I’ve been reading a bit more about endocrine disruptors, because it turns out that I don’t really know any experts that can do the thinking for me. I belatedly decided to read the paper that Dr. John Myers (who I mentioned a couple posts ago) and collaborators wrote on the possible effects of low doses of endocrine disruptors.
That paper contained a general overview of the problem. It had a few interesting examples of responses that were not monotonic with dose. For instance, hormone-mimicking drugs used to treat cancer (Tamoxifen, for example) can cause the cancer to flare briefly, until the concentration of the drug gets high enough to start inhibiting the cancer. This is an interesting result, and seems to be the substance of Dr. Myer’s claim from my last post on this. However, at first I thought that he was saying that a chemical could have no discernible effect at high doses, but a significant one at lower doses. If that were the case, it would severely impact how one carries out toxilogical testing.
So, to get more background, I read a review article cited in Dr. Mayer’s paper. It provides more detail about other ways in which large effects can be produced by small exposures.
The most scandalous suggestion in the review article is that some toxicology studies extrapolate low dose responses from a single high dose measurement, by assuming the relationship between dose and effect follow a linear relationship with zero response at zero dose. That assumption would be invalid if a response saturates. This occurs for many biological systems, because the available chemical receptors get filled as the hormone concentration increases. I find it rather hard to believe that toxicology studies regularly use this assumption, because, frankly, anyone making such an assumption probably shouldn’t have access to a laboratory.
At the very least, I would imagine that toxicology studies would keep testing lower doses until they were sure the response looked linear, and then start extrapolating. That should generally be safe, I would think. The response of a saturating system will get steeper at lower concentrations, so as long as one extrapolates from more than one data point, one will tend to over-estimate the response at lower doses. Therefore, the extrapolation would be conservative. However, at this point, I am reading the review article in a much less worrisome light than the authors meant it to be taken. I am assuming that if an astronomer finds the authors’ point obvious, biologists would already be accounting for it in their work.
Perhaps the concern is that, even if one finds the linear regime of the high-dose response, other responses will have already saturated at doses orders of magnitude lower. In this case, the predictive power of the high-dose studies would be very limited. However, as I mentioned in my last post on this, I would still expect to see the low-dose effect if I test to the point where the high-dose effect is negligible.
Up to now, I have only described saturating response curves, which are monotonic. The review article also suggests that some responses can be non-monotonic. Unfortunately, the first example given in the review article, on how an estrogenic chemical (diethylstilbestrol, or DES) affects prostate development in mice, seems to be a poor choice to make their point about toxicological studies. At low doses, the chemical causes the prostate to grow. At high doses, the prostate ends up smaller, but only because the chemical produces “gross abnormalities in the reproductive organs.” This is a rather trivial example, like saying that getting hit in the head causes headaches at low doses, but cures them at high doses when it kills you. Clearly, at all doses tested, you can tell this chemical (like getting hit in the head) is generally not a good thing.
Likewise, the review article points out that vitamins must be taken at the right dose. When too little vitamins are present, the deficiencies cause diseases. At high doses they can become toxic. However, this example has no bearing on low-dose toxicology, because there is no regime in which one is concerned about getting too low a dose of synthetic hormone-mimicking chemicals.
There are a lot of valid points in the review article. I agree that one has to be concerned that multiple chemicals might have similar responses, so that, for instance, the concentration of any given estrogen-mimicking substance isn’t nearly as important as the sum of the concentrations of all such chemicals. It also seems plausible that very low doses of hormone-mimicking chemicals could affect the development of fetuses, because the chemical signals that allow cells to differentiate can be small. (The book Mutants, One Genetic Variety and the Human Body, by Armand Marie Leroi, describes how a fetus develops very well.)
However, the articles by Dr. Myers et al. and Dr. Welshons et al. are cluttered with examples that don’t seem relevant to the problem at hand. Mostly, I find it hard to believe that it is commonplace for biologists to extrapolate from single data points. If I were in a bad mood, I could dismiss their work as unnecessarily alarmist.
I am trying to reserve judgment, however, because medicine has a lot of mysteries at the moment. I am constantly hearing about rises in the rates of allergies, autism, and cancers. Some of this is probably because the tests to find these conditions are more effective than previously. However, unless it is demonstrated that the increase in rates is caused by people looking harder, it seems important to consider the possibility that other factors of our modern lives might be making them more common.