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Director's Message

March 13, 2015: The Dose Makes the Poison, and the Genes Make the Difference

Christopher P. Austin, M.D.

Often in today’s world, the word “chemical” conjures up a toxic, man-made substance that is undoubtedly harmful to human health. The growing consumer demand for “natural” foods and cosmetics illustrates this trend. Similarly, the word “drug” can have a different meaning depending on whether it’s considered dangerous (heroin) or helpful (aspirin). In the scientific arena, however, the distinctions between these terms are largely artificial. For example, the widely used stroke and heart attack prevention drug warfarin (trade name Coumadin) has another common use as a rat poison.

Despite the various popular definitions of “chemical” and “drug,” from a biological point of view, they are no different: substances in our environment that can alter how our bodies function in some way, whether beneficial, harmful or both depending on how they’re used and the dose. This commonality is important. From a translational science point of view, we need better methods to assess effects — positive and negative — of chemical substances on human health. I have written about several initiatives NCATS has to develop these methods in previous messages.

Part of the challenge in defining these effects is that individual people can vary greatly in their responses to chemicals. Part of this variation is due to the variation in our genomes. Just as these differences make each of us more or less susceptible to developing conditions such as heart disease, genetic variation also can determine how sensitive we are to the helpful or toxic effects of chemicals. This is the crux of the recently announced Precision Medicine Initiative, which aims to use genetic data from individuals to personalize diagnostic and therapeutic strategies. The same approach might be used to assess individual sensitivity to effects of chemical compounds — but the technical challenges have been daunting.

A multidisciplinary team including NCATS scientists recently demonstrated success in overcoming these roadblocks. In a study published in the Jan. 13, 2015, issue of Environmental Health Perspectives, academic and NIH scientists from the Toxicology in the 21st Century program utilized NCATS’ large-scale robotic screening capabilities to test the cells of more than 1,000 individuals with different genetic backgrounds for sensitivity to 179 different therapeutic and industrial chemical compounds. The study, the largest of its kind to date, not only provided new insights into biological mechanisms of human chemical sensitivity but also revealed that for many compounds, individual responses varied more than previously thought. This new information may help regulatory experts develop more accurate ways to determine safe levels of environmental chemicals.

A better grasp of individual differences in sensitivity improves clinical care and public health, increasing the accuracy of predictions about exposure effects. This improved knowledge helps individuals expose themselves only to chemicals and drugs that are likely to be helpful and to avoid those that are not. That’s the promise of “precision environmental exposure,” much like precision medicine.

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences

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