National Institute of Environmental Health Sciences (NIEHS)

Overview of Rare Disease Research Activities

The National Institute of Environmental Health Sciences (NIEHS) supports basic research that has provided important insights into fundamental mechanisms of chemical toxicities and molecular pathways. Basic research is also likely to expound upon areas of rare diseases without explicitly studying the disease in question. In addition, NIEHS conducts a number of research activities aimed specifically at expanding the knowledge of and alleviating rare diseases. Some important examples include insights into Lou Gehrig's disease, pfiesteria, fibrotic lung disease, childhood lead poisonings, and myelodysplastic syndrome.

Recent Scientific Advances in Rare Disease Research

Another NIEHS study of the human health effects of lead is one which focuses on amyotrophic lateral sclerosis (ALS). ALS, also known as Lou Gehrig's disease, is a progressive neurodegenerative disease affecting the motor system of the brain and spinal cord. Environmental risk factors for ALS, including lead, have been studied, but evidence for an association of ALS with any of these factors is inconclusive. To provide more information on this issue, NIEHS is conducting an epidemiologic study of the association of ALS with lead and other environmental risk factors. Data collection for this landmark research study is complete and analysis of results is underway. Results to date indicate that both bone and blood lead levels are elevated in ALS patients and that ALS is associated with both occupational and residential lead exposure. Thus this extensive NIEHS study confirms previous suggestions that ALS is associated with lead exposure. This result suggests that reduction of lead exposure in the population may reduce the burden of neurologic disease as well as preventing acute neurotoxicity. It may also suggest intervention strategies for ALS.

Rare Disease Research Initiatives

NIEHS is working with CDC, and a number of state and local health officials, to help investigate fish kills (pfiesteria) along the Mid-Atlantic seaboard. Since October 1996, thousands of fish have become infested; most of them later die. In addition, some of the watermen and others exposed to waterways in the Chesapeake Bay region recently became ill or have shown signs of developing skin rashes and memory loss. NIEHS is working to see if there is any association between the toxins and these health effects.

A current NIEHS initiative involves research on lead poisoning. About 1 million children in the US have blood lead levels greater than 10 micrograms/deciliter, and 40,000 have levels above 20. These children have lead-associated developmental delay; it is not known whether treatment prevents or reduces such delay once lead exposure has occurred. To address this critical need the NIEHS is doing a multi-center clinical trial, the Treatment of Lead-exposed Children (TLC) trial, to test whether succimer, a drug that lowers blood lead, prevents or reduces lead-associated developmental delay. An orphan drug, succimer is currently approved for children with blood lead levels greater then 45 micrograms/dl. It has a great advantage over other chelating agents in that it can be given orally instead of intravenously and thus not require costly hospitalization. The Succimer trial recruited its 780 children between August 1994 and January 1997. Recruited children are receiving treatment with succimer or placebo and a vitamin-mineral supplement. TLC cleans all the children's houses to suppress lead dust. Three year follow up of the children's growth and development will be complete in December 1999.

Myelodysplastic syndrome is a rare but serious bone marrow disorder that often progresses to acute leukemia. NIEHS has investigated environmental and genetic factors for this condition. Known risk factors include prior chemotherapy, radiation, and exposure to solvents such as benzene. The NIEHS has been investigating the role of enzymes in the body that can detoxify harmful environmental substances and turn them into harmless compounds that can be excreted. The genes that regulate many of these enzymes have been identified and are known to differ between people. The gene for one such enzyme, GSTT1, was four times more likely to be missing in patients diagnosed with myelodysplastic syndrome than in healthy persons. This gene is missing in about 20 percent of the United States' population who may be more susceptible to environmental factors important in the development of this disease.

The NIEHS studies molecular mechanisms of pulmonary fibrosis in order to identify how environmental agents stimulate the growth of lung fibroblasts, the principal target cell in this disease. Pulmonary fibrosis is a problem in major urban areas where ambient industrial emission-source particles are thought to be related to an increased incidence of lung inflammation and asthma. There is also a continuing concern that indoor air pollutants, such as chrysotile asbestos, remain a threat to human health since these fibers are known to cause lung fibrosis. Recently, NIEHS researchers showed that respirable air pollution particles containing metals and endotoxin activate a growth factor receptor system which causes excessive lung fibroblast proliferation. Ongoing NIEHS research will address mechanisms by which inhaled particles disrupt growth factor signaling pathways. Understanding these how air pollution particles alter lung cell signaling pathways will allow us to develop a profile for pollutants that pose a threat to human health and will allow us to develop strategies for the intervention of pulmonary fibrosis.

Rare Disease-Related Program Activities

There are over 30 autoimmune diseases affecting 10 million Americans. These diseases are multifactorial being influenced by genetics, age, gender, reproductive status, hormones and environmental agents (cadmium, lithium, mercury, PCBs, TCDD, organ solvents, silica, and estrogenic pesticides). Low levels of TCDD or diethylstilbestrol during development lead to alterations in the immune system that may predispose it to the development of autoimmune disease. Recent advances in our understanding of genetics, endocrinology, endocrine disrupters, and the development and function of the immune system make this an ideal time to determine the role and interaction of genetic susceptibility and environmental exposures in the etiology of these diseases. It is especially important to define the role (site and mechanism) of exposure to environmental agents including endocrine disrupting agents during the development on the initiation of autoimmune disease later in life and the modulating effects of genetic background and gender.

The NIEHS will host a conference/workshop ("Linking Environmental Agents and Autoimmune Disease: Models and Mechanisms") that will bring together immunologists, developmental biologists, autoimmune specialist molecular biologist and toxicologists in order to define the state-of-the-art, data gaps and future directions/research needed to understand the mechanistic link and importance of environmental agents in the initiation and exacerbation of the various forms of autoimmune diseases.

The Institute will sponsor a workshop ("New Molecular Targets for Neuronal Injury") to integrate new methods and concepts from neurobiology into neurotoxicology. The field of neurotoxicology is recognized as a special area at NIEHS and NIH. As greater demands are placed on funding hypothesis-driven research, the field could benefit from a synergistic interaction with cutting edge research in neurobiology to enhance research progress.

Finally, NIEHS will also sponsor a workshop ("Strategies for Assessing the Implications of Malformed Frogs for Environmental Health") to appraise the environmental and potential public health significance of the increasing reports of malformed frogs in numerous states, across southern Canada, and in Japan, and to identify future actions or directions needed to respond appropriately to this issue. (These frogs may be serving as early environmental sentinels for environmental agents that could also cause adverse human reproductive outcomes.) This workshop represents NIEHS efforts in the emerging field of ecotoxicity, similar to the recently conducted workshop on marine toxins, which address a number of issues (such as Pfiesteria) of great concern to the general public.

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