Table of Contents
1.0 Introduction
2.0 Focus Area: Improved Methods
2.1 Human Health and Ecological Effects Screening and Testing Methods
2.1.1 Toxicity test methods, emphasizing development
2.1.2 Integration and implications of new and emerging approaches in health effects research
2.1.3 Methods for detecting effects of wildlife
2.2 Human Exposure Methods
2.3 Interspecies, Intraspecies, and Target Organ Determinants of Dose Response
2.3.1 Prediction of target tissue dose
2.3.2 Understanding elements involved in health responses (toxicodynamics)
2.3.3 Health hazard assessment methodologies
3.0 Focus Area: Susceptible Populations
4.0 Focus Area: Chemicals in the Environment
5.0 Continuing Targeted Projects
1.0 INTRODUCTION
The ultimate goal of the American Chemistry Council's (ACC) Long-Range Research Initiative (LRI) is to increase knowledge of the potential impacts that chemicals may have on the health of human and wildlife populations and the environment. Achieving this goal requires that the LRI improve the scientific foundation of the risk equation (i.e., hazard times exposure equals risk). The members of ACC have committed to sponsor independent third-party research that will provide valuable assistance to government in making risk assessment judgments about the health and environmental impacts of chemicals, and, more certainty regarding those impacts for the public and manufacturers of those chemicals.
This goal is far too broad for any one organization to tackle alone, so the LRI seeks programs that are complementary to or collaborative with those of others (especially the National Institute of Environmental Health Sciences, NIEHS; the U.S. Environmental Protection Agency, EPA; and the International Council of Chemical Associations, ICCA). The LRI Research Strategy provides a five-year horizon of research needs and priorities, serving as a blueprint for the program. This 2005 program description is organized according to the three Focus Areas in the strategy. They are:
- Improved Methods: building the scientific foundation to evaluate the potential risks of chemicals to public health and the environment.
- Susceptible Populations: identifying vulnerable groups (including children) and characterizing factors that may place those groups at higher risk.
- Chemicals in the Environment: understanding how chemicals move and change along pathways from sources to human and wildlife populations and the environment.
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MAJOR DRIVERS OF THE LRI PROGRAM
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The LRI program for 2005 is composed of approximately 55 active projects, most of which are continuations from prior years. Although this overview document summarizes projects for 2005, much of the program will continue into 2006 because the duration of the typical project is about three years. Projects completed prior to 2005 are not included in this summary. Completed projects can be accessed using the search engine on the LRI website (www.uslri.org).
Each principal investigator has written a project abstract describing his/her work, including publications and presentations that have arisen from it. The purpose of this overview document is to summarize the projects with an emphasis on the value and relevancy of the work. To access the technical abstracts, click on the internal hyperlinks in this document. Some projects have relevance to more than one area or subarea and therefore are cited more than once.
2.0 FOCUS AREA: IMPROVED METHODS
The chemical industry has made visible and firm commitments to fulfill its obligation to understand the potential human health and environmental risks associated with its products and processes. Typically, these risks are assessed based on information collected with a variety of testing, measurement, and modeling methods. Therefore, access to state-of-the-art methods and technologies is essential for effective and efficient implementation of the industry's cornerstone commitment to "know" the potential impacts of its products and processes. The High Production Volume testing program, the endocrine and children's health screening and testing initiatives, the proposed European Union Chemicals Policy (i.e., REACH, Registration, Evaluation and Authorization of Chemicals), and ongoing regulatory and product stewardship testing guarantee that both the volume and pace of data collection will increase for many years to come.
The largest portion of the LRI program focuses on substantially improving the methods for evaluating potential risks of chemicals to human health and the environment. If such methods were improved, then (1) more chemicals could be screened or tested more rapidly and cost-effectively, (2) the results of those screens would be more scientifically infofrmative, and (3) exposures could be measured or estimated more accurately. Many methods are capable of measuring effects in model systems, but assessors have difficulty understanding whether such effects characterized in the laboratory are likely to occur in humans or ecosystems after real-world environmental exposures and whether such effects are likely to be adverse. Mechanistic research can address these problems because this type of approach focuses on the way in which a chemical may exert its effect(s).
Even when substantial information is available, it must be interpreted for likely outcomes in the real world. This interpretation requires advancements in risk assessment methods with a strong scientific foundation that is less reliant on default assumptions (i.e., scientific judgments that are used to fill data gaps).
The methods program is divided into three themes, each having subthemes. They are depicted in the box below.
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IMPROVED METHODS FOCUS AREA THEMES AND SUB-THEMES
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2.1 Human Health and Ecological Effects Screening and Testing Methods
Typically, regulatory agencies require testing of chemicals by exposing animals to doses sufficient to cause effects (i.e., maximum tolerated dose). The purpose is to ensure that the material's full potential of toxicity is observed. However, in most cases, these doses are environmentally unrealistic (often more than a 1,000 times above environmental levels). Much research has demonstrated that such high doses of many chemicals may cause toxicity through mechanisms that do not function at lower concentrations.
Often, results at these high levels require extensive research follow-up to confirm the high-dose observation's lack of relevance, unnecessarily consuming valuable laboratory, animal, and intellectual resources. And, even in the face of such investments, loss or restriction of products may still result from concerns about the high-dose data. The ultimate goal of this component of the Focus Area, therefore, is to develop and refine methods that better enable improved, quantitative estimations of health risks associated with real-world exposures to chemicals.
2.1.1 Toxicity test methods, emphasizing development
Increasingly, the public and regulatory organizations are focusing their attention on understanding the susceptibility of developing organisms to chemical exposures and acting on that susceptibility. For example, a presidential executive order requires EPA to evaluate its regulations for adequacy in protecting infants and children. The Food Quality Protection Act requires an additional 10-fold "protective factor" for infants and children unless it can be demonstrated that the added factor is unnecessary. Such demonstration of susceptibility, or lack thereof, requires more precision and accuracy in tests than the current state-of-the-science supports. This issue is most prominent for effects on the endocrine system, described in more detail in the following section. Therefore, development and interpretation of methods for endocrine-active compounds (EACs) is the largest program of the LRI in this area. However, significant efforts also are being made to understand the developing nervous and immune system.
Endocrine System, Reproduction, and Development
The endocrine organs (e.g., thyroid, pituitary, testes, ovaries, pancreas, adrenal) secrete small amounts of chemicals called "hormones," which are biologically active and are critical to normal physiological functions of the body, including fetal and postnatal development. Scientific evidence indicates that some chemicals in the environment are hormonally active, meaning they have the potential to mimic or interfere with the normal functions of the endocrine system.
Therefore, effects on the endocrine system can be important. In some cases, where wildlife has been exposed to large amounts of some EACs, the EACs have produced adverse effects. What is not yet clear is whether humans are adversely affected by low-level environmental exposures. The key questions are (1) which chemicals have the potential to cause effects (i.e., what methods can best screen chemicals for EAC activity), (2) does exposure to typical environmental levels of these chemicals interfere with endocrine systems to produce adverse effects, and (3) how widespread is the actual or potential risk (e.g., what are the real-world exposures to EACs, and what is the context of these exposures to findings in experimental test systems)?
Governmental and private organizations around the world are seeking answers to these questions. A central need is that they do so using high-quality standardized test methods that can be interpreted appropriately. The LRI has established its EAC program in concert with the International Council of Chemical Associations and governmental organizations to ensure that its program is complementary. The human health portion of the program is discussed here. The wildlife component is described later, in section 2.1.3.
The human health program has three facets: (1) understanding mechanisms by which compounds may interfere with reproductive development, so that the ability to develop new tests and interpret current tests can be improved, (2) advancing new test methods and refining existing methods, and (3) understanding health implications of low-level exposures to mixtures of EACs. An LRI program in collaboration with the National Institute of Environmental Health Sciences (NIEHS) awarded 14 jointly funded competitive grants intended to expand fundamental understanding of potential reproductive and developmental impacts from chemicals. Nine of these grants are still in progress (END0035-01, END0035-04, END0035-05, END0035-07, END0035-08, END0035-10, END0035-11, END0035-12, END0035-14). Specifically, the grants focus on the mechanisms of action of developmental toxicants, using the state-of-the-art tools of genomics, proteomics, and model organisms (including transgenic and gene knock-out genetic animal models). This ACC/NIEHS-funded effort also is intended to increase the national effort to bring more basic biology to bear on current issues in developmental toxicology.
Two ongoing projects investigate "natural" EACs, predominately a plant estrogen called genistein found in dietary soy products (END0004, END0030). Because people typically consume this plant estrogen in large amounts compared to environmental exposures to synthetic EACs , the LRI laboratory animal research program can use this information to make comparisons to humans, improving the ability to interpret animal endocrine tests. In addition, these projects will develop knowledge that can be extrapolated to similarly acting synthetic EACs for which environmental exposures are much lower. Also, because these estrogens are present in feed consumed by laboratory animals, understanding whether they affect the outcome of regulatory tests, particularly tests intended to evaluate EACs, is important (END0011).
Another set of studies evaluates the sensitivity of the developing male reproductive system in animals after exposure to EACs, an issue of increasing public concern. The focus of this research is on molecular events as well as the linkages between molecular changes and adverse outcomes in the neonate and adult (MTH0309, END0008, MTH0307, MTH0403, MTH0501, MTH0503). A few model compounds are being used, including testosterone, phthalates, and other agents that can affect the functioning of male hormones in laboratory animals. Systems biology approaches are being used.
An important feature of some of these studies is the timing of exposure relative to the health outcome and extrapolation to humans (MTH0307, MTH0308). There can be "windows of susceptibility," which are periods of time during development of the fetus or neonate when particular tissues or organ systems are more sensitive to the effects of a compound than at any other time. Knowledge of what these times are for both animal and humans can increase understanding of the appropriateness of regulatory test protocols for assessing reproductive development.
Projects are underway that will help to bring some EAC health studies together into a scientifically robust health assessment. One project (END0017) includes a measurement-based computational characterization of the relationship between exposure to estrogenic EACs and the health outcome (defeminization of the female animal brain during the neonatal period). Research on mechanisms involved will be complementary (MTH0401).
Development of the Nervous and Immune Systems
In recent years, the Organisation for Economic Cooperation and Development (OECD), EPA, and the International Program on Chemical Safety (IPCS) have organized workshops highlighting the need for improved markers of neurotoxicologic damage in the developing nervous system. Recently, EPA's Science Advisory Panel reviewed the agency's test guidelines for neurotoxicology and made several recommendations for improvement, suggesting that current histopathological approaches could be enhanced or replaced by more sophisticated staining techniques and computer-aided analysis. To these ends, project NTX0005 will evaluate the effectiveness of advanced approaches (e.g., computer-aided microscopic analysis) for measuring changes in brain cells (primarily the number of brain cells) as an index of damage in rats. The development of brain structure is important to sexual differentiation and hypothesized to be vulnerable to endocrine-active compounds. Research on this topic focuses on the dose-response of mechanisms involved in the perinatal brain exposed to estrogenic compounds (MTH0401).
The immune system is responsible for defending the body against infectious disease and some cancers. It also can turn upon the body and cause autoimmune diseases. Therefore, because its proper functioning is essential to health and some chemicals can disturb this system, immunotoxicity is a regulatory concern. The multiple components of the immune system in adults make its comprehensive study quite difficult, a difficulty that is even more complex for the developing immune system. Thus, standardized laboratory animal tests for evaluation of immunotoxicity in the developing system currently do not exist. EPA is in the early stages of drafting test guidelines for developmental immunotoxicity, making the LRI's goal of improving the scientific foundation of such tests especially timely.
One project (IMM0101) seeks to understand whether the susceptibility of the developing immune system to some chemicals may be due to a qualitative difference (i.e., does the chemical uniquely affect the developing immune system, but not the adult system) or a quantitative difference (i.e., does the chemical preferentially affect the developing immune system at lower doses than the adult system). Another project (IMM0102) will characterize the optimal time to make immune system measurements after birth, following in utero exposures of animals, as well as seek biomarkers of effects. These objectives will contribute to more cost-effective methods for developmental immunotoxicity evaluations.
2.1.2 Integration and implications of new and emerging approaches in health effects research
This subtheme includes development of new methods and approaches that may revolutionize the science of risk assessment, as opposed to current research that suggests only incremental changes. Thus, many avenues need to be explored, but only some of them may prove viable.
Rapid advancements in molecular biology and genomics offer a new biological paradigm called systems biology with the potential for dramatic impact. Systems biology can be defined briefly as the quantitative study of biological processes as whole parts instead of isolated systems, leading to an understanding of the complex dynamics that underlie physiology in both the normal and diseased states. This holistic approach to understanding the effects of a chemical, from molecular changes, through changes in cells and organs and their defenses, up to health outcomes as a function of magnitude and duration of exposure offers a more integrated approach to human health assessment than do current approaches. Current risk assessment approaches largely deal with "pieces" of this whole series of events, resulting in poor understanding of the relationship between exposure and health outcome. Systems biology provides for a synergistic integration of theory, computation, and experiment and weaves these complex areas together, with potentially large impacts on ensuing risk assessments.
Because of the complexity of systems biology, it requires the assistance of computer-based methods and models to facilitate understanding of the functioning of cells and their potential to be altered by chemicals. This need has driven development of a new scientific area, computational toxicology, which provides mathematical models that reliably express the holistic series of events between exposure and outcome.
Because of its lack of breadth, any compartmentalization limits understanding and is provided simply for the sake of a more organized discussion. Thus, this section is reserved for a few overarching or purely exploratory programs. The many projects that will feed into systems biology studies are presented in other sections.
The CIIT Centers for Health Research has developed a Center for Computational Biology and Extrapolation Modeling to integrate systems biology related projects within CIIT as well as to reach out to other researchers with similar interests. For example, CIIT signed a memorandum of understanding with EPA for joint research in this area.
Many chemicals at high doses affect a large number of genes, as measured by modern genomics methods. Functional genomics research (MTH0402) provides a systematic investigation of the cause-and-effect relationships contained in a large number of altered genes and the resulting toxicological endpoint to identify which alterations are important. Functional genomics can help identify key “cell signaling” pathways leading to various health outcomes. Cell “signaling” is one of the fundamental functions of cells and can be affected by chemicals. Additional systems biology studies (END0008, MTH0304, MTH0305, MTH0307, MTH0308, MTH0309, MTH0403, MTH0501, MTH0503 ) center on programs in male reproductive toxicology and evaluation of reactive gases and are discussed in other sections.
The joint research program sponsored by the LRI and NIEHS also reflects the search for novel approaches to increase the fundamental understanding of the effects of chemicals on reproduction and development. There were 14 jointly funded competitive grants, nine of which are still continuing (END0035-01, END0035-04, END0035-05, END0035-07, END0035-08, END0035-10, END0035-11, END0035-12, END0035-14).
2.1.3 Methods for detecting effects on wildlife
As mentioned earlier (Section 2.1.1), investigators have observed the effects of endocrine-active compounds (EACs) on wildlife. However, large gaps exist between these observations and quantitative methods that can be used for assessing the potential risks to ecosystem populations. In recognition of this problem, EPA has a substantial program to develop and validate methods aimed at assessing the impact of environmental exposures on wildlife. The LRI program is seeking to identify the next generation of such assays for the effects of EACs on several species of environmental importance.
The LRI wildlife program centers on expanding basic understanding of the linkage between laboratory studies, functional changes in organisms, and population impacts in the field. The development of gene array technology (a rapidly expanding approach to molecular-level investigations) to evaluate ecological effects in amphibian and fish models is intended to provide a framework for employing a major new technology to conduct rapid screening to evaluate mechanisms of action and diagnose the status of natural populations (END0101).
A reptile biomarkers study has established a laboratory population of fence lizards as a model for potential use in ecological risk assessment of EACs (END0123). Other projects are developing efficient, field-deployable methods for measuring changes in bird behavior and levels of circulating hormones that are indicative of reproductive success and productivity in the wild (END0301, END0022, END0122). Wildlife is routinely exposed to mixtures, but methods to measure and evaluate effects of EAC mixtures are rudimentary, at best. Hence, project END0020 is designed to develop laboratory models with alligators, fish, and mussels that are predictive of effects in the field.
2.2 Human Exposure Methods
Exposure study results have four major uses: (1) to improve exposure (and hence risk) assessments, (2) to provide guidance for the design of more realistic protocols (i.e., study designs) for exposures used in laboratory animal testing, (3) to make the exposure components of epidemiological studies more quantitative and therefore more useful, and (4) to identify which risk management approaches may be most effective. This theme has two subthemes:
- Development of methods for characterizing and estimating exposures
- Development of knowledge for interpreting and using biomonitoring data
These subthemes are interrelated in the LRI's program and therefore are discussed together. Definitive exposure measurements are often not available or are cost prohibitive to obtain, forcing reliance on models that are rarely based on actual measurement data or evaluated against realistic expectations. One of the greatest barriers is the paucity of cost-effective methods to estimate exposures.
Biomonitoring refers to making measurements of chemicals (or their metabolites) in biological media such as blood and urine. The Centers for Disease Control and Prevention (CDC) is measuring more than 100 chemicals in blood and urine and posting their concentrations on its website (the "Exposure Report Card"). Although the CDC has been very responsible in stating that these levels of chemicals cannot be interpreted for health risk (with minor exceptions, such as for lead), public concern is increasing significantly and regulatory efforts are likely to follow. Signs include: the State of California is considering requiring biomonitoring for many chemicals; the CDC is providing grants to several states to make such measurements; and virtually all current exposure studies include biomonitoring. The national drive to obtain biomonitoring data far exceeds attempts to understand the implications of such data for human health, creating a major knowledge gap.
The LRI has signed a memorandum of understanding with EPA for joint grant solicitations, the first one being awarded to two projects for novel analyses of existing human exposure data. Project EXP0106-01 will characterize multi-pollutant human exposures by linking sources to biomarkers using a model that describes how multi-media pathways contribute to direct routes of exposure. The broad aim of project EXP0106-02 is to develop statistical models for the efficient and appropriate combination of multiple exposure measurements and relate them to a health outcome of interest.
Projects (MTH0311-02 and MTH0311-04) will be comparing biomonitoring data to exposure data in an attempt to better interpret ethylene oxide DNA adducts (i.e., ethylene oxide bound to DNA) and urine and blood levels of benzene metabolites, respectively. Another project will study the relationship between exposure to phthalates and urinary biomarkers in rats and then model this relationship for humans (MTH0308). Projects MTH0311-01 and EXP0106-01 will develop and apply more advanced statistical models to characterize relationships between exposures and biomonitoring data. Project MTH0311-03 will evaluate biomarkers of in utero exposures to background levels of environmental contaminants. Through development of biomarkers for skin exposure (RSK0015-01), investigators seek more effective approaches to making exposure measurements.
2.3 Interspecies, Intraspecies, and Target Organ Determinants of Dose Response
Dose-response assessment is a fundamental component of health assessment (the other being exposure assessment). Current dose-response health assessment methods rely extensively on animal tests and application of conservative default assumptions to estimate risks to humans. These assumptions often are not supported by actual data; e.g., the risks of complex mixtures are estimated by simple addition of the dose-response elements of the individual elements of the mixture. Unfortunately, current approaches to health assessment are unable routinely to deal with (1) quantitative extrapolation of laboratory animal data to humans, (2) population distributions of risk (i.e., a highly quantitative description of the number of people who may actually be affected to various degrees), or (3) the integration of cancer and non-cancer assessments.
The LRI has created a multifaceted approach to improve the fundamental elements of dose-response assessment. The major components include (1) predicting the relationship between external exposure (e.g., air concentrations) and dose to the target tissue that is the proximate event of a health response (e.g., dosimetry and pharmacokinetics, also called toxicokinetics), (2) understanding mechanisms of action and other biological elements involved in a health response (i.e., pharmacodynamics, also called toxicodynamics), and (3) health hazard assessment methods that integrate the first two components with computational approaches to build an assessment that better approximates the real world.
CIIT has developed a systems biology program that evaluates the continuum of effects from molecular changes (e.g., as measured with genomics) through cell and tissue alterations, all the way to health outcomes (e.g., adverse effects), as a function of magnitude and duration of exposure. A project (MTH0402) in “functional genomics,” one of the newer technological approaches, examines molecular pathways involved in early cellular responses to chemicals. Most of these systems biology studies focus on the mechanisms of actions of chemicals on the developing male reproductive system (MTH0501, MTH0502, MTH0503).
2.3.1 Prediction of Target Tissue Dose
The field of pharmacokinetics is one of the largest areas of the LRI program because of the core importance of knowing how a chemical is transported and transformed as it moves from entry to the body to the ultimate target cell and then to either storage in or excretion from the body. This subtheme can be compartmentalized for discussion into three sections. The first relates to understanding reproduction and development and is contained within Section 2.1.1 (END0004, END0030). The other addresses doses to the respiratory tract and is described here. Lastly, some pharmacokinetic studies are designed to identify factors that would increase or decrease dose to the target, thereby affecting susceptibility to chemicals. These projects are discussed later in Section 3 (SUS0302, MTH0308).
Improved exposure-dose-response assessments of inhaled chemicals are basic to scientifically sound regulations of such chemicals, predominantly under the Clean Air Act, but also under other legislation that addresses inhaled chemicals (i.e., for toxics, pesticides, hazardous waste, Superfund, and even drinking water). The science to improve these assessments is grounded in the understanding of mechanistic linkages among components of the overall exposure-dose-response paradigm for inhaled gases and particles and the differences/similarities in these mechanisms between animal species and humans. Such understanding will facilitate more advanced extrapolation of laboratory animal test data to humans, from high to low doses, and from short-term to long-term exposures. The LRI program focuses on the first step, namely the dosimetric relationship between the amount inhaled and the amount at the target site where damage can occur, and the integrated step of the health assessment process itself.
The dosimetry of inhaled materials involves both the physics and chemistry of the material, as well as the complex anatomy, physiology, and biochemistry of the respiratory tract. Therefore, these elements are all studied in projects to predict the dose of inhaled gases and particles on a scale that is associated with specific sites of injury. Although the research encompasses the whole of the respiratory tract, a major focus is on the nasal region because many chemicals of regulatory importance deposit in the nose (about a third of EPA's inhalation guidelines are based upon nasal effects in rodents) and because this region is less understood than the lungs. To ensure scientific integration within its own programs in this area, CIIT created a dosimetry modeling core (MTH0303) and is studying compound-independent factors that influence regional respiratory doses of gases and particles (RES0201). The results of this research provide the fundamental building blocks for other respiratory tract deposition models. Because the nasal cavity is a site of specific interest, the uptake and interaction of the nasal surfaces with gases (hydrogen sulfide, MTH0304, chlorine, RES0005) are being studied. The latter project includes study of the uptake of metals into the brain via nerves in the nose. Such information is important to understanding all the pathways of metals that may reach the brain.
Because there are significant interspecies differences between rodents and humans in anatomy, airflow, and particle deposition patterns in the upper respiratory tract, the impacts of these interspecies dosimetry determinants on quantitative risk assessments are being investigated. For example, the rat is being studied with LRI sponsorship in a manner that is complementary to human studies funded externally to the LRI. Research includes obtaining fundamental data (RES0201, MTH0303) as well as chemical-specific data to fit into a systems biology approach for chlorine (MTH0305, RES0005) and hydrogen sulfide (MTH0304).
2.3.2 Understanding Elements Involved in Health Responses (Toxicodynamics)
Often health assessments rely on the combination of "pieces" of information, rather than a scientifically integrated understanding of the exposure-dose-response continuum. Addressing this problem is difficult, especially in a data-sparse environment. Therefore, the LRI is sponsoring the development of integrated models that are well founded on biologic principles, thus potentially minimizing the need for development of comprehensive data sets on all chemicals. Biologically based dose-response models follow a chemical through all of the pathways from exposure to effect, examining the mechanisms involved, typically for a class of chemicals. The objective of the research is to reduce uncertainties in risk assessment caused by overly simplistic assumptions about the mechanisms of the disease processes.
Exposure-dose-response evaluations with chloroform and chlorine entail the development of biologically based dose-response models that provide improved foundations to extrapolate from animal data to humans and from short-term to long-term responses (MTH0300, MTH0303, MTH0305, RES0005). Finding biomarkers of particle-induced lung effects that can discriminate among biological changes, adverse effects, and disease in animals can be used to better interpret the risk implied in animal inhalation toxicology studies (MTH0404).
The Food Quality Protection Act provided impetus to assess "cumulative risk," which has several definitions, the most common one being the risk resulting from multipathway (e.g., food, air, water, hand-to-mouth) exposure to mixtures of chemicals having similar modes of action. This assessment is quite a challenge because real-world mixtures often have hundreds or thousands of compounds, most of which are not characterized chemically or toxicologically. Therefore, the application of poorly defined or unproven conservative default assumptions is a common occurrence.
The LRI is seeking to alleviate some of these knowledge gaps through the study of interactions of organophosphorus anticholinesterase compounds (widely used in pesticide products) that are often the model chemicals for constructing default assumptions. One project (RSK0009) uses both test tube and whole animal experimentation to gather data essential for supporting refinement of biological-based dose and risk assessment models. Another (MTH0301) will develop a mechanism-based cumulative risk model using pharmacokinetic modeling. Although cumulative risk models are based on chemicals with similar modes of action, some of these assumptions will be evaluated by considering the converse and developing mechanistic and empirical models to describe the interactions of chemicals with different modes of action (RSK0103).
2.3.3 Health Hazard Assessment Methodologies
The purpose of the entire LRI human health-related research program is to improve risk assessment. However, even if health test methods were "perfect," the resulting data would still be used in imperfect health assessment models. This creates an impetus to improve such assessment models. Much of the information arising from studies discussed earlier (Sections 2.3.2 and 2.3.2) will make a major contribution (e.g., understanding the role of pharmacokinetics can reduce uncertainty factors in assessment). However, additional types of targeted research, discussed in this section, are needed to influence assessment methods explicity. A major goal is assessment methods with more realistic uncertainty factors and models that better describe the dose-response curve, and this objective will be well served by the projects already discussed. However, the ultimate goal is to develop and use the science such that knowledge replaces uncertainty factors.
To this end, the LRI is sponsoring a demonstration program using formaldehyde, chlorform, chlorine, and hydrogen sulfide as model chemicals to perform a robust quantitative health assessment without reliance on typical uncertainty factors or linear cancer models. Demonstrations have two values, one in understanding the exposure-dose-response of the chemicals studied and the other in identifying the fundamental types of information needed, thereby enabling others to perform such assessments on additional chemicals. Creating a new mechanism-based human cancer risk assessment for chloroform will require applying novel computational modeling approaches to an extensive existing database (MTH0300). The chlorine assessment will include a "value-of-information" analysis to assess the impact of various types of information on reducing uncertainty in mechanism-based risk assessments for respiratory irritants in general, as well as for chlorine (MTH0305, RES0005). This study will enable default uncertainty factors to be replaced with a formal evaluation of the uncertainty associated with specific components of a risk assessment, such as the animal-to-human extrapolation. Hydrogen sulfide studies will involve correlating molecular and structural changes to doses delivered to sensitive nasal sites (MTH0304).
3.0 FOCUS AREA: SUSCEPTIBLE POPULATIONS
For humans, susceptibility to chemicals can be due to a host of factors that can be categorized broadly into two themes: (1) differences in biological sensitivity, and (2) differences in exposure. The average individual receiving the average exposure to chemicals is typically not at risk. Thus, understanding those factors that will put some populations at higher risk is important. Such understanding facilitates the identification of impacts in susceptible populations and therefore prevention of those impacts. At present, most assessment methodologies assume that all people exposed are very sensitive and they all receive a very high exposure. Such assumptions may be protective, but they do not lead to accurate risk assessments and cost-effective risk management strategies. The current emphasis of the LRI is on understanding the susceptibilities of children, but other factors (e.g., advanced age, gender, genetic make-up) need to be considered as well.
The LRI program includes several research projects on developing or interpreting methods that evaluate susceptibility (see Section 2.1.1). As described below, the LRI program in this Susceptibility Focus Area centers on factors that will influence the relationship between exposure and dose to the target organ and the adequacy of default factors used in risk assessments to protect infants and children. The entire pathway of a chemical within the body, from entry, through complex steps, to storage or elimination is called pharmacokinetics. Pharmacokinetics is a critical path for health outcomes because it controls the dose of the active chemical at the target.
The first step is the entry of chemicals into the body. Because of differences, primarily in physiology and anatomy, an identical amount of chemicals will not enter all people in a population, even if the external exposure is the same. For example, age differences in the respiratory tract will result in children experiencing different deposited doses to specific regions of the lung, depending on the specifics of the inhaled chemical and the specific age. Project SUS0303 will measure behavioral factors in infants and children that can result in differences in exposure and intake (e.g., hand-to-mouth behaviors).
After a chemical enters the body, it is transported to different sites, and most chemicals undergo metabolism, transforming the original chemical to other compounds called metabolites. Some metabolites are less toxic than the original chemical; others are more toxic. The types of metabolites produced and their concentrations depend on the specific nature of the chemical and the specific nature of the metabolism. Factors such as gender, genetic make-up, and age can have a major influence on the type and amount of chemical metabolism, thus affecting the potential for toxicity expression. Disposition of the original chemical and its metabolites is of key importance (e.g., whether it is stored or eliminated quickly from the body). Several LRI projects are measuring and modeling metabolism and disposition.
As discussed earlier, the developing organism is the subject of much attention and regulatory focus. The tests to predict developmental effects are being improved by the LRI (Section 2.1.1) and others. However, advancements require understanding of the mechanisms involved in susceptibility, which in turns requires better understanding of the relationship between dosing of a pregnant animal and the dose to the fetus, as well as the extrapolation of these relationships to humans. To these ends, a pharmacokinetic study is being conducted that involves obtaining data for better models of the period right before and after birth (SUS0302). Other related projects will develop (1) a human pregnancy pharmacokinetic model, based on animal studies and existing human data (MTH0308) and (2) a model of the pharmacokinetics of the two primary male hormones (MTH0307) to better predict effects on the developing male reproductive system.
Gene-environment interactions are hypothesized to be involved in a vast array of health outcomes, including those totally unrelated to chemicals. One project (EPI0009) studies gene-environment interactions by investigating statistical issues critical to the design of epidemiology studies of the interaction between genetic factors of disease and environmental chemicals at the molecular level. This project will create a firmer scientific foundation for this new area of molecular epidemiology. Another study (MTH0403) aims to identify genetic susceptibility factors for effects of endocrine-active compounds on the development of the male reproductive system.
4.0 FOCUS AREA: CHEMICALS IN THE ENVIRONMENT
For a chemical to have the potential to cause effects, it must enter the environment and traverse a complex pathway before a human, wildlife, or other ecological receptors are contacted (i.e., before exposure occurs). Understanding this whole sequence of exposure events is fundamental to both risk assessment and risk management. For example, most regulations seek to reduce exposure based on assumptions about the relationship of the source to exposure. However, with more scientific information, the pathway(s) known to result in highest exposure could be targeted for increased regulatory effectiveness.
Sequences between sources and exposure include events classified as transport and transformation; each is highly dependent on the specific nature of the chemical and the environmental matrices it encounters. For example, some chemicals are destroyed by sunlight very soon after release; others can travel across continents. Some move unchanged through the environment; others are transformed to different chemicals that may have a greater or lesser toxicity than the original. Exposure itself also is complicated. In some notable cases, the food chain becomes contaminated and can serve as a vehicle for humans to be exposed. In some cases, ecosystems are of prime interest. In others, humans are of prime concern.
The LRI program has identified two themes for this Focus Area: (1) human exposure assessment and analysis, and (2) ecosystem exposure analysis. Human exposure priorities are on air toxics because of their potential for imminent impact on consideration of residual risk regulations by EPA (a specific type of regulation under the Clean Air Act).
Ecosystem exposure analyses include several studies to evaluate atmospheric chemistry; especially as it influences air quality models and regulatory strategies. Specifically, this program includes a literature review of the composition of atmospheric aerosols, with an emphasis on organic aerosols, to better inform regulations for particulate matter (ATM0007), and studies of the atmospheric chemistry of ozone formation with a goal of improving ozone air quality models (ATM0008, ATM0011).
A number of investigators are conducting research on human exposure to gaseous air toxics (primarily volatile organic compounds), specifically addressing those elements of exposure assessment that limit the accuracy of regulatory decisions. Accurate estimation of air toxics exposure is complex and is influenced by several factors. These factors include atmospheric chemical reactions that transform the original chemical introduced into the environment, a multiplicity of potential sources of exposure to the same agent, and the highly variable nature of microenvironments and the times that humans spend in them.
However, only outdoor sources are regulated, making it necessary to define the contribution of outdoor sources to exposure and hence risk. Both measurement and modeling approaches will be used. One project (CIE0102-02) seeks to measure the atmospheric formation of air toxics mixtures experimentally and identify the relative toxicological potency of the components. Other investigators will measure indoor, outdoor, and personal exposures in microenvironments in several areas of Boston (CIE0102-03) and Detroit (CIE0102-01). The latter project includes biomonitoring of breath. Both projects will provide useful inputs for human exposure models being developed by EPA. Another project (CIE0102-04) seeks to compare and improve air toxics exposure models that are candidates for regulatory use. This project is unique because collaborators from academia, the EPA exposure laboratory, and the EPA air regulatory office will perform the research.
5.0 CONTINUING TARGETED PROJECTS
Some projects initiated in previous years are not related directly to the Focus Areas, but they are responsive to areas of high-priority interest. These projects include:
- Development of more predictive animal models of occupational respiratory allergy to chemicals (IMM9903). This project involves developing mouse models of airway hyper-responsiveness to chemicals, using advanced approaches that include the identification of potential markers (cytokines) of effects.
- Through genomic studies using transgenic mice, investigators will seek linkages between fetal exposures to endocrine active agents (natural and artificial) and biomarkers of breast cancer in adults (RSK0015-02).
- A recently completed LRI project entailed a broad evaluation of 185 previously published epidemiological studies of mortality and cancer incidence in chemical industry workers, using meta-analytical statistical techniques. A follow-up study extends the original analysis with the aim of gaining a more complete understanding of the potential roles that research methodology and environmental or occupational influences may play in identifying and interpreting the findings of these types of systematic, quantitative analyses. Studies such as these can provide important information regarding where uncertainties in interpretation could be most reduced through additional efforts to collect exposure data (EPI0101).
- Assessing risks to ecosystems is challenging because of the great diversity of subjects and dynamic systems to be evaluated. For example, differences between forests and individual trees of different species have to be considered, as do differences among fish, birds, and land mammals, as well as between rural and urban habitats. This situation is further complicated because environmental data are limited. Therefore, ecosystem risk assessors worldwide are trying to develop a more scientifically sound basis for the necessary guidance on environmental risk estimates and risk management approaches. The LRI’s contribution to this goal is to sponsor projects that demonstrate a novel, systematic approach for identifying and assessing dominant stressors at stream and river sites (EEE0018), and develop a risk assessment scheme to better assess the fate of chemicals and their effects on soil ecosystem structure and functioning (EEE0019).
