Hormesis dose-response relationships

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. 

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

Calabrese EJ, Baldwin LA. 2002. Dose-response relationships of chemotherapeutic agents evidence of hormesis. Crit. Rev. Toxicol. In press... 

Figure 26.1. Hormesis may be defined as a dose-response relationship that is characterized by a biphasic (J- or inverted U-shaped) response. The quantitative features of the typical hermetic responses are similar, with the magnitude of the maximum stimulatory response typically being 30-60% greater than controls, the width of the stimulatory or hermetic zone averaging approximately 10-fold, and the interval from the zero equivalent point to the maximum stimulation averaging four- to fivefold (Calabrese and Blain 2005). [Figure adapted from Nascarella et al. (2009).]...

Despite the strong identification of this concept with Schulz, numerous independent researchers such as Jensen commonly observed this dose-response relationship, often without any apparent knowledge that this biphasic dose-response was actually part of a controversial dose response concept of Schulz. Other investigators created a journal called Cell Stimulation based upon the Arndt-Schulz Law/hormesis concept. However, after what appeared to be a very successful initial six years, the publication was ceased in 1930 for reasons that are unclear. 

Although now there are numerous articles citing hormesis in various scientific databases, there are numerous other terms that have been used to describe dose-response relationships with the same quantitative features of the hormetic dose response. These similar descriptive terms include Yerkes-Dodson Law, nonmonotonic dose-response, nonlinear dose response, J-shaped dose-response, U-shaped dose-response, biphasic dose-response, BELL- haped dose-response, functional antagonism, hormologosis, overcompensation, rebound effect, bitonic, dual effect, bidirectional effect, bimodal effects, Amdt- chulz Law, Hueppe s Rule, and subsidy... 

The hormetic dose-response can occur as an overcompensation to a disruption in homeostasis or as a direct stimulation. The incorporation of a repeated measures analysis component into the study design would be an essential element in both identifying and understanding dose-response relationships. Dose-time-effects relating to hormesis have typically been associated with the concept of a rebound /overcompensation effect with a robust supportive literature. 

Key questions are why is the hormetic dose-response modest, and what are its implications Considerable evidence indicates that hormetic dose-responses represent a modest overcompensation to a disruption in homeostasis. This was observed initially over a century ago by Townsend and extended to other biological models and endpoints in the subsequent decades. This was particularly the case with the research of Branham, who not only replicated the earlier research of Schulz, but clarified the dose-time response relationship. Similar observations were made by Smith, who demonstrated that stimulation of mycelium growth was a reproducible phenomenon except that it occurred only following the UV-induced damage, with the subsequent stimulation representing the modest overcompensation response now called hormesis. 

What is the medical practice of homeopathy How does it address the issue of dose response Why would Hugo Schulz, the developer of the hormesis concept, have thought that he had discovered the underlying principal of homeopathy Critically assess whether there is any scientific relationship between the concept of hormesis and homeopathy. 

The concept of hormesis should be formally considered in structure-activity-relationship (SAR) evaluation studies. If the low-dose stimulatory response is... 

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