Pharmaceuticals in the Exposome

The campaign of fear against hormone replacement therapy entered a new phase last week. A few years ago, results from the Women’s Health Initiative were heavily advertised in the mainstream media. That campaign caused women and their doctors to flee from not only the conventional hormone therapy that was studied but from all hormone use. The conclusion was that post-menopausal women on hormone replacement therapy were at greater risk of breast cancer.

As I commented at the time, the study failed miserably for a variety of reasons, two chief among them. First, and most importantly, the researchers were generalizing from the use of one drug, Prempro, that is not chemically the same as the estrogen and progesterone a woman’s body produces and so would not be expected to have the same biological effect. Second, the design of the study was sloppy about such matters as the actual hormone needs of each woman.

The latest campaign is based on results from the same long-term study that show that women on Prempro are not only more likely to suffer breast cancer but that any cancer that develops is likely to be more deadly. Not by a lot, mind you, but statistically more deadly. The reasons for ignoring this alarm remain the same. All they really tell us is “Don’t take Prempro.” It’s not much of stretch to say that women should avoid hormone therapy using pharmaceuticals as well. But it says absolutely nothing about use of bioidentical estrogen and progesterone.

Everyone involved with this research concludes that the study requires caution with all hormones. That conclusion is based on a false premise, which is that the side effects of a pharmaceutical that imitates an actual hormone can be reasonably assumed to apply to the hormone itself. This is clearly an absurd conclusion based on very faulty logic. If the hormone posed the same risks as the pharmaceutical, one would expect similar risks of breast cancer among pre-menopausal women whose hormones are in the same balance as those of the post-menopausal women taking the pharmaceutical. That, of course, is not true.

On the other hand, there’s a strong case for assuming that the pharmaceutical in fact would have a different biological effect as compared to the actual hormone. The crude way of putting it is that, as far as a woman’s body is concerned, the pharmaceutical is a toxin because it’s not recognizable as native to the woman’s biology. The reason for the chemical difference is financial: in order for the pharmaceutical to be patented, its molecular structure must be different from the actual, naturally occurring hormone. As a chemical, Prempro can’t be the same as the estrogen and progesterone a woman’s body produces.

Another way to look at this is that the pharmaceutical is an endocrine disruptor that has been developed, patented, and prescribed to post-menopausal women. Endocrine disruptors are one of a wide variety of toxins to which we are exposed. In the current issue of Science, Stephen Rappaport and Martyn Smith at UC Berkeley’s School of Public Health discuss the need to increase our understanding of what they call the exposome. Study of the genome is about how genes affect human biology. Study of the exposome is about how environmental exposures affect human biology.

Rappaport and Smith argue that although genome research gets much of the attention and funding, it is the exposome (that is, environmental exposures) that are predominantly at the root of the chronic diseases that plague us. However, the current methodological state of the art for uncovering the causal relationships between environment and disease are weak. The most significant weakness in this research is that it tends to focus on one kind of exposure and one disease—for example, the relationship between exposure to an endocrine disruptor such as bisphenol A and thyroid function. Yet it is commonly accepted that the relationship between environmental exposures and disease is not one-to-one but many-to-many. In order to understand those relationships a project on the scale of the Human Genome Project is required. In other words, a Human Exposome Project.

Pharmaceuticals are in the human exposome. How much?

Between 1999 and 2008, the number of people taking five or more pharmaceuticals almost doubled—from 6.3% to 10.7% of the population. The number taking two or more pharmaceuticals increased from a quarter of the population to a third. It’s an experiment in drug interactions with occasional lip service and little research. More importantly, it is part of the larger experiment of which we are a part, the experiment that subjects us—largely involuntarily—to biologically active environmental exposures. Personally, I don’t think the experiment has turned out very well. While the Human Exposome Project gets off the ground, I think it’s wise to cool it on the experiments.