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 .

RACHEL'S ENVIRONMENT & HEALTH NEWS #752
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