OCDD TEF: 0.0001 or 0.01?

[ttweed@wildrockies.org (Tony Tweedale)]

>>_Env Health Perspectives (snip) p.775-92 for that excelent in-depth review of
>the
>>validity of the TEF system, which says the TEF of OCDD (found in huge
>>quantities) is not >0.000001 but may be 0.01! (as prev. posted here)).
>
>Tony:
>
>What article are you reading?  This is the report of the WHO TEFs reevaluation
>group.  The data was first reported at Dioxin '97 and has been reproduced in
>that EHP article.  There are three charts:  TEFs for mammals, birds and fish.
>For both OCDF and OCDD the TEF was downgraded by a factor of 10 from 0.001 to
>0.0001, <0.0001 and 0.0001 respectively.   I don't see any congener
>reevaluated in the way you mention, however 1,2,3,7,8 PeCDD was upgraded from
>0.5 to 1 in mammals.
>
>Bill Carroll
---

The same review you refer to, Van den Berg, Birnbaum et (22!) al's:  'TEF's
for PCBs, PCDDs, PCDFs for Humans and Wildlife'.  (BTW, I meant above to
say 'less than 0.000001', not greater than)

I should have checked the table before saying this was the new OCDD TEF
(it's not).  Instead I used the Ah-relevant mamamlian LOEL (lowest
observable effect level) I found.  Moreover, I didn't at that time, or now,
find any discussion of why they downgraded the mammalian OCDD TEF tenfold.
Now I note the table cites the same study to downgrade OCDD's TEF by 10X's
*less*, to 0.0001, as the text discussion does in citing the relative
potency as 0.01 (10X's *greater* than the old WHO TEF)!  [the cite is # 87,
Couture, Elwell & Birnbaum 'Dioxin-like effects Observed in Male Rats
Following Exposure to OCDD in a 13-Week Toxicity Study', _Tox & Appl
Pharm._, 83:31-46 ('88)].

It's telling that this 0.01 potency, which is the only discussion of OCDD
TEF (p. 783), is used as an example to emphasize that target tissue doses
are preferable in TEFs, despite that mammalian TEFs are currently
established on administered doses (see p 777).  OCDD induces hepatic CYPA1A
in rats at a  relative potency of 0.01, using actual hepatic concentrations
instead of administered dose.  Further, the danger of under-estimating Ah
activities is also emphasized by the authors, citing inter alia this OCDD
0.01 potency level, which was observed in *subchronic dose* studies,
whereas earlier *acute dose* studies had suggested the <0.000001
TEF/relative potency.  The decreased adsorption of OCDD at high dose is
suggested as the reason.  Not only is OCDD a very common dioxin, but it's
actually found at doses that maximize ingested adsorbtion.  The authors
close their OCDD discussion by inviting a discussion of whether TEFs should
be based on intake or tissue levels.

This review (whose meaning this time I believe I have captured) gives some
emphasize to the importance of striving for such real-world conditons (e.g,
use real world doses, also of delivered doses).  Obviously these are
fundamental toxicologic principles!.  Many other examples illustrating
invalidities of TEFs are given, some to the opposite effect (e.g. on p.784,
2,3,7,8-TCDFs rapid metabolism and lack of bioaccumulation in subchronic
dosing confirmed a TEF of 0.1, despite acute dosing showing a TEF of 1.0).
I find that the text/discussion of published studies, especially reviews w/
divergent authors (e.g. Dr. Stephen Safe here) like this one, frequently
contain more of their total meaning than their abstract or summary tables.
The authors conclude TEFs are  plausible and feasible, but fail to (or
avoid) stating they are predictive.  Rather, they emphase the limits (as
above) of the new TEFs.  So while I would have reported the actual lowering
of OCDD's Ah-potency if I had seen it (thanks for correcting me, that's
impt.), IMO the 0.01 hepatic CYP1A1-induction potency I reported is as
relevant a number, and qualifies as a TEF (based on its Ah-mechanism, on
its realistic doses and pharmacokinetics, and on another fundamental
toxicologic principle:  LOELs).

[IMO, this high dose false-negative problem, generalized, is something that
many evil 19th century style present-day toxicologists (the ones who, in
response to every question, loudly claim  'the dose makes the poison') have
known about for decades.  Pharmacokinetics is much more complex than that.]

I hope you recognize that TEFs, even if ever fully realized  [ie all the
data gaps are filled in and contradictions accounted for (this review is a
major step forward, eg, splitting TEFs into the 3 taxa and discussing the
differences and commonalities; or summarizing a lot of studies on the
additive/antagonist/synnergist issue]  are a vastly inadequate description
of the potential ED toxicities of chemicals?  This review does.  Aside from
the many chemicals that have not yet been studied for Ah-mediated
alterations, there are non-Ah mediated alterations caused by the few
chemicals included in the TEF scheme, and by others  I wont even posit the
problem of non-ED effects (ie toxicology in general) in this age of
molecular biology and total biochemistry!