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LETTER TO THE EDITOR ON FENITROTHION (TOXICOLOGY SCIENCES, 2001)
Citation:
Tamura, H., K. W. Gaido, AND L E. Gray Jr. LETTER TO THE EDITOR ON FENITROTHION (TOXICOLOGY SCIENCES, 2001). TOXICOLOGICAL SCIENCES 62(1):183, (2001).
Impact/Purpose:
Letter to the editor
Description:
Dear Dr. Klaassen:
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 (USEPA 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
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.
Hiroto Tamura
Meijo University
Kevin W. Gaido
David C. Dorman
CIIT Centers for Health Research
L. Earl Gray
U.S. Environmental Protection Agency
References
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, 223 [Abstract].