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#755 - Paracelsus Revisited -- Part 2, 30-Oct-2002

[This is the final part of our 5-part series on
hormone-disrupting chemicals, drawing some conclusions after
reading the last 24 monthly issues of ENVIRONMENTAL HEALTH
PERSPECTIVES (EHP), a peer-reviewed journal published by the
National Institutes of Health. See RACHEL'S #750-754.]

As we saw in RACHEL'S #754, the science of toxicology has been
fundamentally altered by the discovery, 20 years ago, that some
industrial chemicals can interfere with hormones in plants and
animals including humans.

For over 450 years the phrase "the dose makes the poison" has
been used to justify the dispersal of exotic, biologically active
chemicals into the environment because if "the dose makes the
poison" then low doses received through air, water and food
shouldn't matter. Unfortunately as we have seen, low doses DO
matter because

(a) individuals differ in their inherent (genetic) sensitivity;

(b) we are all exposed routinely to mixtures of individual
chemicals, and harmless amounts of individual chemicals can
combine to create harmful mixtures;

(c) some chemicals are only biologically active during particular
times in the development of an organism, so their toxicity must
be assessed during those exact times -- otherwise chemicals may
be deemed biologically weak or inert when in fact they are
powerfully active.

There are other serious problems with chemical regulations
premised on the idea that "the dose makes the poison." The phrase
assumes that the greater the dose the stronger the poison.
Because of this assumption, chemicals are routinely tested on
laboratory animals in high doses because high doses are assumed
to provoke the greatest effect.

We now know that this is not always true and that sometimes the
opposite is true. Sometimes low doses produce greater effects
than high doses. For example, in RACHEL'S #754, we described a
study of Bisphenol A which found that low doses of Bisphenol A
produced a greater biological effect than higher doses. (EHP Vol.
109, No. 7 [July 2001], pgs. 675-680.) In other words, the "dose
response curve" for Bisphenol A is shaped like an upside-down (or
inverted) letter U. Initially, as the dose rises, the response
rises. However, at some point as the dose continues to rise the
response stops rising, then begins to diminish and falls back
toward zero.

It is now well-established that many hormone-disrupting chemicals
exhibit this inverted-U dose-response curve. Such chemicals
disrupt hormones at low doses but not at high doses. What seems
to happen is that the hormone system becomes overwhelmed and
stops responding, so at high doses there is no observable effect.
This turns Paracelsus on his head.

In addition to the Bisphenol A study mentioned above, two other
studies published recently in EHP demonstrate an inverted-U
dose-response curve. First, phytoestrogens (estrogens in plants,
such as soybeans) at low doses inhibit the production of
estrogen; at higher doses the inhibitory effect disappears and
the phytoestrogens behave like estrogen itself, adding to the
effect of the body's own natural estrogen. The dose-response
curve is an inverted U. (This may explain why low doses of
phytoestrogens protect against breast cancer, the authors say.
See EHP Vol. 110, No. 8 [August 2002], pgs. 743-748.)

Second, a study of adult male guppy fish, exposed to certain
pesticides in their food (vinclozolin and DDE, which are known to
disrupt male sex hormones) exhibited shrunken testes, a
significant reduction in numbers of sperm, and "a severe
disruption in male courtship behavior." Some of the measured
effects were greater at a lower dose, demonstrating an inverted-U
dose-response curve. (EHP Vol. 109, No. 10 [October 2001], pgs.
1063-1070.)

The authors of the guppy study did a literature search and found
over 100 published papers reporting an inverted-U dose-response
curve, so this phenomenon is well-established.

This means that traditional toxicological testing at high doses
may miss important effects that only occur at lower doses.
Therefore, low doses will have to be tested.

So Paracelsus's phrase should now be, "The dose of the mixture
makes the poison, but differently for genetically different
individuals and differently at different times during growth and
development, always mindful that lower doses may be more
poisonous than higher doses."

This modern rendition of Paracelsus makes it clear that adequate
toxicity testing is enormously more complex (and therefore much
more expensive) than anyone imagined even 10 years ago.

But the difficulties for modern toxicological science do not stop
there. After we published RACHEL'S #754, Albert Donnay of MCS
Referral & Resources (adonnay@jhu.edu, and
http://www.mcsrr.org/), pointed out that any study of any
toxicant or other stressful exposure is worthless unless it
accounts for (and controls for) each subject's degree of
adaptation to the toxicant, which depends not just on their
degree of genetic sensitivity but also on the timing, intensity
and pattern of their prior exposure.

Adaptation to toxic stressors, also known as acclimitization,
habituation or tolerance, is a general phenomenon in humans and
other animals. We are all familiar with adaptation from our
experience with smokers. When you inhale your first-ever
cigarette, you have an immediate powerful reaction:
light-headedness, heart palpitations, perhaps a general feeling
of illness including nausea. If you persist in inhaling cigarette
smoke, you get used to it, you become "adapted." Pretty soon you
notice that you get a certain "lift" from smoking. Then you
become so adapted that you have to smoke more and more to get the
"lift" you want.

We recognize adaptation in people's everyday experience with
cigarettes, alcohol, and pharmaceutical drugs. It also occurs on
the job where workers can smell strong chemical odors when they
first go to work (for example, in dry cleaning shops) but after a
while their sensory awareness of the odors disappears even though
the odors are still present and noticeable to others who are not
habituated to them. This is adaptation.

Adaptation may occur in response to all kinds of stimuli - - not
just chemicals but also noise, light, touch, heat or cold, and
altitude. In his medical textbook, THE HUMAN SENSES, Frank A.
Geldard writes, "A decline in sensitivity with continuing action
of a stimulus is a very general phenomenon in sensory
psychophysiology and one which intervenes significantly in nearly
all experimental situations."[1, pg. 299] Discussing adaptation
to taste sensations, he writes, "Taste receptors have their
sensitivity automatically reduced by being exposed to a
continuous unvarying stimulus, just as olfactory [smell] organs
do under analogous conditions. In fact, the addition of the sense
of taste completes the catalogue of sense departments displaying
adaptation; this has been found to be an entirely universal
phenomenon in the world of sensation."[1, pg. 513]

The other side of the coin from "adapted" is de-adapted or
"sensitized." When smokers give up cigarettes for a period of
time, they find that they have become "sensitized" to second-hand
smoke. They now notice and react to much lower levels of exposure
than they previously tolerated, moreso even than the average
("naive") person who has never smoked. Sensitization lies at the
other end of the sensory spectrum from adaptation.

So people and laboratory animals vary in their degree of
adaptation, depending on their prior exposure. For any given
stimulus, including toxic chemicals, the naive (never-exposed)
animal, the adapted animal, and the de-adapted or sensitized
animal all react differently.

Classic studies of carbon monoxide reveal the importance of
"degree of adaptation." Carbon monoxide is an odorless,
tasteless, colorless gas created by incomplete combustion of
carbon fuels. Your automobile engine and gas cook stove give off
carbon monoxide. Carbon monoxide displaces oxygen from your red
blood cells and other heme proteins, so a high dose can kill you.

In 1940 Esther M. Killick studied carbon monoxide in detail and
reported her findings.[2] Killick reviewed a 1906 study of guinea
pigs kept in enclosed cages to which carbon monoxide was
introduced in measured quantities. When the carbon monoxide level
was slowly raised over a period of several weeks, the guinea pigs
could adapt to 45% saturation of carbon monoxide in their blood
without apparent ill effect. But when naive animals were
introduced abruptly into this same environment, they died within
a few days. So studies of the toxicity of carbon monoxide will
yield dramatically different results, depending upon the degree
of adaptation of the subjects being studied. So it is with other
toxicants.

At this point Paracelsus's "dose makes the poison" has become
"The dose of the mixture makes the poison, but differently for
genetically different individuals and differently at different
times during growth and development (always mindful that lower
doses may be more poisonous than higher doses), and differently
depending upon the subject's prior history of exposure to this
mixture and their degree of adaptation (or sensitization)
acquired as a result of that history."

By now it must be clear that, in the practical world of everyday
science, testing of chemicals for their effects on environment
and health should entail studies of naive animals, habituated
animals, and sensitized animals. The subjects should be exposed
to mixtures of chemicals in addition to individual chemicals and
the exposures should occur at crucial times during growth and
development. (Discovering those crucial times is a major
challenge by itself.) The effects being studied should include
not only physical changes in the subject, but also behavioral
changes (for example, the guppy's courtship behavior, or a
human's ability to concentrate or tendency toward violence).
Effects on offspring must also be studied because some exposures
leave the exposed parents seemingly unchanged yet damage the
second and subsequent generations of offspring. These ideas --not "the
dose makes the poison" -- should form the basis of
chemical regulations.

In sum, the simple idea that it's OK to put biologically active
chemicals into the workplace, into products, or into the
environment because "the dose makes the poison" is a dead letter.
It is an idea whose time has gone. It is false, misleading,
utterly without merit.

The corresponding idea, that if we just study long enough we'll
discover, for every chemical, a dose that is "safe" for an entire
population of workers, consumers, and the general public, is also
false, misleading and dangerous. It is dead wrong, because there
are not enough laboratories in the world to carry out the needed
investigations on all 80,000 chemicals now in use, nor enough
peer-reviewed journals to report the results. There are just too
many variables to be taken into account simultaneously. This
means that relatively few chemicals will ever be adequately
tested.

If we admit to ourselves that our present system of chemical
regulation is based on false premises and cannot be fixed, we can
begin anew and think in terms of precautionary action: put the
burden of demonstrating safety onto the manufacturers of
chemicals. Chemicals lacking adequate evidence of safety by a
certain deadline will be earmarked for phaseout. This will force
corporate managers to choose which chemicals they really believe
are worth salvaging, and these will be studied feverishly. The
others will eventually be phased out and disappear. The universe
of industrial chemicals will shrink to a much smaller number, and
those remaining will be much better understood. Such a change
will be good for everyone.

==================

[1] Frank A. Geldard, THE HUMAN SENSES (N.Y.: John Wiley, 1972;
second edition; ISBN 0471295701).

[2] Esther M. Killick, "Carbon Monoxide Anoxemia," PHY-SIOLOGICAL
REVIEWS Vol. 20, No. 3 (July 1940), pgs. 313- 344.

Thanks to Albert Donnay for help with this issue.--P.M.