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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. Source

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. Source

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. Source

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. Source

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. Source

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