Hormesis

Hormesis, in which compensatory adaptive changes precede and occur at lower doses than degenerative changes, was detected for half of the toxic drugs for cell proliferation, cell morphology and mitochondria [4, 33]. Hormesis could not be assessed for parameters that normally have low values, such as intracellular calcium measured by fluo4 or membrane permeability measured by toto-3, because assay methods were not sufficiently sensitive. However, for calcium, more sensitive dyes. 

Hormesis is the term used for the phenomenon of stimulatory effects at low-level exposure, and inhibition at high-level exposure. The term derives from the Greek word Hormo which means excite or set in motion, and which is also the root of the word hormone. The concept of hormesis dates back to the 1920s. A substance showing hormesis has the opposite effect in small doses compared to effects at large doses. The definition of hormesis does not imply that low-dose effects are necessarily beneficial, only that they are opposite to high-dose effects. 

According to systematic investigations of peer-reviewed published scientific literamre, thousands of examples of likely hormetic action exist (Calabrese 2005). 

The maximum hormetic stimulatory response is typically a 30%-60% increase of the control value, and this appears to be the case across systems, whether the system is a plant, fish, cell line, mammal, or bacteria. The hormetic response is typically observed at dose levels at 1/10-1/5 of the NOAEL and up to just below the NOAEL. The frequency with which hormesis occurs in toxicity smdies may be quite high. An analysis of several hundred articles selected from a large database of published toxicity studies showed a frequency of 40% (Calabrese 2005). 

Toxicological Risk Assessments of Chemicals A Practical Guide 

A third type of dose response relationship has been proposed, which is increasingly gaining acceptance, and this is the hormetic kind. This kind of dose response, for which there is experimental evidence, involves opposite effects at low doses, giving rise to a U-shaped or J-shaped curve (Fig. 2.11). That is, there may be positive or stimulatory beneficial effects at low doses. For example, some data indicate that at low doses of dioxin, the incidence of certain cancers in animals exposed is less than occurs in controls. Another example is alcohol (ethanol), for which there is evidence from a number of studies that low to moderate intake in man leads to lower levels of cardiovascular disease. Of course, high levels of intake of alcohol are well established to cause liver cirrhosis, various cancers, and also damage to the cardiovascular system. 

However, it must be ascertained if the positive effect is directly related to the toxic effect and whether the same positive effect is observed using a variety of markers. 

Because the positive effects will occur at low doses, showing these experimentally is difficult and it adds a layer of complexity to determining a dose-response relationship for a chemical. 

Such effects may be confused or obscured by normal biological variation, as they are typically only 30% to 60% above the control. Furthermore, if the background level of tumor incidence (or other effect being measured) is low, it may be impossible to assess hormesis. 

Many toxicity studies, especially long-term bioassays carried out to determine potential carcinogenicity, use high-dose levels (e.g., maximum tolerated dose), and consequently, any hormetic response would be missed. To be properly evaluated, more doses and a wider dose response would have to be investigated. 

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For some toxins it is possible to demonstrate an apparent improvement in functional response at levels of exposure which are below a threshold. This effect, which has been termed hormesis , is most effectively demonstrated in the consistently improved longevity of animals whose caloric intake is restricted rather than allowing them to feed ad lib (Tannenbaum, 1942). Clearly in this instance, the observed effects are the result of exposure to a complex mixture of chemicals whose metabolism determines the total amount of energy available to the organism. But it is also possible to show similar effects when single chemicals such as alcohol (Maclure, 1993), or caffeic acid (Lutz et al., 1997) are administered, as well as for more toxic chemicals such as arsenic (Pisciotto and Graziano, 1980) or even tetrachloro-p-dibenzodioxin (TCDD) ( Huff et al., 1994) when administered at very low doses. It is possible that there are toxins that effect a modest, reversible disruption in homeostasis which results in an over-compensation, and that this is the mechanism of the beneficial effect observed. These effects would not be observed in the animal bioassays since to show them it would be necessary to have at least three dose groups below the NOAEL. In addition, the strain of animal used would have to have a very low incidence of disease to show any effect. 

Luckey, T.D. 1980. Hormesis with Ionizing Radiation. CRC Press, Boca Raton, FL. 222 pp. 

Thompson, G.A., J. Smithers, and H. Boxenbaum. 1990. Biphasic mortality response of chipmunks in the wild to single doses of ionizing radiation toxicity and longevity hormesis. Drug Metabol. Rev. 22 269-289. 

Mehendale HM. 1992. Biochemical mechanisms of biphasic dose-response relationships Role of hormesis. In Calabrese EJ, ed. Biological effects of low level exposures to chemicals and radiation. Workshop, Amherst, MA, April 30 - May 1, 1991. Chelsea, Ml Lewis Publishers, Inc., 59-94. 

More complex dose-response relationships than we have encountered thus far, while not new, have come into increased prominence in the past decade. One type pertains to substances we recognize as essential nutrients, and its importance is not in dispute. The second type is said to describe a highly interesting phenomenon called hormesis, but its importance is less clear. 

It seems that large numbers of chemicals, in equally large numbers of test systems, from mammals to insects, vertebrates to invertebrates, microorganisms to plants, exhibit hormetic dose-response relationships. The relationship is not the same as that described earlier for nutrients, in two ways. First, in the case of hormesis the biological response - the toxicity endpoint - is the same in the protective region and in the region of toxicity (i.e., liver cancer incidence is reduced relative to control incidence over a range of low doses, and then as the NOAEL is exceeded, liver cancer incidence increases above that of controls). This is true hormesis. 

In the case of a nutrient there is a low-dose adverse effect due to nutritional inadequacy, but the nature of the adverse effect is completely different from that which becomes manifest as the region of high-dose toxicity is entered. Also, the very large risk associated with severe nutrient deficiency at doses near zero is not at all present in the case of hormesis. 

Hormesis will be a subject of steady and perhaps increasing interest, but whether and in what way it moves to the center of the policy stage for toxic substances is beyond anyone s predictive powers. 

Calabrese, E. J. and Cook, R. R. (2005) Hormesis how it could affect the risk assessment process. Human and Experimental Toxicology. 24, 365-270. 

Finally, the concept of hormesis (Section 4.12), threshold of toxicological concern (Section 4.13), and probabilistic methods for effect assessment (Section 4.14) will be briefly addressed. 

In relation to hormesis (Section 4.12), the dose-response curve can be an inverted U-shaped curve (see Figure 4.3) or a J-shaped curve (see Figure 4.4). 

Bradford Hill, A. 1965. The environment and diseases Association or causation Proc. R. Soc. Med. 58 295-300. Calabrese, E.J. 2005. Paradigm lost, paradigm found The re-emergence of hormesis as a fundamental dose response model in the toxicological sciences. Environ. Pollut. 138 379 12. 

Calabrese, E.J. and L.A. Baldwin. 2002. Hormesis and high-risk groups. Regul. Toxicol. Pharmacol. 35 414- 28. 

Hipkiss, A. R. (2007b). Dietary restriction, glycolysis, hormesis and ageing. Biogerontology 8, 221-224. 

Single-cell resolution Tracks individual live cells and discriminates them from dead cells and extracellular stain allows identification of hormesis and separation of compensatory adaptation from degenerative change allows more accurate identification of sequence of change in different cytotoxicity parameters as cells might not be synchronous or alike in their response... 

For example, mitochondrial reductive capacity is decreased with decreased cell numbers but is increased with cells that are activated, such as lymphocytic immune activation, or if cells adapt to the stress associated with toxicity, such as during mitochondrial biogenesis. Thus, mitochondrial reductive capacity might be either increased or decreased with toxicity. Similar contradictory interpretations might occur with other cellular activities, for which there is a compensatory adaptive increase before their failure. This biphasic change is referred to as hormesis and occurs not only with reductive mitochondrial activity but also with mitochondrial number, cell number, mitochondrial membrane potential, antioxidant system activity and numerous other activities. 

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