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Researchers Find New Risks in Low-Dose Chemical Exposure

Toxicologists have long held that the dose makes the poison: A substance can cause harm only in amounts high enough to overwhelm the body’s defenses.

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Toxicologists have long held that the dose makes the poison: A substance can cause harm only in amounts high enough to overwhelm the body’s defenses. But a major conceptual shift is underway, a leading expert said recently at the American Association for the Advancement of Science (AAAS), with much more attention being paid to low-dose chemical exposures and the impact they can have even many years later.

Chemicals can act like hormones and drugs to disrupt the control of development and function at very low doses, said Linda S. Birnbaum, director of the National Institute of Environmental Health Sciences (NIEHS). And those effects can be particularly telling during certain windows of susceptibility.

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“There are times in your life when you are much more susceptible,” Birnbaum said in the annual Robert C. Barnard Environmental Lecture at AAAS on 24 May. These include periods of active cell differentiation and growth in the womb and in early childhood as well as adolescence, when the brain is continuing to develop.

As an example of such susceptibility, Birnbaum noted a recent review of 23 studies between 2001 and 2010 that found a correlation between a mother’s smoking during pregnancy and an increased risk that her child will become overweight. In many cases, there also was an increased risk of type 2 diabetes by the time the child reaches age 10.

In some cases, a susceptibility to disease also can persist long after the initial insult or exposure has ended, Birnbaum said. Researchers have found, for example, that infants fed almost exclusively on soy-based formula have an increased risk of developing fibroid tumors decades later.

Researchers at NIEHS and elsewhere are starting to learn about some of the underlying biological mechanisms that may explain how exposure to certain chemicals and other stressors during crucial stages of life can lead to untoward health consequences.

Studies in animals suggest that hormone-mimicking chemicals can produce latent effects by subtly altering the structure and expression of DNA molecules. There are modifications in the “packaging” of the genes rather than the underlying DNA sequence itself. Such changes are referred to as epigenetics.

The modifications include addition of molecules, such as methyl groups, at certain sites along the DNA backbone. The changes can persist through multiple cell divisions and promote disease that can appear years or decades after the triggering event.

The effort to better understand the mechanisms of epigenetics has become a major research endeavor, Birnbaum said. “If the last decade was the decade of the genome, the next decade is going to be the decade of the epigenome,” she said.

NIEHS, an arm of the National Institutes of Health that is based in Research Triangle Park, North Carolina, has been pursuing epigenetics both in its intramural research and in its sponsored research. The work includes human studies on the latent effects of hormone-mimicking chemicals, including studies of children with behavioral, mental, and physical abnormalities who were exposed to phthalates (used in plastics), polycyclic aromatic hydrocarbons, or flame retardants while in the womb.

In addition to such chemical exposures, other external influences such as stress, poor nutrition, and infections also can trigger epigenetic changes in cells, Birnbaum said.

In a wide-ranging talk that reflected her more than 30 years as a federal scientist on the front lines of environmental health studies, Birnbaum cautioned that the causes of many diseases are complex, with multiple genes and environmental stressors likely involved.

Chemicals are widely dispersed in the environment, and people often are exposed to many different chemicals at the same time. Also, Birnbaum said, “one exposure can alter your response to a second exposure years later.” The effects of such exposures may be synergistic.

“We need to study combinations of chemicals,” she said, and acknowledged that, in general, “we have been uniquely unsuccessful in studying mixtures of chemicals well.”

The universe of potential bad actors is huge: More than 80,000 chemicals are in use in commerce. Of those, Birnbaum said, “less than 20% have any toxicity information at all.” Of the ones that have been screened, about a dozen (including alcohol, lead, and mercury) have been closely associated with human cognitive impairment. About 100 chemicals have been shown to impair brain development in animal models.

The challenge of linking environmental exposures to identifiable health outcomes is complicated by the sheer number of factors involved, Birnbaum said, including industrial and agricultural chemicals, prescription drugs, byproducts of combustion and industrial processes (such as the chemical dioxin), physical agents such as heat and radiation, substance abuse, and social and economic factors.

“We’ve got to stop looking for simplistic answers,” said Birnbaum, a certified toxicologist who has directed NIEHS and the National Toxicology Program since 2009. Prior to that, she spent 19 years at the Environmental Protection Agency where she directed the largest division focusing on environmental health research.

Still, despite the complexities involved, Birnbaum said research over several decades, in both animals and humans, has clearly identified a number of diseases with known or suspected environmental components. They include:

  • cancers;
  • birth defects such as cleft palate and heart malformations;
  • infertility;
  • lung disorders such as asthma and asbestosis;
  • neurodegenerative diseases such as Parkinson’s;
  • neurodevelopmental disorders such as autism;
  • heart disease due to air pollution and dioxin exposure; and
  • endocrine disorders such as diabetes.

Further progress in understanding the totality of exposures people are subjected to in the environment will depend on better tools for toxicity screening and more powerful methods for analyzing the huge amounts of data generated, Birnbaum said.

Already, she said, NIEHS and other agencies are improving the coordination of federal programs for toxicity testing. New approaches include use of robotic devices that can run up to 10,000 chemicals through at least 70 short-term lab assays at 15 different dose concentrations.

While initially skeptical of such high through-put screening, as it is called, Birnbaum said the large number of cellular and molecular assays, combined with sophisticated statistical analyses, can reveal toxicity pathways not otherwise apparent and chemicals that should be subjected to more intense scrutiny.

Birnbaum noted an Environmental Protection Agency effort called ToxCast that screened 309 different chemicals, many of them pesticides, with 400 rapid, automated tests. Bisphenol A (BPA), a controversial chemical with hormone-like properties that is widely used in food packaging, ranked third in biological activity among the chemicals tested.

“For my money, if I’m going to investigate further, I want to study the chemicals that ‘light up the board,’” Birnbaum said.

She expressed some optimism about the path going forward, particularly with regard to the emerging field of epigenetics. It may be possible, for example, to reverse the attachment of methyl groups along the DNA backbone, she said, and prevent disease. She said some chemotherapy drugs already have been developed to target DNA methylation in a variety of tumors.

More broadly, Birnbaum stressed the importance of viewing environmental health from a population perspective. It is often difficult to pick up exposure impacts in patients seen in a one-on-one setting in the clinic, she said. But over the larger population, patterns emerge, such as the impact of lead exposure on cognitive development in children. And such population-wide exposures can exact a much larger health toll, she said, “than many of the things that we spend a lot of time wondering about that you can pick up in the individual.”

Birnbaum’s bottom-line message was simple enough: “While we can’t do much about changing our genes, we can change our environment.” That’s a challenge, she said, but in its effort to translate bench science into environmental public health, NIEHS is providing both individuals and policy makers some of the information they need to make informed choices.

The Barnard Lecture is organized by the AAAS Science & Technology Fellowships program, which provides public policy education and outreach experiences for accomplished scientists and engineers. Fellowships in congressional offices are funded by approximately 30 partner scientific and engineering societies. Fellowships in executive branch agencies are funded by the hosting offices.

The lectureship is sponsored by the international law firm of Cleary Gottlieb Steen & Hamilton LLP, to honor the late Robert Barnard for his contributions to environmental and public health law and in recognition of his many years of service as a member of the selection committee for the AAAS Fellowships at the U.S. Environmental Protection Agency.