Kevin L. Dreher

Exposure, Health and Ecological Effects Review of Engineered Nanoscale Cerium and Cerium Oxide Associated with its Use as a Fuel Additive

Advances of nanoscale science have produced nanomaterials with unique physical and chemical properties at commercial levels which are now incorporated into over 1000 products. Nanoscale cerium (di) oxide (CeO2) has recently gained a wide range of applications which includes coatings, electronics, biomedical, energy and fuel additives. Many applications of engineered CeO2 nanoparticles are dispersive in nature increasing the risk of exposure and interactions with a variety of environmental media with unknown health, safety and environmental implications. As evident from a risk assessment perspective, the health effects of CeO2 nanoparticles are not only dependent on their intrinsic toxicity but also on the level of exposure to these novel materials. Although this may seem logical, numerous studies have assessed the health effects of nanoparticles without this simple but critical risk assessment perspective. This review extends previous exposure and toxicological assessments for CeO2 particles by summarizing the current state of micro and nano-scale cerium exposure and health risks derived from epidemiology, air quality monitoring, fuel combustion and toxicological studies to serve as a contemporary comprehensive and integrated toxicological assessment. Based on the new information presented in this review there is an ongoing exposure to a large population to new diesel emissions generated using fuel additives containing CeO2 nanoparticles for which the environmental (air quality and climate change) and public health impacts of this new technology are not known. Therefore, there is an absolute critical need for integrated exposure and toxicological studies in order to accurately assess the environmental, ecological and health implications of nanotechnology enabled diesel fuel additives with existing as well as new engine designs and fuel formulations.

Meeting Report: Hazard Assessment for Nanoparticles—Report from an Interdisciplinary Workshop

In this report we present the findings from a nanotoxicology workshop held 6–7 April 2006 at the Woodrow Wilson International Center for Scholars in Washington, DC. Over 2 days, 26 scientists from government, academia, industry, and nonprofit organizations addressed two specific questions: what information is needed to understand the human health impact of engineered nanoparticles and how is this information best obtained? To assess hazards of nanoparticles in the near-term, most participants noted the need to use existing in vivo toxicologic tests because of their greater familiarity and interpretability. For all types of toxicology tests, the best measures of nanoparticle dose need to be determined. Most participants agreed that a standard set of nanoparticles should be validated by laboratories worldwide and made available for benchmarking tests of other newly created nanoparticles. The group concluded that a battery of tests should be developed to uncover particularly hazardous properties. Given the large number of diverse materials, most participants favored a tiered approach. Over the long term, research aimed at developing a mechanistic understanding of the numerous characteristics that influence nanoparticle toxicity was deemed essential. Predicting the potential toxicity of emerging nanoparticles will require hypothesis-driven research that elucidates how physicochemical parameters influence toxic effects on biological systems. Research needs should be determined in the context of the current availability of testing methods for nanoscale particles. Finally, the group identified general policy and strategic opportunities to accelerate the development and implementation of testing protocols and ensure that the information generated is translated effectively for all stakeholders.

Role of soluble metals in oil fly ash-induced airway epithelial injury and cytokine gene expression

Particulate matter (PM) metal content and bioavailability have been hypothesized to play a role in the health effects epidemiologically associated with PM exposure, in particular that associated with emission source PM. Using rat tracheal epithelial cells in primary culture, the present study compared and contrasted the acute airway epithelial effects of an emission source particle, residual oil fly ash (ROFA), with that of its principal constitutive transition metals, namely iron, nickel, and vanadium. Over a 24-h period, exposure to ROFA, vanadium, or nickel plus vanadium, but not to iron or nickel, resulted in increased epithelial permeability, decreased cellular glutathione, cell detachment, and lytic cell injury. Treatment of vanadium-exposed cells with buthionine sulfoximine further increased cytotoxicity. Conversely, treatment with the radical scavenger dimethylthiourea inhibited the effects in a dose-dependent manner. RT-PCR analysis of RNA isolated from ROFA-exposed rat tracheal epithelial cells demonstrated significant macrophage inflammatory protein-2 and interleukin-6 gene expression as early as 6 h after exposure, whereas gene expression of inducible nitric oxide synthase was maximally increased 24 h postexposure. Again, vanadium (not nickel) appeared to be mediating the effects of ROFA on gene expression. Treatment with dimethylthiourea inhibited both ROFA- and vanadium-induced gene expression in a dose-dependent manner. Corresponding effects were observed in interleukin-6 and macrophage inflammatory protein-2 synthesis. In summary, generation of an oxidative stress was critical to induction of the ROFA- or vanadium-induced effects on airway epithelial gene expression, cytokine production, and cytotoxicity.Particulate matter (PM) metal content and bioavailability have been hypothesized to play a role in the health effects epidemiologically associated with PM exposure, in particular that associated with emission source PM. Using rat tracheal epithelial cells in primary culture, the present study compared and contrasted the acute airway epithelial effects of an emission source particle, residual oil fly ash (ROFA), with that of its principal constitutive transition metals, namely iron, nickel, and vanadium. Over a 24-h period, exposure to ROFA, vanadium, or nickel plus vanadium, but not to iron or nickel, resulted in increased epithelial permeability, decreased cellular glutathione, cell detachment, and lytic cell injury. Treatment of vanadium-exposed cells with buthionine sulfoximine further increased cytotoxicity. Conversely, treatment with the radical scavenger dimethylthiourea inhibited the effects in a dose-dependent manner. RT-PCR analysis of RNA isolated from ROFA-exposed rat tracheal epithelial cells demonstrated significant macrophage inflammatory protein-2 and interleukin-6 gene expression as early as 6 h after exposure, whereas gene expression of inducible nitric oxide synthase was maximally increased 24 h postexposure. Again, vanadium (not nickel) appeared to be mediating the effects of ROFA on gene expression. Treatment with dimethylthiourea inhibited both ROFA- and vanadium-induced gene expression in a dose-dependent manner. Corresponding effects were observed in interleukin-6 and macrophage inflammatory protein-2 synthesis. In summary, generation of an oxidative stress was critical to induction of the ROFA- or vanadium-induced effects on airway epithelial gene expression, cytokine production, and cytotoxicity.

Ambient particulate matter and respiratory and cardiovascular illness in adults: particle-borne transition metals and the heart-lung axis(,).

Epidemiological studies have consistently shown associations of exposure to ambient particulate matter (PM) with severe health effects, including mortality and hospitalization, in adults. From the standpoints of both relative risk and attributable risk, the public health burden of ambient PM exposure is potentially greatest in elderly adults with underlying cardiopulmonary illness. Recent experimental data suggest that PM-borne transition metals have toxicity that could be mechanistically relevant to PM-related epidemiological findings. These data may prove to be especially relevant in elderly adults with cardiopulmonary illness. At the same time, important uncertainties remain in the epidemiological and experimental databases, such that the true degree of correspondence between the two is not yet known. In our opinion, this combination of emerging experimental-epidemiological coherence and remaining uncertainty imparts high priority to further research into the health effects of PM-borne transition metals. This research should not be confined to the respiratory system. Rather, it should examine the entire heart-lung axis and should probably consider other body systems (e.g. the vascular system) as well. In this research, close interdisciplinary communication should be sustained and experimental and epidemiological approaches should be coordinated to the maximum feasible extent.

Ozone-induced tissue injury and changes in antioxidant homeostasis in normal and ascorbate-deficient guinea pigs.

It has been reported previously that ozone (O3) toxicity from acute (4 hr) exposure is enhanced by ascorbate (AH2) deficiency in guinea pigs. We hypothesized that lung injury from continuous 1-week O3 exposure would also be increased under conditions of AH2 deficiency because of (1) a diminished antioxidant pool to counteract the oxidant challenge, (2) impaired reparation of tissue injury, and/or (3) altered antioxidant redox homeostasis. Female Hartley guinea pigs (260-330 g) were made AH2 deficient by providing a diet similar to guinea pig chow, but having no AH2. The dietary regimen was started 1 week prior to exposure and was continued during exposure to O3 (0, 0.2, 0.4, or 0.8 ppm, 23 hr/day, 7 days) as well as 1 week post-exposure. Bronchoalveolar lavage (BAL) and tissue AH2 were measured in subgroups at the beginning of exposure (1 week on the AH2-deficient diet), at its termination and 1 week post-exposure. AH2 measured in ear tissue punches proved to be an easy and effective monitor for AH2 deficiency. One week on the AH2-deficient diet caused a 70-80% drop in ear, lung and liver AH2, while AH2 in BAL was decreased by 90%. Immediately after the exposure, total BAL protein and albumin (markers of lung permeability) were increased (approximately 50%) at 0.8 ppm with no difference between the dietary groups. O3 caused an increase in total BAL cells and neutrophils in a concentration-dependent manner with only a slight augmentation due to diet. Exposure to O3 caused an increase in lung and BAL AH2 in normal guinea pigs. Glutathione and uric acid were also increased in the lung and BAL after O3 exposure (40-570%) in both dietary groups, and the levels remained elevated during the recovery period. Lung alpha-tocopherol was not changed due to O3. A significant overall diet-related decrease was seen in AH2-deficient guinea pigs, immediately after the exposure and recovery. In summary, lung injury/inflammation following 1 week O3 exposure and recovery were minimally affected by AH2 deficiency. Antioxidants also appeared to increase in response to O3 exposure despite the deficiency in AH2.

A public-private consortium advances cardiac safety evaluation: achievements of the HESI Cardiac Safety Technical Committee.

INTRODUCTIONnThe evaluation of cardiovascular side-effects is a critical element in the development of all new drugs and chemicals. Cardiac safety issues are a major cause of attrition and withdrawal due to adverse drug reactions (ADRs) in pharmaceutical drug development.nnnMETHODSnThe evolution of the HESI Technical Committee on Cardiac Safety from 2000-2013 is presented as an example of an effective international consortium of academic, government, and industry scientists working to improve cardiac safety.nnnRESULTS AND DISCUSSIONnThe HESI Technical Committee Working Groups facilitated the development of a variety of platforms for resource sharing and communication among experts that led to innovative strategies for improved drug safety. The positive impacts arising from these Working Groups are described in this article.

In vitro screening of metal oxide nanoparticles for effects on neural function using cortical networks on microelectrode arrays

Abstract Nanoparticles (NPs) may translocate to the brain following inhalation or oral exposures, yet higher throughput methods to screen NPs for potential neurotoxicity are lacking. The present study examined effects of 5 CeO2 (5– 1288u2009nm), and 4 TiO2 (6–142u2009nm) NPs and microparticles (MP) on network function in primary cultures of rat cortex on 12 well microelectrode array (MEA) plates. Particles were without cytotoxicity at concentrations ≤50u2009µg/ml. After recording 1u2009h of baseline activity prior to particle (3–50u2009µg/ml) exposure, changes in the total number of spikes (TS) and # of active electrodes (#AEs) were assessed 1, 24, and 48u2009h later. Following the 48u2009h recording, the response to a challenge with the GABAA antagonist bicuculline (BIC; 25u2009µM) was assessed. In all, particles effects were subtle, but 69u2009nm CeO2 and 25u2009nm TiO2 NPs caused concentration-related decreases in TS following 1u2009h exposure. At 48u2009h, 5 and 69u2009nm CeO2 and 25 and 31u2009nm TiO2 decreased #AE, while the two MPs increased #AEs. Following BIC, only 31u2009nm TiO2 produced concentration-related decreases in #AEs, while 1288u2009nm CeO2 caused concentration-related increases in both TS and #AE. The results indicate that some metal oxide particles cause subtle concentration-related changes in spontaneous and/or GABAA receptor-mediated neuronal activity in vitro at times when cytotoxicity is absent, and that MEAs can be used to screen and prioritize nanoparticles for neurotoxicity hazard.

Environmental aging alters Al(OH)3 coating of TiO2 nanoparticles enhancing their photocatalytic and phototoxic activities

As a component of sunscreen formulations, TiO2 engineered nanomaterials (ENM) are coated to prevent reactive oxygen species from causing damage to skin. We investigated the stability of an Al(OH)3 coating by exposing 25 nm Al(OH)3·TiO2 ENM to simulated swimming pool water (SPW) for 45 minutes, 1, 3, 10, or 14 days. Electron microscopy and spectroscopy indicated that exposure to SPW caused a redistribution of the Al(OH)3 coating allowing photocatalytic formation of hydroxyl radicals. Aged ENM showed significantly greater phototoxicity under UVA irradiation than un-aged ENM in a human-derived retinal pigment epithelium cell line (ARPE-19). Photocatalytic activity and phototoxicity of aged Al(OH)3·TiO2 was significantly less than that of the positive control—uncoated P25 TiO2. In summary, the aging of Al(OH)3·TiO2 ENM in SPW redistributed the coating and reduced its protective properties, thereby increasing reactivity and potential phototoxicity.

Biokinetically-Based In Vitro Cardiotoxicity of Residual Oil Fly Ash: Hazard Identification and Mechanisms of Injury

AbstractnEpidemiological studies have associated air pollution particulate matter (PM) exposure with adverse cardiovascular effects. Identification of causal PM sources is critically needed to support regulatory decisions to protect public health. This research examines the in vitro cardiotoxicity of bioavailable constituents of residual oil fly ash (ROFA) employing in vivo, biokinetically-based, concentrations determined from their pulmonary deposition. Pulmonary deposition of ROFA led to a rapid increase in plasma vanadium (V) levels that were prolonged in hypertensive animals without systemic inflammation. ROFA cardiotoxicity was evaluated using neonatal rat cardiomyocyte (RCM) cultures exposed to particle-free leachates of ROFA (ROFA-L) at levels present in exposed rat plasma. Cardiotoxicity was observed at low levels (3.13xa0μg/mL) of ROFA-L 24xa0h post-exposure. Dimethylthiourea (28xa0mM) inhibited ROFA-L-induced cytotoxicity at high (25–12.5xa0μg/mL) doses, suggesting that oxidative stress is responsible at high ROFA-L doses. Cardiotoxicity could not be reproduced using a Vxa0+xa0Nixa0+xa0Fe mixture or a ROFA-L depleted of these metals, suggesting that ROFA-L cardiotoxicity requires the full complement of bioavailable constituents. Susceptibility of RCMs to ROFA-L-induced cytotoxicity was increased following tyrosine phosphorylation inhibition, suggesting that phosphotyrosine signaling pathways play a critical role in regulating ROFA-L-induced cardiotoxicity. These data demonstrate that bioavailable constituents of ROFA are capable of direct adverse cardiac effects.