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(AFTERNOON SESSION, 1:43 P.M., THURSDAY, MARCH 14, 1991) The subcommittee met at 1:43 p.m., in room SD-192, Dirksen Senate Office Building, Hon. Tom Harkin (chairman) presiding.

Present: Senators Harkin, Hatfield, and Specter.






Senator HARKIN. Thank you very much. The subcommittee will resume its sitting.

Dr. Hoel, I want to welcome you before the committee in your first appearance representing the National Institute of Environmental Health Sciences.

We have your budget that totals $254.4 million, which is about 5.6 percent more than last year.

I know the Institute has been interested for a number of years in getting underway on the construction of a new building in Research Triangle Park, NC, where the Institute is located. We will have a chance to talk about that and other issues.

At this time, I would be pleased if you would proceed with any opening statement that you care to make.

Dr. HOEL. Thank you very much, Mr. Chairman. It is, indeed, a pleasure to be here.

Before beginning, I would like to acknowledge Dr. David Rall, who retired last fall after 20 years as the director of NIEHS. During his tenure, he built both the Institute and the National Toxicology Program for which everyone in the environmental health area is indeed indebted.


This afternoon I would like to briefly describe two areas of the many things that NIEHS is involved in, and the first is—and it has already been mentioned—the problems with metal toxicity. I believe that NIEHS has been a leader in the research on metal toxicity and understanding the human health aspects of these toxicants.

In particular, we are thinking these days about lead, mercury, and manganese. There are programs now with regard to lead abatement that a number of the areas of the government are involved with. Our research is continuing with Dr. Needleman of the University of Pittsburgh who is looking at the possible apparent permanent effects of low-level lead exposure on intellectual and psychobehavioral functions.

Also, clinical studies are being carried out to find better drugs to treat lead poisoned children. We are also quite interested, through the contracts mechanism, in the lead transfer from the mother to the fetus, whether this is from bone or diet or just what. We are developing that work.

We finished a major conference on the health effects of lead and, in fact, I have the new publication in Environmental Health Per spectives that came out last November.

In the area of mercury, Dr. Löe has already mentioned the dental amalgams issue aired on the “60 Minutes" TV program. We have begun through one of our research centers-Tom Clarkson at Rochester—a very interesting epidemiological study in the Seychelles Islands where individuals there are exposed to low-level mercury through consumption of fish. We hope to develop a better understanding of the low end of the dose response curve with regard to human exposures.

In the area of manganese, we had a conference earlier this week. This is quite important to the EPA because it is being proposed that manganese be used as a gasoline octane booster in this country. We have to discover what are possible information gaps on health effects. We do not want to create another situation as we had with lead.

So, I think in this area we need both the epidemiological clinical work, exposure understandings, and, in particular, basic work in mechanism so that we concentrate the effects of neurobiology and fetal exposure.



INTERPRETATION OF TOXICOLOGICAL TEST DATA The second area of interest is in interpretation of toxicological test data. Through the National Toxicology Program, NIEHS is involved with generating this for the Federal Government. And what we want to do is to improve the methods for estimating the lowdose effects to man based on the findings in high-dose toxicological studies. And here we are concentrating on generating supplemental information on oncogene activation, pharmacokinetics, receptor binding, cell proliferation, and so forth. The regulatory agencies will be able to incorporate this data with our toxicological findings so that they could do a better job in terms of estimating human health risk from these studies.

We are also quite interested in research in biomarkers for measuring both environmental exposures and molecular effects in people. We see also an important future research area in terms of genetic susceptibility to toxicants.

In these areas, a couple of examples would be the issue of dioxin and the effects at low levels and the idea that it is a receptor mediated effect and what effect this might have with regard to risk assessments in setting low-dose levels. I think we will see some of this during this year. There is quite a concentrated research effort here.

And also with asbestos and the controversies about abatement of asbestos in buildings. Here the argument is concerning the toxi

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:]


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.


NIEHS supports 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

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



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 in animals or identified in epidemiological studies. This information is vital to public may result. To date, only a few studies have been

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


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 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:





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 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


in tne exposed animals as those observed in human


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

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

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 long period of time,


on 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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