Breast Cancer Gene Isolated
A team of researchers at the NIEHS, in collaboration with researchers at the University of Utah Medical Center, have isolated BRCA1, a gene that plays a major role in inherited breast cancer and ovarian cancer.
Scientists believe that BRCA1 is a tumor-suppressor gene, a gene that prevents uncontrolled cell proliferation. Thus, when the gene is inactivated through loss or mutation, cancer can occur.
It has been known for years that the mutant form of BRCA1, which is located on human chromosome 17, predisposes women to breast and ovarian cancers. However, the NIEHS and University of Utah researchers are the first to pinpoint the exact location of BRCA1 and clone it in the laboratory. Using a technique known as positional cloning, the researchers created a detailed map of 17q, the area of the chromosome that contains the breast cancer gene. They then focused on genes in that area expressed in normal breast tissue and compared them with mutational damage in tissue from women known to carry the defective form of BRCA1.
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Gene team. NIEHS Director Kenneth Olden (left) with senior members of the NIEHS team that identified the breast cancer susceptibility gene (left to right): J. Carl Barrett, Roger W. Wiseman, and Andrew Futreal. |
Five percent of breast cancer cases are due to inherited susceptibilities including
BRCA1. Studies of families with defective
BRCA1 genes suggest that more that half the women who carry the gene will be diagnosed with breast cancer by age 50, and 85% will be diagnosed by age 70. Although men in predisposed families also carry the mutant gene, their risk of breast cancer is not significantly increased. Now that the gene has been isolated, studies of the effects of specific mutations will be possible. Kenneth Olden, director of the NIEHS, said, "This represents a landmark discovery with exciting implications for the development of a test to identify women who are at high risk for breast cancer caused by the
BRCA1 gene. However, a great deal of research remains to be done before this discovery will have practical application."
Most women have no family history of breast cancer. It has been thought that "sporadic" breast cancers may involve somatic mutations of BRCA1, mutations that cannot be passed to offspring. However, in examining cancerous tissue from 44 patients without a family history of breast or ovarian cancer, the researchers found BRCA1 mutations in 4 cases. The mutations occurred in all body cells, suggesting that the defective BRCA1 gene was in fact inherited in the same manner as in families with a history of breast cancer.
Because everyone has two copies of each gene, a child has only a 50% chance of inheriting a defective BRCA1 gene. For BRCA1 to cause cancer in a breast cell, both copies of the gene must be lost or damaged. Women born with BRCA1 mutations have one bad copy of the gene, so only one damaging mutation in a breast cell must occur to lead to cancer: they are one step closer to cancer than women without the damaged gene.
BRCA1 is not the only gene involved in familial breast cancer. BRCA2, which has recently been mapped to chromosome 13, has not yet been isolated. However, BRCA2, unlike BRCA1, is not implicated in ovarian cancer.
An increased risk for breast cancer has also been observed in families with Li-Fraumeni syndrome, which is linked to mutations in the p53 tumor-suppressor gene; ataxia-telangiectasia, linked to the AT gene, and congenital retinoblastoma, linked to the RB1 gene.
Although the isolation of BRCA1 has no immediate implications for breast cancer screening and treatment in the general population, it significantly advances the long-term goal of research to mitigate genetic defects. Existing tests for the mutation are used only in individuals from families known to carry the defective gene. Isolation of the gene may lead to development of tests for the gene itself rather than tests based on genetic markers. Such a test would have to be able to identify a variety of mutations spread widely across the gene. Until BRCA1 is better understood, testing for mutations will be limited to research to learn more about the gene.
The introduction of genetic testing into mainstream medical practice has been a major priority issue for the Ethical, Legal, and Social Implications program of the Human Genome Project. In addition, a task force on genetic testing is being set up by the Department of Health and Human Services to consider these issues. The task force will include consumers, geneticists, government officials, and biotechnologists.
In the meantime, a woman with a family history of breast cancer, especially if the cancers were diagnosed at a young age, should discuss early detection procedures for breast cancer with her doctor.
NIEHS Launches Clearinghouse
Where do people go when they have questions about environmental health and related issues? Beginning October 1994, the National Institute of Environmental Health Sciences in Research Triangle Park, NC, will provide a major, national information source and referral point for questions about health and the environment with the establishment of EnviroHealth, an environmental health information clearinghouse, accessible toll-free through 1-800-NIEHS94 (643-4794).
Kenneth Olden, NIEHS director, has given the clearinghouse top priority and asked his staff to analyze the gaps in the availability of environmental health sciences information to the public and developing a plan for implementing the clearinghouse. "The excellent science done at NIEHS is at the heart of our mission, but unless information from our laboratories and our scientists is accessible to a wider public, NIEHS cannot fulfill its mission," Olden said. "The clearinghouse will reach out to environmental journalists, environmental justice organizations, educators, and other target audiences. The public's requests for information and public comments received by the clearinghouse will better enable the institute to respond to the needs of the American people."
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Money for minority health. John Ruffin (left) director of the Office of Research on Minority Health, and Kenneth Olden, director of the NIEHS. |
When appropriate, the clearinghouse will provide written material describing NIEHS research and training programs, and callers will be referred to other clearinghouses, toll-free numbers, federal, state, and local agencies, and information sources as needed. Full use will be made of various computer networks and the developing information superhighway to make information readily available to the public. The Office of Planning and Communications at the NIEHS has worked closely with Information Ventures, Inc., a Philadelphia-based contractor, to bring the Clearinghouse on-line.
Daniel VanderMeer, director of the NIEHS Office of Planning and Communications, has been the NIEHS project officer for the clearinghouse since the beginning planning stages. "The clearinghouse is designed to expand the lines of communications with other institute programs, our university-based centers across the U.S., the NIEHS Division of Intramural Research, and the National Toxicology Program, for example, to ensure the best possible information on a broad range of issues," VanderMeer said. "A central part of our effort will be to develop communications objectives for the institute and the clearinghouse that are specific, attainable, prioritized, measurable, and time specific."
NTP Announces Bioassay Results
The National Toxicology Program presented six more technical reports in its ongoing series of toxicology and carcinogenesis studies. All six reports were approved by the NTP's Board of Scientific Counselors' Technical Reports Subcommittee in a public review held June 21 at the NIEHS. Each report involves a series of long-term studies in which male and female rats or mice were given a range of doses of test chemical followed by extensive histopathologic examination.
* 1-trans-delta-9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, gave no evidence of carcinogenic activity in male or female rats given daily doses of up to 50 milligrams per kilogram body weight for 2 years. In male and female mice, the evidence of carcinogenicity was considered equivocal, based on increased incidences of thyroid gland tumors in animals receiving 125 milligrams per kilogram body weight.
* Acetonitrile, a polar solvent used primarily to extract fatty acids and animal and vegetable oils and for distillation of pharmaceutical products including vitamins and steroids, was tested by inhalation in groups of male and female rats and mice in a series of 13-week and 2-year studies. There was equivocal evidence of carcinogenic activity in male rats based on a slight increase in the incidence of liver neoplasms and no evidence of carcinogenic activity in female rats or in male or female mice.
* Benzethonium chloride, used primarily in cosmetics as a cationic surfactant and an antimicrobial, was tested by dermal application to the backs of male and female rats and mice. Although this regimen resulted in development of epithelial hyperplasia in rats and mice, there was no evidence of carcinogenic activity in either species.
* t-Butyl alcohol has a variety of industrial uses, particularly in perfumes and aerosol sprays and in cosmetics, with annual production in the U.S. nearing three billion pounds. This chemical was administered in drinking water to rats and mice for two years. Male rats exhibited some evidence of carcinogenic activity based on increased incidences of kidney neoplasms, but there was no evidence of carcinogenicity in female rats. Male mice had a marginal increase in thyroid gland tumors, which was judged equivocal evidence of carcinogenic activity, while in female rats the increase in thyroid gland tumors was more pronounced and constituted some evidence of carcinogenic activity.
* 1-Amino-2,4-dibromoanthraquinone is one of a series of five substituted anthraquninone dyes that have been studied by the NTP. When given in the feed, this chemical induced large numbers of neoplasms in a variety of tissues, including the liver, intestine, kidney, and urinary bladder in rats and the liver, forestomach, and lung in mice, and was judged to exhibit clear evidence of carcinogenic activity in both sexes of both species. These results were similar to those observed for all the other substituted anthraquinones studied and may permit judgments of the general carcinogenic nature of this class of compounds.
In a different set of studies, the NTP evaluated three mouse strains for sensitivity to the action of known initiators, promoters, and complete carcinogens. B6C3F1 mice, the strain most frequently used in NTP studies, were compared with two strains of mice known to be sensitive to carcinogens, the SENCAR and Swiss (CD-1), in a series of one-year skin paint studies. All three strains of mice developed skin tumors when given a variety of skin carcinogens, with SENCAR mice exhibiting the greatest sensitivity (earlier onset and increased multiplicity). Although B6C3F1 mice exhibited the lowest overall sensitivity to the initiation/promotion protocol, their response was similar to that of the Swiss and SENCAR mice for complete carcinogens.
K-12 Education Grants Awarded
Schoolchildren across the nation will encounter information on environmental health sciences more than ever before in the coming school years, thanks to seven new grants awarded by the NIEHS. The grants correspond to needs and approaches suggested by a select group of K-12 teachers, scientists, and science education program officials at the Environmental Health Sciences Forum held at the NIEHS in December 1992.
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Booster club. Marian Johnson-Thompson, associate director for institutional development (center), Michael Galvin (left), and Allen Dearry (right) of the NIEHS played key roles in funding science education grants. |
The forum laid the groundwork for the development of a 1993 request for applications entitled "K-12 Environmental Health Sciences Education," directed at funding the development of environmental health sciences materials that could be infused into existing K-12 science curricula on a national basis. The seven grants awarded are described below. Representatives of the projects met at the NIEHS in September, presented their plans and discussed possible collaborations between the projects. This orientation meeting focused on methods of ensuring national distribution of the materials. In addition, awardees will be encouraged to present workshops on their projects at national science teachers' meetings beginning in 1995.
The grants were awarded to the following applicants, given by project title with the name of the project director, the organization receiving the grant, and a brief description of the project.
* Eco Expert: Health Risks in Our Town, Paula R. Brady, Texas Learning Technology Group, Austin, Texas. A high quality, multimedia program that includes a computer-based simulation, hands-on activities, discussions, and background print material. Students assume various roles to explore links between environment and health. Classroom implementation involves extensive use of cooperative groups for carrying out research, peer teaching, and decision making.
* Risky Business: Living in a Chemical World, David L. Eaton, University of Washington, Seattle, Washington. The University of Washington's Department of Environmental Health and Purdue University's Department of Pharmacology will develop four teaching units to be inserted into existing high school science curricula. These curricular materials will use examples in environmental health sciences to teach basic biological principles and an understanding of environmental health risks.
* Ozone: Will It Affect Me? Sarah C. R. Elgin, Washington University, St. Louis, Missouri. The long-term goal of this project is to educate students, teachers, and parents about the potential health effects of ozone, both as a pollutant in the troposphere and as a UV shield in the stratosphere. Students will use information technologies to conduct research, analyze data, develop critical thinking skills, and make discoveries about what scientists do.
* Toxrap: Toxicology, Risk Assessment, and Air Pollution Audrey R. Gotsch, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey. This project will use a participatory action research model to develop educational materials to teach K-8 students about toxicology, risk assessment, and the process of scientific inquiry. Air pollution will be used as a vehicle to teach a framework for understanding and making decisions about environmental health risks.
* Enviromysteries, Gail P. Long, Maryland Public Television, Owings Mills, Maryland. Maryland Public Television and the Johns Hopkins University School of Public Health, Center for Environmental Health Sciences, will develop a set of video-based instructional materials for middle school students to encourage individual and group problem-solving related to water and its impact on human health. The set of materials will include a 12-minute core video to model the inquiry process through a detective mystery format and introduce students to broad environmental concepts related to water.
* My Health, My World, Nancy P. Moreno, Baylor College of Medicine, Houston, Texas. This project will build upon existing links between the Baylor College of Medicine and local school systems. It uses curriculum materials developed at Baylor to target elementary (K-4) students in an effort to develop in the students a stronger sense of self-involvement in environmental health issues. The program will involve students in school, at home and in their communities by using science adventure stories and coloring magazines. The materials, which will be bilingual, will focus on the role of the personal environment in health and on more global relationships between health and the environment.
* Environmental Health Science Action Packs, Claudia K. Probart, Pennsylvania State University, University Park, Pennsylvania. This project will design, produce, and evaluate a package of educational materials for grades 5 through 8. The packages will include instructional modules, interactive computer programs, and videotapes, all designed to be integrated into existing national curricula. Objectives of the materials are to promote awareness of the relationship of the environment to health; increase critical thinking skills; increase interest in environmental science; and provide parental and community involvement.
Dr. Marian Johnson-Thompson, NIEHS director of Institutional Development, who coordinated the Environmental Health Sciences Education Forum, said, "It gives me great pleasure to present forum participants with this end product of a process we began nearly two years ago. That we valued their input and took their suggestions seriously is evident in the nature and quality of the projects."
Alternative Test Systems RFA
A request for applications on the "Development of Mechanistically Based Alternative Methods and Models for Toxicological Research and Testing" was approved at the May 1994 meeting of the National Advisory Environmental Health Sciences Council.
NIEHS has a long-standing commitment to the development of alternative tests. The purpose of the grant is to stimulate expansion of state-of-the-art knowledge and techniques in molecular and cell biology to develop alternative models aimed at improving health hazard identification, species extrapolation, and risk assessment. The official RFA will be available in the fall of 1994. For information on this RFA, please contact the program administrator, Jerrold J. Heindel, PO Box 12233, MD 3-03, Research Triangle Park, NC 27709, (919) 541-0781, FAX (919) 541-2843, Internet: Heindel_j@NEIHS.nih.gov.
NIEHS Initiatives
Developmental Centers
Americans want to live long and healthy lives, and the majority of them achieve that goal. In general, however, members of economically disadvantaged and/or underserved populations are less likely to do so. At every stage of life, these populations suffer disproportionate levels of morbidity and mortality. Additionally, they are often the populations with high degrees of exposure to environmental agents and are frequently the populations with the least information available about the health consequences of exposure to these agents.
The Developmental Centers Program is one aspect of a comprehensive initiative of the NIEHS in Environmental Equity. This program is the first step in establishing core centers that foster multidisciplinary research programs. They must use state-of-the-art science and address as a primary focus environmentally related health problems of economically disadvantaged and/or underserved populations. Projects funded under this initiative are to carry out the developmental steps preceding a center application focused on environmental equity. It is anticipated that successful applicants will have strong research capabilities and meaningful collaborative interactions with organizations/institutions representing the affected communities.
This is a new initiative of the NIEHS. Currently, three projects are funded under this new initiative. This program has attracted outstanding scientists to use their talents and cutting-edge technologies to address the likely causal association between the disproportionate exposure to environmental agents and excess morbidity and mortality among the poor and ethnic minorities.
Global Climate Change
Global climate change will affect many systems such as weather, water resources, transportation, and ecologic and human health. Effects of climate change on ecologic and human health will be mediated by such factors as climate change-associated air pollution, ozone depletion, acid rain, and toxic waste disposal as well as the impact of increased human population on the environment. National and international groups are raising many serious questions about how best to respond to these multiple health threats. Climate change-related efforts of the NIEHS have focused primarily on specific issues like UV-induced phototoxicity of drugs and chemicals, toxicity of chlorofluorocarbons (CFCs) and related chemicals, and general investigations of the health effects from air pollution or hazardous wastes. Targets for increased NIEHS efforts in climate change are 1) participating in WHO/United Nations Environment Program/Intergovernmental Panel on Climate Change committees exploring climate change. This could lead to individual and collaborative research with various governments and agencies concerning climate change impacts on human health; 2) contributing to WHO and the IPCC work groups preparing summaries and proposals for new biomedical research on climate change; and 3) promoting research needs identified from previous conferences and committee works to:
* Assess the adverse human health effects of "cures" of climate change such as CFC replacements, alternative fuels, solar panel constituents, and metals in new batteries.
* Study the mechanisms and possible interventions for adverse effects of increased UV irradiation on immune systems and activation of chemicals and drugs in the skin (phototoxicity).
* Study the toxicology of increasing atmospheric concentrations of pollutant mixtures, especially those involving small particles. Identify the most susceptible populations for these effects.
* Assess human health impacts of climate change effects on biodiversity, including the effect of species losses or increases. This health assessment would include the toxicology of new treatments and drugs needed for new or relocated pests, diseases, or ecology.
Over the years, conferences and international panel discussions on climate change have identified some possible human health dangers from several sources (e.g., use of exotic and heavy metals in energy transducers, increased output of toxic wastes, and development of new air pollutants). Yet there are indications of many other climate change-associated health problems (e.g., serious toxicity resulting from some replacements for CFCs and an increase in asthma and skin cancer incidence worldwide). Increased air pollution and UV irradiation associated with climate change are especially likely to set up conditions favoring increases in asthma and skin cancer. Several NIEHS studies on photosensitization suggest it will be an increasingly serious health problem with many chemicals as climate change worsens and UV exposure increases.
Climate change is controversial. If it occurs, many complex and interactive systems will be affected. Human health effects of climate change and its "cures" could be numerous, and interventions or preventions could be needed quickly. The present efforts are designed to continue ongoing research to develop new prevention/intervention strategies to minimize possibly serious climate-change effects. |
Last Update: June 20, 1998