Hopkin's dioxin model / mechanism Q.'s

[cmcr@ism.net (Cold Mountains Cold Rivers)]

well, dr. sutton may have something when he says "Our [dioxin cancer] model
is unique because it embodies an understanding of the receptor process.",
but i wonder if it is relevant to other effects, such as hormone
disruption?

given:  1. dioxin is not ames (or other mutagen?) positive--i.e. not
genotoxic, 2. Ah/2,3,7,8-tcdd/other protein(s) complexes have been
radiolabelled and observed attaching to dna (to the dioxin responsive
element--dre?) and 3. epa's sab says in its review of epa's reassesment
that _all_ effects are Ah mediated; given this and perhaps other evidence;
i still wonder if dioxin's hormone mimickry and disruption are relevant to
this "yes, virginia, there is a threshold dose" model.  aren't several of
dioxin's biol. markers and effects, including hormone disruption, occuring
at concentrations below the cancer effect--possibly making the whole model
suspect?  eg, the rat or mouse result--a _SINGLE_ low ppq, i recall, dose
of 2,3,7,8-tcdd, delivered direct to the foetus before sexual
differentiation, caused large changes in the sex organs (sorry, i don't
have the reference).

doesn't dioxin attach to Ah & other receptors outside of cells, or at least
outside of the nucleus?  and various non-planar hormone binding xenobiotics
are binding other receptors (eg some pcb's bind the thyroid T-4 receptor),
giving rise to a non-Ah toxicity mechanism, that may not be accounted for
in this model (and i wonder if non-planar pcb's are involved in pcb's
observed non-Ah health effects of pcb's).
                                _ _ _ _ _ _ _

while i'm throwing out mechanism questions, here are a couple more that
have been on my mind:

1.  do natural hormones only become biologically active after fitting to
their receptor because they are incredibly biologically potent?  and what
exactly is causing the changes in tissue growth or tissue differtiation (eg
sex organ development, female to male under the influence of
testoterone)--tissues suffused with hormones?  or is there no "suffusion"
but rather some interaction between the hormone/receptor complex and dna
that causes the tissue differentiatiion/growth?

2.  what is the natural metabolic rate of the thyroid hormone, T-4, which
is structurally very similar to dioxins, and which has iodine in place of
Cl (3 instead of 4, i believe)?  i always hear about the rapid rate of
natural hormone breakdown, as opposed to the synthetic dioxins et al.--but
all halogens make extrordinarily strong bonds to C, so i wonder how T-4
fits in to this scheme...

 well, i'd throw these questions out to sci.med or somewhere, but netscape
2.0's newsgroup browser is unusable, or at least our copy is... regards,

tony tweedale for

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