective Bystander Effects: A Model Approach , 2007, Radiation research.

[134]  B. Scott Low-Dose Radiation-Induced Protective Process and Implications for Risk Assessment, Cancer Prevention, and Cancer Therapy , 2007, Dose-response : a publication of International Hormesis Society.

[135]  H. Tanooka,et al.  Suppression of Thymic Lymphoma Induction by Life-Long Low-Dose-Rate Irradiation Accompanied by Immune Activation in C57BL/6 Mice , 2005, Radiation research.

[136]  E. Calabrese Evidence that hormesis represents an "overcompensation" response to a disruption in homeostasis. , 1999, Ecotoxicology and environmental safety.

[137]  E. Calabrese,et al.  The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview. , 2005, Toxicology and applied pharmacology.

[138]  Edward J Calabrese,et al.  The hormetic dose-response model is more common than the threshold model in toxicology. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[139]  R. Macklis,et al.  Radiation hormesis. , 1991, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[140]  D. V. Law,et al.  Mortality of employees of the United Kingdom Atomic Energy Authority, 1946–97 , 1985, Occupational and Environmental Medicine.

[141]  Y. Takashima,et al.  A Threshold Exists in the Dose–Response Relationship for Somatic Mutation Frequency Induced by X Irradiation of Drosophila , 2004, Radiation research.

[142]  B. Lindell [Radiation and health]. , 1987, Bulletin of the World Health Organization.

[143]  H. Muller,et al.  The manner of dependence of the permissible dose of radiation on the amount of genetic damage. , 1954, Acta radiologica.

[144]  Ronald H. White,et al.  State-of-the-Science Workshop Report: Issues and Approaches in Low-Dose–Response Extrapolation for Environmental Health Risk Assessment , 2008, Environmental health perspectives.

[145]  Wayne B Jonas,et al.  Deconstructing the Placebo Effect and Finding the Meaning Response , 2002, Annals of Internal Medicine.