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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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This means that it is difficult to develop a test method with
general applicability to hormone-like substances.
(1) Overview of the low-dose issue
The low-dose issue is a complex of several topics closely
related one another. Examples are existence of threshold values
and additive or multiplicative effects, adequacy of
extrapolation from high dose data to low dose region, and
linearity of the dose-active relationship. Some of them are
reviewed in the following.
Existence (or non-existence) of a threshold value can be
demonstrated biostatistically assuming a model of the
dose-effect relationship. Earl Gray of EPA found that various
feminization indexes of antiandrogens show similar logistic
curves or S curves, which approach the base line levels insofar
as observed12,13.
Experimental systems independent of homeostasis14
are known to reveal effects at very low doses even in vivo15,16.
Since the living organism detects a low dose of a hormone-like
substance and reacts to it, rather than neglects it, this type
of in vivo studies with particular treatment, though indicative
of low-dose responses of organisms, does not provide information
on deleterious effects of substances.
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Palanza P, Howdeshell KL, Parmigiani S, vom Saal
FS.: Exposure to a low dose of biosphenol A during fetal life or
in adulthood alters maternal behavior in mice. Environ Health
Perspect 110,Suppl.3:415-422,2002. / Schonfelder G, Flick B,
Mayr E, Talsness C, Paul M, Chahoud I.: In utero exposre to low
doses of bisphenol A lead to long-term deleterious effects in
the vagina. Neoplasia 4:98-102, 2002. / Schonfelder G,Wittfoht
W, Hopp H, Talsness CE, Paul M, Chahoud I.: Parent bisphenol A
accumulation in the humanmaternal-fetal-placental unit. Environ
Health Perspect 110: A703-707, 2002. / Tinwell H, Haseman
J,Lefevre PA, Wallis N, Ashby J.: Normal sexual development of
two strains of rat exposed in utero to low doses of bisphenol
A.: Toxicol Sci 68:339-348, 2002./ Wetherill YB, Petre CE, Monk
KR, Puga A,Knudsen KE.: The xenoestrogen bisphenol A induces
innapriopriate androgen receptor activation and mitogenesis in
prostatic adenocarcinoma cells. Mol Cancer Ther 1:515-524, 2002.
/ Ashby J.: Testing for endocrine disruption post-EDSTAC:
extrapolation of low dose rodent effects to humans. Toxicol Lett
120:233-242, 2001 ./ Markey CM, Luque EH, Munoz De Toro M,
Sonnenschein C, Soto AM.] In utero exposre to bisphenol A alters
the development and tissue organization of the mouse mammary
gland. Bio Reprod 65: 1215-1223, 2001. / Markey CM, Michaelson
CL, Veson EC, Sonnenschein C, Soto AM.:The mouse uterotrophic
assay: a reevaluation of its validity in assessing the
estrogenicity of bisphenol A.Environ Health Perspect 109: 55-60,
2001. / Gupta C.: Reproductive malformation of the male
offspring following maternal exposure to estrogenic chemicals.
Proc Soc Exptl Biol Med. 224: 61-68, 2000. / Elswick BA, Welsch
F, Janszen DB.: Effect of different sampling designs on outcome
of endocrine disruptor studies. Reprod Toxicol 14:359-367,
2000./ Oehlmann J, Schulte-Oehlmann U, Tillmann M,Markert B.:
Effect of endocrine disruptors on prosobranch snail (Mollusca:
Gastropoda) in the laboratory.
Part I: Bisphenol A and octylphenol as xeno-estrogen. Ecotoxicol
9: 383-397, 2000. / Tinwell H, Joiner R,Pate I, Soames A, Foster
J, Ashby J.: Uterotrophic activity of bisphenol A in the
immature mouse. Regul Toxicol Pharmacol 32:118-126, 2000. /
Howdeshell KL, Hotchikiss AK, Thayer KA, Vandenbergh JG,vom Saal
FS.: Environmental toxins: Exposure to bisphenol A advances
puberty. Nature 401: 763-764,1999.
12 Gray LE Jr, Ostby J, Monosson E, Kelce WR.:
Environmental antiandrogens: Low doses of the fungicide
vinclozolin alter sexual differentiation of the male rat.
Toxicol Ind Health 15(1-2): 48-64, 1999.
13 Gray LE, Ostby J, Furr J, Wolf CJ, Lambright C, Parks
L, Veeramachaneni DN, Wilson V, Price M,Hotchkiss A, Orlando E,
Guillette L: Effcet of environmental antiandrogens on
reproductive development in expereimental animals. Hum Reprod
Update 7(3): 248-264, 2001.
14 E.g. the uterotrophic bioassay.
15 Kanno J, Onyon L, Haseman J, Fenner-Crisp P, Ashby J,
Owens W: Environ Health Perspect 109(8):785-794, 2001.
16 Considering the fact that the
probability of ligand-receptor association is naturally low at
sufficiently low doses, "practical" threshold values for
carcinogens are recently recognized by some researchers. The
same possibly applies to endocrine disruptors as well. |
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