Hormesis
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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. 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. The same has long been proposed regarding moderate ambient temperature fluctuations, regular exercise and even limited caloric deprivation, as both immune system stimulants and possible longevity factors. The hormesis model has been shown to hold for numerous other substances and environmental fluctuations. Hormesis, then, is the term for generally-favorable biological responses to low exposures to toxins and other stressors. (Such environmental factors that would seem to produce positive responses have also been termed "eustress".)
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Possible explanation
The reason for the hormesis phenomenon is not completely understood. It is conjectured that a low dose challenge with a toxin may jump start certain repair mechanisms in the body, and these mechanisms are efficient enough that they not only neutralize the toxin's effect, but even repair other defects not caused by the toxin. This is similar in principle to viral vector vaccines under development for diseases such as cancer and AIDS.
Similarly, continuing or intermittent mild stressors such as exercise, environmental fluctuations and even food limitations would seem to stimulate tolerance to sudden similar but more severe demands made upon the organism.
Policy consequences
Traditionally, regulatory agencies such as the Environmental Protection Agency (EPA), the Food and Drug Administration (FDA), and the Nuclear Regulatory Commission (NRC) use a threshold model for non-carcinogens, and a linear no-threshold model for carcinogens (including radiation). In the threshold model, anything above a certain dose is considered dangerous, and anything below it safe. In the linear model, there is no safe dosage. Changing to a hormesis model would likely change exposure standards for these toxins in air, water, food and soil. As a result, costs of environmental regulations and cleanup/remediation activities could be lowered.
Wider use of the hormesis model would affect how scientists design and conduct studies and the selection of statistical models that estimate risk.
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 (NCRP), a body commissioned by U.S. Congress, recently released report written by the national experts in the field which states that, for the sake of caution, radiation's effects should be considered to be proportional to the dose an individual receives, regardless of how small that dose is. This report squarely rejects almost all research showing 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).
In the absence of policies to accept hormesis, and with hundreds of billions at stake, as well as many people's livelihoods, the controversy is very active.
Low doses always beneficial?
While the most prominent cases of hormesis show low doses of toxins showing beneficial effects, this is not part of the definition of hormesis. The key is that low doses show the opposite effect of high doses. There are substances where low doses show detrimental effects not seen in high doses, (such as in routine low dosage of animals or humans with antibiotics?)
Known hormetic substances
Vitamins and minerals are well known to show a hormetic response. Low doses are necessary for health, and some are essential to life, but most are toxic in large amounts. Medicines in general benefit at least some fraction of the population, but are generally toxic in large amounts. Some studies show benefits to moderate alcohol consumption, but alcoholism is the well known result of excess consumption.
Opioid analgesics have been shown to have paradoxical effects (increased rather than decreased pain) at extremely small doses, and tiny doses of opioid antagonists are sometimes used to enhance the effects of larger doses of opioid analgesics. <ref>Powell, et al. "Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats"</ref>
Opioid tolerance and dependence are conjectured to result from a shift, over time, in the balance of excitatory (undesired) and inhibitory (desired) effects of these drugs. The precise mechanisms remain unknown and research is continuing. <ref>Crain, S.M., Shen, K.F., "Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment"</ref> <ref>Burns, Lindsay H., "Ultra-low-dose opioid antagonists enhance opioid analgesia while reducing tolerance, dependence and addictive properties"</ref>
Slow acceptance
The acceptance of the hormesis model of dose response has been very slow. 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.<ref>"Information on hormesis". Health Physics Society. Retrieved 26-Feb-2006.</ref>. The notion that hormesis is a widespread or important phenomenon in biological systems is not widely accepted.<ref>Axelrod, Deborah, MD, et al. "'Hormesis'—An Inappropriate Extrapolation from the Specific to the Universal". International Journal of Occupational and Environmental Health, 2004;10:335–339. Retrieved 26-Feb-2006.</ref>
Reasons include:
- Unproveable in an ethical study of humans. This may change now that Chernobyl studies are starting to show far fewer deaths than the no-threshold hypothesis would predict.<ref>Fumento, Michael. "So What Really Happened After Chernobyl?". TCS Daily, 19-Sep-2005. Retrieved 26-Feb-2006.</ref>
- 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.
- 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 common or of any importance
- Toxicology experiments have typically used very few doses and emphasized high doses, thus missing potential hormetic phenomena.
- Hormesis was associated with the medical practice of homeopathy in its early years and was stigmatized as a result.
See also
References
<references/>
- A large amount of information is available from the BELLE (Biological Effects of Low Level Exposure) website.
NOTE: An early version of this article was based on the press handout: "Hormesis: Principal Concepts and Take Home Message", by Edward J. Calabrese, Ph.D., University of Massachusetts, from a hormesis panel discussion, Feb 25, 2004, Washington, DC.de:Hormesis es:Hormesis