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#754 - Paracelsus Revisited, 16-Oct-2002

[This continues our series on hormone disrupting chemicals. See
RACHEL'S #750-753 at http://www.rachel.org. What did I learn by
reading the last 24 issues of ENVIRONMENTAL HEALTH PERSPECTIVES
(EHP), a peer-reviewed journal published by the U.S. National
Institutes of Health?]

The science of toxicology has been fundamentally altered by the
discovery, 20 years ago, that industrial chemicals released into
the environment can disrupt the hormone systems of plants and
animals, including humans.

For more than 450 years, toxicologists have relied on an idea
expressed by Paracelsus in the fifteenth century: "The dose
makes the poison."[1] By this, Paracelsus meant that everything
is poisonous in a high enough dose and, "Even strong poisons
are harmless if the dose is low enough." Implicit in these two
ideas is a third, "The higher the dose, the stronger the
poison." Together, these ideas have been used to justify
dumping billions of tons of biologically-active chemicals into
the environment each year: even the most active were considered
OK to dump because they would be diluted by air and water down
to doses that were considered safe.

This has always been a dubious proposition because a "safe" dose
for one person is not necessarily safe for another. Physicians
have known for centuries that humans (and other animals) vary
greatly in their tendencies toward disease and disability. The
great 12th-century physician and philosopher Moses Maimonides
said in 1190, "The most important consideration in the causation
of disease is the body constitution which becomes afflicted.
Therefore, not all people will die during an epidemic."[2] Some
people are more resistant to germs (and poisons) than other
people.

Everyone recognizes this simple truth about individual
susceptibility to germs and chemicals. Vaccinations make a few
people sick, but most not. If 1000 people walk down the detergent
aisle of their grocery store, a few will react badly to the
fragrant chemicals wafting in the air. These few may begin to
sneeze or cough or break out in hives, though most will not. As
the famous physician Sir William Osler said in 1903, "Variability
is the law of life, and as no two faces are the same, so no two
bodies are alike, and no two individuals react alike and behave
alike under the abnormal conditions which we know as disease."[3]
In other words, "One man's meat is another man's poison."

Therefore, Paracelsus's phrase really should be, "The dose make
the poison, but differently for different individuals."

The "dose makes the poison" justification for industrial dumping
was further weakened by the discovery during the 1950s that DDT
accumulated in birds and other creatures as it moved through the
food chain. Soon bioaccumulation was recognized as a general
phenomenon -- fat-soluble chemicals tend to accumulate in
creatures higher up the food chain, for example, big fish, big
birds, bears, and humans.[4] At the very top of the food web we
find the nursing infant, starting life drinking a dilute solution
of industrial poisons along with mother's milk. (Breast feeding
is still the best way to nourish an infant. But are there really
no consequences of starting life on a diet of dilute
chlorinated solvents and pesticides, as all children do today?)

Traditionally, "the dose makes the poison" refers to single
chemicals because toxicologists rarely study mixtures. As David
O. Carpenter wrote in ENVIRONMENTAL HEALTH PERSPECTIVES earlier
this year, "Most research on the effects of chemicals on biologic
systems is conducted on one chemical at a time. However, in the
real world people are exposed to mixtures, not single chemicals.
Although various substances may have totally independent actions,
in many cases two substances may act at the same site in ways
that can be either additive or nonadditive. Many even more

complex interactions may occur if two chemicals act at different
but related targets. In the extreme case there may be synergistic
effects, in which case the effects of two substances together are
greater than the sum of either effect alone. In reality, most
persons are exposed to many chemicals, not just one or two, and
therefore the effects of a chemical mixture are extremely complex
and may differ for each mixture depending on the chemical
composition. This complexity is a major reason why mixtures have
not been well studied." EHP Vol. 110 Supplement 1 (February,
2002) pgs. 25-42.

Because we are all exposed to mixtures of chemicals every day,
the toxicity of mixtures is an important public health matter. If
insignificant doses of several chemicals add up to a significant
dose then "the dose makes the poison" misrepresents reality and
may put us in harm's way. Two studies published recently in
ENVIRONMENTAL HEALTH PERSPECTIVES examined this question.

The first study tested a mixture of four organochlorine chemicals
(the pesticide Lindane, plus two forms of the pesticide DDT and a
breakdown product of DDT called DDE). Each of these chemicals by
itself is known to behave like the female sex hormone, estrogen,
when tested on human breast cells. The researchers conducting
this study wondered whether low concentrations of these four
chemicals (too low to cause estrogenic effects by themselves)
mixed together would cause an estrogenic effect on human breast
cells -- in other words, could low doses of four separate
chemicals add up to an effective dose?

This study showed unmistakably that these four estrogenic
chemicals at low levels DO add up to an effective dose. This is a
very important finding because it means that chemicals present in
food and water at "harmless" levels may combine with other
"harmless" chemicals in the environment and, together, cause
harm. [EHP Vol. 109, No. 4 (April, 2001), pgs. 391-397.]

Similarly, the second study examined the combined effects of four
chemicals because, the authors of the study said, "The assessment
of mixture effects of estrogenic agents is regarded as an issue
of high priority by many governmental agencies and expert
decision-making bodies all over the world." (Someone needs to
tell this to the NEW YORK TIMES -- see RACHEL'S #750.) Andreas
Kortenkamp and colleagues studied a mixture of 4 chemicals known
to behave like the female sex hormone estrogen: DDT, genistein,
and two alkylphenols (4-N-octylphenol and 4-nonylphenol). The
four chemicals did, in fact, have an additive effect -- the four
chemicals mixed together had greater effect than any of the
chemicals alone. The authors of the study found that combining
very low levels of four different chemicals helps explain how
"low, seemingly insignificant, levels of xenoestrogens
[industrial chemicals that mimic estrogen] may produce
significant effects as mixtures." EHP Vol. 108, No. 10 (October
2000), pgs. 983-987.

So mixtures of "harmless" amounts of chemicals are crucially
important to health. Therefore, Paracelsus's phrase should now
be, "The dose of the MIXTURE makes the poison, but differently
for different individuals."

Unfortunately, assessing the potency of mixtures is immensely
complex. Suppose there are only 100 chemicals that we care about,
but we want to evaluate all possible combinations of four
chemicals among the 100. This seems simple enough until we
realize that there are 3.9 million possible combinations of 100
chemicals taken in groups of 4. In the real world, of course,
there are many more than 100 chemicals to worry about because
there are 80,000 chemicals now in use.

But the newly-discovered difficulties for the old "dose makes the
poison" school of toxicology don't stop there. Many hormones are
only active during a brief period in the life of an organism. To
test whether a chemical disrupts a hormone, it must be tested
during the particular time when that hormone is active. This was
illustrated by a study of Bisphenol A published recently in
ENVIRONMENTAL HEALTH PERSPECTIVES.

Bisphenol A is a chemical used extensively in the manufacture of
polycarbonate plastics, including soft drink containers.
Bisphenol A can also be found in some modern plastics used as
"dental sealants" and in the lacquer lining of tin cans. From
these sources, hundreds of millions of people are being exposed
to low levels of Bisphenol A, without their knowledge or consent.
Bisphenol A is known to be "weakly estrogenic" -- meaning that it
behaves like the female sex hormone, estrogen, but with a potency
about 10,000 times less than pure estrogen. Because it is only
"weakly estrogenic" many toxicologists have assumed that it is
safe to expose hundreds of millions of humans to Bisphenol A and
ethically acceptable to expose people without their informed
consent.

The new study in ENVIRONMENTAL HEALTH PERSPECTIVES reveals that
Bisphenol A is particularly potent in mice exposed near the time
of birth. Pregnant female mice exposed to low levels of Bisphenol
A near the time of birth produce offspring that gain excessive
weight early in life and maintain excessive weight thereafter.
This effect does not occur in mice fed Bisphenol A as adults.
(The study also found that low doses of Bisphenol A produced a
greater effect than higher doses, standing Paracelsus on his
head. More on this in RACHEL'S #755.) According to the authors of
the study, their Bisphenol A data "suggest the need for careful
evaluation of the current levels of exposure [of humans] to this
compound." EHP Vol. 109, No. 7 (July 2001), pgs. 675-680.

The Bisphenol A study drives home the point that chemicals may be
toxic at low levels at a particular time in the life of an
organism, which of course greatly complicates the testing that is
needed to protect public health from industrial toxins.

So Paracelsus's phrase should now be, "The dose of the MIXTURE
makes the poison, but differently for different individuals and
differently at different times during growth and development."

[To be concluded next time.]
--Peter Montague

======

[1] Paracelsus wrote, "Alle Ding sind Gift und nichts ohn Gift;
alein die Dosis macht das ein Ding kein Gift ist [all things are
poison and not without poison; only the dose makes a thing not a
poison]. See
http://www.academicpress.com/pesttox/pdf/krieger_HPT2_foreward.pdf

[2] F. Rosner and S. Munter, editors, THE MEDICAL APHORISMS OF
MOSES MAIMONIDES, Vol. 1, Treatise 3 (New York: Yeshiva
University Press, 1970), pg. 71.

[3] William Osler, "On the educational value of the medical
society," BOSTON MEDICAL AND SURGICAL JOURNAL Vol. 148 (1903),
pgs. 275-279.

[4] See, for example,
http://ace.ace.orst.edu/info/extoxnet/tibs/bioaccum.htm