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The ability to adapt to varying levels of available energy in the form of food in the environment has allowed species to propagate and also thrive during times of energy surplus. However, in times when there is scant food available, similar evolutionary pressures have ensured that physiological systems can adapt to and utilize this food scarcity to their advantage. Considerable research has demonstrated that upon reduction of food intake, there are several beneficial effects upon cardiovascular, endocrinological, immune, and neuronal systems. Some of the effects of caloric restriction, however, tend to be exaggerated in many experimental cases due to biasing of overweight control subjects, yet reduction of total body weight still seems to engender beneficial effects for the individual. Some of the beneficial effects of caloric restriction are believed to arise from a reflexive response to the “stress” of reduced food intake. In conjunction with this is a similar hypothesis, known as “hormesis,” which proposes in a similar vein that other forms of stress, such as toxicological stress, can also engender a “protective” set of physiological responses that shields the individual from further stresses. This chapter discusses how these two theories of protective responses—caloric restriction and hormesis—share many overlapping properties. KeywordsCaloric restriction-Energy homeostasis-Endocrinological-Neuroprotective-Adaptive-Evolutionary
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Hormesis
Mark P. Mattson ·Edward J. Calabrese
Editors
Hormesis
A Revolution in Biology, Toxicology
and Medicine
123
Editors
Mark P. Mattson
Laboratory of Neurosciences
GRC 4F01
National Institute on Aging
5600 Nathan Shock Drive
Baltimore, MD 21224
USA
mattsonm@grc.nia.nih.gov
Edward J. Calabrese
Department of Environmental Health
Sciences
University of Massachusetts
Northeast Regional
Environmental Public
N344 Morrill Science Center
Amherst, MA 01003-5712
USA
edward@schoolph.umass.edu
ISBN 978-1-60761-494-4 e-ISBN 978-1-60761-495-1
DOI 10.1007/978-1-60761-495-1
Springer New York Dordrecht Heidelberg London
Library of Congress Control Number: 2009938828
© Springer Science+Business Media, LLC 2010
All rights reserved. This work may not be translated or copied in whole or in part without the written
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Preface
The term hormesis is defined as “a process in which exposure to a low dose of a
chemical agent or environmental factor that is damaging at higher doses induces an
adaptive beneficial effect on the cell or organism” (Calabrese et al., 2007; Mattson,
2008). To survive and reproduce in harsh competitive environments, organisms and
their cellular components have, through evolution, developed molecular mecha-
nisms to respond adaptively to various hazards or “stressors” that they encounter.
Examples of such stressors include chemicals ingested in food and water (metals,
phytochemicals, etc.), increased energy expenditure (running, fighting, cognitive
challenges, etc.), and reduced energy availability (food scarcity), among others. In
most cases, the response of the cell or organism to the stressor exhibits a biphasic
dose response, with beneficial/adaptive responses at low doses (improved func-
tion, increased resistance to damage and disease) and adverse/destructive effects
(dysfunction, molecular damage, or even death) at high doses. The prevalence of
the biphasic (hormetic) dose response characteristic of biological systems merits
consideration of hormesis as a fundamental principle of biology.
In this book, my colleagues and I present evidence from a range of biological sys-
tems that hormesis is indeed at the epicenter of the molecular and cellular responses
to their environment. Many of the thousands of examples of hormesis (biphasic
dose responses with stimulatory/beneficial effects at low doses and inhibitory/toxic
effects at high doses) come from the field of toxicology (Calabrese, 2008), and yet
the Environmental Protection Agency (EPA) continues to largely ignore the impor-
tant scientific fact of the biphasic dose response. Their approach is to reduce the
levels of “toxins” in the environment as much as possible. However, it is clear that
at least in some cases human health may be adversely affected by removing “toxic”
chemicals from the environment. Prominent examples are metals such as selenium,
zinc, and iron, all of which are toxic when consumed in high amounts but are essen-
tial for health in low amounts (Dodig and Cepelak, 2004; Frassinetti et al., 2006;
Wright and Baccarelli, 2007). Other major, emerging examples are phytochemi-
cals that function as insect repellants (toxins) in plants but stimulate adaptive stress
response pathways when consumed by humans (Cheng and Mattson, 2006).
Of interest, many endogenous cellular signaling pathways exert their effects on
cellular physiology (cell division, the growth of muscle and nerve cells, and even
v
vi Preface
behaviors such as learning and memory) through hormetic mechanisms. For exam-
ple, the excitatory neurotransmitter glutamate is released from presynaptic terminals
at synapses, where it then activates receptors that are coupled to calcium influx
into the dendrites of the postsynaptic neuron. In this way glutamate plays a fun-
damental role in the function of neuronal circuits involved in sensory processing,
motor responses, learning and memory, and emotional behaviors. These low lev-
els of glutamate also activate adaptive stress responses that include the production
of proteins that help to protect the neurons against more-severe stress. These stress
resistance proteins include neurotrophic factors, antioxidant enzymes, and antiapop-
totic proteins such as Bcl2. However, abnormally high levels of glutamate resulting
from increased release and/or decreased removal at synapses can cause the degen-
eration and death of neurons. The latter neurotoxic effects of excessive activation
of glutamate receptors occur in patients with epilepsy, stroke, traumatic brain and
spinal cord injury, and possibly Alzheimer’s, Parkinson’s, and Huntington’s dis-
eases. The situation is similar with other signaling pathways in other tissues and
organs. Consequently, the scientific and biomedical professions should work to elu-
cidate the molecular components of hormetic signaling pathways and apply that
knowledge to the development of novel hormesis-based preventative and therapeutic
interventions for many different human diseases.
This book comprises 10 chapters, with contributions from more than a dozen
authors to the writing of one or more of the chapters. The first chapter describes the
concept of hormesis, the prevalence of biphasic dose responses in biological sys-
tems, and implications of hormesis for the future of science, medicine, and public
policy decisions. The second chapter focuses on the role of hormesis in toxicology
and risk assessment, with a focus on environmental toxins. A chapter that consid-
ers hormesis from an evolutionary perspective provides several examples of how
organisms not only developed mechanisms to respond adaptively to “toxins,” but
also actually incorporated those chemicals into their metabolic systems. The next
three chapters describe several of the most highly conserved signaling mechanisms
that mediate hormetic responses of cells and organisms exposed to subtoxic doses
of chemicals and other stressors. These include G protein–coupled receptors and
signaling pathways that lead to the induction of genes that encode cytoprotective
proteins such as heat-shock proteins, antioxidant enzymes, and growth factors. The
complexity of receptor systems and cellular responses provides a rich venue for
understanding the intricacies of the molecular mediators of hormesis. The health
benefits of exercise and dietary modification (particularly dietary energy restriction)
are well known. Two chapters provide evidence that many of the beneficial effects
of exercise and dietary modification result from activation of hormetic signaling
pathways in cells throughout the body.
Particularly intriguing are the prominent hormetic effects of exercise and dietary
energy restriction on brain health. Data suggest that hormetic mechanisms may be
compromised during aging, and such impairments may contribute to the develop-
ment of a range of age-related diseases. We are in the midst of an epidemic of
obesity and diabetes in the United States, and this major health problem is spread-
ing to industrialized countries in all continents. A chapter describes evidence that
Preface vii
the “couch potato” lifestyle that causes obesity and diabetes does so, in part, by sup-
pressing the activation of hormetic response pathways. The book concludes with a
chapter entitled The Hormetic Pharmacy that considers the role of hormesis-based
mechanisms of action in the future of natural products and man-made drugs for dis-
ease prevention and treatment. Early in the 16th century, Paracelsus recognized that
all drugs are poisonous at high doses and that careful evaluation of dose-response
relationships are necessary for optimizing treatments. In this book we emphasize
our newer recognition of the great potential of hormesis-based approaches for drug
discovery, as well as for the optimization of dietary and lifestyle factors to improve
the quality of life.
References
Calabrese EJ et al. (2007) Biological stress response terminology: integrating the concepts of adap-
tive response and preconditioning stress within a hormetic dose-response framework. Toxicol
Appl Pharmacol 222: 122–128.
Calabrese EJ (2008) Hormesis: why it is important to toxicology and toxicologists. Environ Toxicol
Chem. 27:1451–1474.
Cheng A, Mattson MP (2006) Neurohormetic phytochemicals: low-dose toxins that induce
adaptive neuronal stress responses. Trends Neurosci 29: 632–639.
Dodig S, Cepelak I (2004) The facts and controversies about selenium. Acta Pharm 54: 261–276.
Frassinetti S, Bronzetti G, Caltavuturo L, Cini M, Croce CD (2006) The role of zinc in life: a
review. J Environ Pathol Toxicol Oncol 25: 597–610.
Mattson MP (2008) Hormesis defined. Ageing Res Rev 7: 1–7.
Wright RO, Baccarelli A (2007) Metals and neurotoxicology. J Nutr 137: 2809–2813.
Baltimore, Maryland Mark P. Mattson
Contents
Hormesis: What It Is and Why It Matters ................. 1
Mark P. Mattson and Edward J. Calabrese
Hormesis: Once Marginalized, Evidence Now Supports
Hormesis as the Most Fundamental Dose Response ............ 15
Edward J. Calabrese
The Fundamental Role of Hormesis in Evolution ............. 57
Mark P. Mattson
Transcriptional Mediators of Cellular Hormesis ............. 69
Tae Gen Son, Roy G. Cutler, Mark P. Mattson,
and Simonetta Camandola
The Devil Is in the Dose: Complexity of Receptor Systems
and Responses ................................ 95
Wayne Chadwick and Stuart Maudsley
Exercise-Induced Hormesis ......................... 109
Alexis M. Stranahan and Mark P. Mattson
Dietary Energy Intake, Hormesis, and Health ............... 123
Bronwen Martin, Sunggoan Ji, Caitlin M. White, Stuart Maudsley,
and Mark P. Mattson
Couch Potato: The Antithesis of Hormesis ................. 139
Mark P. Mattson, Alexis Stranahan, and Bronwen Martin
Hormesis and Aging ............................. 153
Suresh I.S. Rattan and Dino Demirovic
The Hormetic Pharmacy: The Future of Natural Products
and Man-Made Drugs in Disease Prevention and Treatment ....... 177
Edward J. Calabrese and Mark P. Mattson
Index ..................................... 199
ix
About the Editors
Mark P. Mattson, Ph.D., is Chief of the Laboratory of Neurosciences at the National
Institute on Aging in Baltimore, where he leads a multifaceted research team that
applies cutting-edge technologies in research aimed at understanding molecular and
cellular mechanisms of brain aging and the pathogenesis of neurodegenerative dis-
orders. He is also a professor in the Department of Neuroscience at Johns Hopkins
University School of Medicine. He has published more than 450 original research
articles and numerous review articles and has edited 10 books in the areas of mecha-
nisms of aging and neurodegenerative disorders. Dr. Mattson has trained more than
60 postdoctoral and predoctoral students and is the most highly cited neuroscientist
in the world.
Edward J. Calabrese, Ph.D., is a professor and Program Director of
Environmental Health Science at the University of Massachusetts in Amherst. His
research focuses on environmental toxicology, with an emphasis on biological fac-
tors, including genetic and nutritional factors that enhance susceptibility to pollutant
toxicity and the environmental implications of toxicological hormesis. Dr. Calabrese
has researched extensively in the area of host factors affecting susceptibility to pol-
lutants and is the author of more than 600 papers in scholarly journals, as well as
24 books in the field of toxicology and environmental pollution. Dr. Calabrese has
received numerous awards, including, most recently, the prestigious Marie Curie
Prize.
xi
Contributors
Mark P. Mattson Laboratory of Neurosciences, National Institute on Aging,
Intramural Research Program, Baltimore, MD 21224, USA,
mattsonm@grc.nia.nih.gov
Edward J. Calabrese Department of Environmental Health Sciences, School of
Public Health and Health Sciences, University of Massachusetts, Amherst, MA
01003, USA, edwardc@schoolph.umass.edu
Tae Gen Son Laboratory of Neurosciences, National Institutes of Health, National
Institute on Aging, Baltimore, MD 21224, USA, sont2@grc.nia.nih.gov
Roy G. Cutler Laboratory of Neurosciences, National Institutes of Health,
National Institute on Aging, Baltimore, MD 21224, cutlerro@grc.nia.nih.gov
Simonetta Camandola Laboratory of Neurosciences, National Institute on Aging,
Intramural Research Program, Baltimore, MD 21224,
camandolasi@grc.nia.nih.gov
Wayne Chadwick Receptor Pharmacology Unit, National Institute on Aging,
National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224,
USA, chadwickwa@nia.nih.gov
Stuart Maudsley Laboratory of Neurosciences, National Institutes of Health,
National Institute on Aging, Baltimore, MD 21224, USA,
maudsleyst@grc.nia.nih.gov
Alexis M. Stranahan Department of Psychological and Brain Sciences, Johns
Hopkins University, Baltimore, MD 21218, USA, alexis.stranahan@jhu.edu
Bronwen Martin Laboratory of Clinical Investigation, National Institutes of
Health, National Institute on Aging, Baltimore, MD 21224, USA,
martinbro@mail.nih.gov
Sunggoan Ji Laboratory of Neurosciences, National Institutes of Health, National
Institute on Aging, Baltimore, MD 21224, USA, jis2@mail.nih.gov
Caitlin M. White Laboratory of Neurosciences, National Institutes of Health,
National Institute on Aging, Baltimore, MD 21224, USA, whitecm2@mail.nih.gov
xiii
xiv Contributors
Suresh I. S. Rattan Laboratory of Cellular Aging, Department of Molecular
Biology, University of Aarhus, DK 8000 Aarhus C, Denmark, rattan@mb.au.dk
Dino Demirovic Laboratory of Cellular Aging, Department of Molecular Biology,
University of Aarhus, DK8000 Aarhus C, Denmark, rattan@mb.au.dk
Hormesis: What It Is and Why It Matters
Mark P. Mattson and Edward J. Calabrese
Abstract Hormesis describes any process in which a cell, organism, or group of
organisms exhibits a biphasic response to exposure to increasing amounts of a sub-
stance or condition (e.g., chemical, sensory stimulus, or metabolic stress); typically,
low-dose exposures elicit a stimulatory or beneficial response, whereas high doses
cause inhibition or toxicity. The biphasic dose-response signature of hormesis is a
common result of experiments in the field of toxicology, but the low-dose data have
been largely ignored, and the prevailing view is that it is important to reduce levels
of toxins as much as possible. However, in many cases, the “toxins” actually have
essential or beneficial effects in low amounts. Prominent examples of such beneficial
“toxins” are trace metals such as selenium, chromium, and zinc. Fundamental inter-
and intracellular signals also exhibit hormetic dose responses, including hormones,
neurotransmitters, growth factors, calcium, and protein kinases. Moreover, everyday
health-promoting lifestyle factors, including exercise and dietary energy restriction,
act, at least in part, through hormetic mechanisms involving activation of adaptive
cellular stress response pathways (ACSRPs). ACSRPs typically involve receptors
coupled to kinases and activation of transcription factors that induce the expression
of cytoprotective proteins such as antioxidant enzymes, protein chaperones, and
growth factors. The recognition and experimental utilization of hormesis is lead-
ing to novel approaches for preventing and treating a range of diseases, including
cancers, cardiovascular disease, and neurodegenerative disorders.
Keywords Adaptation ·Biphasic ·Environmental protection ·Evolution ·
Preconditioning ·Stress ·Toxins
M.P. Mattson (B)
Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program,
Baltimore, MD 21224, USA
e-mail: mattsonm@grc.nia.nih.gov
1
M.P. Mattson, E.J. Calabrese, Hormesis, DOI 10.1007/978-1-60761-495-1_1,
C
Springer Science+Business Media, LLC 2010
2 M.P. Mattson and E.J. Calabrese
Hormesis Is a Fundamental Feature of Biological Systems
A defining characteristic of hormesis is a biphasic dose-response curve, with ben-
eficial or stimulatory effects at low doses and adverse or inhibitory effects at
high doses. Biphasic responses to increasing doses of chemicals have been widely
reported for a range of agents (mercury, arsenic, pesticides, radiation, etc.) and
organisms (bacteria, worms, flies, rodent, humans, and many others). In fact, toxins
more often exhibit a hormetic dose response (low-dose stimulation or beneficial
effect, and high-dose inhibition or toxicity) than they do a linear dose response
(toxicity proportional to the level of exposure). Calabrese has cataloged thousands
of examples of hormetic dose responses in the fields of biology, toxicology, and
medicine (Calabrese and Blain, 2005; Cook and Calabrese, 2006; and see the chap-
ter in this book, Hormesis: Once Marginalized, Evidence Now Supports Hormesis
as the Most Fundamental Dose Response). Examples of hormetic dose response
include the following: low amounts of cadmium improve the reproductive capac-
ity of snails, whereas high doses are lethal (Lefcort et al., 2008); low doses of
radiation increase the growth rate of plants and can increase the lifespan of mice
(Luckey, 1999); and chemicals that can cause cancer when consumed in high
amounts can actually inhibit cancer cell growth when taken in low doses (Calabrese,
2005).
Paracelsus recognized four centuries ago that drugs are actually toxins that have
beneficial effects at low doses (Fig. 1). The biphasic dose-response relation is not
limited to exposures to environmental agents and drugs, however; it permeates biol-
ogy, physiology, and the daily experiences of all organisms. Well-known categories
of agents that exert biphasic effects on human health are minerals and vitamins.
Selenium, a trace element obtained in the diet, is essential for health because it is
necessary for the proper function of at least 30 selenoproteins (Dodig and Cepelak,
2004). However, high levels of selenium are toxic and can even cause death. Vitamin
D is critical for the growth and health of bones and for wound healing, among other
processes, but excessive intake of vitamin D can cause hypercalcemia and associated
pathologies in the kidneys and other organs (Vieth, 2007). Vitamin A is necessary
for proper development of multiple organs and for maintenance of the health of the
eye and other tissues in the adult; however, excessive intake of vitamin A can cause
liver damage, may promote osteoporosis, and may also adversely affect the cardio-
vascular system (Penniston and Tunumihardjo, 2006). Iron is essential for red blood
cell health and also serves important regulatory functions in other cell types, but
excessive iron intake can cause oxidative damage to tissues (Van Gossum and Neve,
1998).
Another example of hormesis centers on glutamate, an amino acid neurotrans-
mitter that is critical for the transfer of electrical activity from one nerve cell to
another in the brain. The relatively low amounts of glutamate released at the synapse
when the brain is engaged in activities such as reading and writing activate adaptive
cellular stress response pathways (ACSRPs) that benefit the nerve cells, promot-
ing their growth and survival (Fig. 2). However, excessive amounts of glutamate
can damage and kill nerve cells in a process called excitotoxicity that occurs during
Hormesis 3
“All things are poison and nothing is without poison, only the
dose permits something not to be poisonous” -Paracelsus
Fig. 1 Paracelsus was a
Swiss-born alchemist and
physician who pioneered the
use of chemicals and minerals
in medicine. He recognized
the importance of the dose of
chemicals in determining
whether they are therapeutic
or toxic, and essentially
predicted the prevalence of
the biphasic nature of the
dose-response curve as
typical of all medicines
Neuron Survival
Glutamate Dose
Adaptive Response
Toxicity
Carbon Monoxide (CO) Level
Brain Function
CO produced
within the brain Inhaled CO
Irreversible
Toxicity
Deficiency
Zone
LOW MEDIUM HIGH
Reversible
Toxicity
Zone
Fig. 2 Hormetic dose responses of nerve cells to the neurotransmitter glutamate and the gaseous
messenger carbon monoxide (CO). Low to medium doses of glutamate mediate synaptic trans-
mission and plasticity, learning and memory, and other behaviors. High amounts of glutamate can
cause excessive calcium influx into neurons, resulting in neuronal damage and death; this occurs
in epilepsy and stroke and may also occur in Alzheimer’s, Parkinson’s, and Huntington’s diseases.
Carbon monoxide is produced by cells in the brain and plays important roles in signaling within
and between neurons and in blood vessel cells. Inhaled CO can result in levels in blood and tissues
that, if sustained, can cause asphyxia and death
4 M.P. Mattson and E.J. Calabrese
severe epileptic seizures, as well as in Alzheimer’s and Parkinson’s diseases. Carbon
monoxide also exerts hormetic effects on cells and organisms. Carbon monoxide
is widely known as a toxic gas present in the exhaust of combustion engines, but
carbon monoxide also is produced by cells in the body, where it serves important
signaling functions promoting blood vessel relaxation and communication between
nerve cells (Kaczorowski and Zuckerbraun, 2007; Fig. 2).
Another class of hormetic molecules in cells comprises oxygen free radicals,
notorious for their ability to damage DNA, proteins, and membrane lipids. Free rad-
icals are believed to play major roles in the aging process and in various diseases,
including cardiovascular and inflammatory diseases, cancers, and neurodegenera-
tive disorders (Giacosa and Filiberti, 1996; Mattson and Liu, 2002). Recent research
has clearly shown, however, that low amounts of some free radicals serve important
functions in cells that involve the activation of ACSRPs (Ridnour et al., 2006; Valko
et al., 2007. One example is superoxide anion radical (O2–.), which is produced by
the activity of the mitochondrial electron transport chain as a byproduct of oxidative
phosphorylation (the process that produces adenosine triphosphate [ATP], the major
cellular energy substrate). Superoxide is normally “detoxified” by the actions of
superoxide dismutases, which convert O2–. to hydrogen peroxide; hydrogen perox-
ide is then converted to water by the actions of catalase and glutathione peroxidase.
Thus, levels of O2–. are normally kept low. However, high amounts of O2–. can
occur in certain conditions (e.g., with reductions in levels of antioxidant enzymes)
and can damage cells by conversion to more highly reactive free radicals, includ-
ing hydroxyl radical and (by interaction with nitric oxide) peroxynitrite (Mattson,
2004). In response to physiological signals such as neurotransmitters, cytokines,
and calcium fluxes, O2–. is produced and mediates the activation of kinases and tran-
scription factors (Camello-Almaraz et al., 2006; Kishida and Klann, 2007). Reactive
oxygen species such as O2–. also mediate responses of immune cells. For exam-
ple, in response to exogenous (allergens) and endogenous (molecules released from
damaged cells) factors, mast cells generate O2–. and other free radicals that induce
degranulation, leukotriene secretion, and cytokine production (Suzuki et al., 2005).
Free radicals also play important roles in signaling processes that regulate vascular
endothelial cell function and blood pressure (Wolin, 1996). Mitochondria normally
produce O2–. in bursts or “flashes” (Wang et al., 2008), and one possible func-
tion of such O2–. flashes is to activate adaptive cellular stress response signaling
pathways.
Hormesis Is a Manifestation of a Fundamental Feature
of Evolution
To survive and propagate, organisms must be able to withstand various hazards
in their environment and outcompete their rivals for limited energy resources.
Mechanisms for responding adaptively to stress are fundamental to the process of
Hormesis 5
evolution and are therefore encoded in the genomes of all organisms. Early life
forms lived in hostile environments where they were subjected to a range of toxic
metals, ultraviolet light, and large changes in temperature. Survival was favored in
organisms that were able to resist these environmental stressors. Various examples
of adaptations to stress selected for during evolution are presented in the chapter in
this book, The Fundamental Role of Hormesis in Evolution. One fundamental means
of coping with exposures to potentially lethal environmental conditions is to move
away from the hazard, which is presumably one driving force for the evolution of
cell and organismal motility. Alternatively, the ability to change physiological pro-
cesses to withstand the noxious agent would have allowed the organism to remain
in its location. Moreover, by responding adaptively to low levels of various environ-
mental stressors, organisms were able to expand the range of environments in which
they could survive. For example, levels of arsenic in soils and drinking water vary
considerably across the globe, and in some areas levels are high enough to cause
sickness and death (Mukherjee et al., 2006). However, low doses of arsenic can
protect cells against oxidative stress and DNA damage (Snow et al., 2005), indicat-
ing the existence of a biphasic (hormetic) profile of arsenic exposure in which low
doses may activate an adaptive stress response that can protect against stress and
disease.
Cells and organisms that were vulnerable to specific environmental factors
evolved to become resistant to the factors. Moreover, in many instances, the organ-
isms evolved in ways that allowed them to utilize “toxic” elements and molecules
to their advantage. One excellent example mentioned earlier is selenium, which
is toxic at high doses and, early in evolution, was likely toxic at lower doses.
During evolution, selenium began to be used by organisms to enhance the func-
tion of certain enzymes, and selenium is now required for the health and survival
of many organisms, including humans (Boosalis, 2008). The calcium ion (Ca2+)is
widely known for its fundamental role in intracellular signaling and as a mediator
of a wide range of cell responses, including proliferation, differentiation, motil-
ity, and secretion (Schreiber, 2005). However, the excessive accumulation of Ca2+
in cells can cause dysfunction and death of the cells, a process implicated in
many diseases, including neurodegenerative disorders and cardiovascular disease
(Allen et al., 1993; Mattson, 2007). Thus, cells have evolved a battery of mech-
anisms to guard against excessive Ca2+ accumulation, including Ca2+ channels
and Ca2+ pumps in the plasma and endoplasmic reticulum membranes and
Ca2+-binding proteins (Fig. 3). Complex arrays of Ca2+ -regulating mechanisms
and Ca2+-mediated signaling pathways have evolved to serve the most sophisti-
cated functions of higher organisms, including the events that occur at synapses
(neurotransmitter release and postsynaptic responses to neurotransmitters) that
are the basis of cognition, reasoning, and the planning of survival strategies
(Blitzer et al., 2005). There are may other examples of potentially toxic chemi-
cals that serve critical physiological functions in low concentrations or controlled
(transient) higher doses as occur during Ca2+ influx and removal in excitable
cells.
6 M.P. Mattson and E.J. Calabrese
Mitochondria
Endoplasmic
Reticulum
Nucleus
Plasma
Membrane
Ca2+
Ca2+
Ca
Ca2+
VDCC
GR
Na+
glucose
ATPase
glutamate
ETC
O2-.
2+
Kinases
TFs
Ca2+
ATP
Fig. 3 Calcium signaling pathways and systems that regulate Ca2+ levels and movements in cells.
The concentration of Ca2+ is much higher outside the cell (1–2 mM) than in the cytoplasm (typ-
ically 100–300 nM). This gradient is established by a plasma membrane that is impermeable to
Ca2+ but contains ATP-dependent pumps (Ca2+ -ATPase) that extrude Ca2+. The plasma membrane
also contains voltage-dependent Ca2+ channels (VDCC) and ligand-gated Ca2+ channels such as
the N-methyl-D-aspartate type of glutamate receptor (GR). The Ca2+ that enters cells through
the latter channels functions as a signal that regulates a range of cellular responses, including
proliferation, differentiation, motility, and gene expression through the activation of kinases and
transcription factors (TFs). Ca2+ is transported into the endoplasmic reticulum via the activity of
the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)
Cellular and Molecular Mediators of Hormetic Responses
How can exposures to low levels of a toxin or other stressful agent result in benefi-
cial effects on cells? Many different signaling pathways have been shown to mediate
adaptive stress responses in cells and organisms, and there are undoubtedly many
more that remain to be discovered. Typically these hormetic pathways involve sen-
sor molecules, intracellular messengers, and transcription factors that induce the
expression of genes that encode cytoprotective proteins. The importance of such
stress resistance proteins in evolution is exemplified by the fact that a large por-
tion of the genes in the genome are involved in stress responses (Cooper et al.,
2003). Several different ACSRPs that mediate hormetic responses to oxidative stress
have been described, including the Nrf-2–ARE pathway (Kang et al., 2005) and
the sirtuin–FOXO pathway (Jiang, 2008). These pathways each culminate in the
nucleus, where they induce the expression of genes encoding an array of proteins
Hormesis 7
that protect cells against stress, including antioxidant enzymes, protein chaperones,
and proteins involved in energy metabolism. These pathways may be activated
rather directly by chemicals. For example, sulforaphane, a chemical present in high
amounts in broccoli, can interact with Nrf-2; resveratrol (present in red grapes and
wine) activates the sirtuin pathway; and allicin (a chemical in garlic and onions) can
activate membrane TRP channels, resulting in calcium influx (Mattson and Cheng,
2006).
On the other hand, many potentially toxic substances and conditions activate
ACSRPs indirectly by inducing a nonspecific oxidative, metabolic, or ionic stress.
Two transcription factors that are activated in many cell types in response to
oxidative and metabolic stress are NF-κB (Mattson and Meffert, 2006) and hypoxia-
inducible factor 1 (HIF1; Loor and Schumacker, 2008). NF-κB coordinates cellular
responses to infection and tissue injury throughout the body. Activation of NF-κB
in immune cells such as lymphocytes and macrophages induces the production of
cytokines such as tumor necrosis factor that function in destroying infectious agents
and removing dead cells in injured tissues. Activation of NF-κB in cells such as neu-
rons promotes their survival by inducing the expression of manganese superoxide
dismutase and Bcl-2, for example (Mattson and Meffert, 2006). Whereas low levels
of NF-κB activation are beneficial, high sustained activation can cause pathological
damage to tissues. HIF1 responds to hypoxia and increased cellular energy demand
as occurs in muscle cells during exercise (Freyssenet, 2007).
One class of highly specialized molecular bodyguards that mediate hormetic
responses is made up of the heat-shock proteins, which serve as chaperones that
protect other proteins against damage (Kim et al., 2006). The production of heat-
shock proteins is rapidly increased not only by high temperatures, but also under
conditions of oxidative and metabolic stress as occur during exposures to chemi-
cal toxins or tissue inflammation. The heat-shock proteins then bind to vulnerable
proteins in different parts of the cell and shield them from attack by oxygen free
radicals and other damaging chemicals. Some molecular bodyguards function as
messengers that leave the neuron exposed to the threat and alert adjacent neurons of
the danger. Growth factors are one such early warning system—they mobilize the
defenses of cells that are within the war zone but not yet under attack. For exam-
ple, in response to multiple stressors, including exercise, ischemia, and exposure
to certain “excitotoxins,” brain cells produce several different growth factors that
promote the survival of their neighbors, including fibroblast growth factor, nerve
growth factor, and brain-derived neurotrophic factor (Mattson et al., 1995).
Hormesis in Medicine: Dose and Frequency of Treatment
Are Both Important
Most, if not all, drugs exhibit hormetic dose responses, with beneficial effects at
therapeutic doses and toxic effects with overdoses. The toxic effects of high doses
may be due to a higher level of action (inhibition or stimulation) at the specific
8 M.P. Mattson and E.J. Calabrese
molecular target of the drug (typically a receptor or enzyme) or may result from
nonspecific effects on metabolism. For example, low doses of β-adrenergic receptor
antagonists are effective in reducing blood pressure, whereas higher concentrations
can cause circulatory collapse (Love and Elshami, 2002). At therapeutic doses,
γ–aminobutyric acid (GABA) receptor agonists such as diazepam (Valium) are
effective in reducing anxiety, whereas at higher concentrations they adversely affect
cognition and motor function (Gorenstein et al., 1994). Aspirin at low doses is effec-
tive in preventing myocardial infarction by inhibiting platelet aggregation and clot
formation; higher doses can reduce pain by inhibiting prostaglandin production but
have the adverse effect of promoting ulcer formation (Vane and Botting, 2003).
Some commonly prescribed drugs may exert their beneficial actions by
hormetic mechanisms. One example comes from studies of psychiatric disorders.
Antidepressants such as fluoxetine (Prozac) and paroxetine (Paxil) stimulate nerve
cells to produce brain-derived neurotrophic factor (BDNF), a protein that promotes
the growth and survival of neurons. Patients who do not respond to antidepres-
sants may benefit from a more dramatic hormetic treatment called electroconvulsive
shock therapy in which nerve cells are vigorously stimulated by passing an electric
current through the brain. The widely prescribed diabetes drug metformin may act,
in part, by inducing a mild stress in the muscle cells similar to what occurs dur-
ing exercise. Both exercise and metformin stimulate the activity of a protein called
AMP-activated protein kinase (AMPK), resulting in increased sensitivity of muscle
cells to insulin.
Not only is the dose a critical determinant of whether an environmental chal-
lenge is beneficial or damaging, but in addition the frequency of exposure is key
because cells must have time to recover to benefit from the stress. The importance
of a recovery period for the accrual of the benefits of exercise is widely recognized.
Less well known is the importance of a recovery period for the beneficial effects of
many other hormetic stressors, including dietary energy restriction, phytochemicals,
and even certain drugs. Although fasting has been part of many religions for thou-
sands of years, its far-reaching health benefits were brought to public attention with
the publication of Upton Sinclair’s The Fasting Cure in 1911. Sinclair described
his experiences and those of several hundred other people whose various maladies
were “cured” by fasting. Studies have demonstrated the ability of regular fasting
to improve the health and function of major organs, including the brain and heart
(Bruce-Keller et al., 1999; Duan et al., 2003; Maswood et al., 2004; Wan et al.,
2003a, 2003b; Mager et al., 2006). The mild stress that occurs during fasting is
important for its beneficial effects, as is a refeeding recovery period to provide the
nutrients necessary for maintaining tissue and organ functions. A major goal of the
fields of pharmacology and medicine should therefore be to establish the dose and
frequency of drug administration that maximize relief of symptoms while mini-
mizing side effects. Unfortunately, the most common approach, that has also been
applied to dietary supplements, assumes that a chemical is most effective when its
concentration in the body is maintained constant. However, this notion may not
apply to drugs and dietary components or supplements that act by a hormetic mech-
anism. Instead, many chemicals may provide an optimal therapeutic benefit when
Hormesis 9
delivered in a pulsatile or intermittent manner that allows a recovery period for cells
to respond adaptively to the stress induced by the chemical.
Are Beneficial Chemicals in Fruits and Vegetables Toxins Acting
at Low Doses?
Emerging evidence suggests that some drugs and health-promoting chemicals in
fruits and vegetables may exert their beneficial effects by activating ACSRPs. The
evidence that consumption of fruits and vegetables is associated with a reduced risk
for cardiovascular disease, certain cancers, and some neurodegenerative disorders
has resulted in efforts to identify the specific chemicals responsible for these health
benefits. Because damage caused by free radicals is involved in most major diseases,
it has been widely believed that the direct antioxidant activity of phytochemicals
is responsible for their beneficial effects. However, most phytochemicals are only
effective as antioxidants when they are present in very high concentrations that are
not achievable by eating normal amounts of fruits and vegetables, and there is often a
biphasic dose-response relationship for phytochemicals (low-dose beneficial effects
and high-dose toxic effects), which argues against an antioxidant mechanism of
action. Moreover, several major clinical trials failed to demonstrate beneficial effects
of high doses of antioxidants for the treatment of cancers, cardiovascular disease,
and Alzheimer’s disease. Based on this kind of information, evolutionary consider-
ations, and our research, we believe that instead of a direct antioxidant mechanism,
many phytochemicals exert their health benefits by inducing mild stress responses
in cells.
One important evolutionary adaptation of plants is the ability to produce toxic
substances and concentrate them in regions such as the skin of fruits and the buds of
leaves to dissuade insects and other organisms from eating them. Hundreds of these
“natural biopesticides” exist but are insufficient in the amounts normally consumed
in our diets to achieve toxic concentrations in the body. Instead, the phytochemicals
activate one or more specific adaptive stress response signal transduction path-
ways and transcription factors (Mattson and Cheng, 2006). For example, chemicals
present in broccoli (sulforaphane) and curry spice (curcumin) activate a protein
located in the cytoplasm called Nrf-2, which then moves to the nucleus, where
it activates genes for antioxidant enzymes and so-called “phase 2 detoxification”
enzymes. A different hormetic pathway was recently found to be activated by resver-
atrol, a phytochemical believed to be responsible for the health benefits of red grapes
and wine. Resveratrol activates sirtuin-1, which in turn stimulates a transcription
factor called FOXO, resulting in the production of proteins that counteract oxida-
tive stress. Other phytochemicals, including allicin (in garlic) and capsaicin (in hot
peppers), induce a mild stress response in cells by causing the opening of pores in
the cell membrane called transient receptor potential (TRP) channels, resulting in
the influx of calcium. The calcium then activates a transcription factor called the
cAMP-response element–binding protein (CREB), which induces the production of
10 M.P. Mattson and E.J. Calabrese
BDNF and other growth factors. Activation of these different pathways by phyto-
chemicals can protect cells against stress and thereby help them to avoid injury and
disease.
Hormesis Is Not Homeopathy
Homeopathy is a 200-year-old theory of medicine based on the work of Samuel
Hahnemann that proposes that agents that produce symptoms of a disease in a
healthy person could be used to treat ill patients. From this is derived the well-
known principle of homeopathy that “like cures like.” Hahnemann believed that
his treatments could be effective at vanishingly low doses, a possibility that gener-
ated skepticism within his homeopathic medical community, as well as within the
broader biomedical community. Homeopathy and the concept of hormesis became
linked through the work of Hugo Schulz at the University of Greiswald in northern
Germany. In the mid 1880s Schulz observed that chemical disinfectants stimulated
the metabolism of yeast at low doses while being inhibitory at higher doses. Schulz
immediately thought that he had discovered the scientific principle underlying the
medical practice of homeopathy. He advocated this perspective until his death in
1932. In general, the work of Schulz had no connection with homeopathy. It was
based on assessing the dose-response continuum, that is, doses that exceeded the
toxic threshold and doses immediately below it. The hormetic dose response is a
normal component of the traditional dose response. Large amounts of experimen-
tally derived data have demonstrated that adaptive responses are observable at doses
immediately below toxic thresholds. This is the hormetic zone, not a dose zone
multiple orders of magnitude below the threshold and into a vanishingly low con-
centration at which molecules may or may not even be present. Thus, the biological
process of hormesis is only linked to the purely human construct of homeopathy
because of a mistake by Hugo Schulz.
Implications of Hormesis for the Practices of Environmental
Protection and Medicine
Ignorance is not bliss. As described and documented throughout the chapters of
this book, the prevalence of hormesis in biological systems demands that data from
full dose-response studies be available to inform those who make decisions regard-
ing the management of environmental hazards and the treatment of patients. Many
chemicals in the environment, particularly those that are natural, although toxic at
high doses, exert beneficial effects at low doses. Examples include metals (selenium,
zinc, iron, etc.), phytochemicals (quercetin, curcumin, sulforaphane, etc.) and gases
(oxygen, carbon monoxide, ozone, etc.). The goal should therefore be to establish
the hormetic range of doses and then take measures to constrain exposures to doses
Hormesis 11
within this optimal range. Eliminating a toxic chemical from the environment with-
out knowing about its biological effects at low doses may result in poorer health
outcomes compared to reducing levels of the chemical to within the hormetic dose
range.
In drug development the usual approach for deciding on a dose of medicine is
to first determine the minimum dose at which toxicity is observed and then set the
therapeutic dose somewhat below the toxic dose. In many cases, the resulting “thera-
peutic” dose may actually coincide with the hormetic dose. For example, therapeutic
doses of antidepressants such as fluoxetine and paroxetine induce an adaptive stress
response in neurons in the brain that results in stimulation of the expression of
BDNF (Martinowich and Lu, 2008). BDNF promotes the growth, plasticity, and
survival of neurons and also induces the production of new neurons from stem cells
in the hippocampus (Mattson et al., 2004). Of interest, the antidepressant effect of
moderate exercise may be mediated by a similar hormetic mechanism involving
BDNF (Li et al., 2008). However, in other cases, the treatment dose may not be
the most effective dose, particularly in cases in which the drug acts by a hormetic
mechanism. For example, very low doses of aspirin (well below doses that are toxic)
reduce the risk of myocardial infarction and stroke (Webster and Douglas, 1987;
Hennekens, 2002). It will be of considerable interest, and of potential clinical impor-
tance, to reevaluate many commonly used drugs in the low (possibly hormetic) dose
range. Incorporation of low doses studied in preclinical models may also identify
agents with “off-target” low-dose beneficial actions.
Acknowledgments This work was supported by the Intramural Research Program of the National
Institute on Aging, National Institutes of Health.
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Hormesis: Once Marginalized, Evidence Now
Supports Hormesis as the Most Fundamental
Dose Response
Edward J. Calabrese
Abstract The biomedical community made a fundamental error on the nature
of the dose-response relationship early in the 20th century and has perpetuated
this error to the present. The error was the byproduct of the conflict between
homeopathy and traditional medicine. To deny support to homeopathy, leaders of
the biomedical community rejected the hormetic biphasic dose-response model,
the proposed explanatory principle of homeopathy. The threshold dose-response
model was adopted as an alternative model, quickly becoming central to toxi-
cology/pharmacology and their numerous applications. Despite its near-universal
acceptance, no attempt was made to validate the ability of the threshold model to
accurately predict responses in the below-threshold zone at the time of acceptance
and throughout the 20th century. In contrast, the hormetic biphasic dose-response
model became marginalized and was excluded from the mainstream of pharma-
cological/toxicological teaching and practice, textbook development, professional
society journal publications, annual meeting presentations, grant funding, and use
in government risk assessment. Over the last decade there has been a resurgence
of interest in hormesis due to findings indicating that hormetic responses are
common, reproducible, and generalizable, as well as independent of biological
model, endpoint, and chemical class/physical stressor. Large-scale studies have
indicated that the threshold model fails to accurately predict responses below
the threshold, whereas the hormetic dose-response model performs very well. These
findings indicate that the biomedical community made an error on the nature of the
dose-response relationship, compromising the accuracy of toxicological and risk
assessment practices, including environmental exposure standards, and impeding
drug discovery/development and drug safety studies.
Keywords Hormesis ·Hormetic ·Biphasic ·U-shaped ·J-shaped ·Dose-response
relationship ·Adaptive response ·Preconditioning ·History of science
E.J. Calabrese (B)
Department of Environmental Health Sciences, School of Public Health and Health Sciences,
University of Massachusetts, Amherst, MA 01003, USA
e-mail: edwardc@schoolph.umass.edu
15
M.P. Mattson, E.J. Calabrese, Hormesis, DOI 10.1007/978-1-60761-495-1_2,
C
Springer Science+Business Media, LLC 2010
16 E.J. Calabrese
Introduction
The dose-response relationship is the central concept within the fields of pharmacol-
ogy and toxicology. It guides how studies are designed and biostatistical modeling is
performed, the general focus of mechanistic research, drug efficacy and safety eval-
uation, and governmental environmental risk assessment practices for protecting
humans and other life against threats to food, water, air, and soil. The dose-response
relationship is also a fundamental concept of biology, in that it is central to evolu-
tionary theory and its underlying processes of mutation, DNA repair, and a plethora
of integrative adaptive responses. Central to the biological and health sciences, the
dose-response relationship is a scientific concept that seems as obvious as it is pro-
found, being nearly universally understood based on common experience. Therein
lies the trap into which the general public and the scientific community have fallen.
Over the last century the scientific community accepted the threshold dose-
response model as a description of how chemical and physical stressor agents affect
the vast range of biological processes across essentially all forms of life and biolog-
ical organization. This concept has become integrated into all biological disciplines
and regulatory practices, quietly evolving into a fundamental concept. Reinforcing
this “scientific” decision on the primacy of the threshold dose-response model is the
general recognition of thresholds in the physical sciences, such as melting, boiling,
and freezing points, and common experiences with medications and other products.
The convergence of agreement on the dose-response model by the scientific com-
munity and the general public is also as important as it is in reinforcing belief in the
validity of this concept, hence its acceptance and status as a central pillar in various
disciplines.
Despite the history of science with its self-correcting features and the wisdom
of the general public’s experiences and its integration of perceptions concerning
the dose-response relationship, both science and the lay public have the relation-
ship wrong. This error has profoundly affected the understanding of evolutionary
biology, the nature of the body’s adaptive response, and the testing and assessment
of drugs and chemicals, adversely affecting the health of individuals and popu-
lations and even national and world economies due to misplaced priorities and
extremely wasteful spending. The error originated in the fields of pharmacology and
toxicology and, like a highly contagious disease, quickly infiltrated all biological
disciplines, as well as government regulatory agencies, including their codified deci-
sions with their non–self-correcting features. This error in judgment on the nature
of the dose-response relationship became accepted in the early decades of the 20th
century and has been perpetuated to the present time (Calabrese, 2005b, Calabrese,
2005c; Calabrese 2007; Calabrese and Baldwin, 2003a), reinforced by a dominant
governmental regulatory and funding culture that strongly influences what scientific
ideas will be studied.
This chapter assesses the history of the dose-response relationship and the
basis of the error by the scientific community concerning it. The chapter proposes
Evidence Now Supports Hormesis 17
the most basic and appropriate dose-response relationship for the biological sci-
ences along with supportive documentation and a perspective on its broad societal
implications.
Historical Antipathies, Rather Than Science, Determined Which
Dose–Response Model Would Dominate Biology
The error that determined what has been long considered the fundamental nature
of the dose-response relationship was rooted in a scientific version of the Hundred
Years’ War, that is, the prolonged and bitter conflict between homeopathy and what
eventually came to be called “traditional” medicine. To citizens of the late 20th
and early 21st centuries, this “medical” conflict would seem to be a minor event,
given the overwhelmingly powerful victory of traditional medicine, and therefore
not likely to be more than a historical footnote. However, this will be shown not
to be the case. As a result of this medical science–based conflict, the basic dose-
response relationship—that is, the biphasic dose-response model—got caught in the
cross-fire and was victimized because it was a central and highly visible feature of
homeopathy.
The linking of the biphasic dose-response relationship to homeopathy was facil-
itated principally by Hugo Schulz (1853–1932), a professor of pharmacology at the
University of Greifswald in northern Germany. Schulz believed that the biphasic
dose responses (i.e., low-dose stimulation and high-dose inhibition) he observed
in laboratory studies (Schulz, 1888) assessing the effects of chemical disinfectants
on yeast metabolism could be broadly generalized and serve as the explanatory
principle of homeopathy. Schulz [1923, with English translation by Crump (see
Crump, 2003)] emphasized the reproducible nature of his findings in an auto-
biographic account of the discovery, a perspective that was strongly supported
by detailed studies (Branham, 1929) specifically designed to reaffirm and gen-
eralize his findings to a wider range of potential antiseptic chemicals. Chester
M. Southam and John Erhlich (Southam and Ehrlich, 1943), forestry researchers at
the University of Idaho who observed that low doses of extracts from the Red Cedar
tree affected the metabolism of multiple fungal strains in a similar biphasic man-
ner, renamed this dose response concept “hormesis” after the Greek word meaning
“to excite.”
Prior to his intellectually transforming studies with yeasts, Schulz was educated
and trained along a traditional biomedical path, with strengths in chemistry and
pharmacology. He was also mentored by Eduard Pfluger, one of the founders of
modern physiology. However, Schulz was quietly open to homeopathic principles
and practices due in large part to an admired and respected family homeopathic
physician friend with whom he had a long and intellectually engaged associa-
tion (Bohme, 1986). At about the time (1882) that Schulz started his career at
18 E.J. Calabrese
Greifswald, research emerged indicating that veratrine, a homeopathic medicine,
was a successful treatment for gastroenteritis. Because the causative bacteria had
recently been identified and cultured, Schulz (Schulz, 1885) seized the opportu-
nity to assess whether this drug acted via the killing of the bacteria. Extensive tests
using a broad range of concentrations revealed that the drug was unable to do so.
Although this observation failed to shake Schulz’s belief in the efficacy of the drug,
it did compel him to conclude that the drug must act via a mechanism other than
cell killing.
Several years later when Schulz (Schulz, 1888) observed the biphasic concen-
tration effects of a broad range of chemical disinfectants on yeast metabolism, he
came to believe that he had determined how the veratrine might have been effec-
tive in the treatment of patients with gastroenteritis. That is, Schulz claimed that
at low doses the drug could induce adaptive processes that permitted the person
to resist the infection and facilitate recovery. He soon extended this hypothesis
to the broader homeopathic field, believing that he had discovered the underlying
explanatory principle of homeopathy.
Schulz quickly became a leader within the homeopathic community, devot-
ing the remainder of his professional life to its further study and intellectual
expansion. Because Schulz was well known in the pharmacological and medical
communities, with numerous publications, as well as active participation on edito-
rial boards of leading professional journals (e.g., Naunyn-Schmiedeberg’s Archives
of Pharmacology) (Starke, 1998), the homeopathic community looked to him to
challenge traditional medicine in hopes of legitimizing their medical practices.
This also meant that Schulz, his findings, and his interpretations became central
in the conflict and the object of considerable criticism by those opposing homeo-
pathic perspectives. The intellectual opposition, that is, traditional medicine, in the
form of pharmacology and eventually its scientific offspring toxicology, could not
accept Schulz’s scientific findings because this would appear as an endorsement of
homeopathy.
A careful analysis of Schulz’s experimentation (Schulz, 1888) would have
revealed that it was not directly relevant to homeopathic medical treatment the-
ory and practice. The vast majority of medical treatments are performed to reduce
existing symptoms of illness and prevent their recurrence. This occurs when the
individual becomes ill and seeks medical assistance. The homeopathic treatment
would normally be expected to be administered after the onset of the illness. In
Schulz’s work and the overwhelming number of examples of hormesis in the pub-
lished literature, the investigations did not involve exposures after the onset of
disease or chemically induced injury. Even though Schulz believed that his findings
were at the core of homeopathic understanding, the scientific community made a
critical error in not challenging his interpretation. However, instead it challenged the
reliability of Schulz’s findings and his dose-response generalization, a decision that
would prove to have far-reaching implications for pharmacology and toxicology.
Given this strategic, although incorrect decision on how to challenge Schulz, two
courses of action emerged: (1) the Schulz biphasic dose-response model (called the
Evidence Now Supports Hormesis 19
Arndt–Schulz law at the time) had to be marginalized, and (2) a credible alterna-
tive had to be formulated, and this becoming the threshold dose-response model,
the model on which 20th century clinical pharmacology, toxicology, and risk
assessment would be based.
The most notable critic of Schulz was Alfred J. Clark (1885–1941), a highly
accomplished pharmacology researcher and scholar, who had considerable influence
among academics and government regulators (Verney and Barcroft, 1941; Gaddum,
1962). Nearly 70 years after his death, Clark remains a highly respected figure in
pharmacology, with graduate fellowships and a distinguished chair in pharmacol-
ogy at Edinburgh named in his honor. Clark (Clark, 1933, 1937) was the author
of several highly influential, multiedition textbooks that criticized Schulz and his
dose-response theories in highly dismissive ways (Calabrese, 2005a) while also
linking him with the “extremist” elements within homeopathy (Clark, 1927). In fact,
Clark’s Handbook of Pharmacology was highly regarded, being published as late as
1970, nearly three decades after his death, and influenced several generations of
pharmacologists and toxicologists.
Clark’s professional successes were due in considerable measure to his careful
and objective evaluation of data and his capacity to obtain and integrate massive
amounts of complex and technical information in scientifically valid and insight-
ful ways. In the case of his analysis of Schulz, such thoroughness and objectivity
were surprisingly below his normally high standards, with a retrospective eval-
uation (Calabrese, 2005a) revealing that Clark was very selective in his use of
the published literature to support his position while failing to report substantial
independent findings that supported Schulz’s work with yeast and disinfectants
(Branham, 1929), as well as his general biphasic dose-response concept (Calabrese
and Baldwin, 2000a, Calabrese and Baldwin, 2000b, Calabrese and Baldwin, 2000c,
Calabrese and Baldwin, 2000d, Calabrese and Baldwin, 2000e). Of particular note
is that Schulz was not in a position to defend himself, given that Clark’s criti-
cisms intensified after Schulz entered retirement in the early 1920s, and Schulz died
(1932) before the first editions of Clark’s two critical books (Clark, 1933, 1937).
Furthermore, when the prominent surgical and biomedical researcher August Bier
came to his defense, political forces were quickly mobilized to strongly criticize the
once-esteemed Bier (Goerig et al., 2000), who had been nominated for the Nobel
Prize in Biology and Medicine on multiple occasions, sending a not-so-subtle mes-
sage to other scientists, even those of considerable achievement and reputation, who
might similarly wander from the “party line.”
Clark’s criticism of homeopathy and Schulz occurred at a time when homeo-
pathic medicine was severely criticized by the so-called Flexner report (Flexner,
1910), which, together with the ongoing efforts by its author, with the backing of
the Rockefeller Foundation, over the next two decades effectively led to the closing
of the vast majority of homeopathic medical schools in the United States (Berliner,
1985). The final intellectual component of the tipping point regarding the dose-
response concept occurred when colleagues of Clark’s (Gaddum, 1933; Bliss, 1935)
(note that Clark’s assistance was acknowledged in the Bliss paper) independently
20 E.J. Calabrese
derived the probit dose-response model to account for resp