Toxicological Sciences 62, 183 (2001)
Copyright © 2001 by the Society of Toxicology
Reply
1 Department of Applied Biochemistry Meijo University Nagoya 468-8502, Japan 2 CIIT Centers for Health Research Research Triangle Park, NC 27709 3 U.S. Environmental Protection Agency Research Triangle Park, NC 27709
To the Editor:
We appreciate the opportunity to respond to Dr. Goodman's comments. As noted by Dr. Goodman, the purpose of our study was to assess whether fenitrothion was an antiandrogen. Our interest in this issue was driven by the close structural similarity between fenitrothion and the potent antiandrogen flutamide. We used a two-tiered approach that included in vitro and in vivo pharmacological screens for antiandrogenic activity. The in vivo screen, often referred to as a Hershberger assay, used castrated rats given testosterone proprionate to maintain normal androgen function. This assay evaluates the ability of a xenobiotic to compete with testosterone for binding to the androgen receptor in vivo. As in all pharmacological competitive assays, the dose of xenobiotic and corresponding concentration of natural ligand (i.e., testosterone) are absolutely critical. We used a dose of testosterone propionate below an ED80 and a fenitrothion dose that resulted in < 10% change in body weight. This design meets the current OECD recommendations for the Hershberger assay and avoids confounding influences due to growth retardation (Marty et al., 2001
).
In Dr. Goodman's final remarks, he posed the question "While the data might be real, are they relevant?" It appears that Dr. Goodman does not question the validity of the reported antiandrogenic effects of fenitrothion but rather questions whether such empirical toxicological data are useful in assessing human risk to fenitrothion and structurally related organophosphate insecticides. In this regard, dose-response studies at "relevant" environmental concentrations are unwarranted in a screening assay (U.S. EPA Endocrine Disruptor Screening and Testing Advisory Committee Final Report, 1998). As indicated in the EDSTAC report, dose response, adversity, and risk assessment issues should be based on data from testing, not on screening assays. Our results are relevant within the context of a tiered screening and testing approach, but do not indicate an adverse health effect. Rather, our study provides strong evidence of an antiandrogen activity for fenitrothion, an observation that requires additional in vivo studies using a wider range of dose levels and appropriate end points. These studies are currently underway at our Institutes.
REFERENCE
Marty, M. S., Johnson, K. A., and Carney, E. W. (2001). Effect of feed restriction on Hershberger and pubertal male assay endpoints. Toxicol. Sci. 60, 285–295.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||