Hormesis
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Hormesis 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".
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[edit] 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. [citation needed]
A more likely explanation is that low doses interact with genetic signaling systems that upregulate gene expression, whereas high doses cause overt toxicity.
[edit] Policy consequences
Regulatory agencies such as the Environmental Protection Agency (EPA), the Food and Drug Administration (FDA), and the Nuclear Regulatory Commission (NRC) 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 proponents of hormesis argue that hanging to a hormesis model would likely change exposure standards for these toxins 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.
[edit] Consistency of low-dose benefits
While some cases of hormesis show low doses of toxins 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.
[edit] Known hormetic substances
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. [1]
[edit] Non-acceptance
The hormesis model of dose response is largely not accepted.
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 U.S. Congress) recently released a report written by national experts in the field which rejects hormesis for ionizing radiation [1]. 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.[2]. The notion that hormesis is a widespread or important phenomenon in biological systems is not widely accepted.[3]
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.
[edit] See also
[edit] References
- ^ Powell, et al. "Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats"
- ^ "Information on hormesis". Health Physics Society. Retrieved 26-Feb-2006.
- ^ 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.
- A large amount of information is available from the BELLE (Biological Effects of Low Level Exposure) website.
- International Hormesis Society
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.
