New Substances Assessment and Control Bureau

Ottawa, Canada

New Substances Assessment and Control Bureau

Ottawa, Canada
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Breznan D.,Environmental Health Science and Research Bureau | Das D.D.,Environmental Health Science and Research Bureau | O'Brien J.S.,Environmental Health Science and Research Bureau | MacKinnon-Roy C.,Environmental Health Science and Research Bureau | And 7 more authors.
Nanotoxicology | Year: 2017

The likelihood of environmental and health impacts of silicon dioxide nanoparticles (SiNPs) has risen, due to their increased use in products and applications. The biological potency of a set of similarly-sized amorphous SiNPs was investigated in a variety of cells to examine the influence of physico-chemical and biological factors on their toxicity. Cellular LDH and ATP, BrdU incorporation, resazurin reduction and cytokine release were measured in human epithelial A549, human THP-1 and mouse J774A.1 macrophage cells exposed for 24 h to suspensions of 5–15, 10–20 and 12 nm SiNPs and reference particles. The SiNPs were characterized in dry state and in suspension to determine their physico-chemical properties. The dose-response data were simplified into particle potency estimates to facilitate the comparison of multiple endpoints of biological effects in cells. Mouse macrophages were the most sensitive to SiNP exposures. Cytotoxicity of the individual cell lines was correlated while the cytokine responses differed, supported by cell type-specific differences in inflammation-associated pathways. SiNP (12 nm), the most cytotoxic and inflammogenic nanoparticle had the highest surface acidity, dry-state agglomerate size, the lowest trace metal and organics content, the smallest surface area and agglomerate size in suspension. Particle surface acidity appeared to be the most significant determinant of the overall biological activity of this set of nanoparticles. Combined with the nanoparticle characterization, integration of the biological potency estimates enabled a comprehensive determination of the cellular reactivity of the SiNPs. The approach shows promise as a useful tool for first-tier screening of SiNP toxicity. © 2017 Crown Copyright. Published by Informa UK Limited, trading as Taylor & Francis Group.


Long A.S.,University of Ottawa | Long A.S.,Environmental Health Science and Research Bureau | Lemieux C.L.,New Substances Assessment and Control Bureau | Gagne R.,Environmental Health Science and Research Bureau | And 3 more authors.
Environmental Science and Technology | Year: 2017

This study evaluates the risk assessment approach currently employed for polycyclic aromatic hydrocarbon (PAH)-contaminated media, wherein carcinogenic hazards are evaluated using a dose-addition model that employs potency equivalency factors (PEFs) for targeted carcinogenic PAHs. Here, MutaMouse mice were subchronically exposed to PAH mixtures (p.o.), and mutagenic potency (MP) values were determined for five tissues. Predicted dose-additive mixture MPs were generated by summing the products of the concentrations and MPs of the individual targeted PAHs; values were compared to the experimental MPs of the mixtures to evaluate dose-additivity. Additionally, the PEF-determined BaP-equivalent concentrations were compared to those determined using a bioassay-derived method (BDM) (i.e., an additivity-independent approach). In bone marrow, mixture mutagenicity was less than dose-additive and the PEF-method provided higher estimates of BaP-equivalents than the BDM. Conversely, mixture mutagenicity in site-of-contact tissues (e.g., small intestine) was generally more than dose-additive and the PEF-method provided lower estimates of BaP-equivalents than the BDM. Overall, this study demonstrates that dose-additive predictions of mixture mutagenic potency based on the concentrations and potencies of a small number of targeted PAHs results in values that are surprisingly close to those determined experimentally, providing support for the dose-additive assumption employed for human health risk assessment of PAH mixtures. © 2017 American Chemical Society.


Mackay D.,Trent University | Hughes D.M.,New Substances Assessment and Control Bureau | Romano M.L.,New Substances Assessment and Control Bureau | Bonnell M.,Environment Canada
Integrated Environmental Assessment and Management | Year: 2014

The initial stage in the assessment and priority setting of chemicals for their potential to cause harm to humans and the environment is usually a hazard assessment employing metrics for persistence, bioaccumulation, and inherent toxicity. This hazard assessment is followed, when necessary, by the more demanding task of risk assessment. Hazard assessment of data and processes influencing persistence are discussed, leading to a number of suggestions for more effective evaluation. These include 1) an initial focus on accurate data for intensive chemical partitioning and reaction half-life properties that are universally applicable as distinct from extensive properties that can be included later on a location-specific basis; 2) separate treatments of near-field and far-field exposures; 3) a focus on persistence and its effect on levels of exposure, especially for substances for which "time to exposure" is less than "time to degradation" and have been termed "pseudo-persistent." We show that "continuously present" is a better descriptor of this concern. Case studies illustrate and support these suggestions. Data on the intensive properties and on exposure pathways are best combined in evaluative multimedia mass balance models that can provide a clear depiction of the likely chemical fate, exposure routes, and levels. The information generated by the mass balance models can serve to justify and direct a full risk assessment that includes region-specific information on chemical quantities, estimates of exposure, and potential for adverse effects. Key Points: We demonstrate the importance of persistence as a criterion for hazard assessment of chemicals. We show the merit of addressing intensive chemical properties before extensive properties, We show the need to address near-field and far-field exposures separately. We introduce the concept of "time to exposure" and use it to show that continuously present is a term preferable to pseudo-persistent. These key points are illustrated using hypothetical case studies involving simple mass balance calculations. © 2014 SETAC.


Decan N.,Environmental Health Science and Research Bureau | Wu D.,Environmental Health Science and Research Bureau | Williams A.,Environmental Health Science and Research Bureau | Bernatchez S.,New Substances Assessment and Control Bureau | And 3 more authors.
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2016

The objectives of the present study were to investigate the underlying mechanisms of genetic and cellular toxicity induced by silica nanoparticles (SiNPs) and determine if such toxicity is influenced by particle size. Commercially available amorphous SiNPs (12 nm, 5-10 nm, and 10-15 nm) and micrometer sized (SiP2 μm) silica were characterised for size, chemical composition, and aggregation state. Mouse lung epithelial (FE1) cells derived from Muta™Mouse were exposed to various concentrations (12.5, 25, 50, 100 μg/ml) of SiNPs and SiP2 μm. Cellular viability, clonogenic potential, oxidative stress, micronucleus formation, and mutant frequency were measured at different post-exposure time points. Cellular internalization of particles was assessed using nanoscale hyperspectral microscopy. Biological pathway and functional perturbations were assessed using DNA microarrays. Detailed characterization of particles confirmed their size, purity, and uniform dispersion in the exposure medium. Decreased cellular viability was observed acutely at 24 h at concentrations higher than 25 μg/ml for all particle types, with SiNPs being the most sensitive; loss of viability was surface area dependent at the lowest concentration tested. However, only SiNP12 showed poor long-term survival. A size-dependent increase in micronucleus formation was also observed for SiNPs. In contrast to the viability results, SiP2 μm exhibited the highest potential to induce oxidative stress compared to the SiNPs at all tested concentrations. Gene ontology and biological pathway analysis revealed significant changes in the expression of genes implicated in lysosomal functions in SiNP12-treated cells, which appear closely associated with higher SiNP12 internalization and lysosomal rearrangements in the cytoplasm of these cells. These results suggest that SiNPs induce cellular and genetic toxicity in a size-dependent manner and that the observed toxicity may be the results of higher particle internalization of smaller SiNP and subsequent lysosomal overload. © 2015 .


Rigden M.,Environmental Health Science and Research Bureau | Pelletier G.,Environmental Health Science and Research Bureau | Pelletier G.,Environmental Health Center | Poon R.,Environmental Health Science and Research Bureau | And 12 more authors.
Archives of Environmental Contamination and Toxicology | Year: 2015

Perfluorooctanoic acid (PFOA) is a persistent environmental contaminant. Activation of the peroxisome proliferator activated receptor alpha (PPARα) resulting from exposure to PFOA has been extensively studied in rodents. However, marked differences in response to peroxisome proliferators prevent extrapolation of rodent PPARα activation to human health risks and additional molecular mechanisms may also be involved in the biological response to PFOA exposure. To further explore the potential involvement of such additional pathways, the effects of PFOA exposure on urinary metabolites were directly compared with those of other well-known PPARα agonists. Male rats were administered PFOA (10, 33, or 100 mg/kg/d), fenofibrate (100 mg/kg/d), or di(2-ethylhexyl)phthalate (100 mg/kg/d) by gavage for 3 consecutive days and allowed to recover for 4 days, and overnight urine was collected. Greater urinary output was observed exclusively in PFOA-treated rats as the total fraction of PFOA excreted in urine increased with the dose administered. Assessment of urinary metabolites (ascorbic acid, quinolinic acid, 8-hydroxy-2'-deoxyguanosine, and malondialdehyde) provided additional information on PFOA's effects on hepatic glucuronic acid and tryptophan-nicotinamide adenine dinucleotide (NAD) pathways and on oxidative stress, whereas increased liver weight and palmitoyl-CoA oxidase activity indicative of PPARα activation and peroxisomal proliferation persisted up to day five after the last exposure. © 2014 Her Majesty the Queen in Right of Canada.


Izadi H.,New Substances Assessment and Control Bureau | Grundy J.E.,New Substances Assessment and Control Bureau | Bose R.,New Substances Assessment and Control Bureau
Risk Analysis | Year: 2012

Repeated-dose studies received by the New Substances Assessment and Control Bureau (NSACB) of Health Canada are used to provide hazard information toward risk calculation. These studies provide a point of departure (POD), traditionally the NOAEL or LOAEL, which is used to extrapolate the quantity of substance above which adverse effects can be expected in humans. This project explored the use of benchmark dose (BMD) modeling as an alternative to this approach for studies with few dose groups. Continuous data from oral repeated-dose studies for chemicals previously assessed by NSACB were reanalyzed using U.S. EPA benchmark dose software (BMDS) to determine the BMD and BMD 95% lower confidence limit (BMDL 05) for each endpoint critical to NOAEL or LOAEL determination for each chemical. Endpoint-specific benchmark dose-response levels , indicative of adversity, were consistently applied. An overall BMD and BMDL 05 were calculated for each chemical using the geometric mean. The POD obtained from benchmark analysis was then compared with the traditional toxicity thresholds originally used for risk assessment. The BMD and BMDL 05 generally were higher than the NOAEL, but lower than the LOAEL. BMDL 05 was generally constant at 57% of the BMD. Benchmark provided a clear advantage in health risk assessment when a LOAEL was the only POD identified, or when dose groups were widely distributed. Although the benchmark method cannot always be applied, in the selected studies with few dose groups it provided a more accurate estimate of the real no-adverse-effect level of a substance. © 2011 Society for Risk Analysis.


PubMed | New Substances Assessment and Control Bureau
Type: Journal Article | Journal: Risk analysis : an official publication of the Society for Risk Analysis | Year: 2012

Repeated-dose studies received by the New Substances Assessment and Control Bureau (NSACB) of Health Canada are used to provide hazard information toward risk calculation. These studies provide a point of departure (POD), traditionally the NOAEL or LOAEL, which is used to extrapolate the quantity of substance above which adverse effects can be expected in humans. This project explored the use of benchmark dose (BMD) modeling as an alternative to this approach for studies with few dose groups. Continuous data from oral repeated-dose studies for chemicals previously assessed by NSACB were reanalyzed using U.S. EPA benchmark dose software (BMDS) to determine the BMD and BMD 95% lower confidence limit (BMDL(05) ) for each endpoint critical to NOAEL or LOAEL determination for each chemical. Endpoint-specific benchmark dose-response levels , indicative of adversity, were consistently applied. An overall BMD and BMDL(05) were calculated for each chemical using the geometric mean. The POD obtained from benchmark analysis was then compared with the traditional toxicity thresholds originally used for risk assessment. The BMD and BMDL(05) generally were higher than the NOAEL, but lower than the LOAEL. BMDL(05) was generally constant at 57% of the BMD. Benchmark provided a clear advantage in health risk assessment when a LOAEL was the only POD identified, or when dose groups were widely distributed. Although the benchmark method cannot always be applied, in the selected studies with few dose groups it provided a more accurate estimate of the real no-adverse-effect level of a substance.

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