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Advisory Committee on Health Effects of Endocrine Disruptors
The Supplement II to the Intermediary Report
1.3.2 |
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The first substantial data related to multiplicative or additive
effects were presented by Soto17
in a paper on the possibility of complex assay systems. The
reports by Kortenkamp and coworkers18,19,20
deserve attention in that clear additivity was established21.
This is not surprising in view of the signal detection mechanism
in hormonal actions. It is an important conclusion that should
trigger discussions from a variety of viewpoints.
The finding that some or other anomalies were observed at dose
levels lower than the known NOEL or NOAEL is an indirect
indication of the non-linearity of the adverse reactions. Grey22
reports the antiandrogen effects of vinclozolin resulting in
feminization as indicated by a decreased anus-genital process
distance and other indicators at levels of 100-200 mg/kg, which
are far lower than the known NOEL (thousands mg/kg).
It is also known that actions of an agent may vary with tissues
of the exposed organism in function and in rank correlation of
the reactions. Nonylphenol (NP), a compound that has
estrogen-like activity, was found to cause a stronger gene
expression in the liver than in the uterus where the expression
by NP is known to be weaker than that by estradiol, suggesting
that other compounds with estrogen-like activity can have
different effects upon different target organs. This phenomenon
should be taken into consideration in studies on complex effects
of endocrine disruptors23.
The oteoblast is one of important target organs of estrogens. A
study on effects of genistein, bisphenol A (BPA) and
diethylstilbestrol (DES) on human osteoblasts (FOB strain)
showed that BPA promoted multiplication more effectively than
BPA24. The biological
implication of this result is still unclear.
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17 Soto AM, Fernandez MF, Luizzi MF, Oles
Karasko AS, Sonnenschein C.: Developing a marker of exposure to
xenoestrogen mixtures in human serum. Environ Health Perspect
105(3): 647-654, 1997.
18 Rajapakse N, Silva E, Kortenkamp A:Combining
xenoestrogens at levels below individual no-observed-effect
concentrations dramatically enhances steroid hormone action.
Environ Health Perspect 110(9): 917-921, 2002.
19 Rajapakse N, Silva E, Kortenkamp A:Combining
xenoestrogens at levels below individual no-observed-effect
concentrations dramatically enhances steroid hormone action.
Environ Health Perspect 110(9): 917-921, 2002.
20 Silva E, Rajaakse N, Kortenkamp A.: Something from
“nothing”—eight weak estrogenic chemicals combined at
concentrations below NOECs produce significant mixture effects.
Environ Sci Technol 36(8): 1751-1756, 2002.
21
The authors' term "synergy" should certainly be read as "additivity".
22 Ostby J, Kelce WR, Lambright C, Wolf CJ, Mann P, Gray
LE Jr.: The fungicide procymidone alters sexual differentiation
in the male rat by acting as an androgen-receptor antagonist in
vivo and in vitro. Toxicol Ind Health 15(1-2): 80-93, 1999.
23 Watanabe H, Suzuki A, Goto M, Lubahn DB, Handa H,
Iguchi T. Tissue-specific estrogenic and non-estrogenic effects
of a zenoestrogen, nonylphenol. J. Mol. Endocr., 33: 243-252,
2004.
24 The mechanism of action is under
investigation, according to the authors. |
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