[Dioxin-l] References about threshold

[Tony Tweedale]

now that the discussion is coming around to the unanswered questions I
asked ~5 days ago (specific q's responding to some good info posted by
Louise), I really wish they'd be answered!  In fact, regarding the
dose-threshold (linear, or single molecule) question, Louise months ago
pointed me to a worthwhile overview of this rapidly evolving critical field
in toxicology ('The Era of Pathway Quantification' in _Science_ 280:852-3
(8 May '98; & associated research article, p. 895-8)) (I see _Science_
followed w/ a special section, 'The Science of Signal Transduction' on 30
Apr '99, begining p. 755, incl. Orphan Nuclear Receptors:..', about
determining the function of recptors w/ unknown function).  I then asked
Louise the same question as now:  even if linear D/R curve down to one
molecule isn't as plausible a pardaigm as a threshold concentration needed
for a biological response, aren't the concentrations in the case of TCDD
and other ED's so low (espec. compared to current exposures), that it's
academic?  Sorry it's such a broad Q., but  it is highly relevant.

Recently, Ron Shore brought up the related excellent obvioous Q. of
persistent ED mechanistic steps at these low [C's], additionally in the
very busy environmentin & outside cells.  vom Saal says less than 100 ppq
(0.1 ppt) estradiol begins to occupy E-receptors in E-responsive cells.
Dramatic estrogenic response in male rats decreased steadily after DES dose
to mother reached 2 ug/kg bw/day [this is from Beyond Pesticides/NCAMPs
adaption of his speech at their '97 annual conference].  Having seen a tape
of the speech once, I recall he also said that E effects occur at
concentrations of just a few hormones per cell.

As available recptors are filled, he says, unpredictable effects begin to
occur, as the estrogen or estrogenic anthropogenic chemical starts to
interact w/ other receptors.  One effect is "receptor down regulation",
where production of receptors decreases, as does the response (at least for
E-R).

[On second thought to my post last week about the Astra-Zenenca team of
Ashby et al showing that the feed vom Saals team used in these various
experiments had estrogenic effects (presumably due to phytoestrogens in
soy, etc.); obviously it seems (now, to me!) that his controls should have
exhibited about the same estrogenic responses as they ate the same amnt of
the feed.  But in many experiments, the estrogenic chemical treated rats
showed estrogenic response (or gave inverted-U shape D/R curve) while his
controls didn't.]

David Bell--can you elaborate on your too brief comments about receptor
binding at 6 pM ('pm' would be abbreviation for molal? anyway).
ppq(uintillion, in rough terms?   Also, what constant is
'Kd'--dissasociation? ...in explanatory mode  --thanks!

Lousie, I think my other question was, is it at all biologically plausible
that one TCDD molecule, glommed onto DNA, can initiate a mutation in the
DNA, as the DNA replicates?  If so, the pure  linear model's inherent
plausibility (long recognized in carcinogensis caused by mutagens (ie,
compounds reactive enuf to damage DNA)) comes into play, as the TCDD caused
mutation is endlessly replicated, leading to some biologic unwanted effect.
If I had other questions in my original post, I'm still interested!.
Thanks,

Tony Tweedale

Causality is a concept not subject to empirical demonstration.      -David Hume

'Letting the Grandchildren Do It:  Environmental Planning in the Age of Oil
[ie, Petrochemicals]...'      -Joseph A. Pratt _Public Historian_:2:28-61
('90)

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