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Chepelev N.L.,Environmental and Radiation Health science Directorate | Meek M.E.B.,University of Ottawa | Yauk C.L.,Environmental and Radiation Health science Directorate
Journal of Applied Toxicology | Year: 2014

Reliable quantification of gene and protein expression has potential to contribute significantly to the characterization of hypothesized modes of action (MOA) or adverse outcome pathways for critical effects of toxicants. Quantitative analysis of gene expression by benchmark dose (BMD) modeling has been facilitated by the development of effective software tools. In contrast, protein expression is still generally quantified by a less robust effect level (no or lowest [adverse] effect levels) approach, which minimizes its potential utility in the consideration of dose-response and temporal concordance for key events in hypothesized MOAs. BMD modeling is applied here to toxicological data on testicular toxicity to investigate its potential utility in analyzing protein expression relevant to the proposed MOA to inform human health risk assessment. The results illustrate how the BMD analysis of protein expression in animal tissues in response to toxicant exposure: (1) complements other toxicity data, and (2) contributes to consideration of the empirical concordance of dose-response relationships, as part of the weight of evidence for hypothesized MOAs to facilitate consideration and application in regulatory risk assessment. Lack of BMD analysis in proteomics has likely limited its use for these purposes. This paper illustrates the added value of BMD modeling to support and strengthen hypothetical MOAs as a basis to facilitate the translation and uptake of the results of proteomic research into risk assessment. © 2014 John Wiley & Sons, Ltd.

Kosarac I.,Environmental and Radiation Health science Directorate | Kubwabo C.,Environmental and Radiation Health science Directorate | Foster W.G.,McMaster University
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2016

Over the last few years, the use of organophosphate flame retardants (OPFRs) has been on the rise; however, there are knowledge gaps in both the human health effects of OPFRs and levels of human exposure. Currently, human biomonitoring data on the levels of OPFR metabolites in the Canadian population are still non-existent. Herein we describe a novel method to measure nine urinary OPFR metabolites using solid phase extraction and ultra performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). The method detection limits were between 0.08 and 0.25 ng/mL for target metabolites. The newly developed and validated method was applied to the analysis of 24 urine samples collected in 2010-12 from pregnant Canadian women. The most frequently detected OPFR metabolite in urine of study participants (detection frequency: 97%) was diphenyl phosphate (DPHP), with concentrations ranging between <0.13-25.2 ng/mL, followed (75%) by the sum of two metabolites (DoCP: Di-o-cresyl phosphate and DpCP: Di-p- cresyl phosphate) of tricresyl phosphate, with concentrations between <0.13-4.38 ng/mL. With the exception of desbutyl-tris-(2-butoxy-ethyl) phosphate which was not detected in any of the samples, all other OPFR metabolites measured were found among study participants with variable detection frequency, suggesting pregnant Canadian women may be exposed to OPFRs. © 2016.

Kosarac I.,Environmental and Radiation Health science Directorate | Kubwabo C.,Environmental and Radiation Health science Directorate | Lalonde K.,Environmental and Radiation Health science Directorate | Foster W.,McMaster University
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2012

Bisphenol A is widely used as a monomer in the manufacture of polycarbonates and epoxy resins, as an antioxidant in polyvinyl chloride (PVC) plastics and as an inhibitor of end polymerisation in PVC. Several different methods have been used to quantify total BPA in biological specimens. However, quantification of both free and conjugated BPA continues to present challenges. Moreover, there is limited data concerning fetal exposure. Therefore, the objective of this study was to develop a new method for the analysis of both free and conjugated BPA in human maternal and umbilical cord blood serum. For the analysis of free BPA, the method consisted of a liquid-liquid extraction followed by a two-step solid-phase extraction sample cleanup on Florisil and Oasis HLB sorbents, derivatization of the extract using N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) and analysis by gas chromatography/tandem mass spectrometry (GC/EI-MS/MS). To determine the amount of conjugated BPA in serum samples, bisphenol A-d6 β-glucuronide (4-[1-(4-hydroxyphenyl)-1-methylethyl-d6]phenyl β-d-glucopyranosiduronic acid) was added to each sample prior to enzymatic deconjugation. The MDL and LOQ for BPA were 0.026. ng/mL and 0.087. ng/mL, respectively. The observed recoveries ranged between 65% and 88%. The new method was applied to the determination of paired human maternal and umbilical cord blood serum samples. The results demonstrated that total BPA concentrations in human maternal serum at mid-pregnancy and at delivery ranged from <0.026. ng/mL to 10.425. ng/mL (median 0.548. ng/mL, n= 12) and <0.026. ng/mL to 3.048. ng/mL (median 1.461. ng/mL), respectively. Results for matching umbilical cord blood serum BPA concentrations were in the range of <0.026-2.569. ng/mL (median 1.823. ng/mL). The concentrations measured in this study agreed well with BPA levels in human serum reported internationally. Only 2 mid-pregnancy serum samples out of 12 contained quantifiable amounts of conjugated BPA, indicating that BPA-glucuronide is not abundant in either human maternal or umbilical cord blood serum. © 2012.

Poulsen S.S.,Helmholtz Center Munich | Poulsen S.S.,Roskilde University | Saber A.T.,Helmholtz Center Munich | Williams A.,Environmental and Radiation Health science Directorate | And 19 more authors.
Toxicology and Applied Pharmacology | Year: 2015

Multi-walled carbon nanotubes (MWCNTs) are an inhomogeneous group of nanomaterials that vary in lengths, shapes and types of metal contamination, which makes hazard evaluation difficult. Here we present a toxicogenomic analysis of female C57BL/6 mouse lungs following a single intratracheal instillation of 0, 18, 54 or 162μg/mouse of a small, curled (CNTSmall, 0.8±0.1μm in length) or large, thick MWCNT (CNTLarge, 4±0.4μm in length). The two MWCNTs were extensively characterized by SEM and TEM imaging, thermogravimetric analysis, and Brunauer-Emmett-Teller surface area analysis. Lung tissues were harvested 24h, 3days and 28days post-exposure. DNA microarrays were used to analyze gene expression, in parallel with analysis of bronchoalveolar lavage fluid, lung histology, DNA damage (comet assay) and the presence of reactive oxygen species (dichlorodihydrofluorescein assay), to profile and characterize related pulmonary endpoints. Overall changes in global transcription following exposure to CNTSmall or CNTLarge were similar. Both MWCNTs elicited strong acute phase and inflammatory responses that peaked at day 3, persisted up to 28days, and were characterized by increased cellular influx in bronchoalveolar lavage fluid, interstitial pneumonia and gene expression changes. However, CNTLarge elicited an earlier onset of inflammation and DNA damage, and induced more fibrosis and a unique fibrotic gene expression signature at day 28, compared to CNTSmall. The results indicate that the extent of change at the molecular level during early response phases following an acute exposure is greater in mice exposed to CNTLarge, which may eventually lead to the different responses observed at day 28. © 2015.

Kubwabo C.,Environmental and Radiation Health science Directorate | Kosarac I.,Environmental and Radiation Health science Directorate | Lalonde K.,Environmental and Radiation Health science Directorate
Chemosphere | Year: 2013

Polyfluoroalkyl phosphate surfactants (PAPS) are used on food contact paper to impart oil/grease resistance and have been shown to be able to migrate into food. The biotransformation of the congeners belonging to this class of compounds is considered to be a potential source of perfluorinated carboxylic acids (PFCAs). In this study, two methods were developed for the determination of seven perfluorinated compounds (PFCs) and eight polyfluorinated disubstituted phosphate surfactants (diPAPS) in human milk. PFCs were extracted from milk using an ion-pairing technique; while the diPAPs extraction involved a sample clean up using solid phase extraction. Analyses of all compounds in this study were performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Of the seven PFCs analyzed in human milk, only perfluorooctanoic acid (PFOA) was detected in eleven out of thirteen (85%) individual human milk samples analyzed, with a concentration range of <0.072 to 0.52ngmL-1. Four diPAPS were detected and quantified in human milk samples. Eight out of thirteen samples contained 4:2 diPAP with a concentration range of <0.01-0.26ngmL-1; 6:2 diPAP was detected in five samples with a concentration range of <0.01-0.14ngmL-1; 8:2 diPAP was detected in only three samples with concentrations of 0.21, 0.27, and 0.30ngmL-1. The 10:2 diPAP was quantified in seven milk samples, with concentration range of <0.01-0.83ngmL-1. No correlation was established between PFCAs and PAPS levels in this small sample size. To the best of the authors' knowledge, this is the first study to report the presence of PAPS in human milk. © 2013.

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