Hormesis
Encyclopedia
Toxin
A toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...
s and other stressors. A pollutant or toxin
Toxin
A toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...
showing hormesis thus has the opposite effect in small doses as in large doses. A related concept is Mithridatism
Mithridatism
Mithridatism is the practice of protecting oneself against a poison by gradually self-administering non-lethal amounts. The word derives from Mithridates VI, the King of Pontus, who so feared being poisoned that he regularly ingested small doses, aiming to develop immunity...
, which refers to the willful exposure to toxins in an attempt to develop immunity against them.
In toxicology
Toxicology
Toxicology is a branch of biology, chemistry, and medicine concerned with the study of the adverse effects of chemicals on living organisms...
, hormesis is a dose response phenomenon characterized by a low dose stimulation, high dose inhibition, resulting in either a J-shaped or an inverted U-shaped dose response. Such environmental factors that would seem to produce positive responses have also been termed “eustress
Eustress
Eustress is a term coined by endocrinologist Hans Selye which is defined in the model of Richard Lazarus as stress that is healthy, or gives one a feeling of fulfillment or other positive feelings. Eustress is a process of exploring potential gains....
”.
The hormesis model of dose response is vigorously debated. The notion that hormesis is a widespread or important phenomenon in biological systems is not widely accepted.
The biochemical mechanisms by which hormesis works are not well understood. It is conjectured that low doses of toxins or other stressors might activate the repair mechanisms of the body. The repair process fixes not only the damage caused by the toxin, but also other low-level damage that might have accumulated before without triggering the repair mechanism.
History
German pharmacologist Hugo Schulz first described such a phenomenon in 1888 following his own observations that the growth of yeast could be stimulated by small doses of poisons. This was coupled with the work of German physician Rudolph Arndt, who studied animals given low doses of drugs, eventually giving rise to the Arndt-Schulz ruleArndt-Schulz rule
Arndt–Schulz rule or Schulz' law is a claimed law concerning the effects of pharmaca or poisons in various concentrations. It states that:...
. Arndt's advocacy of homeopathy
Homeopathy
Homeopathy is a form of alternative medicine in which practitioners claim to treat patients using highly diluted preparations that are believed to cause healthy people to exhibit symptoms that are similar to those exhibited by the patient...
contributed to the rule's diminished credibility in the 1920s and 1930s. The term "hormesis" was coined and used for the first time in a scientific paper by C.M. Southam and J. Ehrlich in 1943 in the journal: Phytopathology, volume 33, pp. 517–541.
Recently, Edward Calabrese has revived the hormesis theory through his research on peppermint
Peppermint
Peppermint is a hybrid mint, a cross between the watermint and spearmint . The plant, indigenous to Europe, is now widespread in cultivation throughout all regions of the world...
plants.
Examples of hormesis
There is an extensive body of research that purports to demonstrate a variety of hormetic effects.Most drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
s are toxic when ingested in large quantities. A quantative measure of this fact is called the therapeutic index
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
. Their beneficial action at correct dosage is not considered an example of hormesis.
Physical exercise
Individuals with low levels of physical activity are at risk for high levels of oxidative stressOxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
, as are individuals engaged in highly intensive exercise programs; however individuals engaged in moderately intensive, regular exercise experience lower levels of oxidative stress. High levels of oxidative stress have been linked by some with the increased incidence of a variety of diseases
,
It has been claimed that this relationship, characterized by positive effects at an intermediate dose of the stressor (exercise), is characteristic of hormesis. However, it is important to point out that there is evidence that the oxidative stress associated with intensive exercise may have long term health benefits. This would imply that oxidative stress, itself, provides an example of hormesis (see section on Mitochondrial hormesis), but physical exercise does not.
Alcohol
Alcoholic beverageAlcoholic beverage
An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...
s are believed to be hormetic in preventing heart disease and stroke, although the benefits of light drinking may have been exaggerated.
Methylmercury and mallard eggs
In 2010, a paper published in the journal Environmental Toxicology & Chemistry showed that low doses of methylmercuryMethylmercury
Methylmercury is an organometallic cation with the formula . It is a bioaccumulative environmental toxicant.-Structure:...
, a potent neurotoxic pollutant, improved the hatching rate of mallard eggs. The author of the study, Gary Heinz, who led the study for the U.S. Geological Survey at the Patuxent Wildlife Research Center
Patuxent Wildlife Research Center
The Patuxent Wildlife Research Center is a biological research center in Maryland. It is one of only 17 research centers in the United States run by the U.S. Geological Survey. This USGS research center is located on the U.S...
in Beltsville, Md., stated that other explanations are possible. For instance, it is possible that the flock he studied might have harbored some low, subclinical infection and that mercury, well known to be antimicrobial, might have killed the infection that otherwise hurt reproduction in the untreated birds.
Hormetic effects in aging
One of the areas where the concept of hormesis has been explored extensively with respect to its applicability is aging. Since the basic survival capacity of any biological system depends on its homeodynamic (homeostatic) ability, biogerontologists proposed that exposing cells and organisms to mild stress should result in the adaptive or hormetic response with various biological benefits. This idea has now gathered a large body of supportive evidence showing that repetitive mild stress exposure has anti-aging effects. Exercise is a paradigm for hormesis in this respect. Some of the mild stresses used for such studies on the application of hormesis in aging research and interventions are heat shock, irradiation, prooxidants, hypergravity and food restriction. Some other natural and synthetic molecules, such as celasterols from medicinal herbs and curcuminCurcumin
Curcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family . The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are natural phenols and are responsible for the yellow color of turmeric...
from the spice turmeric
Turmeric
Turmeric is a rhizomatous herbaceous perennial plant of the ginger family, Zingiberaceae. It is native to tropical South Asia and needs temperatures between 20 °C and 30 °C and a considerable amount of annual rainfall to thrive...
have also been found to have hormetic beneficial effects. Such compounds which bring about their health beneficial effects by stimulating or by modulating stress response pathways in cells have been termed "hormetins". Hormetic interventions have also been proposed at the clinical level, with a variety of stimuli, challenges and stressful actions, that aim to increase the dynamical complexity of the biological systems in humans.
Mitochondrial hormesis
Mitochondria are sometimes described as "cellular power plants" because they generate most of the cell's supply of adenosine triphosphate (ATP), a source of chemical energy. Reactive oxygen speciesReactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
(ROS) have been regarded as unwanted by-products of oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
in mitochondria by the proponents of the free-radical theory of aging promoted by Denham Harman
Denham Harman
Denham Harman , MD, PhD, FACP, FAAA biogerontologist is Professor emeritus at the University of Nebraska Medical Center. Harman is widely known as the "father of the free radical theory of aging".-Background:...
. The free-radical theory
Free-radical theory
The free-radical theory of aging states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most...
suggests that the use of compounds which inactivate ROS, such as so-called antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
s, would lead to a reduction of oxidative stress and thereby produce an increase in lifespan. However in clinical trials the expected health-promoting effects of antioxidants were not found and results suggested that antioxidants may promote cancer in humans. Other studies have now shown that antioxidant supplements may be disease-promoting and increase mortality in humans.
ROS may perform an essential and potentially lifespan-promoting role as redox signaling
Redox signaling
Redox signaling is when free radicals, reactive oxygen species , and other electronically activated species such as nitric oxide act as biological messengers. Arguably, hydrogen sulfide and carbon monoxide are also redox signaling molecules...
molecules which transduce signals from the mitochondrial compartment to other compartments of the cell. Increased formation of reactive oxygen species (ROS) within the mitochondria may cause an adaptive reaction which produces increased stress resistance and a long-term reduction of oxidative stress. This kind of reverse effect of the response to ROS stress has been named mitochondrial hormesis or mitohormesis and is hypothesized to be responsible for the respective lifespan-extending and health-promoting capabilities of glucose restriction and physical exercise.
Hormesis may also be induced by endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
ly produced, potentially toxic agents. For example, mitochondria consume oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
which generates free radicals (reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
) as an inevitable by-product. It was previously proposed on a hypothetical basis that such free radicals may induce an endogenous response culminating in increased defense capacity against exogenous radicals (and possibly other toxic compounds). Recent experimental evidence strongly suggests that this is indeed the case, and that such induction of endogenous free radical production extends life span
Life expectancy
Life expectancy is the expected number of years of life remaining at a given age. It is denoted by ex, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...
of a model organism. Most importantly, this extension of life span is prevented by antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
s, providing direct evidence that toxic radicals may mitohormetically exert life extending and health promoting effects. Since mitochondrial activity was found to be increased in the before-mentioned studies, this effect cannot be explained by an excess of free radicals that might mark mitochondria for destruction by lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
s, with the free radicals acting as a signal within the cell to indicate which mitochondria are ready for destruction, as proposed by Nick Lane
Nick Lane
Nick Lane is a British biochemist. He holds the post of honorary reader and is the first Provost's Venture Research Fellow at University College London and was formerly strategic director at Adelphi MediCine, a medical multimedia company. He is the author of three popular science books and many...
.
Another study on yeasts explains the underlying mechanism of the process that prevents cellular damage by reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
. Whether this concept applies to humans remains to be shown, although recent epidemiological
Epidemiology
Epidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a population. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive...
findings support the process of mitohormesis, and even suggest that some antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
supplements may increase disease prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
in humans.
Controversy
Whether hormesis is common or important is controversial. At least one peer-reviewed article accepts the idea, claiming that over 600 substances show a U-shaped dose-response relationship. Calaberese and Baldwin wrote:- One percent (195 out of 20,285) of the published articles contained 668 dose-response relationships that met the entry criteria.
The idea that low dose effects may be (sometimes strikingly) different is accepted, but that the low dose effect is positive is questionable.
The hypothesis of hormesis has generated the most controversy when applied to ionizing radiation
Ionizing radiation
Ionizing radiation is radiation composed of particles that individually have sufficient energy to remove an electron from an atom or molecule. This ionization produces free radicals, which are atoms or molecules containing unpaired electrons...
. This theory is called radiation hormesis
Radiation hormesis
Radiation hormesis is the hypothesis that low doses of ionizing radiation are beneficial, stimulating the activation of repair mechanisms that protect against disease, that are not activated in absence of ionizing radiation...
. The commonly accepted model of dose response in radiobiology is the linear no-threshold model (LNT), which assumes a strictly linear dependence between the risk of radiation-induced adverse health effects and radiation dose.
The United States National Research Council
United States National Research Council
The National Research Council of the USA is the working arm of the United States National Academies, carrying out most of the studies done in their names.The National Academies include:* National Academy of Sciences...
(part of the National Academy of Sciences
United States National Academy of Sciences
The National Academy of Sciences is a corporation in the United States whose members serve pro bono as "advisers to the nation on science, engineering, and medicine." As a national academy, new members of the organization are elected annually by current members, based on their distinguished and...
), the National Council on Radiation Protection and Measurements
National Council on Radiation Protection and Measurements
The National Council on Radiation Protection and Measurements is a U.S. organization. It has a congressional charter under Title 36 of the United States Code, but this does not imply it has any sort of oversight or supervision from Congress; it is not a government entity.This text appears on the...
(a body commissioned by the United States Congress
United States Congress
The United States Congress is the bicameral legislature of the federal government of the United States, consisting of the Senate and the House of Representatives. The Congress meets in the United States Capitol in Washington, D.C....
) and the United Nations Scientific Committee on the Effects of Ionizing Radiation (UNSCEAR) all agree that radiation hormesis is not clearly shown, nor clearly the rule for radiation doses.
A report commissioned by the French National Academy concluded that there is sufficient evidence for hormesis occurring at low doses and that LNT should be reconsidered as the methodology used to estimate risks from low level sources of radiation, like deep geological repositories
Deep geological repository
A deep geological repository is a nuclear waste repository excavated deep within a stable geologic environment...
for nuclear waste. On the other hand, the United States-based National Council on Radiation Protection and Measurements
National Council on Radiation Protection and Measurements
The National Council on Radiation Protection and Measurements is a U.S. organization. It has a congressional charter under Title 36 of the United States Code, but this does not imply it has any sort of oversight or supervision from Congress; it is not a government entity.This text appears on the...
states that there is insufficient evidence for radiation hormesis and that radiation protection authorities should continue to apply the LNT model for purposes of risk estimation.
Policy consequences
Regulatory agencies such as the Environmental Protection AgencyUnited States Environmental Protection Agency
The U.S. Environmental Protection Agency is an agency of the federal government of the United States charged with protecting human health and the environment, by writing and enforcing regulations based on laws passed by Congress...
(EPA), the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA), and the Nuclear Regulatory Commission
Nuclear Regulatory Commission
The Nuclear Regulatory Commission is an independent agency of the United States government that was established by the Energy Reorganization Act of 1974 from the United States Atomic Energy Commission, and was first opened January 19, 1975...
(NRC) traditionally use a linear no-threshold model
Linear no-threshold model
The linear no-threshold model is a method for predicting the long term, biological damage caused by ionizing radiation and is based on the assumption that the risk is directly proportional to the dose at all dose levels....
for carcinogens (including radiation). In the linear model, the assumption is that there is no dosage that has no risk of causing cancer. While this linear approach remains the default, with sufficient mechanistic evidence suggesting a non-linear dose-response, EPA allows for the derivation of a threshold dose (a.k.a reference dose) below which it is assumed that there is no risk for cancer.
While proponents of hormesis argue that changing to a hormesis model would likely change exposure standards for these toxicants in air, water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
, food
Food
Food is any substance consumed to provide nutritional support for the body. It is usually of plant or animal origin, and contains essential nutrients, such as carbohydrates, fats, proteins, vitamins, or minerals...
and soil
Soil
Soil is a natural body consisting of layers of mineral constituents of variable thicknesses, which differ from the parent materials in their morphological, physical, chemical, and mineralogical characteristics...
, making the standards less strict, other scientists point out that low dose stimulation can have extremely adverse effects. For example, research by Retha Newbold at the US National Institute of Environmental Health Sciences
National Institute of Environmental Health Sciences
The National Institute of Environmental Health Sciences is a part of the National Institutes of Health , which is in turn a part of the Department of Health and Human Services ....
has shown that while relatively high doses of a xenobiotic
Xenobiotic
A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual...
estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
, diethylstilbestrol
Diethylstilbestrol
Diethylstilbestrol is a synthetic nonsteroidal estrogen that was first synthesized in 1938. Human exposure to DES occurred through diverse sources, such as dietary ingestion from supplemented cattle feed and medical treatment for certain conditions, including breast and prostate cancers...
, during fetal development cause weight loss in adulthood, extremely low doses cause grotesque obesity. Similarly, low doses of the phthalate DEHP cause increased allergic responses to allergen
Allergen
An allergen is any substance that can cause an allergy. In technical terms, an allergen is a non-parasitic antigen capable of stimulating a type-I hypersensitivity reaction in atopic individuals....
s, while higher doses have no effect. Low dose stimulation can have profoundly adverse consequences. Wider use of the hormesis model would affect how scientists design and conduct studies and the selection of models that estimate risk. In all likelihood, recognizing that low dose effects can't be predicted from high dose experiments would force a strengthening of public health standards, not their weakening, as hormesis proponents would argue.
See also
- Calorie restrictionCalorie restrictionCaloric restriction , or calorie restriction, is a dietary regimen that restricts calorie intake, where the baseline for the restriction varies, usually being the previous, unrestricted, intake of the subjects...
- Michael RistowMichael RistowMichael Ristow is a German medical researcher who has published influential articles on the metabolic basis of human diseases, including type 2 diabetes, obesity and cancer, as well as general aging processes...
- Petkau effectPetkau effectThe Petkau effect is an early counterexample to linear-effect assumptions usually made about radiation exposure. It was found by Dr. Abram Petkau at the Atomic Energy of Canada Whiteshell Nuclear Research Establishment, Manitoba and published in Health Physics March 1972.Petkau had been...
- Radiation hormesisRadiation hormesisRadiation hormesis is the hypothesis that low doses of ionizing radiation are beneficial, stimulating the activation of repair mechanisms that protect against disease, that are not activated in absence of ionizing radiation...
- Stochastic resonanceStochastic resonanceStochastic resonance is a phenomenon that occurs in a threshold measurement system when an appropriate measure of information transfer is maximized in the presence of a non-zero level of stochastic input noise thereby lowering the response...