Eric N. Liberda

Exposure to inhaled nickel nanoparticles causes a reduction in number and function of bone marrow endothelial progenitor cells

Introduction: Particulate matter (PM), specifically nickel (Ni) found on or in PM, has been associated with an increased risk of mortality in human population studies and significant increases in vascular inflammation, generation of reactive oxygen species, altered vasomotor tone, and potentiated atherosclerosis in murine exposures. Recently, murine inhalation of Ni nanoparticles have been shown to cause pulmonary inflammation that affects cardiovascular tissue and potentiates atherosclerosis. These adverse cardiovascular outcomes may be due to the effects of Ni on endothelial progenitor cells (EPCs), endogenous semi-pluripotent stem cells that aid in endothelial repair. Thus, we hypothesize that Ni nanoparticle exposures decrease cell count and cause impairments in function that may ultimately have significant effects on various cardiovascular diseases, such as, atherosclerosis. Methods: Experiments involving inhaled Ni nanoparticle exposures (2 days/5 h/day at ∼1200 µg/m3, 3 days/5 h/day at ∼700 µg/m3, and 5 days/5 h/day at ∼100 µg/m3), were performed in order to quantify bone marrow resident EPCs using flow cytometry in C57BL/6 mice. Plasma levels of human stromal cell-derived factor 1α (SDF-1α) and vascular endothelial growth factor (VEGF) were assessed by enzyme-linked immunosorbent assay and in vitro functional assessments of cultured EPCs were conducted. Results and conclusions: Significant EPC count differences between exposure and control groups for Ni nanoparticle exposures were observed. Differences in EPC tube formation and chemotaxis were also observed for the Ni nanoparticle exposed group. Plasma VEGF and SDF-1α differences were not statistically significant. In conclusion, this study shows that inhalation of Ni nanoparticles results in functionally impaired EPCs and reduced number in the bone marrow, which may lead to enhanced progression of atherosclerosis.

The Role of Metal Components in the Cardiovascular Effects of PM2.5

Exposure to ambient fine particulate matter (PM2.5) increases risks for cardiovascular disorders (CVD). However, the mechanisms and components responsible for the effects are poorly understood. Based on our previous murine exposure studies, a translational pilot study was conducted in female residents of Jinchang and Zhangye, China, to test the hypothesis that specific chemical component of PM2.5 is responsible for PM2.5 associated CVD. Daily ambient and personal exposures to PM2.5 and 35 elements were measured in the two cities. A total of 60 healthy nonsmoking adult women residents were recruited for measurements of inflammation biomarkers. In addition, circulating endothelial progenitor cells (CEPCs) were also measured in 20 subjects. The ambient levels of PM2.5 were comparable between Jinchang and Zhangye (47.4 and 54.5µg/m3, respectively). However, the levels of nickel, copper, arsenic, and selenium in Jinchang were 82, 26, 12, and 6 fold higher than Zhangye, respectively. The levels of C-reactive protein (3.44±3.46 vs. 1.55±1.13), interleukin-6 (1.65±1.17 vs. 1.09±0.60), and vascular endothelial growth factor (117.6±217.0 vs. 22.7±21.3) were significantly higher in Jinchang. Furthermore, all phenotypes of CEPCs were significantly lower in subjects recruited from Jinchang than those from Zhangye. These results suggest that specific metals may be important components responsible for PM2.5-induced cardiovascular effects and that the reduced capacity of endothelial repair may play a critical role.

Inhaled nickel nanoparticles alter vascular reactivity in C57BL/6 mice

Background: The use of nanoparticles (NPs) in technological applications is rapidly expanding, but the potential health effects associated with NP exposure are still largely unknown. Given epidemiological evidence indicating an association between inhaled ambient ultrafine particles and increased risk of cardiovascular disease morbidity and mortality, it has been suggested that exposure to NPs via inhalation may induce similar cardiovascular responses. Methods: Male C57BL/6 mice were exposed via whole-body inhalation to either filtered air (FA) or nickel hydroxide (NH) NPs (100, 150, or 900 µg/m3) for 1, 3, or 5 consecutive days (5 h/day). At 24-h post-exposure, vascular function in response to a vasoconstrictor, phenylephrine (PE), and a vasodilator, acetylcholine (ACh), was measured in the carotid artery. Results: Carotid arteries from mice exposed to all concentrations of NH-NPs showed statistically significant differences in graded doses of PE-induced contractile responses compared with those from FA mice. Similarly, vessels from NH-NP-exposed mice also demonstrated impaired vasorelaxation following graded doses of ACh as compared with FA mice. Conclusions: These results suggest that short-term exposure to NH-NPs can induce acute endothelial disruption and alter vasoconstriction and vasorelaxation. These findings are consistent with other studies assessing vascular tone and function in the aorta, coronary, and mesenteric vessels from mice exposed to motor vehicular exhaust and concentrated ambient particles.

Dietary exposure of PBDEs resulting from a subsistence diet in three First Nation communities in the James Bay Region of Canada

BACKGROUND Concerns regarding the persistence, bioaccumulation, long-range transport, and adverse health effects of polybrominated dipheyl ethers (PBDEs) have recently come to light. PBDEs may potentially be of concern to indigenous (First Nations) people of Canada who subsist on traditional foods, but there is a paucity of information on this topic. OBJECTIVES AND METHODS To investigate whether the traditional diet is a major source of PBDEs in sub-Arctic First Nations populations of the Hudson Bay Lowlands (James and Hudson Bay),Ontario, Canada, a variety of tissues from wild game and fish were analyzed for PBDE content (n=147) and dietary exposure assessed and compared to the US EPA reference doses (RfDs). In addition, to examine the effect of isolation/industrialization on PBDE body burdens, the blood plasma from three First Nations (Cree Nation of Oujé-Bougoumou, Quebec; Fort Albany First Nation, Ontario; and Weenusk First Nation [Peawanuck], Ontario, Canada) were collected (n=54) and analyzed using a log-linear contingency model. RESULTS AND CONCLUSIONS The mean values of PBDEs in wild meats and fish adjusted for standard consumption values and body weight, did not exceed the US EPA RfD. Log linear modeling of the human PBDE body burden showed that PBDE body burden increases as access to manufactured goods increases. Thus, household dust from material goods containing PBDEs is likely responsible for the human exposure; the traditional First Nations diet appears to be a minor source of PBDEs.

The complexity of hair/blood mercury concentration ratios and its implications.

BACKGROUND The World Health Organization (WHO) recommends a mercury (Hg) hair-to-blood ratio of 250 for the conversion of Hg hair levels to those in whole blood. This encouraged the selection of hair as the preferred analyte because it minimizes collection, storage, and transportation issues. In spite of these advantages, there is concern about inherent uncertainties in the use of this ratio. OBJECTIVES To evaluate the appropriateness of the WHO ratio, we investigated total hair and total blood Hg concentrations in 1333 individuals from 9 First Nations (Aboriginal) communities in northern Québec, Canada. METHODS We grouped participants by sex, age, and community and performed a 3-factor (M)ANOVA for total Hg in hair (0-2 cm), total Hg in blood, and their ratio. In addition, we calculated the percent error associated with the use of the WHO ratio in predicting blood Hg concentrations from hair Hg. For group comparisons, Estimated Marginal Means (EMMS) were calculated following ANOVA. RESULTS At the community level, the error in blood Hg estimated from hair Hg ranged -25% to +24%. Systematic underestimation (-8.4%) occurred for females and overestimation for males (+5.8%). At the individual level, the corresponding error range was -98.7% to 1040%, with observed hair-to-blood ratios spanning 3 to 2845. CONCLUSIONS The application of the ratio endorsed by the WHO would be unreliable for determining individual follow-up. We propose that Hg exposure be assessed by blood measurements when there are human health concerns, and that the singular use of hair and the hair-to-blood concentration conversion be discouraged in establishing individual risk.

The Acute Exposure Effects of Inhaled Nickel Nanoparticles on Murine Endothelial Progenitor Cells

Abstract Introduction: The discovery of endothelial progenitor cells (EPCs) may help to explain observed cardiovascular effects associated with inhaled nickel nanoparticle exposures, such as increases in vascular inflammation, generation of reactive oxygen species, altered vasomotor tone and potentiated atherosclerosis in murine species. Methods: Following an acute whole body inhalation exposure to 500 µg/m3 of nickel nanoparticles for 5 h, bone marrow EPCs from C57BL/6 mice were isolated. EPCs were harvested for their RNA or used in a variety of assays including chemotaxis, tube formation and proliferation. Gene expression was assessed for important receptors involved in EPC mobilization and homing using RT-PCR methods. EPCs, circulating endothelial progenitor cells (CEPCs), circulating endothelial cells (CECs) and endothelial microparticles (EMPs) were quantified on a BD FACSCalibur to examine endothelial damage and repair associated with the exposure. Results and conclusions: Acute exposure to inhaled nickel nanoparticles significantly increased both bone marrow EPCs as well as their levels in circulation (CEPCs). CECs were significantly elevated indicating that endothelial damage occurred due to the exposure. There was no significant difference in EMPs between the two groups. Tube formation and chemotaxis, but not proliferation, of bone marrow EPCs was impaired in the nickel nanoparticle exposed group. These results coincided with a decrease in the mRNA of receptors involved in EPC mobilization and homing. These data provide new insight into how an acute nickel nanoparticle exposure to half of the current Occupational Safety & Health Administration (OSHA) permissible exposure limit may adversely affect EPCs and exacerbate cardiovascular disease states.

In vitro assessment of the inflammatory response of respiratory endothelial cells exposed to particulate matter.

Particulate matter (PM) is a ubiquitous environmental pollutant that has been associated with increased risk of cardiopulmonary mortality and morbidity in urban communities. An increasing body of evidence suggests that inflammation induced by PM may play an important role in the development of cardiovascular diseases. However, airway epithelial cell lines, instead of vascular endothelial cells, are commonly used to investigate the effects of PM with respect to cardiovascular effects. Thus, the present study was conducted using primary human vascular endothelial cells (HMVEC-LB1), human white blood cells (WBC), and their cocultures to evaluate their inflammatory responses to various PM exposures. Enzyme-linked immunosorbent assay (ELISA) kits were used to measure the concentrations of interleukin (IL)-6, soluble intercellular adhesion marker (sICAM-1), and soluble vascular cell adhesion marker (sVCAM-1) in HMVEC-LB1, WBC, and their cocultures after exposure to size-fractionated PM. Pretreatment of cells with inhibitors was performed in order to examine pathways involved in PM-induced cellular responses. IL-6 levels increased significantly in HMVEC-LB1 cells exposed to PM in both a time- and concentration-dependent manner. However, particle exposure for up to 24 h failed to induce any detectable production of sICAM-1 or sVCAM-1 in HMVEC-LB1 cells. IL-6 production in response to size-fractioned PM exposures failed to show evidence of relative importance of particle sizes in their abilities to induce proinflammatory responses. Lastly, cocultures with WBC significantly enhanced particle induced IL-6 release in HMVEC-LB1 cells in a synergistic manner. The present study suggests that HMVEC-LB1 cells can be successfully used as an in vitro model to examine effects of PM exposure.

Mining in subarctic Canada: airborne PM2.5 metal concentrations in two remote First Nations communities.

Airborne particulate matter arising from upwind mining activities is a concern for First Nations communities in the western James Bay region of Ontario, Canada. Aerosol chemical components were collected in 2011 from two communities in northern Ontario. The chemical and mass concentration data of particulate matter collected during this study shows a significant difference in PM2.5 in Attawapiskat compared to Fort Albany. Elemental profiles indicate enhanced levels of some tracers thought to arise from mining activities, such as, K, Ni, and crustal materials. Both communities are remote and isolated from urban and industrial pollution sources, however, Attawapiskat First Nation has significantly enhanced levels of particulate matter, and it is likely that some of this arises from upwind mining activities.

Achieving Control of Occupational Exposures to Engineered Nanomaterials.

Occupational exposures resulting from Engineered Nanomaterials (ENMs) can pose a challenge for applying traditional risk assessment, control, or evaluation standards. This article discusses the limitations in traditional risk management approaches when it comes to ENM exposures, reviews current monitoring options, and suggests an interim management framework until research can meet the standard of evidence required by legislators. The proposed Nanomaterial Occupational Exposure Management Model (NOEM) offers a pragmatic approach that integrates resources from current academic research to provide a framework that can be applied by both industry and regulators. The NOEM Model focuses on addressing three concerns to exposure management: Risk Assessment, Exposure Control, and Exposure Monitoring. The resources supported for meeting these three components involve the integration of the Control Banding Nanotool and Nano Reference Values, both of which have been piloted and accepted through peer-reviewed processes and industry consultation.

An evaluation of the toxicological aspects and potential doses from the inhalation of coal combustion products

This paper reviews toxicological literature pertaining to coal combustion products (CCPs) inhalation and presents case studies on the inhalation of CCPs from the Kingston Fossil Plant area and from the Colbert Fossil Plant CCP landfill site. While most research regarding coal plant emissions focuses on fly ash, this article takes a holistic approach to examining not only emitted particulate matter such as fly ash, but also the theoretical calculated doses of landfilled CCPs. Furthermore, these doses are compared to in vitro and in vivo studies in order to highlight differences between laboratory-based studies and to emphasize the difficulty in extrapolating effects from inhalation exposures. In both case studies, fugitive emissions from the Kingston ash spill or the Colbert CCP-handling operations did not exceed any national ambient air quality standards or reference concentrations for individual components. Adverse effects such as mild pulmonary inflammation noted in the reviewed literature were in response to doses much higher than would be likely to occur in humans exposed to landfilled CCPs. We conclude that the doses for fugitive emissions calculated herein do not appear to be high enough to elicit a measurable adverse response in humans. Implications: This paper is the first study to assess the potential exposure of inhaled coal combustion products (CCPs). Two case studies, the Kingston and Colbert fossil plant sites, are used to calculate theoretical exposures due to CCPs. Additionally, human exposure results are compared to published toxicological in vitro and in vivo data, which highlights the difficulty in extrapolating these studies to humans.