Dose response hormetic

Mehendale HM. 1994. Cellular and molecular foundations of hormetic mechanisms. In Biological effects of low level exposures dose-response relationships. Editor Calabrese EJ. Lewis Publishers. 

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. 

Hormetic effects of low-dose stimulatory and high-dose inhibitory response include parameters of good health such as growth rate, fecundity, and longevity. The dose-response curve for this type of hormetic effect is the inverted U, see Figure 4.3. 

For adverse effects such as carcinogenicity, mutagenicity, and disease incidence, a hormetic effect means low-dose reduction and high-dose enhancement of response. The dose-response curve is the J-shape, see Figure 4.4. 

Rattan, S. I. (2006). Hormetic modulation of aging and longevity by mild heat stress. Dose Response 3, 533-646. 

Galabres, E.J. and Blain, R. 2005. The occurrence of hormetic dose responses in the toxicologi-... 

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. 

Figure 2.11 A hormetic type of dose-response curve where low doses give a positive, beneficial effect and high doses a negative, toxic effect.

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. 

In range extrapolations, responses for the same endpoint are inferred outside the range of the data from which the model was derived. These are most commonly used to calculate low-effect concentrations such as the LC10, LC25, or benchmark effect doses or concentrations from the dose-response line (SETAC 1994), or in the case of human health protection to estimate low-risk exposures such as the 10 6 risk of tumor production (USEPA 1995a see Figure 1.4). In the context of acute responses, the model used for extrapolation (the log dose-probit effect Finney 1971) is well tested and widely used. However, the possibility of stimulatory or hormetic... 

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).

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... 

The implications of hormetic effects for chemotherapeutics also extend to the domain of peptide biology and its relationship to the human genome. Numerous hormetic-like biphasic dose responses exist for peptides, further displaying the broad generalizability of the hormetic concept. Recent assessments of both chemotherapeutic (57) and peptide (58) examples of hormetic effects have been completed. 

If hormetic effects are an evolutionary/biological/toxicological expectation, then it implies that hazard assessment strategies include a protocol to assess its possible occurrence. This has practical importance because hormetic effects may affect both the concept and derivation of the NOAEL. The derivation of the NOAEL could change if the low-dose stimulation were determined to be an adverse effect. The hormetic dose-response continuum in this instance (i.e., both the increase at low doses and the decrease at high doses from the control) could be viewed as adverse. However, if the low-dose stimulation were deemed as beneficial, it would have little direct effect on the concept of the NOAEL, but could affect how the traditional NOAEL is derived (59) as well as challenging the basic goal of the risk assessment process from the exclusive focus on the avoidance of potential harm to also include the concept of benefit. 

Hazard assessment evaluations should incorporate greater opportunity to identify the hormetic portion of the dose-response relationship... 

Despite these impediments to the acceptance of hormesis (even in the presence of compelling data), there are activities that suggest that the hormesis concept could be embraced by society. The widely accepted and well-established observation that ingestion of a daily glass or two of red wine reduces the risk of cardiovascular disease may have preconditioned society to consider the hormetic hypothesis for pollutants and radiation. In addition, the recognition that anticancer agents can both stimulate and inhibit tumor growth via an hormetic dose response may enhance the clinical interest in this concept. 

Figure 7.1 also depicts changes via behaviors, such as occupation, ambient exposure, and predisposition, such as genetic. Logically, it is correct regardless of the shape of the dose-response model. At low dose or at environmental (ambient) exposures, cancer risk assessment models used in regulatory law are either linear or linearized that is, each is a cumulative distribution function of lifetime cancer risk and thus is a monotonic function. Hormetic cancer dose-response models are also probabilistic however, they are nonmonotonic (they are relations). The EPA summarizes the reasons for using statistical and probabilistic methods in risk assessment as follows (EPA 2005) ... 

The data supporting the hormetic dose-response therefore not only far exceeds normal proof of concept criteria but have been employed in the development of drugs for numerous human conditions, thereby satisfying a stronger proof of application requirements. In head-to-head direct comparisons the hormesis model far outcompeted the threshold and linear at low dose models (Calabrese and Baldwin 2001, 2003c Calabrese et al. 2006). In fact, while the threshold model was shown to poorly predict below threshold responses the linear at low-dose models, the LNT models cannot be practically validated in either moderate or large-scale studies. 

Corollary Question Since the J-shaped hormetic (or biphasic) cancer dose-response model yields empirically demonstrated protective (stimulatory) effects at low doses in one or more species, is biologically plausible, and describes a damaging relationship at higher dose that is consistent with the LNT, which of the two is the logical and prudential default model ... 

Although the answer to the first question is legal, and thus beyond the scope of this chapter, the answer to the second question falls well within our framework. We can begin to frame the answers by a limited review of current well-known cancer dose-response models. The hormetic J-shaped model is depicted in Figure 7.2. 

The hermetic dose response can be tested because its low-dose response starts immediately to the left (in the dose-response space) of any hypothetical threshold. Recollecting that the threshold model is the linearized form of the S-shaped toxicological cumulative distribution of responses, this response is generally not within the observations (it is an extrapolation via a probit transformation from the experimental results to a dose intercept). On the other hand, the hormetic dose-response can be either validated or rejected with normal testing protocols, provided that a sufficient number of experimental results are available (five or more). 

---