[Also see ABCs of Toxicology]
[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 Perspcetives 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."
[Concluded below] --Peter Montague
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[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
[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
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 acclimatization, 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 phase-out. 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.
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[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.
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