New Center 137 The newest Environmental Health Sciences Center focuses on agricultural health research. This center at the University of Iowa begins with existing databases on a well-defined rural population exposed to agricultural chemicals. With the creation of the center, a critical mass of researchers have a focal point for enhancing the databases and for additional research on the possible human health effects of a number of different agricultural exposures. Established Centers Each of the Centers has special areas of expertise--metals; agricultural chemicals; occupational and industrial health; air pollution; and water and food pollution. Much of what we know about the health effects of individual chemicals, metals, asbestos, air pollution, and links between nutritional status and susceptibility to environmental chemicals has come from research at these Centers. Examples of recent projects at these Centers are given below. Supplementation of gasoline with methanol has raised concerns that the resultant increase in formaldehyde and carbon particle levels might harm human health. It was learned that binding of formaldehyde to the particulates, required for deep deposition in the lungs, does not occur substantially, and thus the lower tract would not receive the dose of this reactive chemical. The association between environmental tobacco smoke and risk of childhood asthma in Hispanic and Black children was confirmed in a case control in New York. Boys were significantly more sensitive than girls. Center scientists are studying the effects of diet and nutrition on enzymes which catalyze the metabolism of drugs and environmental chemicals. These are important studies because it is known that certain dietary and nutritional factors affect the toxicity/carcinogenicity of these chemicals. For example, vitamins C and E might inhibit cancer by preventing formation of the reactive carcinogen from food materials, and calcium deficiencies are thought to contribute to esophageal and colon cancer in Chinese populations. Charbroiling meats, eating vegetables such as cabbage, and changes in carbohydrate/fat ratios in the diet, also have been found to alter chemical metabolism. Enzyme assays for specific cytochrome P-450 isozymes have been developed to study these effects, and thus the mechanisms of possible inhibition or promotion of carcinogenesis can be studied. Improving Training An additional approach to enhancing trained manpower in environmental health sciences is traineeships for students in medicine or osteopathy to do environmental health-related research. An important goal of the program is to expand professional expertise in diagnosis and treatment of environmentally linked illness. 138 National Institute of Environmental Health Sciences Intramural Research Authorizing Legislation Section 301 and 463 of the Public Health Service 1992 Authorization: Indefinite Act. Cooperation and communication among Institute scientists foster early application of basic science advances to environmental health. Such collaborations also enhance investigations of the mechanisms of human diseases, emphasizing those diseases which may have environmental components. Funding for the Intramural Research program during the last 5 years has been as follows: The The 1992 budget estimate for Intramural Research is $70,302,000, an increase of 4.0 percent over the FY 1991 estimate of $67,615,000. following are examples of efforts supported by this budget activity. Genes, the Environment, Cancer, and Aging The risk of cancer to an individual depends on environmental exposure, individual susceptibility, and age. The incidence of cancer increases greatly in the elderly (with 5th to 6th power of age). Aging can be studied at the cellular level and NIEHS scientists have provided new insights into the molecular basis of this process and how it interacts with environmental change. Normal cells have a finite life span in culture and then undergo a genetically controlled process leading to loss of proliferative capacity (called senescence). In contrast, many environmental carcinogens (including asbestos, hormones, benzene, and arsenic) can cause normal cells to lose this growth control and have an indefinite life span (termed immortal). Reintroduction of normal chromosomes into tumor cells restores their ability to age. NIEHS scientists have mapped the genes controlling cellular senescence in normal cells to specific chromosomes and efforts to clone these genes are in progress. These genes regulate a cascade of events resulting in 139 a block to cell growth. One key protein in this block has been identified as the retinoblastoma gene product. This gene, when deleted, leads to many diverse cancers, including retinoblastomas, osteosarcomas, lung cancer, prostate cancer, and breast cancer. Further studies on these genes and their regulation will yield important insights into both the cancer and aging processes, and the degree to which they are affected by various environmental agents. Biomarkers and Early Detection NIEHS scientists are working to extend the usefulness of a clinical early warning sign of prostate cancer, elevated levels of the enzyme, acid phosphatase. Studies with this enzyme may lead to more sensitive biomarkers for human prostatic cancer and improve early detection. Hormones and Health NIEHS scientists continue to be the world leaders in the study of the role of environmental estrogens in development and health. NIEHS research has shown that estrogenic environmental agents can disrupt reproduction and increase cancer risk, and that these hormone-like substances can influence bone metabolism and cardiovascular health. In studies looking at the effects of plant estrogens in women, NIEHS investigators have found that diets high in soy products, a source of plant estrogens, may lower the level of specific hormones which are critical for normal reproductive function. These findings of biological activity from plant estrogens suggest that further studies are needed to answer such questions as: What effects may these chemicals have on other segments of the population, including babies on soy formula? Do effects of plant estrogens explain some of the differences in illness rates and death rates seen in vegetarians compared to non-vegetarians? Can diet be used to prevent or treat estrogen-related conditions? These questions, raised by the research at NIEHS, are stimulating additional studies both by NIEHS scientists and others interested in this important field. Comparative Mechanisms Methylene chloride is a chemical commonly used in paint strippers, solvents, and some aerosols. NIEHS scientists have shown that rodents develop lung and liver tumors when they inhale methylene chloride. Humans inhale the compound while using these consumer products. NIEHS scientists are studying the cancer-causing mechanism by isolating cancer-linked genes from tumors of exposed mice, by studying exposure at different ages, and by evaluating the influence of changes in the rates of cell proliferation and metabolism of methylene chloride in the development of tumors. These data will help us understand how this environmental carcinogen exerts its effect. Receptors NIEHS scientists are investigating cell receptors that bind to environmental chemicals but have a still-to-be-discovered function in the cell. Work on cell receptors with known biological functions has shown them to be critical to the communication processes in cell growth, differentiation and development. Because cell receptors with identified biological purposes 140 are so vital to normal functioning, our investigators think that these new AIDS and HIV NIEHS research into Acquired Immune Deficiency Syndrome has focused on the basic question of how the human immunodeficiency virus reproduces itself. Institute scientists have developed models of the way the virus makes mistakes as it uses host cells to reproduce. Accurately defining these error-making processes may help in developing defensive strategies-- vaccines or treatments. Understanding then may enable scientists to exploit this viral weakness, preventing the virus from retaining enough accurate information to continue the infection. Molecular Modelling Another rapidly advancing scientific area is molecular modelling. NIEHS scientists are combining knowledge in mathematics, physics, computer science, and basic biology to develop computer models of molecules important to living systems. The models permit scientists to visualize, in two and three dimensions, the structure of the molecules and to manipulate the structures using principles of quantum chemistry and physics. Among the emerging applications of molecular modelling are: predicting what areas of the genetic code may be particularly susceptible to alteration by environmental chemicals, with consequent mutations; and defining the molecular details of an oncogene known as p21 (the 21st protein). This cancer-linked protein or oncogene is found in 30 percent of all human tumors and in 95 percent of pancreatic tumors. Understanding the molecular structure of p21 may permit scientists to better understand the events that trigger cancer. Reproduction and the Environment Twenty percent of women of childbearing age have trouble becoming pregnant. NIEHS scientists are studying the possible role of environmental factors in the problem. NIEHS studies have already found that the period when a fertilized egg implants in the uterus is very sensitive to disturbance by environmental agents. Some infertility related to environmental exposures may be preventable. This presentation last year described the findings from a study of dental assistants exposed to nitrous oxide. The study found that the probability of conception for exposed women in any given fertility cycle was 40 percent of that for women not exposed or exposed to the gas for less than 5 hours. An expansion of that study, which uses probability estimation techniques developed by NIEHS scientists, is examining effects on fertility of mercury-based dental amalgam exposure in the dental assistants. 141 Viruses and Cancer Risk NIEHS scientists are conducting a large mortality study to confirm and expand findings that showed increased risk of leukemia and lymphoma among workers in the meat and poultry industry compared to the general population. NIEHS investigators are also studying whether common poultry retroviruses play a role in cancer risk for workers exposed to the viruses. New tools of molecular biology are being used to look at how infective the poultry viruses are in human cells, whether and how the virus may be incorporated into the genes of normal and tumorous tissue, and what human antibodies respond to the poultry virus exposure. Dose-Response In another approach to developing and using biomarkers, scientists in NIEHS laboratories are comparing the biomarkers in human lymphocytes and placentas from persons exposed to TCDD (tetrachlorodibenzodioxin) or polychlorinated dibenzodioxins and dibenzofurans with the same markers in a laboratory rodent model. The studies are designed to evaluate dose-response relationships and are part of the broader effort to develop more reliable estimates of human health risks following exposure to TCDD and its related compounds. |