Dose-response models hormetic

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) ... 

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 hormetic dose-response model can predict the occurrence of beneficial responses below the toxicological threshold. This can be seen with endpoints such as enhanced longevity, decreased disease incidence, and improved cognition, unlike the threshold and linear at low-dose (LNT) models. 

Chemical interactions can be accounted for. While threshold dose response model can only deal with chemical interactions for responses that exceed a threshold, the hormetic model also does this. These models differ where the interaction occurs in the hormetic stimulatory zone. In the case of the hormetic chemical interactions, the maximum response is still constrained to 30-60% above the control value a characteristic that the threshold and linear at low-dose models do not have. 

A hormetic dose-response model has the same dose-response for all biological models, endpoints, and chemical or physical agents. This means that hormesis can harmonize risk assessment procednres for both carcinogens and noncarcinogens. 

Calabrese, E. J. (2008d). Alzheimer s disease drugs An application of the hormetic dose—response model. Crit Rev Toxicol 38, 419—451. 

Calabrese, E. J., and Baldwin, L. A. (2003c). The hormetic dose response model is more common than the threshold model in toxicology. Toxicol Sci 71, 246-250. 

The hormetic dose response model indicates that the maximum stimulatory response is modest, being best described as a ceiling effect with the maximum response occurring typically between 30 and 60% greater than control responses. The clinical implications of increases of this limited magnitude must be appreciated in order to determine the clinical effectiveness of pharmaceutical agents. 

Should hormetic dose responses have to be demonstrated in each case or can it be assumed to occur if it is in fact far more common than the threshold response Should there be a default dose response model Why Why not ... 

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... 

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. 

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). 

The hormetic dose-response can predict harm below or above the toxicological threshold, and thus it is consistent with positive and negative outcomes, unlike the LNT or the S-shaped models. 

In light of the fact that numerous terms have been employed to describe hormetic dose-responses and often investigators fail to recognize and acknowledge this effect in their published data, a hormetic database was created in order to systematically collect and assess hormetic dose-responses (Calabrese and Baldwin, 1997 Calabrese and Blain, 2005). The information collected has permitted an evaluation of the quantitative features of the hormetic dose-response relationship, but it has also revealed that hormetic dose-responses occur independent of biological model, endpoint measured, and chemical class. Based upon information contained in this database several dozen dose-response relationships were selected in order to demonstrate the occurrence of hormetic dose-responses across model, endpoint, and chemical class (Figure 5.3). 

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. 

Threshold concentration. There are three models of the toxicity of compounds at low concentrations. A compound may have a toxic effect as long as any amount of the compound is available to the organism, and there is no threshold. Only at zero concentration will the effect disappear. Another model is that a threshold dose exists below which the compound exists but no effects can be discerned. A third model, that of hormesis, states that below a certain concentration a compound enhances the survivorship or other variable being observed. The hormetic response can often be seen in algae growth tests where, at low concentrations of a toxicant, a larger biomass is produced. 

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