Our Stolen Futurea book by Theo Colborn, Dianne Dumanoski, and John Peterson Myers
 
 

 

  Thayer, KA, R Melnick, K Burns, D Davis, and J Huff. 2005. Fundamental Flaws of Hormesis for Public Health Decisions. Environmental Health Perspectives, in press.

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In a peer-reviewed commentary published in the scientific journal of the US National Institute of Environmental Health Sciences, 5 scientists from government, academic and independent laboratories challenge proposals that 'hormesis' be used to justify weakening public health standards.

What is hormesis?

Hormesis is a term used to denote 'J-shaped' dose response curves. For example, as dose rises from 0 in the graph to the right, response (red) is initially inhibited, dropping below the level seen without exposure (the blue line). As dose responds above the level at which the lowest response is seen (M), response then rises.

Mathematically, hormetic responses are a subset of what are called non-monotonic dose response curves, in which the slope of the curve changes sign and reverses direction. Below M, the slope is negative, above it, the slope is positive.

In a series of papers, Ed Calabrese and co-authors have argued that hormesis is an widespread adaptive, stimulatory response. For example, while high doses of dioxin causes increases in tumor numbers, Calabrese cites data showing a suppression of tumors at low dose exposure to dioxin.

In his writing, Calabrese goes so far as to speculate "“the hormetic phenomenon response is a common, evolutionary-based strategy to carefully regulate resource allocation in a definable range within the context of the reestablishment and maintenance of homeostasis.”

 
Hormesis has been proposed to be an adaptive response to low-level exposures that has beneficial consequences.  

For example, an organism might benefit by having its immune system stimulated by low doses of a contaminant, so that it is 'prepared' for higher doses.

This interpretation has been used by two of the principal proponents of hormesis, Edward Calabrese and Linda Baldwin, to argue that exposure standards not only are too stringent and costly, but may also perversely cause harm because, if met, they would prevent the beneficial impacts of low-level exposure. Thayer et al.'s assessment in this paper of such logic and the data used to support it reveals flaws in the reasoning and indicates that relaxing public health standards because of hormesis would increase health risks.

Thayer et al. offer 5 main critiques of Calabrese's recommendation that safety standards be weakened because of his conceptualization of hormesis.

1. Thayer et al. observe that the concept of hormesis is based largely on empirical observations-- collections of examples of J-shaped dose-response curves--and does not adequately consider underlying mechanism(s) of action. "Without an understanding of the mechanisms
underlying a hormetic response, it is not appropriate to conclude that hormesis is a uniformly adaptive phenomenon." The mechanism of one family of non-monotonic dose response curves has been thoroughly explored, and the details are not consistent with a beneficial effect.

Few of the responses Calabrese and colleagues have deemed 'hormetic' actually have been demonstrated to be beneficial. And in those that have, rarely have they examined the system for other, simultaneous responses that might be harmful.

Their logic has been to build from those few that have beneficial impacts on one endpoint and extrapolate to all J-shaped response curves, assuming that others are beneficial also. The possibility that stimulation might be adverse is rarely discussed in their writing. Yet examples of adverse effects of stimulation are widespread, for example, cell proliferation.

Thayer et al. dissect a hormesis example presented by Calabrese and Baldwin: low dose suppression of testicular tumors in rats by cadmium. They find two weaknesses. First, the decrease is not statistically significant. Second, at the same dose range, cadmium causes a statistically significant increase in prostate tumors in the same study.

 

Latest news about hormesis

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As Thayer et al. summarize, epidemiological studies of cadmium in people show associations of several adverse outcomes with current exposure levels for the general population. They conclude: "When all these findings are considered, it is improbable that allowing higher levels of cadmium in the environment would provide an overall health benefit for the general population." Thus using one hormetic response to justify laxer cadmium standards is clearly problematic.

2. While Calabrese and his colleagues acknowledge that low dose stimulation can be either beneficial or harmful, in their writing they regularly emphasize its benefical impacts and argue that it be used to justify weakening standards. For example, "Acceptance of hormesis will be difficult, therefore, because agencies will need to accept the possibility (actually the likelihood) that toxic substances, even the most highly toxic (e.g., cadmium, lead, mercury, dioxin, PCBs, etc.) can cause beneficial effects at low doses.

3.Typically, contaminants have more than one effect. If one produces beneficial stimulation at low doses, any policy recommendation must incorporate other effects, which may not be beneficial.

4. Even for cases in which there is only one effect, and it is beneficial, individuals differ in their responsivity to exposure, so that the range of exposures that benefit one individual may harm another.

5. Exposures to one contaminant do not occur in isolation. Any policy recommendation that attempts to incorporate the beneficial impact of a hormetic exposure will need to address the reality that many low doses to related compounds, often acting via similar mechanisms, are occurring simultaneously. As shown by Rajapaske et al., these mixtures can dramatically alter system response.

Thayer et al. offer a series of additional, more detailed criticisms. For example, in an effort to establish how common hormetic responses are, Calabrese and Baldwin survey the toxicological literature for dose-response curves that in their judgment fit a hormetic pattern. They find a large number. But their criteria for identifying a hormetic response does not require that the low-dose stimulatory response differ significantly from control exposures. Hence it virtually certain that their estimation of hormesis's frequency is inflated.

What do Thayer et al. conclude?" While hormetic effects may occur in some instances, it is indeed rare that exposures to toxic, mutagenic, teratogenic and carcinogenic chemicals, even at low exposure levels, would be risk free and provide health benefits for the general public. Portraying chemicals with numerous adverse effects as having "benefits" while ignoring their hazards is irresponsible and does not provide full and objective disclosure."

Editor's Note: One issue not raised by Thayer et al. is funding. Calabrese is supported for his research into hormesis in part via significant grants from the Department of Defense. For example, in 2003 records indicate the Air Force provided over $170,000 in grant support for Calabrese's work. The Air Force is currently involved in two very large public debates over contamination at military bases, over perchlorate and trichloroethylene, which could have major economic consequences for the Department of Defense.

There is no evidence that Calabrese and his colleagues have skewed their research as a result of this funding. It is unfortunate that their main survey of the literature does not use criteria that are based on statistical significance. On the other hand, there are clear biases in the way they summarize the policy implications of their research, briefly acknowledging possible adverse consequences of low dose stimulation but then arguing that applying hormetic concepts to regulations would allow standards to be looser.

Two recent studies of the toxicological literature demonstrate very strong effects of funding source on research outcome. In research on the impact of atrazine on frog development, and in studies of the low dose impacts of bisphenol A, funding by a source with a strong economic interest in the outcome strongly biased the research toward outcomes that were favorable. Whether something similar is occurring in hormesis research remains to be tested.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
   
   

 

 

 

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