Hormesis

A low dose of a chemical agent may trigger from an organism the opposite response to a very high dose.

Hormesis is the term that describes any process in a cell or organism that exhibits a biphasic response to exposure to increasing amounts of a substance or condition.^[1] Within the hormetic zone there is generally a favorable biological responses to low exposures to toxins and other stressors. Hormesis comes from Greek hórmēsis "rapid motion, eagerness", itself from ancient Greek hormáein "to set in motion, impel, urge on". A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses. Hormetics is the term proposed for the study and science of hormesis. A related concept is Mithridatism, which refers to the willful exposure to toxins in an attempt to develop immunity against them.

In toxicology, 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". The hormesis model of dose response is vigorously debated.^[2] The notion that hormesis is important for chemical risks regulations is not widely accepted.^[3]

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 having triggered 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 rule.^[2] Arndt's advocacy of homeopathy contributed to the rule's diminished credibility in the 1920s and 1930s.^[2] The term "hormesis" was coined and used for the first time in a scientific paper by Chester M. Southam and J. Ehrlich in 1943 in the journal: Phytopathology, volume 33, pp. 517–541. Recently, Edward Calabrese has revived the concept of hormesis.^[4][5] The evidence for and importance of hormesis in physiology and health was advanced by Mark Mattson, who elucidated cellular and molecular mechanisms by which the nervous system responds adaptively to mild bioenergetic stresses such as fasting and exercise.^[6] Cells respond to such challenges by increasing their production of neurotrophic factors, DNA repair proteins and antioxidant enzymes.^[7][8][9] Mattson also proposed that the reason that vegetables, fruits, tea and coffee can improve brain health is that they contain ‘noxious’ chemicals that are produced by the plants to protect themselves from being eaten by insects and other organisms.^[10][11] Such phytochemicals trigger hormetic responses in brain cells which can improve brain function and may increase the resistance of neurons to injury and age-related neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease.

Examples

Physical exercise

Individuals with low levels of physical activity are at risk for high levels of oxidative stress, 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.^[12]

It has been claimed that this relationship, characterized by positive effects at an intermediate dose of the stressor (exercise), is characteristic of hormesis.^[12] 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.^[13]

Alcohol

Alcohol is believed to be hormetic in preventing heart disease and stroke,^[14] although the benefits of light drinking may have been exaggerated.^[15][16]

In 2012, researchers at UCLA found that tiny amounts (1 mM, or 0.005%) of ethanol doubled the lifespan of Caenorhabditis elegans, a round worm frequently used in biological studies, that were starved of other nutrients. Higher doses of 0.4% provided no longevity benefit.^[17] However, worms exposed to 0.005% did not develop normally (their development was arrested). The authors argue that the worms were using ethanol as an alternative energy source in the absence of other nutrition, or had initiated a stress response. They did not test the effect of ethanol on worms fed a normal diet.

Methylmercury and mallard eggs

In 2010, a paper published in the journal Environmental Toxicology & Chemistry showed that low doses of methylmercury, a potent neurotoxic pollutant, improved the hatching rate of mallard eggs.^[18] The author of the study, Gary Heinz, who led the study for the U.S. Geological Survey at the Patuxent Wildlife Research Center 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.^[18]

Effects in aging

One of the areas where the concept of hormesis has been explored extensively with respect to its applicability is aging.^[19][20] 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.^[21][22] Exercise is a paradigm for hormesis in this respect.^[22] 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.^[21][22][23] Some other natural and synthetic molecules, such as celasterols from medicinal herbs and curcumin from the spice turmeric have also been found to have hormetic beneficial effects.^[24] Such compounds which bring about their health beneficial effects by stimulating or by modulating stress response pathways in cells have been termed "hormetins".^[21] Hormetic interventions have also been proposed at the clinical level,^[25] with a variety of stimuli, challenges and stressful actions, that aim to increase the dynamical complexity of the biological systems in humans.^[26]

Mitochondria

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 species (ROS) have been regarded as unwanted by-products of oxidative phosphorylation in mitochondria by the proponents of the free-radical theory of aging promoted by Denham Harman. The free-radical theory suggests that the use of compounds which inactivate ROS, such as antioxidants, would lead to a reduction of oxidative stress and thereby produce an increase in lifespan.

ROS may perform an essential and potentially lifespan-promoting role as redox signaling molecules which transduce signals from the mitochondrial compartment to other compartments of the cell.^[27] Increased formation of 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.^[27]

Hormesis may also be induced by endogenously produced, potentially toxic agents. For example, mitochondria consume oxygen which generates free radicals (reactive oxygen species) as a 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).^[28] Recent experimental evidence strongly suggests that this is indeed the case, and that such induction of endogenous free radical production extends life span of a model organism. Most importantly, this extension of life span is prevented by antioxidants, providing direct evidence that toxic radicals may mitohormetically exert life extending and health promoting effects.^[29] Since mitochondrial activity was found to be increased in the previously mentioned studies, this effect cannot be explained by an excess of free radicals that might mark mitochondria for destruction by lysosomes, with the free radicals acting as a signal within the cell to indicate which mitochondria are ready for destruction, as proposed by Nick Lane.^[30]

Whether this concept applies to humans remains to be shown, although recent epidemiological findings support the process of mitohormesis, and even suggest that some antioxidant supplements may increase disease prevalence in humans.^[31]

Ionizing radiation

Hormesis has been observed in a number of cases in humans and animals exposed to chronic low doses of ionizing radiation. In Taiwan recycled radiocontaminated steel was inadvertently used in the construction of over 100 apartment buildings causing the long-term (10 years) exposure of 10,000 people. The average dose rate was 50 mSv/year and a subset of the population (1,000 people) received a total dose of over 4,000 mSv over ten years. In the widely used Linear No Threshold (LNT) theory used by regulatory bodies, the expected cancer deaths in this population would have been 302 with 70 caused by the extra ionizing radiation with the remainder caused by natural background radiation. However the observed cancer rate was quite low at 7 cancer deaths when 232 would be predicted by the LNT theory. Ionizing radiation hormesis appears to be at work. Described by Professor Charles L. Sanders, Korea Advanced Institute of Science and Technology.^[32]

Taiwan's National Cancer Registry (first study)

Cancer risks in a population with prolonged low dose-rate gamma-radiation exposure in radiocontaminated buildings, 1983-2002. The results suggest that prolonged low dose-rate radiation exposure appeared to increase risks of developing certain cancers in specific subgroups of this population in Taiwan.^[33]

Taiwan's National Cancer Registry (second study, two years later)

A significant radiation risk was observed for leukemia excluding chronic lymphocytic leukemia (HR(100mGy) 1.19, 90% CI 1.01-1.31). Breast cancer exhibited a marginally significant dose response (HR(100mGy) 1.12, 90% CI 0.99-1.21). The results further strengthen the association between protracted low-dose radiation and cancer risks, especially for breast cancers and leukemia, in this unique cohort population.^[34]

Chemical and ionizing radiation combined

No experiment can be performed in perfect isolation. Thick lead shielding around a chemical dose experiment to rule out the effects of ionizing radiation is built and rigorously controlled for in the laboratory, and certainly not the field. Likewise the same applies for ionizing radiation studies because by definition ionization radiation creates a cascade of new chemicals in the body which combine with whatever other environmental exposure is occurring during the measurement period.

The resulting confusion in the low dose exposure field (radiation and chemical) arise from lack of consideration of this concept as described by Mothersill and Seymory.^[35] Mothersill and Seymory state "Most of the arguments about whether radiation is ‘good for you’ or ‘bad for you’ fail due to lack of consideration of the hierarchical level at which the effect occurs and because most of the arguments are anthropocentric. For example cell death is seen as a ‘bad’ effect but if it removes a potentially carcinogenic cell from the population of cells in a tissue it could prevent cancer starting and could be seen as 'good’."

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."^[36] 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. This theory is called radiation hormesis. For policy making purposes, 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 (part of the National Academy of Sciences),^[37] the National Council on Radiation Protection and Measurements (a body commissioned by the United States Congress)^[38] 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 for nuclear waste.^[39] On the other hand, the United States-based National Council on Radiation Protection and Measurements 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.^[38]

Policy consequences

Regulatory agencies such as the Environmental Protection Agency (EPA), the Food and Drug Administration (FDA), and the Nuclear Regulatory Commission (NRC) traditionally use a linear no-threshold model 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 (also known as 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, food and soil, making the standards less strict, other scientists point out that low dose stimulation can have extremely adverse effects. Similarly, low doses of the phthalate DEHP cause increased allergic responses to allergens, while higher doses have no effect. 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.

Hormesis remains largely unknown to the public. Any policy change ought to consider hormesis first as a public health issue (versus an industrial regulatory issue). This would include the assessment of the public concern regarding exposure to small toxic doses. In addition, impact of hormesis policy change upon the management of industrial risks should be studied.^[40]

See also

• Calorie restriction
• Michael Ristow
• Petkau effect
• Radiation hormesis
• Stochastic resonance
• Arndt–Schulz rule
• Mithridatism

References

Further reading

• Mattson, Mark P.; Calabrese, Edward J., eds. (2009). "Hormesis: A Revolution in Biology, Toxicology and Medicine". New York: Humana Press. ISBN 978-1-60761-495-1. 

External links

• International Dose-Response Society