Hormesis



Hormesis (from Greek hórmēsis "rapid motion, eagerness," from ancient Greek hormáein "to set in motion, impel, urge on") is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses. A related concept is Mithridatism, which refers to the willful exposure to toxins in an attempt to develop immunity against them. Hormetics is the term proposed for the study and science of hormesis.

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. The notion that hormesis is important for chemical risks regulations 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 rule. Arndt's advocacy of homeopathy 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 plants.

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.

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 beverages are believed to be hormetic in preventing heart disease and stroke, although the benefits of light drinking may have been exaggerated.

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. Higher doses of 0.4% provided no longevity benefit.

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. 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.

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 curcumin from the spice turmeric 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.

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. 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.

Hormesis may also be induced by endogenously produced, potentially toxic agents. For example, mitochondria consume oxygen which generates free radicals (reactive oxygen species) 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 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. 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 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.

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.

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. 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), the National Council on Radiation Protection and Measurements (a body commissioned by the United States Congress) 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. 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.

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 (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, food and soil, 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 has shown that while relatively high doses of a xenobiotic estrogen, diethylstilbestrol, 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 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.