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Stefan Trapp - One of the best experts on this subject based on the ideXlab platform.
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methods for estimating the bioconcentration factor of ionizable organic Chemicals
Environmental Toxicology and Chemistry, 2009Co-Authors: Wenjing Fu, Antonio Franco, Stefan TrappAbstract:The bioaccumulation potential is an important criterion in Risk Assessment of Chemicals. Several regressions between bioconcentration factor (BCF) in fish and octanol-water partition coefficient (KOW) have been developed for neutral organic compounds, but very few approaches address the BCF of ionizable compounds. A database with BCFs of 73 acids and 65 bases was collected from the literature. The BCF estimation method recommended by the Technical Guidance Document (TGD) for Chemical Risk Assessment in the European Union was tested for ionizing substances using log KOW (corrected for the neutral species, log[fn·KOW]) and log D (sum of log KOW of neutral and ionic molecule, apparent log KOW) as predictors. In addition, the method of Meylan et al. (Environ Toxicol Chem 1999; 18:664–672) for ionizable compounds and a dynamic cell model based on the Fick-Nernst-Planck equation were tested. Moreover, our own regressions for the BCF were established from log KOW and pKa. The bioaccumulation of lipophilic compounds depends mainly on their lipophilicity, and the best predictor is log D. Dissociation, the pH-dependent ion trap, and electrical attraction of cations impact the BCF. Several methods showed acceptable results. The TGD regressions gave good predictions when log(fn·KOW) or log D were used as a predictor instead of log KOW. The new regressions to log KOW and pKa performed similarly, with mean errors of approximately 0.4. The method of Meylan et al. did not perform as well. The cell model showed weak results for acids but was among the best methods for bases.
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modeling the exposure of children and adults via diet to Chemicals in the environment with crop specific models
Environmental Pollution, 2009Co-Authors: Charlotte Nielsen Legind, Stefan TrappAbstract:Exposure to Chemicals via diet is a major uptake pathway for many compounds but is often estimated in a rather generic way. We use a new model framework (NMF) with crop-specific models to predict the dietary intake by 4-5-year-old children and 14-75-year-old women of three environmental compounds from their background concentrations in soil and air. Calculated daily intakes of benzo(a)pyrene and 2,3,7,8-TCDD are in good agreement with measured results from diet studies. The major source of both compounds in human diet is deposition from air. Inhalation of air and ingestion of soil play a minor role. Children take up more than twice the amount than adults per kg bodyweight, due to higher consumption per kg bodyweight. Contrary, the methods for indirect human exposure suggested in the Technical Guidance Document (TGD) for Chemical Risk Assessment in the EU lead to overprediction, due to unrealistic consumption data and a false root model.
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environmental chemistry methods for estimating the bioconcentration factor of ionizable organic Chemicals
2009Co-Authors: Wenjing Fu, Antonio Franco, Stefan TrappAbstract:The bioaccumulation potential is an important criterion in Risk Assessment of Chemicals. Several regressions between bioconcentration factor (BCF) in fish and octanol-water partition coefficient (KOW) have been developed for neutral organic com- pounds, but very few approaches address the BCF of ionizable compounds. A database with BCFs of 73 acids and 65 bases was collected from the literature. The BCF estimation method recommended by the Technical Guidance Document (TGD) for Chemical Risk Assessment in the European Union was tested for ionizing substances using log KOW (corrected for the neutral species, log( fn ·KOW)) and log D (sum of logKOW of neutral and ionic molecule, apparent log KOW) as predictors. In addition, the method of Meylan et al. (Environ Toxicol Chem 1999; 18:664-672) for ionizable compounds and a dynamic cell model based on the Fick- Nernst-Planck equation were tested. Moreover, our own regressions for the BCF were established from log KOW and pKa. The bioaccumulation of lipophilic compounds depends mainly on their lipophilicity, and the best predictor is log D. Dissociation, the pH-dependent ion trap, and electrical attraction of cations impact the BCF. Several methods showed acceptable results. The TGD regressions gave good predictions when log( fn ·KOW )o r logD were used as a predictor instead of log KOW. The new regressions to log KOW and pKa performed similarly, with mean errors of approximately 0.4. The method of Meylan et al. did not perform as well. The cell model showed weak results for acids but was among the best methods for bases.
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coupled mother child model for bioaccumulation of pops in nursing infants
Environmental Pollution, 2008Co-Authors: Stefan Trapp, L M Bomholtz, Charlotte Nielsen LegindAbstract:Bioaccumulation of persistent organic pollutants (POPs) leads to high levels in human milk and high doses of POPs for nursing infants. This is currently not considered in Chemical Risk Assessment. A coupled model for bioaccumulation of organic Chemicals in breast-feeding mother and nursing infant was developed and tested for a series of organic compounds. The bioaccumulation factors (BAFs) in mother, breast milk and child were predicted to vary with logK(OW) and, for volatile compounds, with K(AW) and concentration in air. The concentrations of POPs in the infant body increase the first half year to about factor 3 above mother and decline thereafter to lower levels. The predicted results are close to empirical data and to an empirical regression. The new mother-child model is compact due to its easy structure and the analytical matrix solution. It could be added to existing exposure and Risk Assessment systems, such as EUSES.
Melvin E. Andersen - One of the best experts on this subject based on the ideXlab platform.
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identifying qualitative differences in pparα signaling networks in human and rat hepatocytes and their significance for next generation Chemical Risk Assessment methods
Toxicology in Vitro, 2020Co-Authors: Patrick D Mcmullen, Sudin Bhattacharya, Courtney G Woods, Salil N Pendse, Mary Mcbride, Valerie Y Soldatow, Chad Deisenroth, Edward L Lecluyse, Rebecca A Clewell, Melvin E. AndersenAbstract:Abstract In this paper, we evaluate the PPARα signaling network in rats, examining transcriptional responses in primary hepatocytes exposed to a PPARα specific ligand, GW7647. These transcriptomic studies were complemented with ChIP-seq studies of PPARα binding and transcription binding motif identification for PPARα responsive genes. We also conducted a limited study of GW7647 dosing the in intact rat to examine differences in transcriptional responses for primary hepatocytes in vitro and in the intact liver. The rat network has a much larger number of down-regulated genes and pathways than we had found in the human and the PPARα binding motifs in rat differed for upregulated and down regulated genes. Based on these results and comparison with our previous work with the human PPARα signaling network, we identified qualitative differences in the transcriptional networks controlled by PPARα activation in the two species that provide an explanation of the interspecies differences in the responses of humans and rodents to GW7647 and likely to other PPARα agonists. These studies also allow some observations on the manner in which in vitro, fit-for-purpose assays in human hepatocytes could form the basis for Risk Assessment without recourse to in-life studies in rodents or other test species.
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integrating pathway based transcriptomic data into quantitative Chemical Risk Assessment a five Chemical case study
Mutation Research, 2012Co-Authors: Russell S Thomas, Harvey J Clewell, Bruce C Allen, Longlong Yang, Eric Healy, Melvin E. AndersenAbstract:The traditional approach for performing a Chemical Risk Assessment is time and resource intensive leading to a limited number of published Assessments on which to base human health decisions. In comparison, most contaminated sites contain Chemicals without published reference values or cancer slope factors that are not considered quantitatively in the overall hazard index calculation. The integration of transcriptomic technology into the Risk Assessment process may provide an efficient means to evaluate quantitatively the health Risks associated with data poor Chemicals. In a previous study, female B6C3F1 mice were exposed to multiple concentrations of five Chemicals that were positive for lung and/or liver tumor formation in a two-year rodent cancer bioassay. The mice were exposed for a period of 13 weeks and the target tissues were analyzed for traditional histological and organ weight changes and transcriptional changes using microarrays. In this study, the dose-response changes in gene expression were analyzed using a benchmark dose (BMD) approach and the responses grouped based on pathways. A comparison of the transcriptional BMD values with those for the traditional non-cancer and cancer apical endpoints showed a high degree of correlation for specific pathways. Many of the correlated pathways have been implicated in non-cancer and cancer disease pathogenesis. The results demonstrate that transcriptomic changes in pathways can be used to estimate non-cancer and cancer points-of-departure for use in quantitative Risk Assessments and have identified potential toxicity pathways involved in Chemically induced mouse lung and liver responses.
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application of transcriptional benchmark dose values in quantitative cancer and noncancer Risk Assessment
Toxicological Sciences, 2011Co-Authors: Russell S Thomas, Harvey J Clewell, Bruce C Allen, Scott C Wesselkamper, Nina Ching Y Wang, Jay Q Zhao, Jason C Lambert, Janet K Hesswilson, Melvin E. AndersenAbstract:: The traditional approach for estimating noncancer and cancer reference values in quantitative Chemical Risk Assessment is time and resource intensive. The extent and nature of the studies required under the traditional approach has limited the number of Chemicals with published Risk Assessments. In this study, female mice were exposed for 13 weeks to multiple concentrations of five Chemicals that were positive in a 2-year cancer bioassay. Traditional histological and organ weight changes were evaluated, and gene expression microarray analysis was performed on the target tissues. The histological, organ weight changes, and the original tumor incidences in the original cancer bioassay were analyzed using standard benchmark dose (BMD) methods to identify noncancer and cancer points of departure, respectively. The dose-related changes in gene expression were also analyzed using a BMD approach and the responses grouped based on cellular biological processes. A comparison of the transcriptional BMD values with those for the traditional noncancer and cancer apical endpoints showed a high degree of correlation for specific cellular biological processes. For Chemicals with human exposure data, the transcriptional BMD values were also used to calculate a margin of exposure. The margins of exposure ranged from 1900 to 54,000. Both the correlation between the BMD values for the transcriptional and apical endpoints and the margin of exposure analysis suggest that transcriptional BMD values may be used as potential points of departure for noncancer and cancer Risk Assessment.
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toxicity testing in the 21st century implications for human health Risk Assessment
Risk Analysis, 2009Co-Authors: Daniel Krewski, Melvin E. Andersen, Ellen Mantus, Lauren ZeiseAbstract:At the request of the Environmental Protection Agency, the National Research Council (NRC) recently completed a major report entitled Toxicity Testing in the 21st Century: A Vision and a Strategy. The terms of reference for this report were to develop a long-range vision and strategic plan to advance the practices of toxicity testing and human health Assessment of environmental agents. The report describes how current and anticipated scientific advances can be expected to transform toxicity testing to permit broader coverage of the universe of potentially toxic Chemicals to which humans may be exposed, using more timely and more cost-effective methods for toxicity testing. The report envisages greatly expanded use of high- and medium-throughput in vitro screening assays, computational toxicology, and systems biology, along with other emerging high-content testing methodologies, such as functional genomics and transcriptomics. When fully implemented, the vision will transform the ways toxicity testing and Chemical Risk Assessment are conducted, moving away from measuring apical health endpoints in experimental animals toward identification of significant perturbations of toxicity pathways using in vitro tests in human cells and cell lines. Population-based studies incorporating relevant biomarkers will also be useful in identifying pathway perturbations directly in humans and in interpreting the results of in vitro tests in the context of human health Risk Assessment. The present article summarizes and extends the NRC report and examines its implications for Risk Assessment practice.
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Toxicokinetic modeling and its applications in Chemical Risk Assessment.
Toxicology letters, 2003Co-Authors: Melvin E. AndersenAbstract:In recent years physiologically based pharmacokinetic (PBPK) modeling has found frequent application in Risk Assessments where PBPK models serve as important adjuncts to studies on modes of action of xenobiotics. In this regard, studies on mode of action provide insight into both the sites/mechanisms of action and the form of the xenobiotic associated with toxic responses. Validated PBPK models permit calculation of tissue doses of xenobiotics and metabolites for a variety of conditions, i.e. at low-doses, in different animal species, and in different members of a human population. In this manner, these PBPK models support the low-dose and interspecies extrapolations that are important components of current Risk Assessment methodologies. PBPK models are sometimes referred to as physiological toxicokinetic (PT) models to emphasize their application with compounds causing toxic responses. Pharmacokinetic (PK) modeling in general has a rich history. Data-based PK compartmental models were developed in the 1930's when only primitive tools were available for solving sets of differential equations. These models were expanded in the 1960's and 1970's to accommodate new observations on dose-dependent elimination and flow-limited metabolism. The application of clearance concepts brought many new insights about the disposition of drugs in the body. In the 1970's PBPK/PT models were developed to evaluate metabolism of volatile compounds of occupational importance, and, for the first time, dose-dependent processes in toxicology were included in PBPK models in order to assess the conditions under which saturation of metabolic and elimination processes lead to non-linear dose response relationships. In the 1980's insights from Chemical engineers and occupational toxicology were combined to develop PBPK/PT models to support Risk Assessment with methylene chloride and other solvents. The 1990's witnessed explosive growth in Risk Assessment applications of PBPK/PT models and in applying sensitivity and variability methods to evaluate model performance. Some of the compounds examined in detail include butadiene, styrene, glycol ethers, dioxins and organic esters/aids. This paper outlines the history of PBPK/PT modeling, emphasizes more recent applications of PBPK/TK models in health Risk Assessment, and discusses the Risk Assessment perspective provided by modern uses of these modeling approaches.
Russell S Thomas - One of the best experts on this subject based on the ideXlab platform.
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the next generation blueprint of computational toxicology at the u s environmental protection agency
Toxicological Sciences, 2019Co-Authors: Russell S Thomas, Maureen R Gwinn, Tina Bahadori, Christopher M Grulke, Chad Deisenroth, Timothy J Buckley, John Cowden, Kathie L Dionisio, Jeffrey B Frithsen, Joshua A HarrillAbstract:The U.S. Environmental Protection Agency (EPA) is faced with the challenge of efficiently and credibly evaluating Chemical safety often with limited or no available toxicity data. The expanding number of Chemicals found in commerce and the environment, coupled with time and resource requirements for traditional toxicity testing and exposure characterization, continue to underscore the need for new approaches. In 2005, EPA charted a new course to address this challenge by embracing computational toxicology (CompTox) and investing in the technologies and capabilities to push the field forward. The return on this investment has been demonstrated through results and applications across a range of human and environmental health problems, as well as initial application to regulatory decision-making within programs such as the EPA’s Endocrine Disruptor Screening Program. The CompTox initiative at EPA is more than a decade old. This manuscript presents a blueprint to guide the strategic and operational direction over the next 5 years. The primary goal is to obtain broader acceptance of the CompTox approaches for application to higher tier regulatory decisions, such as Chemical Assessments. To achieve this goal, the blueprint expands and refines the use of high-throughput and computational modeling approaches to transform the components in Chemical Risk Assessment, while systematically addressing key challenges that have hindered progress. In addition, the blueprint outlines additional investments in cross-cutting efforts to characterize uncertainty and variability, develop software and information technology tools, provide outreach and training, and establish scientific confidence for application to different public health and environmental regulatory decisions.
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accelerating the pace of Chemical Risk Assessment
Chemical Research in Toxicology, 2018Co-Authors: Robert J Kavlock, Maureen R Gwinn, Tina Bahadori, Tara S Bartonmaclaren, Mike Rasenberg, Russell S ThomasAbstract:Changes in Chemical regulations worldwide have increased the demand for new data on Chemical safety. New approach methodologies (NAMs) are defined broadly here as including in silico approaches and in chemico and in vitro assays, as well as the inclusion of information from the exposure of Chemicals in the context of hazard [European Chemicals Agency, “New Approach Methodologies in Regulatory Science”, 2016]. NAMs for toxicity testing, including alternatives to animal testing approaches, have shown promise to provide a large amount of data to fill information gaps in both hazard and exposure. In order to increase experience with the new data and to advance the applications of NAM data to evaluate the safety of data-poor Chemicals, demonstration case studies have to be developed to build confidence in their usability. Case studies can be used to explore the domains of applicability of the NAM data and identify areas that would benefit from further research, development, and application. To ensure that this...
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Chemical Risk Assessment traditional vs public health perspectives
American Journal of Public Health, 2017Co-Authors: Maureen R Gwinn, Daniel A Axelrad, Tina Bahadori, David Bussard, Wayne E Cascio, Kacee Deener, David J Dix, Russell S Thomas, Robert J Kavlock, Thomas A BurkeAbstract:Preventing adverse health effects of environmental Chemical exposure is fundamental to protecting individual and public health. When done efficiently and properly, Chemical Risk Assessment enables Risk management actions that minimize the incidence and effects of environmentally induced diseases related to Chemical exposure. However, traditional Chemical Risk Assessment is faced with multiple challenges with respect to predicting and preventing disease in human populations, and epidemiological studies increasingly report observations of adverse health effects at exposure levels predicted from animal studies to be safe for humans. This discordance reinforces concerns about the adequacy of contemporary Risk Assessment practices for protecting public health.It is becoming clear that to protect public health more effectively, future Risk Assessments will need to use the full range of available data, draw on innovative methods to integrate diverse data streams, and consider health endpoints that also reflect t...
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Recommended approaches in the application of toxicogenomics to derive points of departure for Chemical Risk Assessment
Archives of Toxicology, 2017Co-Authors: Reza Farmahin, Russell S Thomas, Andrew Williams, Byron Kuo, Nikolai L. Chepelev, Tara S. Barton-maclaren, Ivan H. Curran, Andy Nong, Michael G. Wade, Carole L. YaukAbstract:There is increasing interest in the use of quantitative transcriptomic data to determine benchmark dose (BMD) and estimate a point of departure (POD) for human health Risk Assessment. Although studies have shown that transcriptional PODs correlate with those derived from apical endpoint changes, there is no consensus on the process used to derive a transcriptional POD. Specifically, the subsets of informative genes that produce BMDs that best approximate the doses at which adverse apical effects occur have not been defined. To determine the best way to select predictive groups of genes, we used published microarray data from dose–response studies on six Chemicals in rats exposed orally for 5, 14, 28, and 90 days. We evaluated eight approaches for selecting genes for POD derivation and three previously proposed approaches (the lowest pathway BMD, and the mean and median BMD of all genes). The relationship between transcriptional BMDs derived using these 11 approaches and PODs derived from apical data that might be used in Chemical Risk Assessment was examined. Transcriptional BMD values for all 11 approaches were remarkably aligned with corresponding apical PODs, with the vast majority of toxicogenomics PODs being within tenfold of those derived from apical endpoints. We identified at least four approaches that produce BMDs that are effective estimates of apical PODs across multiple sampling time points. Our results support that a variety of approaches can be used to derive reproducible transcriptional PODs that are consistent with PODs produced from traditional methods for Chemical Risk Assessment.
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temporal concordance between apical and transcriptional points of departure for Chemical Risk Assessment
Toxicological Sciences, 2013Co-Authors: Russell S Thomas, Longlong Yang, Eric Healy, Scott C Wesselkamper, Nina Ching Y Wang, Jay Q Zhao, Dan D Petersen, Jason C Lambert, Ila Cote, Michael B BlackAbstract:The number of legacy Chemicals without toxicity reference values combined with the rate of new Chemical development is overwhelming the capacity of the traditional Risk Assessment paradigm. More efficient approaches are needed to quantitatively estimate Chemical Risks. In this study, rats were dosed orally with multiple doses of six Chemicals for 5 days and 2, 4, and 13 weeks. Target organs were analyzed for traditional histological and organ weight changes and transcriptional changes using microarrays. Histological and organ weight changes in this study and the tumor incidences in the original cancer bioassays were analyzed using benchmark dose (BMD) methods to identify noncancer and cancer points of departure. The dose-response changes in gene expression were also analyzed using BMD methods and the responses grouped based on signaling pathways. A comparison of transcriptional BMD values for the most sensitive pathway with BMD values for the noncancer and cancer apical endpoints showed a high degree of correlation at all time points. When the analysis included data from an earlier study with eight additional Chemicals, transcriptional BMD values for the most sensitive pathway were significantly correlated with noncancer (r = 0.827, p = 0.0031) and cancer-related (r = 0.940, p = 0.0002) BMD values at 13 weeks. The average ratio of apical-to-transcriptional BMD values was less than two, suggesting that for the current Chemicals, transcriptional perturbation did not occur at significantly lower doses than apical responses. Based on our results, we propose a
Martin Scheringer - One of the best experts on this subject based on the ideXlab platform.
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environmental fate and exposure models advances and challenges in 21st century Chemical Risk Assessment
Environmental Science: Processes & Impacts, 2018Co-Authors: Antonio Di Guardo, Todd Gouin, Matthew Macleod, Martin ScheringerAbstract:Environmental fate and exposure models are a powerful means to integrate information on Chemicals, their partitioning and degradation behaviour, the environmental scenario and the emissions in order to compile a picture of Chemical distribution and fluxes in the multimedia environment. A 1995 pioneering book, resulting from a series of workshops among model developers and users, reported the main advantages and identified needs for research in the field of multimedia fate models. Considerable efforts were devoted to their improvement in the past 25 years and many aspects were refined; notably the inclusion of nanomaterials among the modelled substances, the development of models at different spatial and temporal scales, the estimation of Chemical properties and emission data, the incorporation of additional environmental media and processes, the integration of sensitivity and uncertainty analysis in the simulations. However, some challenging issues remain and require research efforts and attention: the need of methods to estimate partition coefficients for polar and ionizable Chemical in the environment, a better description of bioavailability in different environments as well as the requirement of injecting more ecological realism in exposure predictions to account for the diversity of ecosystem structures and functions in Risk Assessment. Finally, to transfer new scientific developments into the realm of regulatory Risk Assessment, we propose the formation of expert groups that compare, discuss and recommend model modifications and updates and help develop practical tools for Risk Assessment.
Yumei Tan - One of the best experts on this subject based on the ideXlab platform.
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pbpk model reporting template for Chemical Risk Assessment applications
Regulatory Toxicology and Pharmacology, 2020Co-Authors: Yumei Tan, Melissa Chan, Amechi Chukwudebe, Jeanne Y Domoradzki, Jeffrey W Fisher, Eric C Hack, Paul M Hinderliter, Kota Hirasawa, Jeremy A Leonard, Annie LumenAbstract:Physiologically-based pharmacokinetic (PBPK) modeling analysis does not stand on its own for regulatory purposes but is a robust tool to support drug/Chemical safety Assessment. While the development of PBPK models have grown steadily since their emergence, only a handful of models have been accepted to support regulatory purposes due to obstacles such as the lack of a standardized template for reporting PBPK analysis. Here, we expand the existing guidances designed for pharmaceutical applications by recommending additional elements that are relevant to environmental Chemicals. This harmonized reporting template can be adopted and customized by public health agencies receiving PBPK model submission, and it can also serve as general guidance for submitting PBPK-related studies for publication in journals or other modeling sharing purposes. The current effort represents one of several ongoing collaborations among the PBPK modeling and Risk Assessment communities to promote, when appropriate, incorporating PBPK modeling to characterize the influence of pharmacokinetics on safety decisions made by regulatory agencies.
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uses of nhanes biomarker data for Chemical Risk Assessment trends challenges and opportunities
Environmental Health Perspectives, 2015Co-Authors: Jon R Sobus, Yumei Tan, Robert S Dewoskin, Joachim D Pleil, Martin B Phillips, Barbara Jane George, Krista Y Christensen, Dina M Schreinemachers, Marc A Williams, Elaine Cohen A HubalAbstract:BackgroundEach year, the U.S. NHANES measures hundreds of Chemical biomarkers in samples from thousands of study participants. These biomarker measurements are used to establish population referenc...