Hormesis



Hormesis (from Greek hormæin, meaning “to excite”) 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 than in large doses.

As an example, challenging mice with small doses of gamma ray radiation shortly before irradiating them with very high levels of gamma rays actually decreases the likelihood of cancer. There is a similar effect when dioxin is given to rats.

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”.

However, that hormesis is common or important has not been fully established. Indeed, the idea that low dose effects may be (sometimes strikingly) different is accepted, but that the low dose effect is positive is questionable. In one of the better studied areas of hormesis, radiation hormesis 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.

The biochemical mechanisms by which hormesis works are not well understood. It is conjectured that a low dose challenge with a toxin may trigger certain repair mechanisms in the body, and these mechanisms, having been initiated, are efficient enough that they not only neutralize the toxin's effect, but even repair other defects not caused by the toxin.

History
German pharmacologist Hugo Schulz first descibed hormesis in 1888 following his own observations that the growth of yeast could be stimulated small doses of poisons. This was coupled with the work of German physician Rudolph Arndt, who studied animal 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.

Mitohormesis (Mitochondrial Hormesis)
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 cumulating in increased defense capacity against exogenous radicals (and possibly other toxic compounds). Recent experimental evidence from Michael Ristow's laboratory 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 induction 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, and that the free radicals act as a signal within the cell indicating which mitochondria are ready for destruction, as proposed by the non-fiction writer Nick Lane.

Consistency of low-dose benefits
While some cases of hormesis show low doses of toxicants showing beneficial effects, others show profoundly adverse effects. The key is that low doses show the opposite effect of high doses. There are many examples where low doses cause detrimental effects not seen in high doses.

Hormesis is a subset of the more general case of dose-response curves that are characterized mathematically as being non-monotonic. In non-monotonic dose response curves, the slope of the curve changes sign as the dose changes. This change in sign means, on a practical basis, that high dose experiments cannot predict low dose results. The observation that non-monotonic dose response curves are common violates one of the core assumptions of toxicology, that "the dose makes the poison." Decades of research setting health standards have been premised on this assumption. The prevalence of non-monotonic dose response curves means that many health standards may be too weak.

Known hormetic substances and the application of hormesis as an anti-aging intervention
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 repetive 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 a spice turmeric have also shown 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".

Alcohol
Alcoholic beverages are believed to be hormetic in preventing heart disease and stroke, although the benefits of light drinking may have been exaggerated or may not exist at all.

Free Radicals / Reactive Oxygen Species
As stated above ("mitohormesis") mitochondrial free radicals have been shown by Michael Ristow and co-workers to exert life extending effects in a model organism by promoting increased stress resistance. Whether this concept applies to humans remains to be shown, although recent epidemiological findings support the process of mitohormesis, and even suggest that antioxidants may increase disease prevalence in humans.

Non-acceptance
The hormesis model of dose response is still a matter of debate.

The study of hormesis has been best developed, perhaps, in the field of ionizing radiation. The United States-based National Council on Radiation Protection and Measurements (a body commissioned by the United States Congress) recently released a report written by national experts in the field which rejects hormesis for ionizing radiation. This is done partly for the sake of caution and partly for the lack of contrary evidence. They conclude that the model that is effective at high doses, that radiation's effects should be considered to be proportional to the dose an individual receives, should be used at low doses as well. This report squarely rejects almost all research showing radiation induced hormesis as being flawed in some way (i.e. the cancer a study focuses on does not exist in humans, a clear threshold could not be established in humans, the assumptions are seriously flawed, the hormetic effect is too short to be useful).

Radiation hormesis is not generally accepted by The International Commission on Radiological Protection (ICRP), its U.S. counterpart, the National Council on Radiation Protection and Measurements (NCRP), the National Research Council Committees on the Biological Effects of Ionizing Radiation (the BEIR Committees), or the U.S. regulatory agencies. . The notion that hormesis is a widespread or important phenomenon in biological systems is not widely accepted.

Reasons include:
 * No well-documented long-term positive effects.
 * Unproveable in an ethical study of humans.
 * Counterintuitive result; unless a clear mechanism is established then there is often skepticism about small or marginally significant effects unless these have been independently replicated. On the other hand, there are detailed studies at the level of gene regulation showing that low doses cause effects that can't be predicted from high dose experiments.
 * Concern about publication bias; studies that show positive effects are more likely to be published than repeats that fail to show the same effect.
 * While some chemicals might indeed have paradoxical effects at low doses, there is no particular reason to expect such effects to be positive. Endocrinologists for decades have documented many non-monotonic dose response curves, so it is not surprising that these 'paradoxical' effects are noted with increasing frequency as toxicologists have begun to focus on contaminants that interfere with hormone action. The logical flaw by proponents of hormesis has been to assume the effects tend to be positive.  Most are not.

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 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. 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 statistical 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.