Dose response hormesis

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 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. 

Galabrese, E.J. 2004. Hormesis from marginalization to mainstream. A case for hormesis as the default dose-response model in risk assessment. Toxicology and Applied Pharmacology 197 125-136. 

Calabrese EJ, Baldwin LA. Hormesis the dose-response revolution. Annu Rev Pharmacol Toxicol 2003 43 175-197. 

Figure 11.4 Nonconventional dose-response relationship involving low-dose effects and compensation. (I) True initiation of the response followed by a compensatory response that returns the effects to the 0% level. (II) A negative response due to overcompensation (hormesis) followed by recovery to the 0% effect level. (Ill) The standard sigmoidal dose-response relationship.

There is a class of curvilinear dose-response relationships in toxicological and epidemiological studies that may be described as U-shaped or J-shaped curves. Other terms such as biphasic, and more recently hormesis, have been used to refer to paradoxical effects of low-level toxicants. In brief, these dose-response curves reflect an apparent improvement or reversal in the effect of an otherwise toxic agent. These... 

Calabrese EJ. 2005. Paradigm lost, paradigm found the re-emergence of hormesis as a fundamental dose-response model in the toxicological sciences. Environ Pollut... 

Pickrell J.A., Oehme, F.W. (2005). Examining the risks and benefits of replacing traditional dose-response with hormesis. Hum. Exp. Toxicol. 24 259-64. 

Sakai, K. (2006). Biological responses to low dose radiation -hormesis and adaptive responses. Yakugaku Zasshi 126 827-31. 

Figure 1 Idealized dose-response curves for the (a) hormesis, (b) linear, and (c) threshold hypotheses. A positive toxic effect is regarded as detrimental, whereas a negative toxic effect is beneficial (hormetic).

Calabrese EJ and Baldwin LA (2001) Hormesis U-shaped dose responses and their centrality in toxicology. Trends in Pharmacological Sciences 22 285-291. 

Calabrese EJ and Baldwin LA (2003) Hormesis The dose-response relationship. Annual Review of Pharmacology and Toxicology 43 175-197. 

Cairns, J.C., Jr. 1986. The myth of the most sensitive species. Bioscience 36 670-672. Calabrese, E.J. and L.A. Baldwin. 2003. Hormesis the dose-response revolution. 

In 1996, we received a grant from the Texas Institute for Advanced Chemical Technology (TIACT) at Texas A M to assess whether the hormesis hypothesis was toxicologically credible. We set forth to make initial judgments on the existence of hormesis based on the conformity of published dose responses to the hormetic /3-curve (Figure 1). In order to assess this in an objective manner, we developed a priori criteria based on study designfeatures, quantitative characteristics of the dose response, statistical power, and reproducibility of experimental findings. These... 

Figure 3 Stylized dose-response curves reflecting the relative distribution of stimulatory dose ranges. Note the maximum stimulatory response is usually 130%—160% of the control value regardless of the width of the stimulatory dose range the inverted U-shaped curve was used for illustrative purposes only, whereas examples in the hormesis database include both inverted U- and U-(J-) shaped curves depending upon the endpoint measured. Modified from Calabrese (30).

---