Environmental and Occupational Toxicology Division Safe Environments Programme Health Canada, P.L. 0803D Tunney's Pasture, Ottawa, Ontario K1A 0L2, Canada E-mail: mike_wade{at}hc-sc.gc.ca.
To the Editor:
Dr. Calabrese has correctly pointed out that we did observe biphasic responses of several endpoints, specifically, total epididymal sperm, and natural killer cell activity in male rats exposed subchronically to a mixture of organochlorines and metals (Wade et al., 2002). In each case, the lowest dose of the mixture caused a statistically significant increase in the parameter while, at the highest dose tested, there was either no change (epididymal sperm) or a significant reduction in response relative to control (natural killer-cell activity). Both responses do fit the model of a hormetic response (Calabrese and Baldwin, 2001a
,b
) in that the response at the low-dose could not be predicted by extrapolation from responses at higher doses, and the low-dose responses could be described as beneficial or adaptive (i.e., increased cauda epididymal sperm suggests improved fertility due to a larger number of sperm available per ejaculate, and increased natural killer-cell activity, suggesting more efficient neutralization of pathogens). As these responses were the only endpoints seen to change at this low dose in the current study, it is difficult for us to describe the dose as hazardous, unlike the obvious adverse effects that are seen in animals exposed to 100-fold (reduced urea nitrogen, reduced epididymis weight) or 1000-fold (increased liver weight, increased kidney weight) higher doses. The purpose of the study was to assess hazards of exposure to this mixture. We felt it very difficult to argue that these isolated observations, showing marginal, albeit statistically significant and apparently adaptive responses at the lowest dose would provide sufficient weight of evidence of adverse effects to merit concluding that the mixture is toxic at this lowest dose. While these observations are intriguing and, perhaps, could generate hypotheses for further investigation, it was felt that, in the current context and in the absence of scientific consensus on the importance of hormetic responses for risk assessment (Jonas, 2001
; Roberts, 2001
), they were not meaningful for hazard identification.
REFERENCES
Calabrese, E. J., and Baldwin, L. A. (2001a). Hormesis: A generalizable and unifying hypothesis. Crit. Rev. Toxicol. 31, 353424.[ISI][Medline]
Calabrese, E. J., and Baldwin, L. A. (2001b). The frequency of U-shaped dose responses in the toxicological literature. Toxicol. Sci. 62, 330338.
Jonas, W. B. (2001). A critique of "The scientific foundations of hormesis." Crit. Rev. Toxicol. 31, 625629.[ISI][Medline]
Roberts, S. M. (2001). Another view of the scientific foundations of hormesis. Crit. Rev. Toxicol. 31, 631635.[ISI][Medline]
Wade, M. G., Foster, W. G., Younglai, E. V., McMahon, A., Leingartner, K., Yagminas, A., Blakey, D., Fournier, M., Desaulniers, 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, 131143.