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Advisory Committee on Health Effects of Endocrine Disruptors
The Supplement II to the Intermediary Report
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(2) Highly sensitive periods and the low dose issue
A considerable amount of data exist which associate the fetal,
neonatal and adolescent periods with the low-dose issue50.
Such data can be interpreted as effects via nuclear or membrane
receptors51.
Another approach is to examine the issues of threshold values,
nonlinear dose-effect relationships and additive reactions with
a new concept for effects at dose levels which are not detected
by untreated adult animals. Since studies on the effects of
suspected endocrine disruptors on the living body often require
confirmation or repetition, while the mechanisms of action are
difficult to elucidate, systematic gathering of relevant
information should be continued.
Note: Researchers of the U.S. FDA52,53
and EPA54 confirmed nonlinear
reactions. British researchers55
reported results on additive reactions at low doses, though in a
limited range, which are believed to be linked with the "fetal
window" phenomena56, or
idiopathic effects seen in the fetal period.
(3) Homeostatic regulatory system: the focus of the effects
on organisms
Effects of endocrine disruptors on the homeostatic regulatory
system are now the focus of the studies in this field57.
The knowledge obtained so far indicates that further intensive
studies are needed on the immune system, thyroid-central nerve
system, and behavior.
Note: Effects on the immune system are not fully described in
Global Assessment and therefore need enhancement. It is believed
that modifications on the immunologic signals by xenobiotic
elements such as tin or arsenic upstream the receptor binding
region lie in the background of those complex actions.
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50 Rajapakse N et al.
Combining xenoestrogens at levels below individual
no-observed-effect concentrations dramatically enhances steroid
hormone action. Environ Health Perspect, 110: 917-921, 2002.
Irreversible reactions in neonates were observed in some
systems, as noticed in Global Assessment.
51 Health and Labor Research report
(group led by Inoue)
52 Guo TL, White KL Jr, Brown RD,
Delclos et al. Toxicol Appl Pharmacol. 181: 219227, 2002.
53 See note 30.
54 G. Ankley: Personal communication.
55 Rajapakse N et al.: Environ
Health Perspect 110: 917-921, 2002./ Silva E et al. Environ Sci
Technol 36: 1751-1756, 2002.
56 See note 47. Microarray analysis
of effects of DES administration to neonate mice in three days
after birth, the critical period of estrogen activity in the
vagina, is reported in Health and Labor Research report (Inoue
group). It was shown using receptor inhibitors that DES
activates EGF growth factor-erbB receptor system through
phosphorylation of estrogen response genes in the epithelium,
which triggers formation of an estradiol-independent activation
loop involving phosphorylation of the MAPK and Akt systems as
well as the AF-1 region.
57 The concept of hormones has been
extended to include all substances released from cells into the
blood including cytokines. Tissues bearing receptors for those
substances are possible targets of endocrine disruptors. Effects
on the immune, nerve and behavioral systems are important, since
all of these homeostatic regulatory systems have communication
systems with memory capacity. Combined effects with catabolism
are one of the domains poorly addressed. |
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