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cological effects of fiber type and size and so on. And this depends upon basic research.

PREPARED STATEMENT So, my message here is that we need the basic research that ties with the applied toxicological findings so that we can do a better job in terms of handling health-risk assessments.

I thank you and would be happy to answer any questions. (The statement follows:

STATEMENT OF DR. DAVID HOEL

The National Institute of Environmental Health Sciences (NIEHS) is unique among the research institutes of the National Institutes of Health because its focus centers on environmental health effects. Because these exposures occur throughout life, NIEHS research touches on all aspects of human development, from conception and birth throughout life.

The NIEHS is committed to developing the necessary scientific base the world community requires to deal effectively with environmental health problems. Through its efforts to seek the causes of environmentally related diseases and disorders, and to identify ways to prevent them, the Institute is the primary center for environmental health research in the world. Its long-term goals

to develop the extensive research base, advanced scientific methodology, and carefully trained manpower essential to understand, and ultimately prevent, adverse effects of exposure to environmental agents.

are

NIEHS suppor research and training programs conducted in universities and studies in private research laboratories throughout the U.S. This work is of the highest quality and productivity. Non-federal scientists supported by NIEHS make an unique contribution to the field of environmental health sciences but I would like to stress our intramural program and the current and planned efforts of NIEHS scientists.

Much of NIEHS's research involves study of fundamental biologic processes and how environmental agents interfere with these

processes at the cellular and molecular levels. Basic research seeks to understand the underlying mechanisms of environmental diseases and to develop effective interventions. Basic research is vital to public health officials in designing disease intervention strategies and in developing public policy. NIEHS research into the mechanisms of asbestos-caused illnesses illustrates these points.

Toxicological and epidemiological studies of asbestos-exposed populations have contributed to our understanding, yet more precise managements of risks from low-level exposures to predominantly short fibers require an understanding of the biological mechanisms involved. NIEHS scientists are conducting the basic research needed to understand the mechanisms of biological action of asbestos and to better define the significance of certain key parameters such as

fiber type,

fiber size and lung clearance mechanisms. We have shown that chrysotile asbestos particles inhaled into the lung attract lung "scavenger" cells, known as macrophages, to where the particles are lodged. These macrophages secrete proteins which appear to initiate a defensive fibrogenic response. An understanding of the basic mechanisms involved in asbestos-induced diseases will allow more precise and meaningful risk assessments and may even provide the basis for developing new approaches to disease intervention and prevention. Such assessments are vital for developing and implementing public health protection and disease prevention programs. Knowledge of the mechanisms of action for asbestos fibers also may allow meaningful risk assessments for other fibers such as fiber glass, mineral wool and ceramic fibers which are being developed and used in place of asbestos. NIEHS scientists and those supported by NIEHS are conducting this basic research.

Basic research at NIEHS serves another important function. It provides the foundation by which scientists can explain the relevance to humans of health effects found in long-term toxicological studies conducted

animals or identified in epidemiological studies. This information is vital to public

in

officials as they attempt to evaluate the possible impacts on human health from an environmental agent and compare that risk with the costs and effectiveness of regulations. Toxicological studies are of the utmost importance in the identification of adverse human health risks including cancer and reproduction. NIEHS is using the phenomenal increase

in scientific tools and techniques to understand the molecular basis of the results of toxicity studies. These tools greatly improve the ability to identify chemicals that may cause cancer developmental disorders in humans. In addition, NIEHS scientists are conducting research designed to determine the relevance of the findings of toxicologic studies in rodents (and in other non-human species) to actual environmental and occupational exposure conditions encountered by people. Highlights of NIEHS research in this area include:

or

Cancer is a multi-step process which is characterized at the cellular level by abnormal and

uncontrolled cell replication. Increasing evidence suggests that sets of cellular genes appear to be targets for genetic alterations that contribute to this uncontrolled growth. The development of many types of cancer requires changes in at least two classes of cellular genes: genes which can "turn on" normal cell growth and replication and genes that can "turn off" cell growth and replication. This is a complex interactive molecular system to regulate cellular growth and is not entirely understood; however, we do know that environmental agents are capable of interacting with these genes and, in the process, can initiate tumor formation.

At NIEHS, we examine the consequences of gene damage and the development of chemically induced rodent tumors.

NIEHS now routinely examines tumors arising from its long-term rodent studies. If the test chemical damages the same genes in the exposed animals as those observed in human tumors, then the chemical in question would appear to have the ability to alter genes which are involved in the development of human cancer. For example, a cancer gene, called K-ras, is found in 40% of a common type of human lung tumor. We have shown that some important environmental carcinogens (1,3-butediene and methylene chloride) involve the K-ras gene in the process of development of mouse lung tumors. This information together with data on human exposure to the chemical is pertinent for the design of regulatory policies aimed at reducing exposures to these common chemicals in both workers and the general public.

Most chemically induced tumors are thought to be initiated when the chemical interacts with DNA to interfere with normal cell growth and reproduction. However, NIEHS scientists and others have conducted toxicological studies in which tumors develop in the absence of any demonstrated interaction between the chemical and DNA.

It is important that NIEHS conduct the kinds of studies needed to explain how these "non-genotoxic chemicals" can induce tumors. NIEHS is studying a mechanism by which some chemicals appear to act in part by damaging normal tissue, for example, liver cells leading to increased cell proliferation to replace the damaged tissue. In theory, when this elevated rate of cell replacement together with chemical exposure is sustained over a long period of time, cancer may result. To date, only a few studies have been done the relationship of sustained cell proliferation at dose levels which also cause cancer. If this possible mechanism of action is proven to be a significant cause of cancer, the findings will have important public health implications in evaluation of the effects of levels of exposures common in the general population. If non-genotoxic chemicals cause cancer only in the

presence of tissue damage and the resulting increased production of new cells, these cancers may have different relevance at lower levels of exposure. NIEHS research will reduce much of the current uncertainty regarding the relationship between increased cell proliferation and the development of cancer.

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In addition to the important research in gene regulation and cell

proliferation and other studies of chemically induced carcinogenesis, NIEHS scientists are studying a range of other possible mechanisms by which environmental agents cause adverse effects in people. Investigations of infertility, conception, and birth defects are important from an environmental health viewpoint, since outcomes in these areas may provide the earliest and most sensitive indicators of

exposures

to hazardous environmental agents. Exposures to hazardous environmental agents such as lead, mercury, and some estrogenic substances, retinoids, vitamin A, and alcohol are known to produce serious congenital malformations. Environmental agents can also cause the fertilized egg to fail to implant in the uterus and to be lost or, if implantation occurs, may result in subsequent functional or structural defects in the child. Until very recently, much of the research in this field has been based on the gross observation of these events in humans or in laboratory animals. Recent advances in molecular biology now make it possible to study sensitive mechanisms of implantation, morphogenesis and growth in animals that, potentially, have great relevance for humans. For example, NIEHS scientists have identified some genes that are essential in the regulation of development in fruit flies and that may have counterparts that play similar roles in mammals, including humans. Molecular-based research into morphogenesis and growth could generate new knowledge of the mechanisms underlying many types of birth defects, and provide research benefits applicable to cancer, genetics, and gene therapy as well. Elucidation of the target genes in laboratory models associated with specific environmental insults could significantly improve the assessment of potential human risks from exposures to these same agents and might also have important therapeutic implications. NIEHS intends to initiate a greatly expanded effort in this area because of its tremendous potential for improving human reproductive health.

Molecular modelling is another new tool the NIEHS is beginning to exploit in environmental health research. We are excited about the possibility that theoretical chemistry can provide techniques that are useful in studying how biologic molecules such as DNA and proteins change their shape. This optimism is fueled by the development of basic theories and experimental data in chemistry and physics and by the development of high speed computers that have vast information storage capability. A major effort by NIEHS at present is to understand how the ras protein mentioned earlier is involved in causing cancer.

The normal cellular ras can be converted to the cancer-linked form by a single amino acid change. Computer derived comparisons between the normal and cancer-causing

reveal proteins differences that are probably related

to

the drastic differences in biochemical functions of the proteins and which, additionally, may help in the design of drugs which target the cancer-causing protein. From our experience with the studies of the ras proteins, we also plan to study proteins implicated in AIDS.

Over the past 20 years, NIEHS research has provided a major source of data used in State and Federal programs to set targets for improved air quality, and NIEHS-supported studies proved that reducing levels of criteria pollutants and air toxins does have a beneficial effect on public health. In the reauthorization of the Clean Air Act (CAA) in 1990, Congress emphasized the importance of NIEHS's research and authorized a specific role for the Institute in basic health-related

air

research. In addition, the authorization addresses the Institute's involvement in education and training of physicians in environmental health and mandates a study to determine the levels of exposure to mercury that may cause human toxicity. We have reviewed these specific research and training responsibilities to determine what additional efforts we can make within our current resources.

In summary, I wish to emphasize that the NIEHS continues to serve

the

Nation's principal focus for research in the environmental health sciences. Funds appropriated for the NIEHS support state-of-the-art epidemiologic and toxicologic studies that identify potential environmental hazards; the development

and application powerful new scientific methods for

in environmental epidemiology and toxicology; and a program of basic

as

of

use

biomedical research without which it is impossible to determine the actual contribution of environmental agents to the burden of human illness.

Mr. Chairman, the budget request for the National Institute of Environmental Health Sciences 18 $254, 484,000. I am pleased to answer your questions.

BIOGRAPHICAL SKETCH OF DR. DAVID HOEL

November 18, 1939,

Los Angeles, California

Education: A.B. University of California at Berkeley (Mathematics and Statistics with highest honors), 1961; Ph.D. University of North Carolina at Chapel Hill, 1966.

Professional History: 1966-67, Postdoctoral Traineeship in
Biostatistics, USPHS. 1967-68, Senior Mathematician, Westinghouse
Research Laboratories. 1968-70, Statistician, Oak Ridge National
Laboratory 1970-present, Adjunct Professor, Department of
Biostatistics, University of North Carolina. 1970-73, Mathematical
Statistician, National Institute of Environmental Health Sciences
(NIEHS). 1973-81, Chief, Biometry Branch, NIEHS. 1977-79, Acting
Scientific Director, NIEHS. 1979-80, Visiting Scientist,
Epidemiology Department, Radiation Effects Research Foundation,
Hiroshima, Japan. 1984-86, Director, Radiation Effects Research
Foundation, Hiroshima, Japan. 1981-present, Director, Division of
Biometry and Risk Assessment, NIEHS.
1990-present, Acting Director, NIEHS and National Toxicology
Program.
Professional Organization: American Statistical Association; Royal
Statistical Society; Biometric Society; International Statistical
Institute; Society for Risk Analysis; Collegium Ramazzini;
Institute of Medicine, NAS.

Honors, Awards: Associate Editor, Journal of Statistical Computation and Simulation, 1972-78. Associate Editor, Journal of the American Statistical Association, 1973-79. Editorial Board, Environmental Health Perspectives, 1973-present. Fellow, American Statistical Association, 1974. citation Classic, Institute for Scientific Information, 1975. Biometrics Section Representative, on the Council of the American Statistical Association, 1975-76. Editorial Board of the Journal of Toxicology and Environmental Health, 1975-79. NIH Director's Award, 1977. Mortimer Spiegelman Gold Medal Award, APHA, 1977. Program Chairman, Biometric Society Spring Meetings, Chapel Hill, 1977. Editorial Board of Communications in Statistics, 1977-79. Member, Scientific Advisory Board, National Center

for

Toxicological Research, 1977-80. Regional Committee of the Biometric Society (ENAR), 1973-75, 197880.

Representative, Institute of Mathematical Statistics to the Biology Section, AAAS, 1978-81. Editorial Advisory Board, Journal of Statistical Computation and Simulation, 1978-present. Secretary, Biometrics Section, American Statistical Association, 1979. Editorial Board, Journal of Environmental Pathology and Toxicology, 1979-80. Member, International Statistical Institute, 1980. PHS Superior Service Award, 1980. Editorial

Board, Fundamental and Applied Toxicology, 1981-86. Council of the Society for Risk Analysis, 1982-85. Editorial Board, IMA Journal of Mathematics Applied in Medicine and Biology. 1983-88. SES Award, 1983, 87, 88, 89. Section Editor, Journal of Environmental Pathology. Toxicology and Oncology, 1986-present. Member, Council of Fellows, Collegium Ramazzini, 1987. Editorial Board, Risk Analysis, 1987-90. Contributing Editor, American Journal of Industrial Medicine, 1987-present. Associate Editor, Environmental Research, 1987-present. Associate Editor, Journal

of Communications in Statistics, 1987-present. Member, Institute of Medicine, NAS, 1988. Associate Editor, Biological Monitoring: An International Journal, 1988-90.

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