Modernizing Approaches to Chemical Risk Assessment

Transcription

1 L R I R E S E A R C H S T R A T E G Y Modernizing Approaches to Chemical Risk Assessment

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4 The American Chemistry Council represents the companies that make the products that make modern life possible, while working to protect the environment, public health, and the security of our nation. Founded in 1872, our support for research and initiatives that serve our communities and customers continues to this day. Our member companies have committed to implement a set of goals and guidelines that go above and beyond federal regulation on health, safety, security and the environment. Good science needs good questions. Together, we can find the answers that will ensure a brighter, cleaner, safer and more prosperous tomorrow.

5 Contents Executive Summary iii 1 Introduction Developing and Updating a Strategy for the LRI Program Goals and Principles of the LRI Major Drivers of the LRI Program Criteria for Identification and Prioritization of the Research Portfolio Program Balance and Impact Balancing Core and Issue-Driven Research Creating an Impact Research Areas to Modernize Risk Assessment New Technologies for Toxicity Testing Real-World Exposures Susceptible Populations 11 2 New Technologies for Toxicity Testing What is the Issue? Research Needs 14 3 Real-World Exposures What is the Issue? Research Needs 16 4 Susceptible Populations What is the Issue? Research Needs 17 5 Chemical Industry Leadership Building Scientific Consensus Through Fostering Communication of Research Findings Early Career Awards 20 6 References 21 i

6 From Data to Decisions: Informing Regulatory Policy The LRI research will address the growing gap between advancements in the new technologies and the science to interpret and understand the emerging data. Key questions include what research is needed to bridge this knowledge gap; how to harness the data to better inform decisions about public health; and how best to communicate research outcomes as they evolve.

7 Executive Summary New technologies to test effects of chemicals and detect them in the environment are revolutionizing risk assessment, as practiced by all interested groups globally, including regulators, industry health and safety experts, NGO s, and the public. If done in a scientifically robust way, this approach would be of great benefit because risks could be understood better, faster, and cheaper. However, the leading edge of the technology has left behind the means to accurately interpret the data resulting from that technology. Thus, a multitude of data will exist, and all interested groups will use their own interpretation, which cannot yet be supported by the science. The ability of these modern technologies (e.g., genomics and high throughput assays) to rapidly generate volumes of data that might characterize hazard properties of materials is truly impressive and alluring. These technologies demonstrate changes in model systems without knowledge of what those changes mean (minor compensation or adversity) or how they relate to the exposure and doses people would actually receive. Without investment in the science of interpretation, the tendency will be to rely on high-throughput hazard data or biomonitoring as a surrogate for risk assessment. The federal government is investing hundreds of millions of dollars in pursuing the technology. The crucial niche that LRI can fill will be making sense of the resulting deluge of data and improving the understanding and interpretation of results from predictive studies that use the new technologies. The LRI science community will facilitate translation of data into meaningful information that can be used effectively in risk-based decision-making. The LRI Research Strategy ( ) is designed to achieve: Effective interpretation of the health implications of data from the new technologies for toxicological testing that are revolutionizing risk-based decisionmaking; Innovative tools to characterize biologically relevant environmental exposures and their implication for health risks especially as related to the new technologies; and Improved assessments of susceptible populations, especially children, by understanding genetic influences and gene-environment interactions. To achieve these goals, the Strategy provides the framework for a multi-year (2009 to 2015) investment, with each year anticipated to be in the range of $10-15 million. The exact budget amount each year will be based on the specific annual plans that are developed. Chemical industry product stewardship commitments, such as the Global Product Strategy, have been implemented to promote the safety of our products through their lifecycle. These commitments have been driven in part by international regulatory processes and in part by the public s expectation that the chemical industry know its products. Judicious use of new scientific tools and the data generated by these tools will help us meet our commitments by enabling us to improve the scientific understanding of the potential role that our chemicals may have on human health and the environment and by helping to revolutionize risk-based decision-making. The knowledge generated by the LRI will be critical to our Global Product Strategy (ICCA, 2008) and will position the industry as a leader in providing safe, useful products for society. iii

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9 1 Introduction In January 1999, the chemical industry, through the American Chemistry Council (ACC), initiated a visionary program called the Long- Range Research Initiative (LRI) to sponsor research that is aligned with health and environmental issues of highest priority to society and the chemical industry. The goal of the LRI is to improve the practices of human risk assessment. Existing practices have been in use for more than half a century, and rely heavily on default assumptions and approaches that have come increasingly under question as our understanding of the underlying science becomes more sophisticated (National Research Council (NRC), 2007a, b). To provide more accurate and cost-effective information for decision-making, risk assessment practices must be modified to accommodate new science and technology. The LRI Research Strategy ( ) is designed to modernize risk assessment by achieving: Effective interpretation of the results of new technologies for toxicity testing that are revolutionizing risk-based decision-making; Innovative tools to characterize and predict environmentally relevant exposures and their relevance to health risks; and Improved assessments of susceptible populations, especially children, by understanding genetic influences and gene-environment. In working toward its goal, the LRI funds research that enables others to perform more accurate chemical-specific studies and assessments, provides leadership to other research funding institutions to seek fundamental advancements, and pursues opportunities to facilitate moving new scientific information into practice. Essentially, the program acts as a multiplier, extending its influence far beyond its boundaries by fostering understanding, cooperation, and capacity building of all responsible partners. The LRI s goal is well aligned with the mission of ACC (see text box below). Fulfilling the ACC mission requires information from high quality scientific research to ensure that society is provided with safe products of chemistry that will enhance their lives. Through the LRI, the members of ACC have committed to sponsor independent third-party research. Since LRI s inception, ACC has invested over $200 million in the program. With guidance offered by scientists from industry, academia, and government, LRI research has and will The American Chemistry Council s mission is to deliver business value to its members through exceptional advocacy based on enhanced member performance, high quality scientific research, communications, effective participation in the political process, and a commitment to sustainable development through member contributions to economic, environmental, and societal progress. 1

10 continue to provide valuable assistance to government and others in making risk assessment judgments about the health and environmental impacts of chemicals. LRI studies also contribute to greater certainty about those impacts among the public, chemical manufacturers, and users of chemicals. 1.1 Developing and Updating a Strategy for the LRI Program Developing and implementing an effective LRI research program requires the guidance of a strategic program plan and accompanying processes. In 2002, the LRI Strategic Science Team (SST), a group of member company and public experts that provides guidance to the LRI and reports to ACC s Board Research Committee (BRC), developed the initial research strategy for the program (ACC 2002). This document provides an update to the 2002 LRI Research Strategy (see text box below for highlights of the new strategy) and provides the framework for the development of annual research plans. What s New in the 2009 LRI Research Strategy? A focus on the need to revolutionize chemical risk assessment by updating research areas to be more responsive to the underlying science and the practice of risk assessment. An Impact Program that aims to realize and deliver the value of the LRI research program and to increase the utility of the research results. Center-like multidisciplinary approaches that require integrated and innovative solutions to complex environmental health issues. A mixed portfolio of issue-driven and core research areas to enable both the program s long-range vision and the need to be nimble and responsive to emerging scientific priorities. Workshops and Early Career Awards to facilitate impact delivery and to enhance program outreach. Similar to the 2002 LRI Research Strategy, this updated strategy was developed with input from ACC teams, including the Public Health and Science Policy Team, Chemical Products and Technology Division, and the Environment Team. The revised version addressing these groups comments was approved by the SST and was forwarded to the BRC that approved it in June Although this strategy is expected to be stable over the next several years, new knowledge or events could intervene, resulting in a change in priorities. Therefore, each year, the SST will review the strategy to ensure that it remains responsive to current human health and environmental issues. Each year, the strategy will be used to guide the SST when developing the annual plan, which includes recommendations on new research topics that should be sponsored the following year(s) in the competitive request for proposal (RfP) program, and a budget, which is expected to be in the range of $15 million annually. The highest priorities for the RfP program then will be further defined and translated into research projects funded through a competitive, peer-reviewed process. The remaining sections of this introduction describe the foundation used to develop the research program, including the goals of the LRI and the principles under which it operates; drivers for the program; the criteria used for selecting research areas; an overview of the updated research areas; and other, non-rfp funding opportunities. 1.2 Goals and Principles of the LRI ACC s LRI is part of a larger research initiative under the auspices of the International Council of Chemical Associations (ICCA). The ICCA global LRI is implemented under the responsibility of the three regions (America, Japan, and Europe). Through its LRI commitment, the ICCA aims to better understand the potential impacts that chemicals may have on the health of humans, wildlife and the environment; support robust and informed decisionmaking; and improve public confidence with decisions based on a scientific understanding of risk. 2

11 Goals of the ICCA LRI Extend knowledge worldwide on the health, safety, and environmental impacts of the chemical industry s products and processes; Support informed risk management decisions by increasing scientific knowledge through research; Develop new tools to assess chemicals, especially as new questions emerge about potential health and environmental impacts; and Coordinate research of ICCA member associations to achieve international scientific participation in the research process and to create synergy among the research projects. Projects are implemented in cooperation with the scientific community and government institutions. Results are published and shared freely with the public, regulators, industry, and the academic and government communities. ACC s LRI is a component of the global LRI program, and the two programs have consistent strategies (ICCA, 2005). For example, while extending knowledge on environmental (ecological) impact is a key goal of the global LRI, ACC s current tactical focus on human health is acknowledged as a result of resource limitations. However, the European program has a considerable current tactical emphasis on environmental impact that helps achieve this goal for the global ICCA. The goals of the ICCA LRI are presented in the text box above. To achieve significant scientific advances in its funded research projects, ICCA developed principles to govern the conduct of the LRI. These principles also extend to Responsible Care practices in order to promote the safe use of chemicals. ICCA s LRI principles call for: Scientific Excellence. Research will pursue scientific excellence by using the best scientists and by seeking advances in scientific understanding. Transparency and Action. The research process will be transparent, results will be made public, and industry will act on the results in a timely fashion. Fair and Unbiased Conduct. The research process will prevent conflicts of interest and guard against bias in decision-making. Chemical Industry Relevance. Research needs and priorities will be set with consideration of the relevance of the research to the chemical industry and to meet the overall goal of funding research that increases scientific understanding about the potential health and environmental impacts of chemicals. 1.3 Major Drivers of the LRI Program The chemical industry has never before been faced by the threat of de-selection as it is now, with consequent adverse impact on the public s access to products useful to their lives. International scientific initiatives are driving the public and regulators towards poorly informed decisions that affect the future viability of our products and our ability to do business. These decisions will be increasingly driven by the output of a whole new generation of scientific tools including modeling, 3

12 genomics, and high-throughput assays. These tests rapidly measure the effects of chemicals on cells, tissues, and organisms. While some may use the data generated by these tools to advocate for increased regulation or deselection, in fact, using these data, the chemical industry is now positioned to effectively advocate for more sciencebased, data-driven decision-making. The LRI is a global leader in the interpretation of data generated by these new technologies. Chemical industry Product Stewardship commitments such as the Global Product Strategy have been implemented to promote the safety of our products through their lifecycle. These commitments have been driven in part by international regulatory processes and in part by the public s expectation that the chemical industry know its products. Judicious use of new scientific tools and the data generated by these tools will help us meet our commitments by enabling us to improve the scientific understanding of the potential role that chemicals may have on human health and by helping to revolutionize risk-based decisionmaking. Furthermore, as a result of the advent of new technologies, the chemical industry has never been as well positioned as it is now to effectively engage the scientific communities and advocate for science-based decision-making. The urgent need for the industry to have access to state-of-art science underpinning chemical risk assessments strongly supports the chemical industry s investment in the LRI. The LRI has developed a new research strategy to take advantage of the opportunities offered. They include: Public Demand That Industry Know Its Products. Through Responsible Care, the chemical industry is committed to understanding the potential health and environmental risks associated with the production, use, and disposal of its products. In general, 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 in health and environmental science, such as those being pursued by the LRI, are essential for industry to meet its product stewardship commitments effectively and efficiently. Demands for Risk-Related Information. The U.S. Environmental Protection Agency (EPA) develops and requires industry to apply test guidelines for toxic substances and pesticides under the Toxic Substances Control Act (TSCA) and the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), respectively. In addition, the Clean Air Act requires information and assessments for hazardous air pollutants and criteria pollutants, based on health and exposure data as well as application of exposure models. The risk assessments flowing from the information gathered in these studies often are based on methods that are difficult to interpret in terms of adverse effects and use models with multiple conservative assumptions, very few of which have yet been verified. The methods employed in conducting these tests and assessments must be resource-efficient in terms of their scientific validity, global acceptance, cost-effectiveness, and use of animals. Even more importantly, however, testing paradigms must be based on sound scientific principles to reduce reliance on default assumptions. It is also crucial to be able to interpret whether the study results 4

13 demonstrate adversity or reflect only normal homeostatic compensation to environmental or other physiological influences. The LRI program seeks these kinds of advancements. TSCA Reform. TSCA and EPA s implementation of that law will be under increasing scrutiny in the months and years ahead. While TSCA and EPA s actions are protective of health and the environment, the statute was not designed to address the complexities of and developments in modern science or society s expectations of the chemical industry. The industry should expect TSCA to be modified and should advocate for changes in the federal chemical management system that will address these issues. A cornerstone of any revision will be science policy decisions on how to conduct risk assessments, which will include consideration of how to incorporate the state-ofthe-science of health dose-response and exposure analysis. Thus, the scientific consensus on the new technologies will be crucial. There is no doubt that a plethora of data and opinions will exist. There is also no doubt that the ability to predict exposures, especially to children, with a reasonable degree of accuracy will heavily impact the ultimate risk assessment. By moving the science of risk assessment forward, the LRI program will contribute significantly to the foundation of a revised TSCA. Demands for Knowledge on Potential Risks to Children, as Embodied in Legislation and Voluntary Programs. Legislation, such as the Food Quality Protection Act (FQPA), and voluntary programs, such as the Voluntary Children s Chemical Evaluation Program, identify children as a susceptible population because of their potential for higher exposures than adults to some chemicals and the added biological sensitivity of developing physiological systems (e.g., the nervous system, reproductive system). Therefore, society has placed a priority on protecting children. The chemical industry is performing its mandated testing responsibilities plus volunteering to go further than what is mandated, particularly in the Endocrine and the Voluntary Children s Health Screening and Testing Initiatives. The quality and quantity of these contributions is directly dependent on the state-ofthe-science underpinning the screening and test methods used and the assessment methods employed to estimate risks to children. Hence, the demand for improved methods. International Public Concern over Endocrine- Active Compounds, as well as U.S. Legislative Mandates (e.g., FQPA, Safe Drinking Water Act). Information on the effects of endocrine-active agents on wildlife and the potential for effects on humans has prompted a multitude of studies by many institutions. As with all other research, understanding endocrine issues requires the development and application of advanced methods, such as those being pursued by the LRI that can be interpreted in terms of the severity of the outcome. Emerging Approaches to Chemical Assessment and Management. The implementation of the European Union s REACH, combined with the increased hazard and exposure data resulting from various voluntary and regulatory programs (including U.S. EPA s Chemical Assessment and Management Program, ChAMP and the Strategic Approach to International Chemicals Management, SAICM), necessitate risk assessment methods that reflect state-of-the-art science and practice. Current models still rely on conservative assumptions that likely overestimate true risks. Improving risk assessment 5

14 methods will enable more accurate interpretations of information derived from both existing and new studies, and will provide guidance to industry and regulators about the most effective and efficient risk management strategies. Bringing more advanced science to assessment approaches is a major LRI objective. Extended High Production Volume (EHPV) Chemical Program. The EHPV chemical testing program has and will continue to result in a significant increase in the volume and pace of data collection for many years to come. However, the ability to predict risk accurately from such information will be limited to the state of the art of risk assessment, which relies heavily on unproven default assumptions that can be resolved only through research of the type being performed by the LRI. Homeland Security. Attacks involving chemicals are one of the significant potential national threats. If such attacks occur, emergency officials will need to estimate risk rapidly. Because a chemical of known potency is likely to be used or released, the greatest uncertainty will be exposures. One of the LRI s aims is to conduct research that will help reduce uncertainties associated with estimating potential exposures. Reduced Use of Animals. The LRI supports the development of testing and research methods that reduce the unnecessary use of animals. Reliable alternatives to animal testing are not currently available for the broad range of toxicity testing now required. Research to reduce, refine, and replace the need for laboratory animals will continue. This goal may be realized through (1) developing or improving animal tests so that they provide high quality answers with fewer animals; (2) devising new methods (e.g., with cell lines) that avoid the use of animals while providing meaningful results; and (3) improved methods using genomic technologies that are expected to reduce the reliance on animals in the long term. Frequently, these new procedures will result in both reduced costs and reduced time to obtain the results. 1.4 Criteria for Identification and Prioritization of the Research Portfolio The chemical industry seeks to improve quality of life by providing safe, essential, and innovative products. The LRI aims to ensure a sustainable and healthy future by enabling industry, regulators and society as a whole to make knowledgeable decisions based on high quality scientific information. Furthermore, the LRI science informs ACC s highest advocacy priorities in chemical regulation, management, and health. It also enables member companies to fulfill their product stewardship obligations. However, because the LRI does not have the resources to engage in all research areas of interest, the research program must apply criteria to identify those issues of greatest alignment with its goals. The following criteria were applied in determining the main research areas that are discussed later in this strategy, and will also be used when selecting RfPs to be developed as part of the annual research plan. Value of the Research in Protecting Public Health. The LRI program should affect major science-based regulatory decisions enough to make a difference. For example, will a particular research topic address large populations that might experience irreversible effects, or small populations with a risk of transient effects? Value and Relevance to the Chemical Industry. The LRI will be working in one niche of a larger area. Thus, the work will be scoped to have a significant impact on the larger topic under study by others. For example, will the specific topic enable interpretation of the results of a larger body of work (e.g., toxicogenomics, biomonitoring)? Impact on a Specific Research Field. The research to be undertaken should make a significant contribution to the overall research field. It should complement existing efforts and fill critical gaps that are not addressed by programs currently funded by other organizations or agencies. The LRI should focus on targeted areas and be identified as a major sponsor and intellectual contributor in the field. Collaboration with Other Organizations. Insofar as possible, the LRI program should collaborate with other 6

15 funding institutions (including ICCA partners in the LRI), so that the LRI can expand the level of research effort devoted to issues of interest to the industry and provide expertise to others. Timing and Feasibility. Even though LRI research may in some cases take several years to complete, projects should have tangible interim milestones. The research should be able to achieve the stated goals with the funds and time allocated. 1.5 Program Balance and Impact The LRI program has continuously worked to balance different types of research, all of which are needed to improve the science base on which industry, government, and the public manage chemical products. As a sciencebased enterprise, the LRI is committed to helping others make decisions based on objective criteria for the development and management of chemicals. To achieve this, it is important to support both core research and issuedriven research and also to develop a plan to deliver impact from the research once it has been completed Balancing Core and Issue-Driven Research A mix of core and issue-driven research is important to the value of the LRI program (see text box on next page). Core research will add to the base of knowledge needed for scientifically sound decision-making. Core research should comprise percent of the program, because it enables far larger research programs (e.g., those of the federal government) to be more relevant to decision-making. Issue-driven research, which is built on a previously established foundation of core research, is more targeted and typically addresses nearer-term needs. Although its importance is high, it should account for a smaller proportion of the program because its impact is narrowly restricted to a specific issue. For example, validating a particular test on one organ system (issue-driven) can be immensely valuable for that test, but understanding the relationship of real-world exposure to dose (core) can apply to an array of tests on all organ systems. Core and Issue-Driven Research Core research aims to provide broader, more generic information that will help improve understanding of many problems now and in the future. This includes acquiring more of a systematic understanding of the physical, chemical, and biological processes that are affected by environmental agents and the development of broadly applicable research tools (e.g., better measurement techniques, more accurate models) (NRC, 1997). Issue-driven research is targeted at understanding and solving particular, identified environmental and exposure issues (NRC, 1997) Creating an Impact Often an excessively long time elapses from completion of a body of work, its general acceptance by the scientific community, its incorporation into general practice, and its acceptance for regulatory use. To speed this process, the LRI develops an Impact Program to increase the actual use of research findings in decision-making. The focus is on LRI-sponsored research, but extends to related research sponsored by others. Thus, the LRI program acts as a multiplier, expanding its influence far beyond its boundaries by fostering understanding, cooperation, and capacity building of all responsible partners. To these ends, each RfP topic includes a research component as well as an impact plan that is designed concurrently and part of the funding for that particular topic. The LRI Impact Program is accomplished in collaboration with the ACC Public Health and Science Policy Team to synergize their respective areas of expertise. As an example, the impact plan for the Risk Assessment RfP released in 2007 was created to generate more discussion in the scientific community about developing and applying advanced assessment methods both by sponsoring several symposia at high-profile society meetings and by sponsoring a multi-day workshop in partnership with other major organizations that would feature the results of the RfP projects. Other impact 7

16 plans provide ways for the research knowledge to be transmitted to the broader audiences, such as policy makers and the public. Additionally, for another 2007 RfP that funded projects to validate an alternative method that targets the reproductive system, the impact plan aims to provide publications with a plain English summary to organizations involved in endocrine tests (e.g., EPA, OECD) and to meet with the appropriate individuals at EPA to brief them on the results of the work. 1.6 Research Areas to Modernize Risk Assessment A critical question in risk assessment, now and well into the future, is whether susceptible human populations, such as children, are more likely to experience adverse effects from exposure to chemicals. At present, this question is addressed by scientists and policy-makers by drawing on laboratory data from rodents that have been exposed to chemicals at levels that dramatically exceed those present in the environment. The results are then extrapolated to estimate which exposure levels would produce adverse effects in humans, and whether humans would likely experience exposures at those levels. The quantitative process used to identify the exposure levels and the associated risks involves numerous uncertainty factors and application of conservative default assumptions. Scientific experts in the field recognize that improvements in this risk assessment are critically needed. However, bringing the science of risk assessment into the 21st century requires a visionary rethinking of toxicity testing and its context for real-world exposures; patching the existing system will not be an effective solution. The NRC was realistic about the scientific and resource barriers to achieving this vision. The challenge to the LRI is devising research areas that can be relevant both today and tomorrow as this vision comes closer to fulfillment. The LRI strategy emphasizes three areas (see text box on next page) that are essential to interpretation of the results of modern research, rather than duplicating efforts pursued by groups with greater funding. This approach enhances the broader use of data and provides direction to others seeking projects that will put the puzzle into place. Thus, these research areas are not meant to be comprehensive; rather, they are meant to be effective and synergistic. The U.S. government currently invests more than $1 billion per year for research programs (and associated administration) that investigate the health risks of chemicals. Since its inception, the LRI has identified and pursued research areas that are inadequately covered by federally-sponsored research and that fill a niche that would otherwise not be filled. The LRI chose to develop a program that improves the ability to interpret the results of the federal effort so the results are more relevant to improving risk assessment. These three research areas are intrinsically linked: progress on one without the others will not advance the goal of risk assessment. Hence, balance is essential. That balance involves far more than equal allocation of LRI funds; it incorporates understanding of federal program allocations, scientific readiness, magnitude of the need, and the iterative nature of research. In order to tackle all of these issues in an integrated manner, the LRI has identified the need for a center-type research approach that will transition the LRI from a series of silo investments to a 8

17 more harmonized approach in order to derive integrated research that deals with the complexity of science. The issues and research needs for each of the areas is described in more detail in the sections that follow New Technologies for Toxicity Testing Under voluntary and regulatory commitments, industry and the government conduct extensive (and expensive) chemical-specific testing using 50 to 60-year-old methods with laboratory rodents, producing data that are used by decision-makers despite their questionable relevance. Because the fundamental flaws of these methods are well recognized, several national and international efforts are underway to shift to new biological tools (e.g., genomics, high-throughput assays, perturbations of toxicity pathways, computational toxicology) that are being developed to revolutionize risk-based decision-making. The goal is to improve the accuracy and efficiency of predicting human health outcomes, based on laboratory data using human cells in vitro and much more limited animal studies. However, there is a danger that the indiscriminate and uninformed use of these methods will result in a massive new body of data that itself cannot be interpreted in terms of human risk (NRC, 2007b). To address these risks and problems, the NRC (2007a) developed a vision that outlines the foundation for examining the key relationships between exposures to environmental chemicals and ultimate expression of adverse toxic responses. The ability of these modern technologies to rapidly generate volumes of data that might characterize hazard properties of materials is truly impressive and at times seductive. For example, a single microarray test of gene expression changes following several doses of one chemical may result in over one million data points. Without the chemical industry s engagement and investment in the science of interpretation, the tendency will be to rely on highthroughput hazard data as a surrogate for risk assessment. The invaluable niche that LRI can fill will be making sense of the deluge of data and improving our understanding and interpretation of results from predictive studies that use LRI Research Areas 1. New technologies for toxicity testing. This area focuses on the effective interpretation of data generated by the new biological tools (e.g., genomics, high-throughput assays, modeling). Although these tools will be used to revolutionize risk assessment, the key issues remain: What is the relationship between doses used in these studies and doses that would be received in the real-world? What does the chemical do when different doses reach sensitive cells? What do observed effects mean in terms of human risk (e.g., adverse effects or minor compensatory changes? 2. Real-world exposures. This area concentrates on developing innovative tools to characterize and predict environmentally relevant exposures and their relationship to health risks. The key issues are: What do biomonitoring data mean in terms of human risk? Where does the chemical go in the environment? How much reaches humans and sensitive cells? What do observed exposures and effects mean in terms of human risk? 3. Susceptible populations. This area targets understanding factors, especially genetic influences and gene-environment interactions, that affect susceptibility. Children are of particular interest. The key issues are: What factors increase susceptibility to chemicals? How can genetic and epigenetic factors be incorporated into risk assessment? 9

18 the new technologies. The LRI scientific community will advocate for the need to translate data into meaningful information that can be used effectively in risk-based decision-making. The main goal of this research area is to develop methods and approaches to enable improved use of the new technologies by evaluating the relationship between dose and perturbations in the biological system and by identifying those perturbations that are adaptive versus those that cause cell/tissue/organ injury. Toxicity testing is approaching a pivotal point where it is poised to take advantage of the revolution in biology and biotechnology. All chemicals even pure water can be toxic at a high enough dose, so knowing the real dose is crucial to estimating risk. This research area will improve the accuracy of risk assessment by helping to forge a science-based bridge between laboratory exposure-dose-response and real-world exposures and doses. Many methods of today and the future are capable of estimating human exposures through measuring and modeling environmental concentrations. A prominent example is biomonitoring, which provides an extensive National Research Council s report Toxicity Testing in the 21 st Century: a Vision and a Strategy (2007a) Two topic areas support this goal: (1) prediction of target cell dose (by modeling), particularly in assays using highthroughput technologies, to enable linkage to real-world exposure in concert with Research Area 2 on Exposure and (2) dose response analysis for perturbations of toxicity pathways in ways that synergize with and help interpret a larger federal effort to bring toxicity testing into the 21 st century Real-World Exposures The goal for this research area is to improve the ability to understand and predict human exposure (the contact between concentrations of a chemical and a person over a period of time) and dose (the amount of chemical that enters the body and its fate as it moves to sensitive cells). Although exposure is half of risk assessment, it is rarely studied. 10

19 amount of information on concentrations of chemicals in the body at the time of measurement, without knowledge of what exposures were involved or what health effects might occur. Existing and future laboratory health tests correlate effects to exposure/dose in that artificial environment. The challenge is determining whether such laboratory-observed effects are likely to happen in humans following real-world environmental exposures, and if so, how many people, by subpopulation (e.g., children), are likely to be affected. The new technologies involving in vitro systems of cells and tissue present an even greater challenge to relate to actual human exposures. Thus, relating environmental human doses to laboratory doses (often with in vitro systems) is increasingly important. The main goal of this research area is to contribute to the development of computational exposure and dose models, many of which will include probabilistic features. The work will contribute to modernizing exposure science to be more predictive and responsive to the growing needs of risk assessment. Four topic areas pertaining to this research area are (1) interpreting biomonitoring data via extrapolation to exposure and dose, to make more sense of this expanding database; (2) developing models that link exposuredose in the real-world to the laboratory world to provide perspective and relevance to laboratory findings; (3) improving exposure factors for children that, with more scientific information, would have a significant impact on exposure model results; and (4) identifying scientific criteria that reliably predict whether a chemical persists in the environment and bioaccumulates. are backed up by risk assessment practices that include additional default factors to replace uncertainties. For example, procedures for noncancer health assessments include application of an adjustment factor less than or equal to 10-fold to deal with age (emphasis on children). Exposure factors used for children also make worst-case assumptions when information is missing. Concerns about protecting susceptible populations are expanding due to the advent of new technologies for health and exposure studies. The main goal of this area is to enable risk assessments to more accurately and quantitatively incorporate susceptibility from several perspectives: the identity of susceptibility factors, their mode-of action and impact on risk outcome, and their prevalence in the population. The topic areas are: (1) identification of computational approaches to incorporate gene-environment interactions into risk assessment and (2) development of approaches to incorporate epigenetics into risk assessment practices Susceptible Populations This research area is deliberately overlapped with the other two to ensure it receives appropriate attention. Average people receiving typical environmental exposures are very unlikely to be at risk. However, those people who receive higher-than-average exposure and/ or doses or who have heightened tissue/cell susceptibility are more likely to be at risk. Therefore, most environmental regulations center on susceptible populations, which 11

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21 2 New Technologies for Toxicity Testing 2.1 What is the Issue? A significant challenge facing toxicology and risk sciences is to develop improved approaches that define the potential biological and toxicological consequences, especially those associated with low-dose chemical exposures. This challenge was accepted by two NRC Committees Committee on Toxicity Testing and Assessment of Environmental Agents and Committee on Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment (NRC, 2007a and 2007b), which laid out new approaches to toxicity testing based on evaluating perturbations in toxicity pathways, linked with modes of action of perturbations to model dose-response, with consideration of environmentally relevant doses. Consider the example of a chemical under study in which a very high exposure/dose causes cancer mortality, a medium exposure/dose causes liver pathology, and a lower exposure/dose causes an adaptive change in liver enzymes. Current approaches would label this chemical a carcinogen, although the relationship of environmental levels to such study results are unknown and may be so low as to cause no change at all. Such dose-dependent transitions reflect different modes of action at different doses. Although many recognize the soundness of this theory, scientific data to robustly describe such modes of actions for many chemicals of concern does not now exist. Advanced technologies can show changes in gene expression and other endpoints due to exposure to chemicals. Even with these approaches, there is a discontinuity between realworld human exposures (including consideration of dose) and laboratory exposures (including laboratory exposures adjusted to be equivalent human doses) that result in effects. This disconnect can be traced to two complex issues. The first is dose rate. Humans in the real world are typically exposed intermittently in a very variable fashion. Laboratory animals and cell cultures are typically exposed in a regimented way (e.g., constantly over the duration of the study on a specific schedule, such as once a day, to the same concentration). Dose rate can also be influenced by many factors (e.g., age, genetics). The rate at which the dose reaches sensitive cells often has a significant influence on the response, so it must be accounted for in comparing the real and the laboratory worlds. The second issue is the mathematical representation of the two assessment elements. For example, exposure may be represented probabilistically and effects deterministically. Because scientists in exposure disciplines and health disciplines often work independently of each other, creating linkages requires additional research. In our view, the emergence of the new technological tools presents not only a challenge, but also a significant opportunity for the chemical industry to be proactive. The industry is positioned to embrace these new and potentially more efficient and effective tools to assess the effects of chemicals. We believe these tools will enable regulators and the industry to make better decisions about chemicals and to speak to their safety using a stronger scientific basis. This research area will focus on how technological advancements can be used to improve the science of 13

22 risk assessment and how the massive amount of data generated by new technologies can be interpreted. The goal is to provide leadership to modernize risk assessment approaches for informed public health and consumer decision-making. 2.2 Research Needs PBPK/Dosimetry Modeling: Prediction of Target Cell Dose. Physiologically based pharmacokinetic (PBPK) modeling should be used to identify amounts of the parent compound or its toxic metabolites at specific target sites at particular points in time after laboratory exposure of animals, along with exposures of cells/tissues used in high-throughput assays to refine estimates of internal dose relative to external exposures. This research should be designed to facilitate comparison with predicted delivered doses in humans receiving real-world exposure, as well as comparison with biomonitoring data (Research Area 2 on page 8). Dose-Response Analysis for Perturbations of Toxicity Pathways. This need, described in more detail by the NRC (2007a), is far broader than feasible even at current federal funding levels. For the LRI to contribute in a meaningful way, it must find a niche that has exponential impact. That niche is to develop computational systems biology models for a limited number of prototypical chemicals, focusing on understanding the mode of action at various doses, including those that are environmentally relevant. High-throughput and high-content technologies (e.g., toxicogenomics) and computational systems biology modeling technologies will be used to explore responses at environmentally relevant doses. Comparison of such responses with higher-dose responses may be necessary in order to identify potential key drivers of high- versus low-dose responses to chemicals; e.g., dosedependent transitions from homeostasis to adversity/cell dysfunction. Thus, the chemicals selected for study using new technologies should have existing data bases from traditional toxicity testing. This goal can be advanced by synergistic interaction with EPA s ToxCast TM program. ToxCast TM is positioned in Phase 1 ( ) to profile over 300 well-characterized commercial chemicals under a variety of potential hazard scenarios using over 400 endpoints from high-throughput and genomic tools to identify their effects on test biological systems and compare the results to those from traditional toxicity testing. Phase II ( ) is planned to involve about 1000 chemicals and over 300 endpoints. The resulting publicly available database will have an immense amount of toxicology data that will be exceedingly difficult, if not impossible in many cases, to use reliably in risk assessment without research of the sort that can be accomplished by the LRI program. 14

23 3 Real-World Exposures 3.1 What is the Issue? Risk assessments to protect public health are an integration of exposure assessments and health assessments. But comparatively little attention is paid to research for exposure assessment, and many of the models used in risk assessment are unverified and contain conservative assumptions to address uncertainties in existing information. In the present risk assessment practice, most human health risks are extrapolated from findings in high-dose animal toxicity studies. As we move into the high throughput technology future, extrapolations from in vitro systems will be more prevalent. Without comparison of these laboratory findings to real-world exposures, assessments and subsequent decision-making will be weighted to the potential hazard, rather than the risk. Already, human biomonitoring and other environmental contaminant monitoring programs are increasingly confirming that, for many chemicals, real-world human exposures are often several orders of magnitude below even the lowest doses used in standard animal toxicity studies. Thus, this area has the potential to have very high impact on risk assessment, if targeted studies are performed. As in the rest of the LRI program, this area will seek to provide leadership by filling in niches to make better use of related research activities of other research organizations. EPA requires that all regulations must be protective of children, and include evaluations of health and exposure. These evaluations have significant safety factors built into their assumptions about children s exposures (e.g., the FQPA explicitly calls for an additional 10-fold adjustment factor). EPA s new age groupings (the < 3 months, 2 to < 6 months, and 3 to < 6 year-old age groupings) and the updated Child- Specific Exposure Factors Handbook will strongly influence how exposure assessments are conducted. Furthermore, EPA is revising its Guidelines for Exposure Assessment that were originally published in All of these activities create a unique opportunity to bring more science into the process. Biomonitoring is the measurement of chemicals or their metabolites in biological matrices. In that sense, it is real world; the implications of body burdens are unclear. Recent expansion of large-scale, high quality human biomonitoring programs (e.g., the Centers for Disease Control and Prevention (CDC) Exposure Report Card ) indicate that broad segments of the population carry low-level body burdens of a wide variety of exogenous substances, including industrial chemicals. Yet, with very few exceptions, assessing how these body burden data relate to chemical exposures and doses (which provide linkages to health effects) is not possible given the current state of knowledge. This research area contains a linked issue-directed research topic, namely the classification and management of persistent, bioaccumulative toxicants (PBTs). EPA, the European Union, Japan, and Canada strictly regulate PBTs. Conceptually, concern is understandably heightened over chemicals that are toxic, persist in the environment, and accumulate in the body. Unfortunately, the screening criteria for classifying chemicals as PBTs are sometimes inaccurate, missing some chemicals and including others that are not in fact PBTs. Regulators are aware of this 15

24 problem, but even when presented with sound data showing that a particular compound is not actually a PBT, sometimes proceed with the label based on rigid adherence to published criteria. The need here is to improve the fundamental science so that regulators can revise the criteria to accurately identify PBTs. The effort needed is largely (but not solely) an exposure and dose issue, placing it in this research area. 3.2 Research Needs Interpreting Biomonitoring Data. The NRC (2006) has called for a prioritized research program to interpret biomonitoring data. The ICCA LRI, led by ACC s LRI, has an existing program consistent with the NRC s recommendations. The LRI program aims to develop improved methods to understand and interpret biomonitoring information, and apply those methods to exposure and risk assessment. The program includes research to develop tools to relate body burden data effectively to real-life exposure and dose scenarios and ultimately to adverse effects. More details on LRI s biomonitoring program are available in the ICCA-LRI biomonitoring research strategy (ICCA 2006) and Bahadori et al. (2007). Computational Links of Exposure and Effects. LRI research has in the past contributed to the development of models that predict fate and transport, environmental concentrations, exposures, and doses. In the next phase, research is needed to combine various models to contribute to the development of a source-to-effect modeling framework, to evaluate the framework using multiple chemicals and exposure scenarios, and to improve the computational efficiency for the approach. This research will transform exposure assessment into a more predictive science that can be use in modern risk assessment approaches. Even if extensive knowledge were available on the exposure-dose relationship for humans in their natural environment and animals/cell systems in their laboratory environments, this information needs to be related, preferably via probabilistic modeling, to account for population variability and uncertainty. Hence, computational approaches that reliably link laboratory findings to the real world will be developed. In addition, simple, reliable screening models need to be developed and validated in order to predict exposures to chemicals based on the life cycle of intended product use and the physical-chemical properties of the chemicals. This research includes the expansion of QSAR and computational chemistry methods to predict exposures as well as methods to predict release into the environment during the product life cycle. Several screening level models are currently under development in the U.S. (EPA s ORD), Canada, and Europe. Research in this area should be coordinated with these groups to develop an international approach for chemical screening. Characterizing Exposure Processes and Improving Child Exposure Factors. Exposure factors that may affect susceptibility can include activities, behaviors, and scenarios that bring pregnant women or developing organisms into contact with a chemical of concern. Of particular concern are factors that potentially can result in high-end environmental exposures. For example, a child s behaviors will result in different exposures than those of adults (e.g., hand contact with the floor, extensive hand-to-mouth contacts). Data are needed that other researchers can use to expand upon and improve those elements of available exposure models that have the greatest uncertainty and variability. Factors selected for investigation will be those that potentially will have the greatest impact on the exposure assessment when uncertainties are reduced. Improving the Science to Accurately Screen Chemicals for PBT Characteristics. This program initially will identify which criteria are major determinants of the outcomes of regulatory assessments. For example, is the octanol-water partition coefficient a major element of the screen and if, so, is it an accurate predictor of persistence? Research directed at those most sensitive criteria will then be the subject of study. 16

25 4 Susceptible Populations 4.1 What is the Issue? Classically, the concern over susceptible populations has centered on children because of the vulnerability of developing systems and increased doses to some chemicals due to child behavior and physiology. Over the last several years, scientists have discovered more about gene-environment interactions and the influence of age at both ends of the spectrum. Although such interactions and influences are definitely important, the database is still too sparse to apply this knowledge to risk assessment, with some exceptions (the major one being for children). Subtle differences in genetic factors cause people to respond differently to the same environmental exposure. This explains why some individuals have a fairly low risk of developing a disease as a result of an environmental exposure, while others are much more vulnerable. Completed LRI projects have made inroads on this topic (e.g., LRI, 2005), demonstrating its promise to understanding vulnerability to chemicals. Many programs such as the National Institutes of Health (NIH)-wide Gene and Environment Initiative aim to identify the genetic and environmental bases for diseases. The emerging knowledge and research activities provide both impetus and opportunity to incorporate this science into risk assessment. Interest in the epigenetic effects of chemicals is rapidly increasing (e.g., the scientific journal Epigenetics was launched in 2008). Epigenetics related to toxicology is generally defined at a heritable (but sometimes reversible) effect on genes, without a direct effect on DNA. Historically, environmentally related epigenetic research has been common, but under different names (e.g., some developmental toxicity effects). However, with the advent of genomic technologies and their application to the biology of development, this research area has been refined and intensified, as reflected in the new biologically oriented name. 4.2 Research Needs The overarching research need is to consider and integrate this area in developing programs under the other two areas. Doing so will add scientific depth plus be economically synergistic. Identification of Computational Approaches to Incorporate Gene-Environment Interactions into Risk Assessment. Existing knowledge on polymorphisms of metabolism of chemicals needs to be harnessed in the form of PBPK models, with indications of prevalence of those polymorphisms in the population. Ultimately, the goal is to identify properties of chemicals that may be subject to widely prevalent polymorphisms so that screening assessments can identify their potential for population risk. Although the initial focus will be on the dose elements of gene-environment interactions, it will be important to follow progress on the response element of gene-environment interactions. Such research is likely to increase understanding of the mode-of-action of chemicals, revealing properties that would be predicted to be less or more toxic. Uncertainties are inevitable. At issue, then, is 17

26 identifying those uncertainties having the greatest impact and seeking to add knowledge for clarity. Development of Approaches to Incorporate Epigenetics into Risk Assessment Practices. As knowledge accumulates on the role of epigenetics in natural development, more and more studies will examine the effect of chemicals on this process. It is unlikely that resulting data will be directly usable in risk assessment, other than to put pressure on maintaining conservative defaults even when adequate information is available. Therefore, timely interpretative research is needed to increase the utility of the body of work of others. Focus will be on chemical mode-of-actions involving DNA methylation and chromatin structure. 18

27 5 Chemical Industry Leadership The primary goal of the LRI is to accomplish research that makes a difference in risk assessment, through the research itself and through the Impact Program that brings research findings into practice. In addition to specific research findings, the LRI demonstrates that the chemical industry is an important part of the solution to creating safe, useful products for society. For a small investment, the LRI can do more, specifically by effectively communicating the value of the LRI program by cosponsoring external workshops and conferences and by reinstituting the Early Career Award program. 5.1 Building Scientific Consensus Through Fostering Communication of Research Findings Actual changes in risk assessment practices begin with research, but must move through a scientific consensus stage, which requires outreach and alliances with all stakeholders interested in furthering risk assessment. Therefore, the LRI has developed a communications strategy to help convey the program s results and value to other scientists and decision-makers. This strategy is multifaceted and goes beyond peer-reviewed publications, which are the foundation that provide knowledge and credibility. Targeted workshops and conferences are arguably the most important tool of the LRI communication strategy. The LRI will be the primary sponsor of several workshops as part of the Impact Program for each RfP. Furthermore, the LRI will co-sponsor meetings intended to advance thinking and practices of risk assessment. For a small investment (often in the $10,000 $20,000 range), the chemical industry can get positive visibility as a contributor and provide leadership and initiative to help move the consensus process along more rapidly. Encouraging multi-sector involvement at LRI-funded workshops and symposia at high-profile scientific society annual meetings will foster interactions with the scientific and regulatory communities. For example, in September 2007, the International Council of Chemical Associations jointly sponsored an international workshop with the U.S. Environmental Protection Agency, which centered on challenges in the application of biomonitoring research to public health. The workshop provided a basis for continued collaboration among interested stakeholders, for maintenance and expansion of partnerships in biomonitoring research and application, for the improvement of networking across stakeholders to further maximize resources, and for continued research into the public health applications of human biomonitoring. This meeting, the third in a series, significantly fostered interactions between the various stakeholders and enhanced the industry s leadership position on this important topic. 19

28 5.2 Early Career Awards As discussed earlier, the scientific processes underlying risk assessment are being revolutionized. Most of the achievements will come from the next generation of scientists, making training for the future leaders fundamental to success. The Early Career Awards program is intended to enhance career development for researchers early in their career at academic institutions in North America, who are focusing on the potential impacts of chemicals on human health and the environment. This program can contribute significantly to training. From 2001 through 2004, 11 Early Career Awards of $100,000 each were competitively awarded to investigators through scientific societies. To conserve funds, this program was then discontinued. As part of this 2009 to 2015 strategy, the LRI will reinstitute the program, but at a smaller scale of one award per year in the range of $50,000 to $100,000. The award mechanism will be via a professional society (i.e., the Society of Toxicology, the International Society of Exposure Science) and will rotate each year. The SST will decide the award amount and mechanism on an annual basis. Regardless of the amount and mechanism, the funded research will be relevant to the goals of the LRI that are outlined in this strategy, and will also require that significant interaction occur between the LRI and the Early Career awardee. 20

29 6 References American Chemistry Council (ACC) Long- Range Research Initiative Research Strategy. October. asp?cid=1449&did=9090. Bahadori T, Phillips RD, Money CD, Quackenboss JJ, Clewell HJ, Bus JS, Robison SH, Humphris CJ, Parekh AA, Osborn K, and Kauffman RM Making sense of human biomonitoring data: Findings and recommendations of a workshop. J Expo Sci Environ Epidemiol 17(4): International Council of Chemical Associations (ICCA) Long-Range Research Initiative Global Research Strategy. March. com/s_acc/bin.asp?cid=1389&did=5075&doc=file. PDF. ICCA Interpretation of Human Biomonitoring Data: A Research Strategy. ICCA LRI Planning Group. September 18, ICCA Global Product Strategy (accessed 2008) policyissues.asp?sid=1&vid=123&cid=1453&did=53 15&RTID=0&CIDQS=&Taxonomy=&specialSearch. National Research Council (NRC) Building a Foundation for Sound Environmental Decisions. Committee on Research Opportunities and Priorities for EPA. Board on Environmental Studies and Toxicology. ISBN: National Academy Press, Washington, D.C. NRC Human Biomonitoring for Environmental Chemicals, Board on Environmental Studies and Toxicology. National Academies Press, Washington, D.C. NRC. 2007a. Toxicity Testing in the 21 st Century: A Vision and A Strategy. Committee on Toxicity Testing and Assessment of Environmental Agents. Board on Environmental Studies and Toxicology. National Academies Press, Washington, D.C. NRC. 2007b. Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment. Board on Environmental Studies and Toxicology. National Academies Press, Washington, D.C. LRI Considering Genetic Differences in Risk Assessment: An LRI Perspective (accessed 2008) asp?cid=1405&did=

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