DEPARTMENT OF HEALTH AND HUMAN SERVICES

NATIONAL INSTITUTES OF HEALTH

Fiscal Year 2006 Budget Request

Witness appearing before the

House Subcommittee on Labor-HHS-Education Appropriations

Kenneth Olden, Ph.D., Sc.D., L.H.D., Director

National Institute of Environmental Health Sciences

March 9, 2005

William Beldon, Deputy Assistant Secretary, Budget

Number range CHAPTERMr. Chairman and Members of the Committee:

I am pleased to present the Fiscal Year (FY) 2006 President's budget
request for the National Institute of Environmental Health Sciences
(NIEHS). The FY 2006 budget includes \$647,608,000, an increase of
\$3,103,000 over the FY 2005 enacted level of \$644,505,000 comparable
for transfers proposed in the President's request.

INTRODUCTION

*"Genetics loads the gun, but environment pulls the trigger."*

Judith Stern, University of California, Davis

The Nation needs better information to promulgate evidence-based
environmental health regulatory policies and to prevent or cure most
chronic diseases. This paucity of information has an enormous impact on
the world's economy, both in terms of costs associated with health care
and with regulatory compliance. In large measure, this situation exists
because we still do not understand what role the environment plays in
human health and disease. The application of knowledge and technologies
developed through the pursuit of the Human Genome Project offers great
promise for elucidating mechanisms of gene-environment interactions in
the development of complex diseases.

For years, the environment was considered to have a minor role in the
etiology of human illness. But, in recent years, the thinking has
shifted in favor of gene-environment interactions. For example, recent
studies show that no more than one-third of the cancer burden can be
attributed to the action of genes alone (Verkasala, et al., 1999, *Int.
J. Cancer* 83:743-749; Lichlenstein, et al., 2000, *NEJM* 343:78-85),
only 15% of Parkinson's Disease (Tanner et al., 1999, *JAMA*,
281:341-346), and about a third of autoimmune diseases (Powell, et al.,
1999, *Env. Health Pers.* 107 (Suppl. 5), 667-672). A more recent study
reported that 90% of individuals with severe heart disease have at least
one or more of four classic risk factors captured in the current
definition of the environment (Khat et al., 2003, *JAMA* 290:899-904).
Because of these and other findings, it is now generally accepted that
more informative, cost-effective, high-throughput methods for assessing
and predicting risk resulting from environmental exposures will need to
be developed. Otherwise, we will not be able to prevent or cure most
chronic diseases, and the costs associated with health care and
environmental regulatory compliancy will continue to escalate.

Starting in 1997, NIEHS developed several new research initiatives to
respond to this urgent need. Such programs include: the Environmental
Genome Project (Kaiser, 1997, *Science* 278:569-570; Brown and Hartwell,
1998, *Nat. Genet*. 18:91-93), the National Center for Toxicogenomics
(Kaiser, 2003, *Science* 300:563), and the Mouse Sequencing Project
(*Nature* 432: 5, 2004). While the results from these three initiatives
will provide information relevant to most chronic diseases, other
research programs have been developed to address specific diseases such
as breast cancer, Parkinson Disease, and autism. Today, I will briefly
describe several of these initiatives and their implications for human
health and disease.

GENETIC DIFFERENCES IN SUSCEPTIBILITY TO DRUGS AND ENVIRONMENT

Individuals vary, often significantly, in their response to
environmental agents. This variability provides a high "background
noise" when scientists examine human populations to identify
environmental links to disease, often masking important environmental
contributors to disease risk. Fortunately, the Human Genome Project
created tools that can help identify the genetic variations in
environmental response genes that can lead to such wide differences in
disease susceptibility. NIEHS developed the Environmental Genome Project
(EGP) to catalogue these genetic variants (polymorphisms) and to
identify the ones that play a role in human susceptibility to
environmental agents. This information is already being used in
epidemiological studies to better pinpoint environmental contributors to
disease. Also, several important variants have been discovered that are
associated with risk for chronic illnesses such as leukemia,
cardiovascular disease, and neuronal dysfunction.

ANIMAL MODELS PREDISPOSED TO ENVIRONMENTAL RISK

The usefulness of the susceptibility data generated in the EGP is
enhanced by the availability of animal models with the exact sequence
variations discovered by resequencing of the human environmental
response genes. Therefore, NIEHS developed a university-based Mouse
Genomics Centers Consortium to create mice with such variations and
provide them to the scientific community. To date, approximately 20
well-characterized mouse models have been developed. These models
represent a variety of disease endpoints, including: Werner's syndrome
(aging disorder), diabetes, mammary cancer, gastrointestinal and bladder
cancer, prostate cancer, and skin cancer.

EFFORT TO IMPROVE RELEVANCE OF ANIMAL MODELS

Environmental health scientists often use mice to predict how
environmental agents might affect people. Although mouse studies can
indicate the potential of an exposure to cause cancer and other
diseases, there is no way to precisely extrapolate these study results
to the risk in humans. Information on the similarities and differences
in homologous genes between human and mouse is important to improve
accuracy in predicting human risk. While laboratory mice might look
alike, the 100 different strains used in medical research differ
significantly in their behavior, physiology and susceptibility to drugs
and environmental agents (e.g., carcinogens), and scientists are eager
to discover the differences in the genetic sequences that underlie these
traits, with the goal of finding counterparts in humans. NIEHS initiated
a mouse sequencing project to decipher the genomes of the 15 mouse
strains used most frequently in research to predict human risk. Such
data will improve environmental risk assessment decisions and will help
researchers in choosing the most appropriate strain for studying
toxicity.

SISTER STUDY OF BREAST CANCER

A unique study exploring gene-environment interactions in breast cancer
development has begun nationwide recruitment. It will look at how genes,
activities of daily life, and environmental exposures affect breast
cancer risk. To get the information quickly, this study is recruiting
50,000 symptom-free women who have a sister that had breast cancer.
These women are at increased risk of breast cancer, share many genes
with their affected sibling, and would have experienced many of the same
exposures. For these reasons, it is expected that a sufficient number of
women will develop breast cancer within 10 years and their genes and
exposures can be compared with those of women in the study who did not
develop the cancer. A broad range of exposures will be examined,
including personal care and household products, workplace exposures, and
dietary factors, along with genetic analysis. The principal investigator
has the active support of the American Cancer Society, Sisters Network,
Inc., the Susan G. Komen Breast Cancer Foundation, and the Y-ME Breast
Cancer Organization.

PARKINSON'S DISEASE

A major impediment in Parkinson's Disease (PD) research has been the
lack of rapid communication between epidemiologists, laboratory
researchers, and clinicians which prevents the type of multidisciplinary
approach this field needs. To encourage advances in this important area
of study, Number range CHAPTERNIEHS developed a multidisciplinary
Collaborative Centers Program for Parkinson's Disease Environmental
Research. This multi-institutional approach is designed to accelerate
the identification of genetic and environmental factors leading to PD.
Collectively, the three centers have expertise in basic neurosciences,
human genetics, clinical research, and epidemiology, as well as
long-standing interactions with patient groups. Accomplishments to date
include: efforts to discover new PD susceptibility genes; development of
a registry in California to track the disease; development of mouse
models with specific alterations in genes suspected of playing a role in
PD, and efforts to develop a primate model of PD that exhibits the most
prominent clinical features of the disease.

AUTISM

Autism is a devastating behavioral disorder that most likely arises from
underlying genetic susceptibilities interacting with specific
environmental exposures during pre- or postnatal development. A number
of people have suspected that the mercury-containing compound
thimerosal, used to preserve childhood vaccines, could be an
environmental trigger for autism development, based on the established
neurotoxicity of higher doses of mercury. Extensive epidemiological
studies, however, have failed to provide any association between
vaccines and autism. It is possible, however, that only a subset of
children are susceptible to mercury effects, perhaps when coupled with
an immunological challenge. Preliminary animal studies have provided an
intriguing clue to possible susceptibilities that NIEHS is now pursuing.
In these studies, different mouse strains were exposed to thimerosal at
ages and doses that corresponded to the standard protocol for childhood
vaccinations. Only the immunologically deficient strain of mouse
exhibited a response. In these mice, behavioral effects were reported
and morphological changes were observed in the brain. However, this
study did not have sufficient power to be definitive. Fortunately, the
NIEHS already had two Children's Environmental Health and Disease
Prevention Research Centers devoted to autism. Thus, the Institute
provided a supplement to one of these Centers to do more extensive
testing of thimerosal in autoimmune-prone (SJL) mice. This Center has
expertise in evaluating critical social behaviors, as well as the
ability to conduct state-of-the-art stereology to measure brain effects
such as volume changes and changes in cell number occur. This more
extensive look at thimerosal-immune co-contributors to brain damage may
provide better insight into this disorder than previous studies have. In
addition, the same Center is recruiting a cohort of 700 autistic
children, and appropriate control subjects, to further examine the role
of gene-environment interactions in the etiology of autism.

OBESITY AND THE BUILT ENVIRONMENT

Obesity is a major contributor to human disease and rising health care
costs. NIEHS is collaborating with the Robert Wood Johnson Foundation to
examine how community design influences physical activity. This
so-called Active Living Design Program is working with local governments
to influence city planning and land use decisions. The program's impact
on physical activity, obesity, and other health indicators will be
assessed. The Institute is also encouraging research to evaluate the
role of "in utero," neonatal, and pre-puberty exposures to environmental
estrogens and other compounds in the onset and development of obesity,
as well as examining gene-environment interactions that favor weight
gain.

NANOTECHNOLOGY

Nanotechnology is an exciting area of research with broad implications
for multiple industries, including medicine and communication. For
example, nanoscale devices have the potential to deliver therapeutic and
imaging agents to specific cells and tissues in ways not presently
possible. However, when bulk material is converted to ultrafine
nanoparticles, its physical, chemical, and biological properties can be
altered in ways that might adversely affect health. So, while many
laboratories are focused on exploiting the rich potential of these
agents, there is little activity to assess their toxicological
properties. NIEHS, under the auspices of the National Toxicology Program
(NTP), has initiated a program to evaluate the toxicological properties
of the major classes of nanoscale materials and will investigate
fundamental questions such as: How are nanoscale materials absorbed,
distributed in the body, and taken up by cells? Are there novel
toxicological interactions? What are the appropriate detection and
quantification methods for nanoscale particles?

NIH ROADMAP AND ENVIRONMENTAL HEALTH RESEARCH

The ability to investigate and understand issues in environmental health
requires collaboration between many scientific disciplines:
epidemiology, toxicology, molecular biology, clinical sciences, and many
others. Thus, Roadmap initiatives such as the Interdisciplinary Research
Planning Centers will greatly enhance NIEHS' work. Examples include: the
use of geographic/spatial methodologies to address combined genetic,
social, and environmental factors on child health and development, and
an effort to redefine computational genomics with emphasis on
gene-environment interactions in alcoholism, atherosclerosis and breast
cancer. Both projects have strong ties to other significant NIEHS-funded
programs at the same institutions.

Thank you for the opportunity to comment on the important work supported
by the NIEHS. I will be happy to answer any questions you might have.

DEPARTMENT OF HEALTH AND HUMAN SERVICES

NATIONAL INSTITUTES OF HEALTH

BIOGRAPHICAL SKETCH

**NAME** Kenneth Olden, Ph.D., Sc.D., L.H.D.

**POSITION** Director, National Institute of Environmental Health
Sciences

(NIEHS) and Director, National Toxicology Program (NTP)

**BIRTHPLACE** Parrottsville, Tennessee

**DATE OF BIRTH** July 22, 1938

**EDUCATION** B.S., Knoxville College, 1960; M.S., University of
Michigan,

1964; Ph.D., Temple University, 1970 (research done in

absentia at the University of Rochester).

**EXPERIENCE**

1991-April 2005 Director, NIEHS and NTP

1985-1991 Director of the Howard University Cancer Center and

Professor and Chairman of the Department of Oncology,

Howard University Medical School

1984-1985 Associate Director for Basic Research and Deputy Director,

Howard University Cancer Center, and Professor of Oncology,

Howard University Medical School

1982-1984 Associate Director for Research and Deputy Director,\
Howard University Cancer Center, and Associate Professor of

Oncology, Howard University Medical School

1979-1982 Associate Director for Research, Howard University Cancer

Center, and Associate Professor of Oncology,\
Howard University Medical School

1978-1979 Research Biologist, Division of Cancer Biology and Diagnosis,\
National Cancer Institute

1977-1978 Expert (Biochemistry) Division of Cancer Biology and
Diagnosis, National Cancer Institute

1974-1977 Senior Staff Fellow, Division of Cancer Biology and
Diagnosis,\
National Cancer Institute

1970-1974 Research Fellow and Instructor of Physiology,\
Harvard University Medical School

1964-1965 Research Assistant, Department of Biological Chemistry,\
Columbia University

**PROFESSIONAL ORGANIZATIONS** (Active and Inactive)

> American Society for Cell Biology; American Society of Biological
> Chemistry;

American Association of Cancer Research; Society for Biological Response

> Modifiers; Metastasis Research Society, International Society for the
> Study of Comparative Oncology, Inc., Sigma XI, Society of Toxicology,
> North Carolina Institute of Medicine.

**HONORS AND AWARDS**

> Elected to membership in the Institute of Medicine of the National
> Academy of Sciences in 1994. American College of Toxicology=s First
> Distinguished Service Award, 1995. HHS Secretary=s Distinguished
> Service Award, 1995. Presidential Meritorious Executive Rank Award and
> City of Medicine Award, 1996. Presidential Distinguished Executive
> Rank Award, 1997. NIH Quality of Work Life Award, 1997 and 1998. The
> Academy of Toxicological Sciences Fellow, 2000. Honoree at Jubilation
> Concert 2000, by Children=s Health Environmental Coalition for
> Leadership Role in Children=s Environmental Health Research. The
> American Public Health Association Calver Award, 2002. Cincinnati
> Children=s Environmental Health Award, 2002. Honorary Doctorate of
> Science Degree -University of Rochester and Honorary Doctorate of
> Humane Letters Degree - College of Charleston, 2003. Honorary
> Doctorate of Science Degree - University of Medicine & Dentistry of
> New Jersey, 2004. Lifetime Mentoring Award - University of Pittsburgh,
> 2004. 2004 Senator Frank R. Lautenberg Annual Award - University of
> Medicine & Dentistry of New Jersey, 2004. Public Communications
> Award - Society of Toxicology, 2004.

Department of Health and Human Services

Office of Budget

William R. Beldon

Mr. Beldon is currently serving as Deputy Assistant Secretary, Budget in
the Department of Health and Human Services. He has been a Division
Director in the Budget Office for sixteen years, most recently as
Director of the Division of Discretionary Programs. Mr. Beldon started
in federal service as an auditor in the Health, Education and Welfare
Financial Management Intern program. Over the course of more than 30
years in the Budget Office, Mr. Beldon has held Program Analyst, Branch
Chief and Division Director positions. Mr. Beldon received a Bachelor's
Degree in History and Political Science from Marshall University and
attended the University of Pittsburgh where he studied Public
Administration. He resides in Fort Washington, Maryland.