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DEPARTMENT OF HEALTH AND HUMAN SERVICES

NATIONAL INSTITUTES OF HEALTH

NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

Fiscal Year 2005 Budget Request

April 2004

Kenneth Olden, Ph.D., Sc.D., L.H.D., Director
National Institute of Environmental Health Sciences

William Beldon - Acting Deputy Assistant Secretary for Budget, HHS

I am pleased to present the President's budget for the National Institute of Environmental Health Sciences (NIEHS). The fiscal year (FY) 2005 budget is $650,027,000, an increase of $18,964,000 over the comparable FY 2004 appropriation.

INTRODUCTION

Most complex diseases arise from the interplay between biology, environment and behavior. It is the NIEHS' mission to understand this interplay as it translates into increased disease risk. Thanks to the rare confluence of technology breakthroughs in analysis of genes and proteins and their recent application to the environmental health sciences, gene-environment interactions can now be investigated with more rigor and specificity. Our new opportunities within the framework of the NIH Roadmap also offer promise for a more rapid understanding and translation of this knowledge into improved public health. I will outline several of the NIEHS' most important efforts.

• GENES AND ENVIRONMENT

  There are two principal avenues for exploration of the complex interplay between genes and environment. One is to look at the variations of genes themselves, and the other is to examine how genes respond to environmental stressors. In the case of the first approach, NIEHS is conducting the Environmental Genome Project (EGP) an effort to resequence 544 "environmentally responsive" genes - genes which are thought to be involved in an individual's susceptibility to environmental exposures - and to identify alleles or genetic variants associated with these genes. The key objective of the EGP is to discover and characterize these alleles or genetic variants, called polymorphisms, and to define their roles in the pathways by which environmental agents exert their effects on human health and disease.

  Last April, the EGP completed the first phase, publishing a catalog of variation in over 200 genes responsible for detoxifying environmental compounds such as pesticides, as well as metabolizing natural biological components such as hormones. Over 17,000 single nucleotide polymorphisms (SNPs) were identified, with more than 1,000 in coding sequences. This information is already being used to make significant scientific discoveries. For example, it was found that people suffering from benzene-induced leukemia lack a certain SNP in the gene responsible for utilizing a vitamin B, folate, that healthy people have. Thus, the ability to metabolize folate might relate to the relative risk of developing leukemia among benzene workers.

  To aid in the functional characterization of SNPs in both coding and regulatory sequences of specific genes, NIEHS initiated the Mouse Genetic Variation Mapping Initiative. The mouse is the most widely used mammalian model system for the study of human health and disease for several reasons, including the fact that the genomes of mice and other mammals are highly conserved. Most human genes have counterparts in the mouse genome; thus, cloning of a gene in one species often leads to cloning of the corresponding gene in the other. The mouse also offers well developed toxicological and pathology databases and molecular genetic techniques for construction of gene knockout strains. Data generated using rodent models have been used widely in preparation of environmental regulatory policy and by the pharmaceutical industry.

  One of the greatest challenges for comparative toxicogenomics is the integration of the vast amount of genomic information being generated for a variety of model organisms. At present, there are several disparate but complementary databases on genomic sequences. Most of these databases provide data on gene and genome sequences for individual animal species. These databases do not provide a means to link the genome data to specific environmental chemicals or to toxicological and biological endpoints. They also do not enable researchers to compare information about potentially similar genes and biological responses across multiple species.

  Integrating the large number of disparate data sets is the goal of the Comparative Toxicogenomics Database (CTD). The CTD was developed through a collaboration of five NIEHS-funded Marine and Freshwater Biomedical Sciences Centers. The goal of the CTD is to develop a comparative database that links sequence information for genes that are relevant to toxicology to information about gene expression, toxicology and biological processes. The primary focus of the CTD is on marine and aquatic organisms as model systems for human diseases. The initial focus is also on genes that have been identified through the NIEHS' EGP as important for toxicology in these model systems. However, the database will eventually merge all gene sequence information generated on all vertebrates and invertebrates, including aquatic organisms, worms, flies, rodents, and people. The CTD provides information about gene curation and annotation (gene synonyms, sets and functions) and links between gene sequence and toxicity data published in the scientific literature. These aspects of the database represent an important advancement for comparative toxicogenomics. Understanding these mechanisms will allow more informed assessment of human risk by extrapolating toxicity data from animal models to people and will provide a mechanism by which members of the research community can share their data and promote fruitful avenues for future toxicological research.

  At present, the CTD is the only fully curated, publicly available database of its kind in the world. However, it serves as a prototype database and data resource for more comprehensive efforts ongoing at the NIEHS. The centerpiece for these discoveries is the NIEHS' National Center for Toxicogenomics (NCT), which uses a multidisciplinary approach to identify genes and proteins affected by specific environmental exposures. When a person is exposed to a chemical, physical, or biological agent, cells in the body may respond by switching on some genes and switching off others, potentially changing the proteins that are produced by the cells. The on/off pattern of various genes is different for each specific exposure, creating a characteristic pattern or "signature," which scientists hope will be useful in classifying chemicals by their effects on various cellular processes. By constructing and populating a database of chemical effects on biological systems, the NCT is assisting the field of environmental health research to evolve into an information science in which gene and protein expression datasets are compiled and made readily available to the scientific community. By building on the data infrastructure being developed through the CTD and other databases, NIEHS scientists are developing the sequence-driven and context-documents Chemical Effects in Biological Systems (CEBS) knowledge base. CEBS is planned as a public toxicogenomics knowledge base that combines and integrates scientific data from a multitude of public domain data sources. These data sources include studies of genetic polymorphisms, gene expression and proteomics, metabolism and toxicology. Once sufficient high quality data have been accumulated and assimilated, it will become possible to characterize an unknown environmental exposure by comparing its gene and/or protein expression profile to compendia of expression profiles in the database. Ultimately, the NCT will develop the capacity to use gene expression signatures and other data to facilitate characterization of toxicants and their biological effects. Through the predictive capabilities expected from toxicogenomics, adverse toxicity in clinical trials will be reduced and the efficiency of bringing new therapeutics to the public will be increased; adverse effects from long-term use or from combinations of therapeutic agents will be better understood and reduced. The final payoff for investing in CTD and CEBS will be more rational environmental health policy and an improved understanding of gene-environment contributions to the major causes of human death and disease.

• OBESITY AND ENVIRONMENT

  Environment and behavior intersect in fundamental ways, intersecting with our biology but also with each other. In no area of public health is this more apparent than with the problem of obesity. There is a growing body of literature that illustrates the negative physical and mental health effects of unregulated and poor urban, rural, and suburban development and planning. These studies have documented increased rates of obesity, diabetes, depression, anxiety, and heart disease in these poorly developed areas. For example, in sprawling communities, higher dependence on motor vehicles has resulted in polluting the atmosphere with ground-level ozone and particulate matter, contributing to human health problems such as lung and cardiovascular disease. People most affected by air pollution include older adults with pre-existing diseases; children, especially those with asthma; persons with inadequate health care; and even healthy individuals who work and exercise outdoors. Lack of safe sidewalks in growing urban areas has resulted in a reduction in the number of children walking or biking to schools. Today, only 10 percent of children walk or bicycle to school - a 40 percent reduction over the last 20 years (according to researchers in Urban Land). Research suggests that inadequate urban planning, such as a lack of bike paths and sidewalks, results in a more sedentary lifestyle of children, which, in turn, may be a factor in the growing rates of childhood obesity. All of these examples demonstrate how the physical or built environment influences choices that ultimately affect health.

  The NIEHS is designing a program as part of the trans-NIH obesity initiative which is designed to examine how the built environment affects obesity and the effectiveness of changes in community planning, design, and development in reducing the extent of obesity and associated comorbidities. These intervention research projects will develop tools to characterize and measure individual and population-level indicators of healthful communities - and of residents' lifestyles and behaviors - that prevent or reduce obesity. We hope that not only will studies of interaction between parameters of the built environment and individual lifestyle choices and behaviors help delineate factors that can prevent or reduce obesity, but also that this work will point the way towards new, cost-effective intervention strategies that promote healthful environments and behaviors.

  In a related initiative, NIEHS is partnering with the Robert Wood Johnson Foundation to support a program called Active Living by Design, which will provide support to 25 communities across the country to implement active living programs, policies, and communication strategies to improve community development and promote more healthy lifestyles. The NIEHS is providing an evaluation component to the program to determine the efficacy of various policies and promotions in reducing obesity.

  It is critical to delineate the role and impact of community design, planning, and development on individual and population health by understanding the contribution of urban/rural planning (i.e., land use decisions), housing structure, transportation issues, and the availability of public and green spaces as determinants of mental health, physical activity, nutrition, and access to healthy foods. In turn, modifying such parameters may reduce the prevalence of obesity in adults and children. This research effort will require integrated, interdisciplinary research teams, including biomedical scientists, behavioral scientists, social scientists, clinicians, epidemiologists, urban planners, developers, and architects, as well as active participation of community members. It is expected that such research will result in a greater understanding of the health benefits of living in communities that promote healthful environments and behaviors and may also impact policy for land use and public health.

• TOXICOLOGICAL EVALUATION OF NANOSCALE MATERIALS

  Nanoscale materials are a broadly defined set of substances where at least one critical dimension is less than 100 nm. Ultrafine particulate matter, e.g. the very smallest particles of soot from such sources as diesel exhaust, is a well-known example of ambient nanoparticles; however, this initiative will initially focus on manufactured nanomaterials of current or projected commercial importance. Nanoscale materials can in theory be engineered from nearly any chemical substance; semiconductor nanocrystals, organic dendrimers, and carbon fullerenes and carbon nanotubes are a few of the many examples. Nanoscale materials are already appearing in commerce as industrial and consumer products and as novel drug delivery formulations. Commercial applications and resultant opportunities for human exposure may differ substantially for nanoscale vs. "bulk" materials.

  Currently there is very little research focus on the toxicology of manufactured nanomaterials. Studies from the ultrafine particle inhalation toxicology literature hint at the complexity of the topic and suggest that nanoparticle size can impact toxicity equally if not more so than chemical composition. There are indications in the literature that manufactured nanomaterials may distribute in the body in unpredictable ways and that certain nanoparticles have been observed to preferentially accumulate in particular organelles. Surface properties can be changed by coating nanoparticles with different materials, but surface chemistry also is influenced by the size of the particle. This interaction of surface area and particle composition in eliciting biological responses adds an extra dimension of complexity in evaluating potential adverse events that may result from exposure to these materials.

  The National Toxicology Program (NTP) is developing a broad-based research program to address potential human health hazards associated with the manufacture and use of nanoscale materials. The intent of the NTP/NIEHS research program is to evaluate the toxicological properties of major nanomaterials classes which represent a cross-section of composition, size, surface coatings, and physico-chemical properties, and use these as model systems to investigate fundamental questions concerning if and how nanomaterials can interact with biological systems. Some of these fundamental questions include: What are the appropriate methods for detection and quantification of nanoscale particles in tissues? How are nanoparticles absorbed, distributed in the body and taken up by cells? Are there novel toxicological interactions?

  Discussion and review of efforts in this area has highlighted the need for studies of nanoscale materials that not only apply existing toxicology testing methodologies, but also explore the development of appropriate novel toxicological methods to adequately assess potential human health effects. The NIEHS is looking ahead to be able to supplement our critically inadequate knowledge of this rapidly emerging technology.

• NIH ROADMAP AND NIEHS

  The NIH Roadmap emphasizes a number of critically important improvements to the infrastructure of research in this country which will have a positive impact on the productivity of the NIEHS' research programs. Several of the overarching themes of the Roadmap have been previously identified and incorporated into research directions for the NIEHS, including most of the "New Pathways to Discovery" (structural biology, biological pathways and networks, molecular libraries, and bioinformatics) as well as the need for developing interdisciplinary and multidisciplinary team approaches to research (such as found in our Children's Centers for Environmental Health and Disease Prevention Research and our Consortium Centers programs for Parkinson's Disease and breast cancer).

  Both the scientific opportunities and the scale and complexity of environmental health research have changed dramatically over the past decade. Simplistic models and reductionist approaches to understanding of toxicity are giving way to more holistic or systems biological approaches that allow us to investigate multiple molecular events, pathways and interactive networks simultaneously. In part, this evolution in scale and complexity is the result of a voluminous literature, derived from epidemiological studies as well as human and animal experiments, which show that human health and disease are the result of complex interactions involving genetic, environmental, behavioral, and age-related factors often combined with random or stochastic events. Also, investments in the genomic sciences over the past 25 years have led to the development of new knowledge, resources and powerful technologies for use in probing biological events at the molecular level. But to untangle the complex interactions between genes, environment and behavior to prevent human illness, we will need even more powerful tools, new databases and resources, and more robust institutional infrastructures to translate the science into the practice of public health and medicine.

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