Rachel's Gets It Wrong.......

[ttweed@wildrockies.org (Tony Tweedale)]

After seeing a couple of my generalized rants about low dose toxicology,
Vivien Mountford (vivmount@greener.u-net.com, a toxicologist who posts
occassionally to either this list or Sierra's conseq-env-hormones list)
clued me into an interesting  _Science_ research paper (and associated
reporting article) on pathway signalling quantification (see Ferrell &
Machleder 'The Biochemical Basis of an All-or-None Cell Fate Switch in
Xenopus Oocytes' _Science_ 280:895-8 (8 May '98) and "the Era of Pathway
Quantification' on p 852-3).  _Science_ points out that from ~1980 on we've
been moving away from simply sorting out biochem pathway regulatory factors
(feedback, cooperativity, phosphorilization, covalent modification) and
into quantifying the # of molecules needed to begin/sustain particular
biochem. reaction effect, or a step in an effect.  Powerful basic
systems--calcium biochem, Krebs metabolic cycle, hemoglobin, many hormone
systems--are being sussed-out for their normal (hyperbolic, ie greater
response at lower doses), sub or ultrasensitivity.

If you extrapolate (below the dose levels actually tested at) to a D/R
curve that shows zero effect at several low doses (ie some greater dose is
needed for any effect, i.e. the "threshold dose" effect) you are veering
away from reality, ar at least only allowing for one possibility when there
are several others that result in some effect.  But a response is something
of an an all-or nothing concept (while a dose is a continous variable), so
biology can be fasciinating-- a little can trigger a big effect, or not  As
I've said here before, Frederick vom Saal, endocrinologist, talks of doses
of a hormone or its exogenous mimic needing to be extraordinarily low--more
than a few hormones in a cell can "flood out" the available receptors and
essentially shut-down the entire hormonal response (prostate gland
effects).  Tho he didn't give any more detail than this (in an abbreviated
talk), this would seem to be an elaboration of a supersensitive response
model.  Elsewhere, the mutagenic (DNA damaging) mechanism of cancer (one of
sevral documented) is heavily critiqued, and I know little about it, but
the impresson I have is that so far its no-threshold assumption (ie that a
single DNA mutation can cause cancer, due essentially to its perpetual
replication) is still valid.  (Not that continual mutations are a likely to
be protective of cancer, I guess!).

Dr. Howd, I would appreciate a reprint of your (neter alia) review, per you
offer below (use my address at the bottom).  Perhaps you could also post a
brief summary of why you believe _Rachel's_ drew the wrong conclusions from
the review--I'd be happy to repost it to dioxin-list.  Ditto for any
contribution Dr. Mountford may care to make to this discussion.
---

>--Listproc-inner-1100
>Date: Sat, 29 May 1999 12:00:07 -0400 (EDT)
>From: "Alex J. Sagady & Associates" <ajs@sagady.com>
>To: dioxin-l@essential.org, ecojustice@igc.org
>Subject: Rachel's Gets It Wrong.......
>Message-ID: <199905291600.MAA11657@mail2.voyager.net>
>Mime-Version: 1.0
>Content-Type: text/plain; charset="us-ascii"
>
>Date: Sat, 29 May 1999 08:45:28 -0700 (PDT)
>From: Bob Howd <BHOWD@oehha.ca.gov>
>Subject: Fwd: Rachel #652: The Waning Days of Risk Assessment
>Sender: riskanal@bbs.pnl.gov
>To: ajs@sagady.com
>Reply-to: Bob Howd <BHOWD@oehha.ca.gov>
>Originator: riskanal@listserv.pnl.gov
>
>The newsletter forwarded by Gary Napp (RACHEL'S ENVIRONMENT & HEALTH =
>WEEKLY #652) was written by the newsletter editor, Peter Montague, with =
>specific reference to a review of risk assessment procedures and policies* =
>written by me and two colleagues at Cal/EPA.  Several statements and =
>conclusions in this newsletter are falsely credited to us.   For example, =
>the newsletter says,=20
>
><<Furthermore Fan, Howd and Davis point out that
>    =20
>** Genetic damage is a non-threshold event. That is, any amount=20
>of a gene-damaging substance can cause damage. Only zero is=20
>safe. If such damage occurs in a germ cell, it may be inherited=20
>by successive generations.
>
>** Likewise, damage to the developmental system is a=20
>non-threshold event. A single exposure by an effective toxin may=20
>cause damage and such an exposure may have lifelong effects.=20
>Only zero is safe.>>
>
>We did not write these statements, nor make these conclusions.  We did not =
>declare "Only zero is safe" for any chemical, including mutagenic =
>carcinogens.   The Rachel newsletter radically misrepresents our discussion=
> of risk assessment procedures.   =20
>
>Please see our review for our actual discussion and conclusions (reprints =
>available upon request). =20
>
>
>* A. Fan, R. Howd, and B. Davis, "Risk Assessment of Environmental =
>Chemicals," ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY Vol. 35 (1995), =
>pgs. 341-368.
>
>
>Robert A. Howd, Ph.D.
>OEHHA, Cal/EPA
>1515 Clay St., 16th Fl.
>Oakland, CA 94612
>bhowd@oehha.ca.gov

---

Tony Tweedale
224 E. Pine (2)
Missoula, MT 59802-4541
406-542-1709 tel. [& Fax--must call me 1st)]