Environmental Health Institute Blends Toxicology And Molecular Biology

Situated equidistant from Raleigh, Durham, and Chapel Hill, N.C.--smack in the middle of the Research Triangle--sits the only National Institutes of Health institutional campus outside of the Washington, D.C., Beltway. The National Institute of Environmental Health Sciences (NIEHS) is currently responsible for nearly 50 percent of all federally funded research on such subjects. It commands a diverse research agenda that covers populations and geographical boundaries far beyond the triangle or the Beltway. Working with the sixth smallest budget of the 17 NIH institutes--$273 million for fiscal year 1995--NIEHS investigations cover thousands of environmental agents, affecting almost every human system, and conditions that afflict humans at every stage of life. At the same time, institute director Kenneth Olden, who was appointed in 1991, is in the midst of redefining the institute's approach to environmental health research in light of new advances in molecular biological techniques. Olden, the first African American to head an NIH institute (J.Mervis, The Scientist, July 22, 1991, page 3), describes his efforts as blending new biomedical methodologies with the classic toxicological approaches used by the institute and fomenting better integration of the basic- and applied-science missions of the institute. "What we should be doing is identifying which environmental agents cause diseases, how they cause diseases, and then try and prevent those diseases," Olden declares. "What we do is support basic research that is oriented toward preventing disease." Thus far, his initiatives have been well received by many environmental scientists inside and outside NIEHS. "The institute achieves an excellent balance between very solid basic mechanistic research and the applied side of environmental science," observes Phil Hanawalt, a professor of biology at Stanford University and past president of the Reston, Va.-based Environmental Mutagen Society. "Ken Olden brings a sincere interest in developing a mechanism-based mode for assessing the risk of environmental agents to humans." NIEHS was created as an NIH division in 1966, becoming a full institute in 1969. At the time of its establishment a congressional mandate decreed that all new agencies had to be located more than 50 miles from Washington, D.C., because of a consensus among policymakers that the D.C. area was becoming "too insular," as one NIEHS official put it. Because of this and a strong bid from the North Carolina congressional delegation, the institute was located in the then-fledgling Research Triangle Park. NIEHS has both an applied mandate--through the National Toxicology Program (NTP), which conducts all federally funded toxicological studies on chemical compounds--and a fundamental research objective to study the mechanisms underlying environmentally related diseases. The institute's $129 million budget for intramural research--half of its $273 million total--supports nearly 400 scientists and technicians working in three programs: environmental toxicology, environmental carcinogenesis, and environmental biology and medicine. Anne Sassaman, director of the division of extramural research and training, describes the overall research programs at the institute as "tremendously diverse." The institute, she says, "probably covers more [areas] than any other [NIH] program, except for the general medical sciences institute, because we cover essentially all environmental agents except for infectious disease organisms." She also notes that NIEHS investigations involve conditions affecting the course of the entire human lifespan, from exposures to harmful substances in utero to effects on the elderly, and the effects on most human systems, with a variety of disease outcomes. In fact, the institute's almost 600 extramural grants involve research on nearly 20 human organs and tissue types. Another $129 million of the NIEHS budget goes to support extramural research grants, 16 percent of which funds centers of environmental health science research at 23 universities. An additional $85 million, beyond the NIH budget appropriation of $273 million, comes from other government entities, such as the Environmental Protection Agency to administer health and safety training and research. According to J. Carl Barrett, NIEHS acting scientific director, environmental agents act in two general ways to disrupt normal human functions: by mutating genes and by perturbing the signaling pathways of cells. In general, the agents being studied are primarily industrial or agricultural chemicals. However, Barrett notes, "we don't like to think of [the environment] too restrictively; we also consider such factors as diet, air and water pollution, electromagnetic fields, and lifestyle." Just as the institute defines the environment broadly, Olden also points out that the agency has expanded its role in public policy decision-making. "I felt we were not aggressive enough in talking about the quality of science that goes into the decision process" behind environmental regulations. To heighten NIEHS's part in providing an enhanced scientific basis for setting environmental policy, the institute also supports work in such areas as risk assessment. Hanawalt also notes a need at the federal level for more meaningful tests to assess the risk to humans of chemicals found in the environment, an area in which "the institute really serves a key role. It appreciates the need to have a close association between the people who are doing basic mechanistic studies and those who are carrying out the [toxicological] testing [through the NTP]." Much of the basic research at the institute in such areas as cell-membrane biology, mechanisms of DNA replication and repair, and mutagenesis are conducted in the many labs and sections of the environmental biology and medicine branch. Martin A. Rodbell, corecipient of the 1994 Nobel Prize in medicine or physiology for his work on G-proteins, officially retired from NIEHS in June 1994, but still maintains a lab at the institute, where he conducts basic research on signal transduction (E.R. Silverman, The Scientist, Nov. 28, 1994, page 1). Another focus of NIEHS research, says Dale Sandler, chief of the environmental and molecular epidemiology section, is an increasing emphasis on combining basic molecular biological studies and epidemiological methods to identify risk factors of disease. "We're looking at environmental risk factors for molecularly defined subgroups," Sandler reports. In one study, her group looked at the presence or absence of the ras oncogene in a sample of cancer patients (J.A. Taylor et al., "Ras oncogene activation and occupational exposures in acute myoloid leukemia," Journal of the National Cancer Institute, 84:1626-32, 1992). "What we found was very exciting to us. The tumors that were ras positive [were found to be] in leukemia patients [who were] four times more likely to have been working with solvent-type chemicals, compared to the control group. And those that were ras negative were not different from the control at all." The study is currently being replicated with a larger sample population. Sandler notes that other epidemiological research at NIEHS addresses the fact that "exposure [to harmful substances] can do something besides give you cancer or kill you." There are a host of other human health problems that arise from environmental agents, including reproductive and developmental disorders, respiratory problems such as asthma, and neuroendocrine diseases, an area of research that has been neglected, say environmental scientists. Because of this, says Sandler, "we are developing the methodological tools" to look at such disease outcomes as birth defects, kidney disease, and neurological disorders. Another noncancer research area is the effect of environmental agents on reproduction. "We've started out with the simple task of trying to develop epidemiological tools to look at reproduction," remarks Allen Wilcox, chief of the epidemiology branch and chief of the reproductive section. His group is currently surveying women to assess how many menstrual cycles it takes for them to become pregnant. "One of the most interesting studies was when we looked at women who were dental assistants," notes Wilcox (A. Rowland et al., "Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide," New England Journal of Medicine, 327:993-7, 1992). Assessing exposure to mercury in dental fillings was the main reason for conducting the study, but "to our surprise, there was only a rough relationship of mercury exposure to fertility. But we did find a strong effect of nitrous oxide," which in animal studies has been shown to affect the hormonal regulation of estrogens. "We published the nitrous oxide finding, and it has been used as the basis for new recommendations for providing adequate ventilation in the workplace." Another lab in which reproductive biology figures prominently is that of Kenneth Korach, chief of the receptor biology section. His team works on chemicals that mimic estrogen, concentrating on investigating the estrogen hormone receptor on the surface of certain cell types. Polychlorinated biphenyls, or PCBs, are one of the more familiar classes of compounds thought to mimic natural estrogen. What all of the mimics seem to share with estrogen is an aromatic or phenolic ring structure, explains Korach. The clinical toxicity of estrogen mimics starts with the estrogen-like compounds binding to the cell receptor. "At that point," says Korach, "the compound can either mimic the hormone, producing more hormonal activity, or stop the natural hormone from working." In men, these hormonal mimickers are thought to interfere with spermatogenesis, leading to low sperm counts, and in women the chemicals cause various disorders of the reproductive tract. Recently, Korach's lab has developed a mouse that has no functional estrogen receptor (K.S. Korach, "Insights from the study of animals lacking functional estrogen receptor," Science, 266:1524-7, 1994). "In the future," he says, "what we plan to do is treat these mice with various compounds such as DDT or kepone that have been described as having hormonal activity and see, in the absence of a functional receptor, whether these compounds are still able to trigger some of the hormonal effects." DISCUSSING ENVIRONMENTAL HEALTH Environmental Health Perspectives, Journal of the National Institute of Environmental Health Sciences (NIEHS) Gary E.R. Hookand George Lucier, editors NIEHS P.O. Box 12233 Research Triangle Park, N.C. 27709 (919) 541-3406 Fax: (919) 541-0273 E-mail: hook@niehs.nih.gov Society of Toxicology Meryl H. Karol, president Shawn Lopez, executive director 1767 Business Center Dr., Suite 302 Reston, Va. 22090 (703) 438-3115 Fax: (703) 438-3113 E-mail: 73162.506@compuserve.com 3,800 members American Association for Cancer Research Inc. Joseph R. Bertino, president Margaret Foti, executive director Public Ledger Building, Suite 816 150 S. Independence Mall West Philadelphia, Pa. 19106-3483 (215) 440-9300 Fax: (215) 440-9313 E-mail: aacr@aol.com 10,100 members Environmental Mutagen Society Ray Tice, president Rick Guggolz, executive director 11250 Roger Bacon Dr., Suite 8 Reston, Va. 22090 (703) 437-4377 Fax: (703) 435-4390 E-mail: emsdmg@aol.com 1,200 members Although the National Cancer Institute (NCI) is the main NIH agency for cancer research, NIEHS collaborates with NCI on several studies, sponsors cancer-related proj-ects such as Sandler's, and maintains its own intramural environmental carcinogenesis program. The research goal of the three laboratories under this division focuses on identifying critical target genes for cancer and how environmental agents act upon them to initiate cancerous growth, relates acting scientific director Barrett, who is also the program's chief. Roger Wiseman, a senior staff fellow in the molecular carcinogenesis lab, became involved in the identification of the BRCA1 breast-cancer gene, along with NIEHS postdoctoral fellow Andrew Futreal, through their work on cancers in mice induced by butadiene, an organic chemical that is used in the rubber industry. "One of the first things we found in those studies was that the mouse chromosome 11 is the most frequent site of allele loss in mouse mammary tumors induced by butadiene," Wiseman recounts. "Interestingly, those tumors arose from a 10-part-per-million exposure, which is quite comparable to human exposures in real settings." Wiseman is currently developing a BRCA1 knockout mouse (S. Benowitz, The Scientist, Jan. 23, 1995, page 1) to understand how the gene works and to test such breast-cancer therapies as tamoxifen. Of the three intramural branches at NIEHS, the environmental toxicology program is "probably the most applied," says George Lucier, its director. This is primarily because NTP resides in this branch. Ninety percent of NTP is administered by NIEHS, with the remainder under the direction of the National Institute of Occupational Safety and Health and the Food and Drug Administration. As NIEHS director, Olden also coordinates and administers NTP. Lucier describes NTP's four-part mission: to provide toxicological information on chemicals of public-health interest; develop and validate better methods of toxicological testing; generate data that strengthen the scientific foundation on which risk assessments are made; and communicate findings of safety and health interest to the public, industry, and scientific communities. "One of the things that we've done over the years is test to see if chemicals cause cancer in rodents," says Lucier, who is also coeditor of the institute's journal, Environmental Health Perspectives. These data are used by such agencies as EPA to make regulations on the use of certain chemicals. "The problem is that there are about 70,000 chemicals in commerce today and we only have toxicological data on 10 to 20 percent of them," notes Lucier. "Each one of these tests is a two-year bioassay that costs about $3 million by the time it's all said and done. So, obviously, we're really limited in our ability to make a dent in those thousands of chemicals. What we've been trying to do is to ask: What can some of the new tools of molecular biology do for us to improve the way we provide these evaluations?" (For a review, see L. Lang, "Mouse or molecules? Mechanism-based toxicology in cancer risk assessment," Environmental Health Perspectives, 103:334-7, 1995.) The toxicology program also tests other types of potentially harmful environmental agents. For instance, Gary Boorman, chief of the pathology branch, and his team are trying to clarify some of the questions surrounding the association between proximity to powerline electromagnetic fields and the incidence of leukemia. "We've set up a series of animal studies, exposing them to 60 hertz magnetic fields--the powerline frequency," he relates. "We're looking at neuroendocrine effects, birth defects, and effects on reproduction. And we're six months into a cancer study." He explains: "The animal studies offer the advantage of controlling a lot of variables," such as diet and the amount of exposure time and dose, that can't be constrained in human epidemiological studies. He expects the first results to be released in June. For more information about grants administered by NIEHS, contact Anne Sassaman, Division of Extramural Research and Training, NIEHS, P.O. Box 12233, Research Triangle Park, N.C. 27709-2233; (919) 541-7723. Fax: (919) 541-2843. E-mail: sassaman@niehs.nih.gov.

Environmental Health Institute Blends Toxicology And Molecular Biology

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