The Dose Makes the Poison

I was listening to NPR’s Living on Earth this morning, and my curiosity was piqued by a piece on endocrine disrupting compounds. Over the past 12 years or so, scientists have been suggesting that some chemicals that are found to be harmless at high doses might have important biological effects at low doses. This idea is important, because widely-used chemicals such as bisphenol-A (used in food containers) are thought to be harmful to human metabolism. Bisphenol-A has been banned in Europe and Canada, but is still widely used in the U.S. It is a serious issue, because some scientists believe the subtle effects of these compounds could be contributing to the rise in allergies and some cancers in the U.S.

The piece was an interview with Dr. J. Peterson Myers. The piece answered the question about how endocrine disrupting compounds act: they mimic hormones and interfere with the the ability of genes to produce proteins. The part that got me curious was the following claim about their effects:

I should emphasize that it’s not even close to brand spanking new. It’s solid in endocrinology. This is something that physicians have to structure their drug deliveries around. They know that at low doses you can cause effects that don’t happen at high doses. In fact, you can cause the opposite effect.

This seems to imply that the low-dose effect disappears at high doses.

With most toxins, there is a threshold level at which they begins to have harmful effects. For instance, at low doses, botulinum toxin merely paralyzes muscles locally in the body. As Botox, the toxin is used in cosmetic treatments to smooth wrinkles, and prevent the facial expression of emotion (okay, the second effect may not be the intended one). However, at high doses, the toxin causes botulism, a potentially-fatal form of food poisoning. Examples like this inspired the aphorism, “The dose makes the poison.”

The example given in the radio piece of an endocrine disruptor that acts different at low and high doses was Tamoxifen. Tamoxifen is used to prevent the recurrence of breast cancer. At high doses, the drug, and by-products of the drug made by the body, binds to estrogen receptors in the breast. Breast cancer tumor cells require estrogen to grow, so Tamoxifen prevents the growth of tumor cells. However, it turns out that in the uterus, Tamoxifen acts more like estrogen, and can encourage the growth of uterine cancer.

Unfortunately, the effects of Tamoxifen that I have been able to find (note that I am not a biologist, and don’t really know how to search the relevant literature) don’t seem to address the original question I had. Tamoxifen, at the same dose, acts differently on estrogen receptors in different parts of the body. It also acts differently on various hormonal receptors in fish. However, I was not able to find an explanation on how it might be harmful at low doses, but beneficial or benign at high doses.

I can construct a thought experiment, in which a chemical interacts badly with a receptor at low doses, but has a beneficial reaction at a higher dose. The bad reaction at low doses would be a side-effect of its use at higher doses. However, I can’t figure out how to get rid of the bad interaction from the low dose. Shouldn’t it always be identifiable?

Perhaps I am missing the point. It is possible that the problem is that the EPA doesn’t look for the kind of detrimental effects that are characteristic of endocrine disrupting compounds, including elevated long-term risks of cancer. In that case, complaining about the doses tested misses the point. The real problem could be that the testing methods aren’t designed to catch subtle-enough effects.

So, the cumulative effects on an individual of exposure to many different endocrine disrupting compounds might be important. I am going to try to find an expert to explain this better to me. Take this post as the start of a teaching moment: one was or another, it is an example of a “near-miss.”