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5 Onset of adverse effects in the living body
Analysis of exposure in the living body should take the
mechanisms of action in the living human body into account. (1)
Existence of the receptor of the substance in question, (2)
existence of hormone-like activities, and (3) mechanisms of
metabolism and detoxification should be considered.
(1) Existence of receptors
As receptors corresponding to endocrine disruptors, receptors
similar to those corresponding to endogenous estrogens in cells
derived from human adrenal cortex (H295R cells) and human
mammary gland cells (T47D). Further studies on human
endometerium cells (HHUA) and cells derived from the human
mammary gland (MCF-7) demonstrated binding of endocrine
disruptors with estrogen receptors α and β. In addition, search
for unknown orphan receptors revealed that receptors related to
retinoic acid are also involved.
(2) Existence of hormone-like activities
Pesticides (p,p'-DDT, p,p'-DDD, o,p'-DDT, o,p'-DDD and dicofol),
flavonoids (6-hydroxyflavone, apigenin, daidzein, genistein,
biochanin A and formononetin), and organotin compounds (bis(tributyltin)
oxide (TBTO), tributyltin chloride (TBT), diphenyltin dichloride
(DBT) and triphenyltin chloride (TPT)) were found to inhibit
cortisol production of human adrenal cortex cells, and to
stimulate multiplication of mammary gland and endometerium
cells. Furthermore, it was found that tributyltin probably
influences the induction of oral immunologic tolerance of mice,
benzo[a]pyrene affects the differentiation process of
trophoblastic stem cell strain (TS cells) of rats, and phthalic
acid esters possibly have widespread influences on gene
expression by modifying methylation state of the genome DNA.
Which effects develop (or not) within the range of body burden
of these substances is now under study.
(3) Metabolic and detoxification mechanisms in humans
There is still much room for study on metabolism and
detoxification mechanisms.
Most of BPA in rats was found to be conjugated with glucuronic
acid in the digestive tract and the liver, while probably not
metabolized in the kidney and simply filtrated and excreted.
Discovery of β-glucuronidase, which recovers the original BPA
molecule by decomposing the glucuronic acid conjugate, was a
further step to understanding reactions in humans.
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