Summit Toxicology

Lyons, CO, United States

Summit Toxicology

Lyons, CO, United States
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Thompson C.M.,ToxStrategies Inc. | Proctor D.M.,ToxStrategies Inc. | Suh M.,ToxStrategies Inc. | Haws L.C.,ToxStrategies Inc. | And 2 more authors.
Critical Reviews in Toxicology | Year: 2013

Chronic exposure to high concentrations of hexavalent chromium (Cr(VI)) in drinking water causes intestinal adenomas and carcinomas in mice, but not in rats. Cr(VI) causes damage to intestinal villi and crypt hyperplasia in mice after only one week of exposure. After two years of exposure, intestinal damage and crypt hyperplasia are evident in mice (but not rats), as are intestinal tumors. Although Cr(VI) has genotoxic properties, these findings suggest that intestinal tumors in mice arise as a result of chronic mucosal injury. To better understand the mode of action (MOA) of Cr(VI) in the intestine, a 90-day drinking water study was conducted to collect histological, biochemical, toxicogenomic and pharmacokinetic data in intestinal tissues. Using MOA analyses and human relevance frameworks proposed by national and international regulatory agencies, the weight of evidence supports a cytotoxic MOA with the following key events: (a) absorption of Cr(VI) from the intestinal lumen, (b) toxicity to intestinal villi, (c) crypt regenerative hyperplasia and (d) clonal expansion of mutations within the crypt stem cells, resulting in late onset tumorigenesis. This article summarizes the data supporting each key event in the MOA, as well as data that argue against a mutagenic MOA for Cr(VI)-induced intestinal tumors. © 2013 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.


Pyatt D.,Summit Toxicology | Pyatt D.,University of Colorado | Hays S.,Summit Toxicology
Chemico-Biological Interactions | Year: 2010

Chronic exposure to high concentrations of benzene is an established cause of acute myeloid leukemia (AML) in occupationally exposed workers. Based on this association, it is not unreasonable to assume that children could also get AML if they were exposed to comparable levels of benzene. Fortunately, reports of such exposures and subsequent AML development in children are non-existent. However, the question of whether children can develop leukemia at far lower, environmental levels of benzene remains. The existing scientific evidence relevant to this question will be addressed in this review. While positive findings have been reported, the collective literature does not indicate that exposure to environmental levels of benzene is related to an increased risk of childhood leukemia. Our understanding of this important issue would be strengthened by additional studies that accurately characterize exposures as well as differentiate between the various forms of leukemias observed in children. © 2010 Elsevier Ireland Ltd.


Boogaard P.J.,Royal Dutch Shell | Hays S.M.,Summit Toxicology | Aylward L.L.,Summit Toxicology
Regulatory Toxicology and Pharmacology | Year: 2011

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 health hazards. As with analogues 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 gives a snapshot of internal or absorbed dose of a chemical and is often the most reliable exposure assessment methodology as it integrates exposures from all routes. For human risk management human biomonitoring data can be interpreted using the recently developed concept of Biomonitoring Equivalents (BE). Basically, a BE translates an established reference value into a biomarker concentration using toxicokinetic data. If the results of an exposure assessment using human biomonitoring 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. 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. © 2010 Elsevier Inc.


Aylward L.L.,Summit Toxicology | Hays S.M.,Summit Toxicology
Journal of Applied Toxicology | Year: 2011

The US Environmental Protection Agency (US EPA) Toxcast™ program has the stated goal of predicting hazard, characterizing toxicity pathways and prioritizing the toxicity testing of environmental chemicals through the use of in vitro high-throughput screening (HTS) assays. This analysis integrates data from biomonitoring and from in vivo toxicity and pharmacokinetic studies to examine the physiological relevance of the tested and responding in vitro concentrations for five case study chemicals: triclosan, 2,4-dichlorophenoxyacetic acid, perfluorooctanoic acid, monobutyl phthalate and mono-2(ethylhexyl)phthalate. This analysis also examines the ToxCast™ phase 1 data set for approximately 50 chemicals belonging to four 'common mechanism groups' which have been the subject of cumulative risk assessments by the US EPA for both the pattern of key responses and the relative potencies of included chemicals compared with the in vivo relative potencies. Responding concentrations in vitro were generally in the range of serum or plasma concentrations associated with no-observed to lowest-observed effect levels for the case study chemicals, while available biomonitoring data demonstrating actual exposures were generally lower. ToxCast™ assay endpoints related to acetylcholinesterase (AChE) inhibition had low sensitivity for detecting organophosphate pesticides but good sensitivity for detecting N-methyl carbamates. However, in vitro relative potencies did not correlate with in vivo potency. Both qualitative and quantitative predictive power is probably affected by the lack of comprehensive metabolic activity in most current in vitro systems explored in the ToxCast™ program, and this remains a fundamental challenge for high-throughput toxicity screening efforts. © 2011 John Wiley & Sons, Ltd.


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.


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)


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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