Hormesis NOAEL

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. 

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. 

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). 

In addition to satisfying entry and evaluative criteria for hormesis, a complementary perspective on the issue of whether the low-dose stimulation could have occurred by random process was devised. Of the nearly 1800 doses below the NOAEL, an assessment was made of the proportion of responses that statistically significantly differed from the control in the direction of hormesis or in the opposite direction. If the responses were random, one would expect that the response would vary similarly for either possibility. However, responses displaying statistical significance in the hormetic direction occurred 32 times more frequently than the opposite Thus, these findings strikingly support the conclusion that the hormetic responses cannot be explained by random processes (12). 

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