Justification Narrative

Authorizing Legislation: Section 301 of the Public Health Service Act, as amended.

Budget Authority:

This document provides justification for the Fiscal Year (FY) 2006 activities of the National Institute of Environmental Health Sciences (NIEHS), including HIV/AIDS activities. A more detailed description of the justification of NIH-wide FY 2006 AIDS activities can be found in the NIH section entitled "Office of AIDS Research (OAR)."

Introduction

Presently, 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 compliancy. 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 during the pursuit of the Human Genome Project offers great promise for elucidating mechanisms of gene-environment interactions involved in the development of complex diseases.

For years, the environment was considered to have a minor role in the etiology of human illness; this was, in part, because only radiation, synthetic chemicals and industrial by-products were included in the definition of the environment. But now that the definition of the environment has been expanded to include diet and nutrition, behavior and other social and cultural factors, the thinking is shifting in favor of gene-environment interactions. In fact, studies are now being reported that blow away the myth that "bad genes" are responsible for the majority of human morbidity and mortality. 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 can (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 and continuing through 2004, 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 generic information relevant to most chronic diseases, other research programs have been developed to address specific diseases such as breast cancer, Parkinson's Disease, and autism.

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Story of Discovery: Why Do People Differ In How They Respond To Drugs?

Physicians prescribe the same drug to different people with the same medical condition, but the success of a particular drug treatment for a disease differs dramatically in different individuals. Improvements are seen in many individuals, with perhaps some small side effects. However, in some individuals, uncomfortable and even life-threatening side effects occur. For other individuals, the therapeutic benefits are minimal or nonexistent. Doctors have struggled for years to balance the benefit of pharmaceuticals against the possibility of adverse effects in their patients and the unexplained non-response of some individuals to treatment with what should have been the appropriate drug. This challenge has been difficult because they have no way of predicting who will respond favorably to drug treatment or who will be exquisitely susceptible to undesirable side effects. Unfortunately, adverse drug reactions are a major source of death in the U.S. New information is emerging that may, in the future, give physicians a greater ability to predict drug effects and to tailor drug use to the individual patient, depending on his/her inherited ability to handle the drug. A major source of this information comes from years of investment in environmental health research.

Environmental compounds, such as pesticides and pharmaceuticals, use the same metabolic machinery that processes the substances in our diet. Specialized proteins (enzymes) break down, or metabolize, these compounds so that they can be eliminated from the body. The primary metabolic proteins are found in the liver and are known as cytochrome P-450s (CYP). This large class has numerous subgroups, or subfamilies, which have been extensively studied for the past four decades by environmental scientists. This rich body of information has matched specific P-450s with the individual environmental agents or pharmaceutical drugs they metabolize. More recently, with improved genetic tools, scientists have begun to delve into how the activity of a specific P-450 on a specific compound can vary among individuals. We now know that the genes coding for P-450s can have subtle genetic variations that translate into slight differences in otherwise identical proteins. These differences can make a P-450 that is more efficient, or less efficient, in breaking down its target compound or even cause a particular P-450 to be completely absent in certain individuals. In turn, these alterations in efficiency in P-450 activity are the basis for how some people respond well, and some poorly, to the same drug. Correlating P-450 variations with changes in ability to metabolize particular drugs will enable us to correctly identify which individuals are best suited to a particular drug therapy and to identify which patients need an alternative drug.

One CYP subfamily currently being studied by NIEHS supported scientists is the CYP2C subfamily. It is responsible for the metabolism of 20-30% of clinically used drugs and a number of pesticides and herbicides. NIEHS researchers discovered some of these CYP2C enzymes and later showed that all members of this subfamily are genetically variable. The distribution of these variations is different among ethnic groups, causing some to handle certain drugs poorly and thus be more susceptible to toxic and even life-threatening effects of drugs at doses that would be therapeutic in the general population. These scientists developed genetic tests for clinical use in people. In these tests, genetic variations in one enzyme, CYP2C9, were shown to affect the metabolism of important drugs including anti-diabetes drugs such as tolbutamide, drugs for epilepsy such as phenytoin, the anticoagulant warfarin used to prevent clotting, diuretics and hypertensive drugs, and numerous non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and celebrex.

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CYP2C19 is another clinically important enzyme discovered at NIEHS that metabolizes a wide variety of human drugs such as an important class of anti-ulcer drugs, proton pump inhibitors (the most commonly used is omeprazole or Prilosec). People can be divided into extensive metabolizers (EMs) or poor metabolizers (PMs) of drugs metabolized by CYP2C19. About 2 to 5% of Caucasian are poor metabolizers, as are 5% of African Americans, 13-23% of Asians, and 38-100% of some populations of Polynesia and Micronesia. This enzyme has been shown to have 9 to 12 inherited defective variants, all of which were discovered by NIEHS scientists. Recent studies show the genetic makeup of the individual markedly affects the cure rate for peptic and duodenal ulcers in patients treated with omeprazole and an antibiotic (and genotype could affect cure rates of numerous other proton pump inhibitors metabolized by CYP2C19) because of the marked differences in metabolism of this drug in different individuals.

A third enzyme, CYP2C8, metabolizes the anti-breast cancer drug, paclitaxel. Genetic variations in this enzyme have been shown to affect the metabolism of paclitaxel. As the role of subtle genetic variation in this drug metabolizing enzyme becomes better defined, simple blood tests could be devised to assay these variants. Physicians could then use this information to better select individuals who would benefit from this drug, thus helping reduce toxic side effects of chemotherapy while optimizing its cure rate for breast cancer.

Many people take two or more drugs, and administration of one drug can affect how fast the person metabolizes a second or third drug. We can also become tolerant to a drug after repeated dosage due to increased metabolism of the drug. NIEHS researchers have identified mechanisms that affect this process and some classes of drugs and herbal remedies which may make a second drug less efficacious when the patient takes more than one drug. Armed with this type of information, physicians could much better manage multi-drug therapies in their clients.

NIEHS scientists are continuing to improve their understanding of individual gene-drug interactions. They are also working toward bringing this information to a practical application. They are developing genetic tests for these polymorphisms that could be used in clinical trials. The ultimate goal is that genetic tests will be available in the future, in clinical settings to personalize drug treatment, to avoid unexpected and life-threatening toxicity due to genetic differences, and to provide the appropriate drug that will produce the best therapeutic benefit for each particular patient. Once a patient's genotype for a panel of P-450s is determined and available in his clinical record, his physician will be able to predict which drugs will be most effective in this patient, and which drugs would be likely to produce dangerous side effects and should thus be avoided.

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Science Advances

Protein Identified that Halts Progression of Alzheimer's Disease

Background: Alzheimer's disease progresses when a toxic protein, known as "beta-amyloid," attacks the brain's nerve cells involved in learning and memory. The beta-amyloid creates sticky plaques and tangles that gradually disable nerve cells, producing memory loss.

Advance: Scientists studied mice genetically engineered with defective genes taken from human patients with early-onset Alzheimer's disease. As expected, the defective genes produced mice with higher-than-normal levels of the toxic beta-amyloid protein. Surprisingly, these mice did not exhibit symptoms of Alzheimer's disease. Looking more closely, the researchers discovered that levels of a specific protein, transthyretin, had increased dramatically in the brains of these mice. When given antibodies that prevented transthyretin from reacting with beta-amyloid, the mice showed the expected brain cell death. Thus, it appeared that transthyretin was able to protect brain cells from toxic effects of beta-amyloid. To further verify this finding, test tube studies were done in cultured brain cells from the human cortex. These studies showed that pretreating these cells with transthyretin protein minimized brain cell death following exposure to toxic beta-amyloid.

Implications: Researchers have identified a protein in the brain that halts the progression of Alzheimer's disease in human brain tissue. The protein, known as transthyretin, protects brain cells from gradual deterioration by blocking another toxic protein that contributes to the disease process. This discovery provides a new avenue of exploration, where drugs could be developed that boost the brain's levels of transthyretin or methods could be developed for depositing it directly in the brain. It holds the promise of early pretreatment of people at high risk for Alzheimer's disease so they can prevent its development, as well as a possible means to treat people in early stages of the disease so that it doesn't progress and they preserve a higher level of cognitive function.

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New Tool to Study Gene Function

Background: RNA silencing is a recently discovered phenomenon that allows genes to be turned off through use of double-stranded RNA. This discovery is being used in laboratories around the world to study gene function and therapeutic applications are being investigated to treat diseases such as cancer, AIDS, hepatitis, Parkinsons disease, and macular degeneration. The short, double-stranded RNA species that direct this process of gene shut down are called small interfering RNAs or siRNAs. Plants have an RNA silencing system that acts as an "immune system" to protect against molecular parasites including RNA viruses. As a result, many plant viruses have adapted mechanisms to suppress gene silencing. One of these viruses (p19) has been shown to suppress RNA silencing by binding to siRNAs. Advance: Investigators determined the three-dimensional atomic structure of a specific viral protein and its siRNA. By using biochemical and plant assays, they showed that the p19 protein binds very tightly to siRNAs and selects for the siRNAs based on the length of the double-stranded RNA and apparently not the sequence of the RNA. Implications: By producing p19 protein, the virus can prevent the destruction of its RNA genome and protein-coding messenger RNAs by suppressing the plant's protective RNA silencing system. Furthermore, because p19 is not specific for viral siRNAs, it can be used as a tool to understand the mechanism of RNA silencing in other organisms, such as humans. A clear grasp of the process by which RNA silencing occurs will be important for its application in research and therapeutic efforts.

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Dietary Boron Might Help in Treatment or Prevention of Prostate Cancer

Background: Prostate-specific antigen (PSA) is a well-established marker of prostate cancer. The involvement of PSA in several early events leading to the development of malignant prostate tumors has made it a target for prevention and intervention. There are data that suggest an enzymatic regulatory role for dietary boron, which is an inhibitor of serine protease proteins such as PSA. This study asked the question "Could dietary supplementation with boron (as boric acid) inhibit PSA and reduce the development and proliferation of prostate carcinomas in mice?"

Advance: Investigators implanted human prostate cancer cells into mice and monitored development of resulting tumors both with, and without, boron supplementation. Supplementation was shown to be beneficial in two ways: (1) the size of tumors was decreased in mice exposed to the low and high dose of boron by 38% and 25%, respectively and (2) serum PSA levels decreased by 88.6% and 86.4%, respectively, as compared to the control group. In addition the boron-supplemented group appeared to have less active cell growth than did the non-supplemented group, indicating that these might be less aggressive tumors. Also, expression of a growth factor indicative of cancer risk was markedly reduced in the tumors of the boron-dosed group compared to controls.

Implication: Low-level boron supplementation reduced tumor size as well as improving several tumor characteristics. This promising model is being evaluated in further studies.

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Supplementing with Antioxidants can Help Asthmatic Children

Background: Asthma is a severe respiratory disease whose incidence appears to be increasing. There is some evidence that dietary supplements such as antioxidants can modify the severity of asthma, or even lower our risk of developing it.

Asthma arises from inflammation and constriction of the lung's airways. It is known that the environmental pollutant, ozone, can cause airway inflammation by placing an oxidative burden on lung tissue. Thus, antioxidants might provide a way to reduce ozone-induced asthma. An NIEHS scientist working with investigators at the Mexican National Institute of Public Health studied a group of asthmatic children in Mexico City, an area of high ozone exposure, and found that supplementation with antioxidant vitamins C and E did, in fact, counteract the decreased lung function arising from ozone. There was, however, substantial variability in the effect seen among different children. Thinking that genetic differences might account for some of this variability, the scientists decided to examine the study group by their genetic ability to produce glutathione S-transferase (GSTM1), one of the enzymes that play a major role in protecting cells against oxidative damage.

Advance: GSTM1-deficient children given antioxidant vitamins C and E showed the greatest protection against ozone-induced decreases in lung function. GSTM1-deficient children who were given a placebo (i.e., a tablet with no antioxidants) showed no such protection. Those children who had a fully functioning GSTM1 (i.e., GSTM1 positive) did not exhibit ozone-induced decreases in lung function, regardless of antioxidant status. These results help establish the critical role of GSTM1 in protecting the lungs against oxidative stress, as well as identifying a genetic subtype of children (those lacking GSTM1) that would benefit from antioxidant supplementation.

Implication: Asthmatic children with a GSTM1 genetic deficiency appear to be more susceptible to the deleterious effects of ozone and derive greater benefit from antioxidant supplementation.

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NIH Roadmap

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. This circumstance underscores the interest of NIEHS in the first round of Roadmap awards, especially the Interdisciplinary Research Planning Centers, which include a number of exciting projects that will greatly enhance NIEHS's work. One award, at Duke University, will fund investigators to use geographic/spatial methodologies to address combined genetic, social, and environmental factors on child health and development; particular endpoints of interest are autism, ADHD, asthma and obesity. Another project, at the University of North Carolina, is an effort to redefine computational genomics, including a significant emphasis on gene-environment interactions in alcoholism, atherosclerosis and breast cancer. The investigators on this project have strong ties to other significant NIEHS-funded efforts at the same institution: the Toxicogenomics Research Center and the Center for Environmental Health and Susceptibility. The latter Center is also affiliated with another interdisciplinary Roadmap grant focusing on "An interdisciplinary Strategy for Obesity."

An exciting supplemental Roadmap award will enable researchers at Johns Hopkins University to develop and apply statistical methods to incorporate social and behavioral variables into epidemiologic studies of environmental pollutants and health. The intent is to establish an integrated statistical approach for social and environmental epidemiology to characterize risk of a targeted environmental agent while taking other environmental variables into account. This research will provide evidence on health and environmental exposures and will contribute to the statistical methodology in the field of environmental epidemiology and to the foundation of policy decisions, as well as assist researchers in answering challenging questions posed by policy makers.

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Initiatives

Harnessing Genomic Tools for Environmental Medicine

Environmental Genome Project (EGP): 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. This variability often masks important environmental contributors to disease risk and is a major impediment in environmental medicine. 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 EGP in 1997 (Kaiser, 1997, Science, 278:569-570; Brown and Hartwell, 1998, Nat. Genet., 18:91-93) to catalogue these genetic variants (polymorphisms) and to identify the ones that play a role in human susceptibility to environmental agents. This information is being used in epidemiological studies to better pinpoint environmental contributors to disease. Some recent accomplishments include:

• 325 environmental response genes have been resequenced and entered into a public database. Of the greater than 43,000 single nucleotide polymorphisms (SNPs) identified in these genes, more than 2,185 were within the coding region. Only about 30% of the identified SNPs had been previously known. Thus, 70% of these discoveries represent new opportunities for identifying important genetic susceptibilities to adverse environmental effects.
• SNPs variants of the paraoxonase gene (PON1) were examined. This gene is associated with risk to cardiovascular disease, as well as regulating response to neurotoxic agents such as organophosphate pesticides and chemical warfare agents. Certain variants were identified that altered the effectiveness of PON1 in ways that could increase risk to cardiovascular disease and neurotoxic agents, as well as possibly influencing susceptibility to Gulf War Syndrome.
• Leukemia risk as it relates to SNPs variants identified in the Environmental Genome Project was examined. In one gene that prevents oxidative damage from quinones, individual SNPs were found that increased susceptibility to developing leukemia. Thus, in the 5-20% of the population carrying this variant, exposures to benzene, radiation, and chemotherapeutic agents would confer a greater risk of developing leukemia than in people not having this polymorphism.
• Several functional SNPs that affect enzymes involved in folate metabolism were identified by the Environmental Genome Project. These variants were found to reduce leukemia risk 2-fold to 3-fold in individuals with one copy and 3-fold to 10-fold in individuals with two copies of these variants.

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By the end of 2005, the current 525 candidate genes will be resequenced. NIEHS is currently taking nominations for genes to resequence in FY 2006 and beyond. It is expected that some of these genes will be ones implicated in diseases for which NIEHS has major programmatic interest. Such diseases include asthma, Parkinson's Disease, and other neurodegenerative diseases.

Additionally, as new SNPs models are put in a repository, the extramural community will be encouraged to use these models to explore gene-environment interactions and the functional significance of these genetic variants on human disease.

Comparative Mouse Genomics Centers Consortium: The EGP created the Comparative Mouse Genomics Centers Consortium (CMGCC) to develop transgenic and knockout mouse models based on human DNA sequence variants in environmentally responsive genes. These mouse models are tools to improve understanding of the biological significance of human DNA polymorphisms. At present, the CMGCC has developed 17 single nucleotide polymorphism (SNP) mouse strains available for use by the extramural scientific community. These models exhibit a variety of disease endpoints, including: Werner's Syndrome (aging disorder); diabetes; mammary cancer; gastrointestinal and bladder cancer; prostate cancer; and skin cancer. The Centers have also developed 22 "tools" mouse strains that can help assess important genetic events such as: frame shift indicators; LOH (loss of heterozygosity) indicators; transition indicators; deletion; prostate cancer; and conditional targeting. The available SNP and tools mouse strains may be obtained by directly contacting CMGCC Directors (http://www.niehs.nih.gov/cmgcc/centers.htm). The strains will also be available from the NCRR Mutant Mouse Regional Resource Centers (MMRC) and the NCI Mouse Models of Human Cancers Consortium (MMHCC) Mouse Repository in the near future (mid 2005). CMGCC investigators are currently constructing an additional 20 SNP mouse strains and 3 tools strains.

Genomic Effort to Improve Relevance of Toxicological Testing in Mice: Environmental scientists often use mice to study how environmental agents might be expected to affect people. Although mouse studies can, in a general sense, 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. An important step will be when the individual response genes in both mice and humans are identified and when individual differences (polymorphisms) in these genes are identified both among the different mouse strains and among people. The Environmental Genome Project is identifying the human part of this equation. The mouse component is now being addressed by the NIEHS. A contract has been awarded that will sequence the DNA of 15 mouse strains to pinpoint their genetic differences. DNA sequencing of the entire genome for each strain is expected to be completed by the end of 2006. This information will provide a basis for studies of why they differ in their susceptibility to certain diseases and toxic reactions to environmental agents. Susceptibility differences among various lines can be used to identify genes associated with complex diseases. The ultimate benefit will be to improve our ability to use these mice to study the molecular basis of human diseases such as obesity, cancer, hypertension, diabetes, psychiatric disorders, and aging.

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Disease Focused Environmental Medicine

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. In order to get the information quickly, this study recruits 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 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. A number of advocacy groups are working with the NIEHS on this project, including 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, NIEHS developed a multidisciplinary Collaborative Centers Program for Parkinson's Disease Environmental Research (CCPDER) in 2002. 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. A number of important accomplishments through CCPDER and other supported scientists have emerged this past year.

• Molecular Epidemiology of PD: Efforts to discover new PD susceptibility genes are underway. Based on preliminary data, this work has led to two U.S. and international patent applications and collaborations with pharmaceutical companies to develop disease modifying therapies directed to specific molecular targets. Once new susceptibility genes are discovered and validated, they will be used to define pathogenesis pathways and provide new targets for disease modifying therapies.
• PD Registry: There is no uniform tracking system for PD, a major hurdle in finding clues for environmental triggers of this disease. CCPDER researchers thought that California would be an ideal place to start a comprehensive registry on PD prevalence and distribution. Among California's assets were (1) its agricultural base (and, thus, exposure to agricultural chemicals that might play a role in PD), (2) demographic diversity, (3) population size, (4) experience with registries, and (5) experience in tracking other diseases. The NIEHS and the Michael J. Fox Foundation are cofunding the development of this registry with the State of California. This registry will help to identify the role of environmental factors in the development of PD.
• PD Mouse Model: Rodents have traditionally served the research community's need for inexpensive animals that can duplicate life-long exposure scenarios in a relatively brief period of time. For the purpose of studying gene-environment interactions, the mouse is a particularly attractive model. A number of mouse models are being created that have specific alterations in the genes suspected of playing a role in PD development. CCPDER scientists have constructed a mouse model using the herbicide, rotenone, that appears to reproduce a number of the hallmarks of human PD. Such models can be used to determine critical gene-environment trigger for PD development.
• PD Monkey Model: Although mice will be an inexpensive and easy model to use, primates remain the animals most relevant for simulating human responses. For some years the research community has been able to duplicate in monkeys the rigidity and loss of muscle control found in human PD by administering the synthetic chemical, MPTP. This model is limited, though, because it does not develop the characteristic brain lesions seen in human PD, called Lewy bodies. CCPDER scientists, in pilot tests, have found that chronic administration of rotenone to monkeys leads to structures in the brain that look like Lewy bodies. If this finding is validated in a larger sample, it will provide a more relevant model for testing therapeutic interventions, as well as gene-environment connections for PD.

Autism: Autism is a devastating behavioral disorder that appears in childhood and lasts a lifetime. Its prevalence might be increasing, although changing diagnostic standards and greater awareness make it difficult to interpret time trends. Genetic factors are suspected of playing a role in autism because it often runs in families. Genetic factors alone, though, are unlikely to provide a full account of autism etiologies. Past studies have shown that "in utero"exposure to an environmental agent, thalidomide, dramatically increases autism risk. As with most disease, autism most likely arises from underlying genetic susceptibilities interacting with specific environmental triggers at particular times of life (in this case, early periods of pre or postnatal development) that confer enhanced vulnerability. 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 and make clear that the very large increase in autism prevalence over the past ten years cannot be attributed to vaccination.

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It is possible, however, that only a subset of children are susceptible to mercury effects, perhaps when coupled with an immunological challenge. Because the genetic susceptibilities of autism and most other neurodevelopmental disorders are not yet known, current epidemiological studies are unable to identify small susceptible cohorts that might be particularly vulnerable to the effects of thimerosal. Preliminary animal studies have provided an intriguing clue 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 seen and morphological changes were observed in the brain. This study did not have sufficient power to be definitive, but it did provide clues that are worth exploring. Fortunately the NIEHS already had two Children's Environmental Health and Disease Prevention Research Centers devoted to autism. It has provided a supplement to one of these 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. This more extensive look at thimerosal-immune co-contributors to brain damage will provide better insight into gene-environment parameters of this disorder than previous studies have.

NIEHS has also undertaken a number of studies to help regulators determine if the extensive body of literature on the mercury form, methyl mercury, can be extrapolated to predict effects on the mercury form used in thimerosal, ethyl mercury. Prior to these studies there was a paucity of data on ethyl mercury distribution and toxicity in the body. Regulators were assuming the two compounds, both of which are organic, might act in a similar way, but had no data from which to work. NIEHS co-sponsored studies in infant monkeys given a vaccination schedule similar to that in humans. Blood levels and tissue distribution of mercury is being compared among monkeys given thimerosal (ethyl mercury) by intramuscular injection and those given oral methyl mercury. Similar experiments were conducted in the more common laboratory animal, the mouse. Both studies have been completed and the results indicate that ethylmercury from thimerosal (intramuscular injection) is excreted much more rapidly from blood and brain than methyl mercury (oral dosing).

NIEHS, through its Centers, is supporting other research relevant to autism. It is recruiting a cohort of 700 autistic children, in addition to control subjects, in California. This study will be examining possible environmental triggers for this disease, with results available after 2006. Animal models are also being developed that will enable researchers to assess social behavior in developing and mature animals. Such models could then be used to examine the effects of various toxicants, including thimerosal, on the development and performance of these behaviors. Another study is examining molecular and cellular mechanisms that might underlie some of the idiosyncratic responses within autistic children to chemicals they might have been exposed to during early stages of brain development. This project will use a variety of cellular and animal models to address immunotoxic and neurotoxic actions of environmental agents of interest.

Children's Health: Exposures that occur very early in life can have greater adverse effect than the same exposures incurred later in life. This unique life stage vulnerability has been a particular focus of NIEHS research. Centers for Children's Environmental Health and Disease Prevention Research were developed in 1998. These Centers recently conducted the first study in humans of the developmental impact of insecticides, as well as providing evidence of a positive health effect from a federal ban of two insecticides. This study measured the impact on fetal growth of two insecticides - chlorpyrifos and diazinon - whose use in households was banned by the federal government starting in 2000. In this study, researchers measured the levels of the two insecticides in blood drawn from the umbilical cords after delivery, both before and after the ban, and correlated those levels with the babies' birth weight and length. They found that prior to January 2001, newborns with combined insecticide exposures in the highest 26th percentile weighed almost half a pound less and were shorter than infants with no detectable pesticide levels. However, when they looked as the relationship between insecticide exposures and fetal growth after January 2001, the exposure levels had reduced substantially and the impact on weight and length was no longer apparent. The differences in fetal growth observed were comparable to differences between babies whose mothers smoke during pregnancy compared to those whose mothers do not. Because low birth weight is the leading cause of infant mortality in the U.S., this study demonstrates the potential power of reducing adverse environmental exposures as a way of improving human health.

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The Centers are only one part of NIEHS research in children's health. There is also an extensive intramural and extramural portfolio examining the environment's impact on this vulnerable stage of life. Among the recent findings are:

• New data suggest that pollutants from vehicle emissions and fossil fuels hinder lung development in children and limit breathing capacity for a lifetime. 1,756 school children in Southern California were studied from 4th grade through 12th grade and their "forced expiratory volume" (the volume of air that can be exhaled after taking a deep breath) was assessed regularly, as were the levels of air pollutants where they lived. Over the eight-year period, the children living in polluted communities were five times more likely to have clinically low lung function (less than 80% of expected breathing capacity) compared to children living in communities with cleaner air. This finding is significant because lungs grow to full capacity during the teenage years, stop growing around age 18, then lung capacity gradually declines at the rate of 1% per year.
• A program that targets allergens and tobacco smoke in the home was found to successfully reduce asthma symptoms in inner-city children.
• A large-scale cleft palate study found specific polymorphisms of a gene regulating folate metabolism that appeared to increase risk of cleft palate for children when their mothers took folate supplements during pregnancy.
• A new study suggested that eating more vegetables, fruit and protein before pregnancy lowered risk of having a child develop leukemia, the most common childhood cancer in this country.

Obesity: A major contributor to rising health costs is the growing problem of obesity. Currently 65% of the U.S. population is considered overweight or obese (National Center for Health Statistics. Health, United States, 2004). Excess weight is associated with an increased risk of Type 2 diabetes, heart disease, and several types of cancer. A group at Emory University analyzed health costs from 1987 - 2001 and found that medical bills for obese people constituted 27% of the growth in overall health care spending (Thorpe, et al. Health Affairs. Oct 20, 2004, W4:480-486). Indeed, treating obese patients was 37% more expensive than medical care for normal-weight patients. Environment plays a key role in promoting weight problems. The NIEHS has an Obesity and the Built Environment initiative that examines environmental components of obesity. It involves a five-year evaluation of communities across the U.S. that, through the Robert Wood Johnson Foundation' Active Living by Design Program, are developing new community design and communications strategies to improve physical activity. These improvements involve collaborations among city planning, transportation, crime prevention, traffic safety, land use, and other public entities. The NIEHS will examine the program's impact on physical activity, obesity, and other health indicators and compare these results against communities that have not improved their surroundings to encourage physical activity (Washington Post, Nov 8, 2004). The Institute is also encouraging research to evaluate the role of "in utero", neonatal, and prepubertal 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.

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Toxicology

Nanotechnology: Environmental medicine as practiced by NIEHS is as much about the exposures of the future as it is about exposures of the past. Initiatives to understand the potential adverse effects of technologies using newly generated nanoparticles illustrate this proactive approach. Nanoparticles (i.e., particles on the order of 1/1000th of the width of a hair) are an exciting area of research in biomedicine and other industries. Smaller than human cells, 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 negatively 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) is addressing this troublesome knowledge gap. It has initiated a program to evaluate the toxicological properties of major nanoscale materials classes 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?

Currently studies are looking at absorption of nanoparticles through skin. If they are found to be absorbed, then phototoxicity studies will be initiated in FY 2005 and FY 2006 to examine nanoparticles found in common sunscreens. General questions concerning absorption and fate once in the body of oral and inhaled nanoparticles are also being addressed. Findings from these initial studies will help focus further targeted toxicologic charactizations of effects on the immune and respiratory systems in FY 2006.

Metabolomics (study of small molecules): Newly gained knowledge and recent technological innovations have advanced the ability to observe effects of environmental exposures in human beings at the molecular level. These advances emerged in part from the mapping of the human genome and are enabling toxicology and biomedical science to achieve personalized assessments of environmental exposures and health risk. In this new sphere of metabolomics, key small molecules (metabolites) in the biochemical processes of the body are easily obtained from human subjects in urine, blood, saliva, or tissue samples and can be profiled to establish their normal molecular patterns in the healthy functioning individual, and to detect changes that denote modification and dysfunction of these molecules produced by exposure to environmental agents. These observations have the advantage of being made directly in the human population and in real-time continuity in living subjects, using samples obtained with minimally invasive procedures. As such technology produces data consistently and predictably from laboratory to laboratory - as such data is harmonized, as scientists say - these techniques may provide a rapid and cost-effective means of determining risk of environmental exposures and in developing means for intervention in, and prevention of, hazardous exposures.

Researchers refer to metabolomics as complementary to proteomics (study of proteins) and transcriptomics (study of RNA, or the transcribed products of genes) - which profile proteins and gene transcripts respectively in biological systems. Collectively, the three disciplines - metabolomics, proteomics and transcriptomics - provide the comprehensive view of exposure and health that is needed to decipher complex exposure-and-disease relationships and the interplay between genes and the environment in disease occurrence. NIEHS takes a leadership role in this revolution in biomedical science and public health and is a central player in the formation of a new international Metabolomics Society, with the mission of promoting development in this field through collaboration between academic, government and private sector researchers, and enhancing publication of research advances. NIEHS has disseminated a Request for Applications for research in metabolomics as a tool to advance environmental health and will make its first awards funding university investigators in early 2005.

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Other Areas of Interest

Trans-agency Collaborations

Environmental Monitoring Project with USGS:

The NIEHS and the U.S. Geological Survey (USGS) are developing an innovative approach to environmental monitoring that is more cost efficient and of greater local and national use than current methods. Mercury exposure was studied in the first pilot test of this technique using geo-spatial data and bioinformatics techniques overlaid with fish tissue sampling data of mercury exposure.

Mercury in consumable fish is a health hazard because the brain of an unborn child can sustain permanent damage if a pregnant woman eats mercury-contaminated fish. For this reason, mercury concentrations are regularly measured in fish samples taken from streams, ponds, and rivers across the country. This information, spanning several decades, is kept in databases maintained by the USGS, the EPA, and state agencies. The samples are of fish of varying sizes, a fact that interferes with using this data to accurately predict what levels would exist in larger, predatory fish, which are the ones most eaten by humans. In the pilot projects, NIEHS and USGS developed statistical tools that could account for differences in mercury concentrations due to different species, sizes, and sample types. This "normalizing" of the data provided the key that was needed to meaningfully extrapolate a wide variety of data into mercury levels as they would appear in relevant types of fish that are consumed. This information can now be used in developing fish consumption advisories. Furthermore, this normalized data allows scientists to use the USGS database to assess trends in fish-mercury concentrations in the Nation's waterways. It also dramatically lowers sampling costs because this model provides a way to use data from a single sample to estimate mercury concentrations in many different types of fish. This database and the maps it generates are publicly available through a Web site and can be used by environmental health scientists and health agencies across the country. One significant outcome is that the EPA, after reviewing the NIEHS/USGS model, has found it a powerful tool and expects to use it to help EPA achieve its goals of reducing mercury exposures nationwide, as well as to develop cost-benefit analysis of regulatory actions designed to reduce mercury emissions in air (which ultimately deposit in water).

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Oceans and Human Health with NSF:

The NIEHS and the National Science Foundation (NSF) created four joint Centers for Oceans and Human Health last year. These centers combine the strengths of NIEHS and NSF in biological and physical sciences to enhance federal research on how oceans affect human health. The centers will bring together experts in biomedical and oceanographic sciences for the first time to study the effects of harmful algal blooms, marine pathogens, and the oceans' vast potential for drug discovery. The combined expertise of the participants will accelerate the pace of scientific discovery, ranging from the development of new sensors for early warning systems to enhanced progress in finding novel compounds with pharmaceutical potential.

The NIH Neuroscience Blueprint:

Overview -- The Blueprint is a framework to enhance cooperation among fifteen NIH Institutes and Centers that support research on the nervous system. Over the past decade, driven by the science, the NIH neuroscience Institutes and Centers have increasingly joined forces through initiatives and working groups focused on specific disorders. The Blueprint builds on this foundation, making collaboration a day-to-day part of how the NIH does business in neuroscience. By pooling resources and expertise, the Blueprint can take advantage of economies of scale, confront challenges too large for any single Institute, and develop research tools and infrastructure that will serve the entire neuroscience community.

FY2005 -- For fiscal year 2005, the Blueprint participants are developing an initial set of initiatives focused on tools, resources, and training that can have a quick and substantial impact because each builds on existing programs. These initiatives, with the participation of all Blueprint Institutes, include an inventory of neuroscience tools funded by the NIH and other government agencies, enhancement of training in the neurobiology of disease for basic neuroscientists, and expansion of ongoing gene expression database efforts.

FY2006 -- Advances in the neurosciences and the emergence of powerful new technologies offer many opportunities for Blueprint activities that will enhance the effectiveness and efficiency of neuroscience research. Blueprint initiatives for fiscal year 2006 will include systematic development of genetically engineered mouse strains of critical importance to research on nervous system and its diseases and training in critical cross cutting areas such as neuroimaging and computational biology.

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Budget Policy

The Fiscal Year 2006 budget request for the NIEHS is $647,608,000, an increase of $3,103,000 and 0.5 percent over the FY 2005 Appropriation. Also included in the FY 2006 request, is NIEHS' support for the trans-NIH Roadmap initiatives, estimated at 0.89% of the FY 2006 budget request. This Roadmap funding is distributed through the mechanisms of support, consistent with the anticipated funding for the Roadmap initiatives. A full description of this trans-NIH program may be found in the NIH Overview.

A five year history of FTEs and Funding Levels for NIEHS are shown in the graphs on the following page. Note that the Fiscal Year 2003 and prior FTE figures are not comparable to the figures in the succeeding years due to NIH's consolidations.

NIH's highest priority is the funding of medical research through research project grants (RPGs). Support for RPGs allows NIH to sustain the scientific momentum of investigator-initiated research while pursuing new research opportunities. We estimate that the average cost of competing RPGs will be $330,000 in FY 2006. While no inflationary increases are provided for direct, recurring costs in non-competing RPGs, where NIEHS has committed to a programmatic increase in an award, such increases will be provided.

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Advancement in medical research is dependent on attracting, training, and retaining the best and the brightest individuals to pursue careers in biomedical and behavioral research. In the FY 2006 request, most stipend levels for individuals supported by the Ruth L. Kirschstein National Research Service Awards are maintained at the FY 2005 levels. To help prevent the potential attrition of our next generation of highly trained post-doctoral trainees, stipend levels for post-docs with 1-2 years of experience are increased by 4.0%. This will bring these stipends closer to the goal NIH established for post-doc stipends in March, 2000. In addition, individual post-doctoral fellows will receive an increase of $500 in their institutional allowance for rising health benefit costs. The need for increased health benefits is particularly acute for these post-doctoral trainees, who, because of their age and stage of life are more likely to have family responsibilities. The increase in stipends and health insurance are financed within the FY 2006 request by reducing the number of Full-Time Training Positions, because NIH believes that it is important to properly support and adequately compensate those who are participating in these training programs, so that the programs can continue to attract and retain the trainees most likely to pursue careers in biomedical, behavioral and clinical research. NIEHS will support 509 pre- and post doctoral trainees in full-time training positions.

The Fiscal Year 2006 request includes funding for 38 research centers, 118 other research grants, including 52 clinical career awards, and 106 R&D contracts. Intramural Research receives an increase of 1.6 percent and includes funds for supporting a laboratory for the newly appointed NIEHS director. Research Management and Support receives an increase of 0.5 percent. NIEHS is participating in the NIH Neuroscience Blueprint. The FY 2006 request includes $.2 million for a variety of Neuroscience Blueprint initiatives, including neuroscience cores, training initiatives, and the Neuromouse project. The mechanism distribution by dollars and percent change are displayed below and on the following page.

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