Toxicology: The learning curve

"Near the end of an adventurous life spent wandering the fortress towns of central Europe, clashing with blood-letters and other tradition-bound healers of the day, the irascible sixteenth-century physician Paracelsus wrote a defence of his unorthodox use of mercury, opium and other potentially dangerous medicines. “All things are poison, and nothing is without poison: the dose alone makes a thing not poison,” he wrote. Centuries later, after many of his once-radical ideas found wide acceptance, Paracelsus's pronouncement would be distilled into a pithy phrase that became foundational dogma for the modern science of toxicology: 'the dose makes the poison.'"

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"But what if the Paracelsian presumption is wrong? What if, for a large and potent class of compounds, lower doses pose higher risks? A growing number of academic researchers are making just such a claim for endocrine disrupters, a large group of synthetic chemicals able to interact with cellular hormone receptors. These compounds, which range from the common weed killer atrazine and the plasticizer bisphenol A (BPA) to the antibacterial agent triclosan (used in cleansers) and the vineyard fungicide vinclozolin, don't play by the usual rules of toxicology. On the basis of conventional high-dose testing, regulators have set maximum acceptable levels for each of them that assume all doses below that level are safe. But academic researchers who have studied a wider range of doses, including very low ones found in the everyday environment, say that their experiments usually do not generate the tidy, familiar 'ski-slope' dose-response graphs of classic toxicology. Instead, most endocrine disrupters have 'non-monotonic' dose-response curves, meaning that their slopes change at least once from negative to positive, or vice versa, forming 'U' shapes, inverted 'U's or even stranger shapes that resemble undulating Chinese dragons.

'We're seeing that for every one of these compounds we test, there will be a non-monotonic response — every one!' says Frederick vom Saal, a neurobiologist at the University of Missouri-Columbia, who has been sounding the alarm about endocrine disrupters since the 1970s. 'Low doses of endocrine disrupters act in ways that are totally unpredicted by the traditional approaches of toxicology.' Vom Saal and his colleagues believe that very low doses of these compounds in the environment are contributing to a wide range of human health problems — including obesity, diabetes, cancer, cardiovascular disease, and infertility and other disorders related to sexual development.

Many toxicologists, however, are not convinced — especially those in industry or government who have spent their careers deeply involved in traditional risk assessment. Although they acknowledge that endocrine disrupters have unusual toxicological quirks, they say that the work of vom Saal and like-minded researchers is still insufficiently replicated, too reliant on unvalidated assays and too focused on end points such as organ weight, precancerous growths and changes in the activity of genes and proteins, which may not pose significant health threats. 'If we're going to take this seriously, we need to have some evidence of a real phenomenon that happens not just in the hands of one researcher and one test, something repeatable that can stand up to scientific scrutiny about how it could lead to real health effects we want to avoid,' says Lorenz Rhomberg, a toxicologist at the environmental-consulting firm Gradient in Cambridge, Massachusetts. Rhomberg also serves as a consultant on endocrine disrupters to the American Chemistry Council, an association of chemical manufacturers.

Vom Saal and his colleagues counter that this is precisely the type of systematic evidence they can now provide, thanks to a boom in endocrine-disrupter research. The most comprehensive review yet of the field1, published in March, included more than 600 studies — almost half of them published within the past five years — and found credible evidence of non-monotonic responses with low-dose health effects in 18 endocrine disrupters, including BPA, atrazine and vinclozolin. 'We kept hearing from our critics that there aren't enough examples to prove this phenomenon is real, so we took that as a challenge,' says Laura Vandenberg, a postdoctoral fellow at Tufts University in Medford, Massachusetts, and the lead author of the review.

Government officials in Europe and the United States are paying attention. 'I find the Vandenberg review to be quite compelling and quite convincing,' says Linda Birnbaum, director of the US National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina. In an April editorial in the NIEHS-published journal Environmental Health Perspectives, Birnbaum argued that “it is time to start the conversation” about incorporating low doses and non-monotonic relationships into regulatory decisions2. At a European Commission scientific conference on endocrine disrupters this June in Brussels, delegates failed to reach a consensus on the importance of non-monotonicity at low doses but they did agree that existing regulations need to be stricter, according to Björn Hansen, who heads the chemicals unit at the commission's Directorate-General for Environment in Brussels. In the United States, meanwhile, the Environmental Protection Agency (EPA) and the Food and Drug Administration (FDA) are showing a new willingness to at least discuss the issue — although they say that major regulatory revisions are not on the table for now.

Big changes are unlikely, some observers suggest, as long as the field remains so polarized. 'There is a very large divide out there between the risk assessors and the endocrine scientists,' says Thomas Neltner, who studies chemical food additives at the non-profit Pew Health Group in Washington DC, which has been trying to arrange a rapprochement through a series of scientific meetings. “Our feeling is that the two sides have been talking past each other.'"

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