Letter

Edward J. Calabrese

Department of Environmental Health Sciences Morrill I, N344 University of Massachusetts Amherst, MA 01003 edwardc{at}schoolph.umass.edu

To the Editor:

We were pleased to read the recent report of Wade et al.(2002) that assessed the effects of a subchronic exposure to a complex mixture of persistent contaminants on various responses in the Sprague-Dawley male rat. Of particular interest was the study design that included a concurrent control and 4 treatment groups at 1, 10, 100, and 1000 times (x) the so-called safe dose of each chemical in the mixture. While the authors determined that the study demonstrated possible adverse effects to various systems at high doses (100 and 1000x), they concluded that the various safety indices (MRLs, RfDs, TDIs) provide adequate protection for adult male rats. We would like to draw attention to several findings of the article that indicate hormetic-like biphasic dose-response relationships of both selected immune and reproductive functions. That is, the mixture enhanced various aspects of immune responsiveness and sperm production at low doses while being inhibitory at higher doses (see their Tables 5 and 6). Our principal point is that these low-dose stimulatory responses, although recognized by the authors, were not explicitly incorporated into the health evaluative appraisal of their report. Yet, the findings are, in fact, of considerable importance since most people are exposed to relatively low levels of such contaminants. This being the case, it is imperative that attempts be made to place the low-dose responses in a public health context.

Another aspect of their findings that was not discussed was the possible range of the stimulatory responses below the apparent NOAEL. In our work on hormetic responses we find that such low-dose stimulatory responses range from 5- to > 1000-fold, with the majority being <= 20-fold. While it may not be possible to provide the type of confident interpretation that we suggest without additional experimentation, researchers need to consider the implications of their data from the entire dose-response continuum and not restrict their interpretation to the traditional toxicological paradigm that has long ignored possible sub-NOAEL effects and their biological interpretations. Hormetic-like biphasic dose responses are quite common in the toxicological literature (Calabrese and Baldwin, 2001aGo,bGo,cGo) and should no longer be ignored.

REFERENCES

Calabrese, E. J., and Baldwin, L. A. (2001a). The frequency of U-shaped dose responses in the toxicological literature. Toxicol. Sci. 62, 330–338.[Abstract/Free Full Text]

Calabrese, E. J., and Baldwin, L. A. (2001b). Hormesis: U-shaped dose responses and their centrality in toxicology. Trends Pharmacol. Sci. 22, 285–291.[ISI][Medline]

Calabrese, E. J., and Baldwin, L. A. (2001c). U-shaped dose responses in biology, toxicology and public health. Annu. Rev. Public Health 22, 15–33.[ISI][Medline]

Wade, M. G., Foster, W. G., Younglai, E. V., McMahon, A., Leingartner, K., Yagminas, A., Blakely, D., Fournier, M., Dsaulniers, D., and Hughes, C. L. (2002). Effects of subchronic exposure to a complex mixture of persistent contaminants in male rats: Systemic, immune, and reproductive effects. Toxicol. Sci. 67, 131–143.[Abstract/Free Full Text]





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