Summit Toxicology

Lyons, CO, United States

Summit Toxicology

Lyons, CO, United States

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Hays S.M.,Summit Toxicology | Macey K.,Health Canada | Nong A.,Health Canada | Aylward L.L.,Summit Toxicology
Regulatory Toxicology and Pharmacology | Year: 2014

Selenium is an essential nutrient for human health with a narrow range between essentiality and toxicity. Selenium is incorporated into several proteins that perform important functions in the body. With insufficient selenium intake, the most notable effect is Keshan disease, an endemic cardiomyopathy in children. Conversely, excessive selenium intake can result in selenosis, manifested as brittle nails and hair and gastro-intestinal disorders. As such, guidance values have been established to protect against both insufficient and excessive selenium exposures. Dietary Reference Intakes (DRIs) have been established as standard reference values for nutritional adequacy in North America. To protect against selenosis resulting from exposure to excessive amounts of selenium, several government and non-governmental agencies have established a range of guidance values. Exposure to selenium is primarily through the diet, but monitoring selenium intake is difficult. Biomonitoring is a useful means of assessing and monitoring selenium status for both insufficient and excessive exposures. However, to be able to interpret selenium biomonitoring data, levels associated with both DRIs and toxicity guidance values are required. Biomonitoring Equivalents (BEs) were developed for selenium in whole blood, plasma and urine. The BEs associated with assuring adequate selenium intake (Estimated Average Requirements - EAR) are 100, 80 and 10. μg/L in whole blood, plasma and urine, respectively. The BEs associated with protection against selenosis range from 400 to 480. μg/L in whole blood, 180-230. μg/L in plasma, and 90-110. μg/L in urine. These BE values can be used by both regulatory agencies and public health officials to interpret selenium biomonitoring data in a health risk context. © 2014 Elsevier Inc.

Angerer J.,Ruhr University Bochum | Aylward L.L.,Summit Toxicology | Hays S.M.,Summit Toxicology | Heinzow B.,The University of Notre Dame Australia | Wilhelm M.,Ruhr University Bochum
International Journal of Hygiene and Environmental Health | Year: 2011

Human biomonitoring (HBM) data is a very useful metric for assessing human's exposures to chemicals in commerce. To assess the potential health risks associated with the presence of chemicals in blood, urine or other biological matrix requires HBM assessment values. While HBM assessment values based on human exposure-response data remain the most highly valuable and interpretable assessment values, enough data exists for such values for very few chemicals. As a consequence, efforts have been undertaken to derive HBM assessment values in which external dose based guidance values such as tolerable daily intakes have been translated into equivalent biomonitoring levels. The development of HBM values by the German HBM Commission and Biomonitoring Equivalents by Summit Toxicology has resulted in conceptually similar assessment values. The review of the development of these values provided here demonstrates examples and approaches that can be used to broaden the range of chemicals for which such assessment values can be derived. Efforts to date have resulted in the publication of HBM assessment values for more than 80 chemicals, and now provide tools that can be used for the evaluation of HBM data across chemicals and populations. © 2011 Elsevier GmbH.

Aylward L.L.,Summit Toxicology | Kirman C.R.,Summit Toxicology | Adgate J.L.,Aurora University | McKenzie L.M.,Aurora University | Hays S.M.,Summit Toxicology
Journal of Exposure Science and Environmental Epidemiology | Year: 2012

Biomarker concentrations in spot samples of blood and urine are implicitly interpreted as direct surrogates for long-term exposure magnitude in a variety of contexts including (1) epidemiological studies of potential health outcomes associated with general population chemical exposure, and (2) cross-sectional population biomonitoring studies. However, numerous factors in addition to exposure magnitude influence biomarker concentrations in spot samples, including temporal variation in spot samples because of elimination kinetics. The influence of half-life of elimination relative to exposure interval is examined here using simple first-order pharmacokinetic simulations of urinary concentrations in spot samples collected at random times relative to exposure events. Repeated exposures were modeled for each individual in the simulation with exposure amounts drawn from lognormal distributions with varying geometric standard deviations. Relative variation in predicted spot sample concentrations was greater than the variation in underlying dose distributions when the half-life of elimination was shorter than the interval between exposures, with the degree of relative variation increasing as the ratio of half-life to exposure interval decreased. Results of the modeling agreed well with data from a serial urine collection data set from the Centers for Disease Control. Data from previous studies examining intra-class correlation coefficients for a range of chemicals relying upon repeated sampling support the importance of considering the half-life relative to exposure frequency in design and interpretation of studies using spot samples for exposure classification and exposure estimation. The modeling and data sets presented here provide tools that can assist in interpretation of variability in cross-sectional biomonitoring studies and in design of studies utilizing biomonitoring data as markers for exposure. © 2012 Nature America, Inc. All rights reserved.

Aylward L.L.,Summit Toxicology | Hays S.M.,Summit Toxicology
International Journal of Hygiene and Environmental Health | Year: 2011

Hexabromocyclododecane (HBCD) is a brominated flame retardant compound that has been the subject of recent interest and risk assessment efforts due to its detection in a variety of environmental media and in human biological matrices. Because the exposure pathways for HBCD may be varied and exposure estimation uncertain, biomonitoring for HBCD in humans shows promise as a means of reflecting integrated human exposures to HBCD with lower uncertainty than through estimation of external exposures via multiple pathways. Data from numerous biomonitoring studies of HBCD over the past decade indicate that the central tendency of lipid-adjusted serum and human milk concentrations is approximately 1. ng/g lipid, with upper bound levels of approximately 20. ng/g lipid. Recent risk assessment evaluations from Health Canada and the European Union have identified points of departure of 10 and 20. mg/kg. day, respectively, from rat repeated dose studies. The corresponding measured or estimated lipid-adjusted tissue concentrations in the laboratory animals at these points of departure range from 120,000 to 190,000. ng/g lipid. In comparison to these concentrations, the biomonitored human serum and milk concentrations indicate margins of exposure (MOEs) of 6000 to more than 100,000, which are greatly in excess of target MOE values. The use of internal dose measures (both from measurements of tissue concentrations in animal toxicology studies and from human biomonitoring studies) provides risk managers with highly relevant exposure information that is less uncertain than estimated external doses. © 2011 Elsevier GmbH.

Aylward L.L.,Summit Toxicology | Collins J.J.,Dow Chemical Company | Bodner K.M.,Dow Chemical Company | Wilken M.,Dow Chemical Company | Bodnar C.M.,Dow Chemical Company
Environmental Health Perspectives | Year: 2013

Background: Exposure reconstructions and risk assessments for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other dioxins rely on estimates of elimination rates. Limited data are available on elimination rates for congeners other than TCDD. Objectives: We estimated apparent elimination rates using a simple first-order one-compartment model for selected dioxin congeners based on repeated blood sampling in a previously studied population. Methods: Blood samples collected from 56 former chlorophenol workers in 2004-2005 and again in 2010 were analyzed for dioxin congeners. We calculated the apparent elimination half-life in each individual for each dioxin congener and examined factors potentially influencing elimination rates and the impact of estimated ongoing background exposures on rate estimates. Results: Mean concentrations of all dioxin congeners in the sampled participants declined between sampling times. Median apparent half-lives of elimination based on changes in estimated mass in the body were generally consistent with previous estimates and ranged from 6.8 years (1,2,3,7,8,9-hexachlorodibenzo-p-dioxin) to 11.6 years (pentachlorodibenzo-p-dioxin), with a composite half-life of 9.3 years for TCDD toxic equivalents. None of the factors examined, including age, smoking status, body mass index or change in body mass index, initial measured concentration, or chloracne diagnosis, was consistently associated with the estimated elimination rates in this population. Inclusion of plausible estimates of ongoing background exposures decreased apparent half-lives by approximately 10%. Available concentration-dependent toxicokinetic models for TCDD underpredicted observed elimination rates for concentrations < 100 ppt. Conclusions: The estimated elimination rates from this relatively large serial sampling study can inform occupational and environmental exposure and serum evaluations for dioxin compounds.

Buchanan S.S.,Aurora Pharmaceutical | Buchanan S.S.,Schering | Pyatt D.W.,Summit Toxicology | Carpenter J.F.,Aurora Pharmaceutical
PLoS ONE | Year: 2010

Progenitor cell therapies show great promise, but their potential for clinical applications requires improved storage and transportation. Desiccated cells stored at ambient temperature would provide economic and practical advantages over approaches employing cell freezing and subzero temperature storage. The objectives of this study were to assess a method for loading the stabilizing sugar, trehalose, into hematopoietic stem and progenitor cells (HPC) and to evaluate the effects of subsequent freeze-drying and storage at ambient temperature on differentiation and clonogenic potential. HPC were isolated from human umbilical cord blood and loaded with trehalose using an endogenous cell surface receptor, termed P2Z. Solution containing trehalose-loaded HPC was placed into vials, which were transferred to a tray freeze-dryer and removed during each step of the freeze-drying process to assess differentiation and clonogenic potential. Control groups for these experiments were freshly isolated HPC. Control cells formed 1450±230 CFU-GM, 430±140 BFU-E, and 50±40 CFUGEMM per 50 μL. Compared to the values for the control cells, there was no statistical difference observed for cells removed at the end of the freezing step or at the end of primary drying. There was a gradual decrease in the number of CFU-GM and BFU-E for cells removed at different temperatures during secondary drying; however, there were no significant differences in the number of CFU-GEMM. To determine storage stability of lyophilized HPC, cells were stored for 4 weeks at 25oC in the dark. Cells reconstituted immediately after lyophilization produced 580690 CFU-GM (~40%, relative to unprocessed controls p<0.0001), 170670 BFU-E (~40%, p,0.0001), and 41622 CFU-GEMM (~82%, p = 0.4171), and cells reconstituted after 28 days at room temperature produced 5136170 CFU-GM (~35%, relative to unprocessed controls, p <0.0001), 112668 BFU-E (~26%, p<0.0001), and 36617 CFU-GEMM (~82%, p = 0.2164) These studies are the first to document high level retention of CFU-GEMM following lyophilization and storage for 4 weeks at 25uC. This type of flexible storage stability would potentially permit the ability to ship and store HPC without the need for refrigeration. © 2010 Buchanan et al.

Aylward L.L.,Summit Toxicology | Lorber M.,U.S. Environmental Protection Agency | Hays S.M.,Summit Toxicology
Journal of Exposure Science and Environmental Epidemiology | Year: 2011

Exposure assessment analyses conducted in Europe have concluded that the primary pathway of exposure to di(2-ethylhexyl) phthalate (DEHP) is through the diet. The purpose of this study is to evaluate whether urinary DEHP metabolite data from the 2007-2008 National Health and Nutritional Examination Survey (NHANES) demonstrate relationships with reported food-fasting time consistent with diet as the predominant exposure pathway. Previous controlled-dosing data demonstrate that DEHP metabolite concentrations in urine first rise and then decline over time, with first-order elimination becoming evident at about 6 h post exposure. Regression of the concentrations of four key DEHP metabolites vs reported fasting times between 6 and 18 h in adults resulted in apparent population-based urinary elimination half-lives, consistent with those previously determined in a controlled-dosing experiment, supporting the importance of the dietary pathway for DEHP. For fasting times less than about 6 h, sampling session (morning, afternoon, or evening) affected the measured metabolite concentrations. Evening samples showed the highest metabolite concentrations, supporting a hypothesis of recent daily dietary exposures from multiple meals, whereas morning and afternoon samples for fasting times less than 6 h were similar and somewhat lower than evening samples, consistent with less-substantial early day dietary exposure. Variations in children's bodyweight-normalized creatinine excretion and food intake rates contribute to a strong inverse relationship between urinary DEHP metabolite concentrations and age under age 18. Finally, a previously published pharmacokinetic model for DEHP demonstrates that time since previous urinary void, a parameter not measured in NHANES, is predicted to result in non-random effects on measured urinary concentrations. © 2011 Nature America, Inc. All rights reserved.

Population biomonitoring data sets such as the Canadian Health Measures Survey (CHMS) and the United States National Health and Nutrition Examination Survey (NHANES) collect and analyze spot urine samples for analysis for biomarkers of exposure to non-persistent chemicals. Estimation of population intakes using such data sets in a risk-assessment context requires consideration of intra- and inter-individual variability to understand the relationship between variation in the biomarker concentrations and variation in the underlying daily and longer-term intakes. Two intensive data sets with a total of 16 individuals with collection and measurement of serial urine voids over multiple days were used to examine these relationships using methyl paraben, triclosan, bisphenol A (BPA), monoethyl phthalate (MEP), and mono-2-ethylhexyl hydroxyl phthalate (MEHHP) as example compounds. Composited 24 h voids were constructed mathematically from the individual collected voids, and concentrations for each 24 h period and average multiday concentrations were calculated for each individual in the data sets. Geometric mean and 95th percentiles were compared to assess the relationship between distributions in spot sample concentrations and the 24 h and multiday collection averages. In these data sets, spot sample concentrations at the 95th percentile were similar to or slightly higher than the 95th percentile of the distribution of all 24 h composite void concentrations, but tended to overestimate the maximum of the multiday concentration averages for most analytes (usually by less than a factor of 2). These observations can assist in the interpretation of population distributions of spot samples for frequently detected analytes with relatively short elimination half-lives.Journal of Exposure Science and Environmental Epidemiology advance online publication, 5 October 2016; doi:10.1038/jes.2016.54. © 2016 The Author(s)

Boogaard P.J.,Royal Dutch Shell | Aylward L.L.,Summit Toxicology | Hays S.M.,Summit Toxicology
International Journal of Hygiene and Environmental Health | Year: 2012

REACH requires health risk management for workers and the general population and introduced the concept of Derived No-Effect Level (DNEL). DNELs must be derived for all substances that are classified as hazardous. In analogy to other health-risk based guidance values, such as reference doses (RfDs) and tolerable daily intakes (TDIs), risk to health is considered negligible if the actual exposure is less than the DNEL. Exposure assessment is relatively simple for occupational situations but more complex for the general public, in which exposure may occur via multiple pathways, routes, and media. For such complex or partially defined exposure scenarios, human biomonitoring (HBM) gives a snapshot of the internal or absorbed dose of a chemical and is often the most reliable exposure assessment methodology. For human risk management, HBM data can be interpreted using the recently developed concept of Biomonitoring Equivalents (BEs). Basically, a BE translates an established reference value into a biomarker concentration using toxicokinetic data. If the results of an exposure assessment using HBM indicate that the levels measured are below the DNEL-based BE (BE DNEL), it would indicate that the combined exposure via all potential exposure routes is unlikely to pose a risk to human health and that health risk management measures might not be needed. Hence, BEs do not challenge existing risk assessments but rather build upon them to help risk management, the ultimate goal of any risk assessment. A challenge in implementing this approach forms the limited availability of toxicokinetic information for many substances. However, methodologies such as generic physiologically based toxicokinetic models, which allow estimation of biomarker concentrations based on physicochemical properties, are being developed for less data-rich chemicals. Acceptance of the use of BE by regulatory authorities will allow initial screening of population exposure to chemicals to identify those chemicals requiring more detailed risk and exposure assessment, assisting in priority setting and ultimately leading to improved product stewardship and risk management. © 2011 Elsevier GmbH.

Natelson E.A.,Cornell University | Pyatt D.,Summit Toxicology | Pyatt D.,University of Colorado at Denver
Advances in Hematology | Year: 2013

Myelodysplastic syndromes (MDS) are clonal myeloid disorders characterized by progressive peripheral blood cytopenias associated with ineffective myelopoiesis. They are typically considered neoplasms because of frequent genetic aberrations and patient-limited survival with progression to acute myeloid leukemia (AML) or death related to the consequences of bone marrow failure including infection, hemorrhage, and iron overload. A progression to AML has always been recognized among the myeloproliferative disorders (MPD) but occurs only rarely among those with essential thrombocythemia (ET). Yet, the World Health Organization (WHO) has chosen to apply the designation myeloproliferative neoplasms (MPN), for all MPD but has not similarly recommended that all MDS become the myelodysplastic neoplasms (MDN). This apparent dichotomy may reflect the extremely diverse nature of MDS. Moreover, the term MDS is occasionally inappropriately applied to hematologic disorders associated with acquired morphologic myelodysplastic features which may rather represent potentially reversible hematological responses to immune-mediated factors, nutritional deficiency states, and disordered myelopoietic responses to various pharmaceutical, herbal, or other potentially myelotoxic compounds. We emphasize the clinical settings, and the histopathologic features, of such AMD that should trigger a search for a reversible underlying condition that may be nonneoplastic and not MDS. © 2013 Ethan A. Natelson and David Pyatt.

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