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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 proteins reveal 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


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 of powerful

scientific methods for use in environmental epidemiology and toxicology; and a program of basic



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 is $254, 484,000. I am pleased to answer your questions.


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.


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.

CONSTRUCTION OF NEW BUILDING Senator HARKIN. Dr. Hoel, thank you very much.

For a number of years, the committee has been aware of your Institute's interest in constructing a new building to replace your north campus building in Research Triangle Park. I understand the lease on your existing building expires in May and that you are anticipating the costs of improvement for safety and air handling plus inflation will increase the rental costs by up to 50 percent at renewal time. So, this seems to make the option of building even more cost effective. Once again, however, there is no funding requested in the NIH buildings and facilities budget for construction costs of your building.

What would you expect the savings to be if we built a new building for the Institute as opposed to continuing rental expenses?

Dr. Hoel. I think if our rental costs did not go up-and, as I say, these are some old buildings that are

Senator HARKIN. If they do not go up.

Dr. HOEL. If they do not go up, I understand that it would be about a 13-year payback on that lease. We do not know how much they are going to go up. If they go up 50 percent, of course, that 13-year estimate would be considerably less. So, it would both be the advantage of bringing our scientists together, plus, I think, it would be economical from the government's standpoint to construct this facility.

Senator HARKIN. Dr. Raub, what kind of priority do you place on this building?

Dr. RAUB. As we look at it over the longer term, it is clear that there are the advantages that Dr. Hoel indicates with respect to that facility. For the immediate future, we have been wrestling with the enormous problems of infrastructure on the NIH campus in Bethesda, and we have given a higher priority to those issues only because it literally means keeping the enterprise going as opposed to achieving some further improvements or some longer term cost savings.

We have identified the NIEHS needs in our professional judgments budgets and will continue to do that.

Senator HARKIN. I understand there is supposed to be two modules. One is a lab and one is an office module?

Dr. HOEL. Yes; that's correct.

Senator HARKIN. Which of the two would be the higher priority for the Institute?

Dr. HOEL. Well, sir, it would be the laboratory.
Senator HARKIN. Could we just proceed with one?
Dr. HOEL. Yes.

Senator HARKIN. One last question I have, Dr. Hoel, is last year the committee provided you and your Institute with an increase of $1.5 million to begin research on additional chemical compounds. The committee asked that you give the highest priority to research on those chemicals encountered by farmers, their families, and agricultural workers. I had asked that question earlier in a different vein.

But tell the committee what is underway now with regard to research into the health effects of agricultural chemicals.

Dr. HOEL. I think the most important thing we have started, which we had not done in the past, is to form a group of experts to concentrate on a particular area. We are starting with agricultural chemicals to see which ones they believe to be of the greatest importance from a public health standpoint with regard to toxicological testing—what types of tests and so on. They can advise us as to what the priorities should be.

Then the second issue would be what are we doing in terms of the toxicity testing. It is a long process in terms of nomination and going through preliminary research and testing. In 1991, among our subchronic tests we are beginning 21, of which 3 are agricultural chemicals, and of the chronic tests, we are beginning, 13, of which 1 is agricultural. In 1992, of our subchronics, we will begin 14, of which 4 are agricultural, and of the chronics, 2 of the 12 are agricultural.

We have many competing issues here. For example, research on electromagnetic fields will begin. The retroviral vector that was mentioned relative to gene therapy will be tested. And so, there are quite a few other competing issues.

QUESTIONS SUBMITTED BY THE SUBCOMMITTEE Senator HARKIN. Thank you very much, Dr. Hoel. There will be some additional questions which will be submitted for your response in the record.

[The following questions were not asked at the hearing, but were submitted to the Institute for response subsequent to the hearing:)



Question. The Clean Air act Amendments which passed last October placed a number of requirements on your Institute to perform air pollution studies. More specifically, the studies are to identify the critical toxic elements in the air and the level at which they become health hazards. These additional responsibilities I understand would cost your Institute approximately $8 million.

Why is there no request for these funds?

Answer. When the Clean Air Act Amendments were signed into law on November 15, 1990, the process of preparation of the budget request for NIEHS for fiscal year 1992 was too far along to permit the major revisions and recalculations needed to justify additional funds to support a major expansion of research into the health effects of air toxics. However, our internal planning process tracked the progress of the Clean Air Act Amendments relating to health effects research over the summer of 1990 in anticipation of passage and enactment. We have completed a research plan which describes and sets priorities for additional studies authorized in the new law including biomedical, epidemiologic, and toxicologic studies intended to characterize the health risks of the air toxics cited in the 'reauthorization.


Question. Last year, the Committee raised a concern that your National Toxicology Program (NTP) has developed a number of non-animal methods, or tests, that could be used for examining the health effects of chemical compounds but funding has been too short to validate these tests, In fact, the budget of the portion of the National Toxicology Program which validates nonanimal tests dropped from $5.7 million in 1984 to $2.8 million in 1990.

I see you are requesting $3.9 million for this program in 1992.

What can you tell the Committee about your efforts to validate these non-animal tests?

Answer. Since NTP's establishment, it has given high priority to development and validation of toxicologic assay methods which may reduce the use of whole animals and/or provide other non-animal models in toxicologic studies. One of our major efforts has been in the extensive validation of short-term mutagenicity studies. We have learned that a small battery of assays, including the bacterial Salmonella assay, identifies mutagenic activity and that a positive in-vitro mutagenicity result is a clear signal that a chemical is likely to be carcinogenic in animals. A negative mutagenicity result, however, is unclear regarding carcinogenicity. The demonstration that the existing short-term methods were severely limited for identifying carcinogens dictated that we explore methods that reduce our dependence on animals. New efforts will be directed to specific projects thať utilize computer-assisted chemical analysis and the latest methods of gene manipulation to develop non-animal models.

Question. To what extent will the validation of these tests help reduce the use of animals in your research?

Answer. One effort to reduce the use of animals in research is in the area of computer-assisted chemical analysis of the diverse chemical classes that have been assayed for cancer and other toxic endpoints. If such information proves diagnostic, it could be used to reduce the necessity to test additional chemicals within a given class, thereby reducing numbers of animal studies needed. Another major effort enables researchers to transfer and direct the expression of genes into cells. As knowledge of molecular aspects of cancer improves, it becomes increasingly possible to introduce and activate metabolically important genes in cultured cells so that individual cells can assume many of the functions found in intact tissues in animals.

Among the

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