Relevance of the rat lung tumor response to particle overload for human risk assessment—Update and interpretation of new data since ILSI 2000

The relevance of particle-overload related lung tumors in rats for human risk assessment following chronic inhalation exposures to poorly soluble particulates (PSP) has been a controversial issue for more than three decades. In 1998, an ILSI (International Life Sciences) Working Group of health scientists was convened to address this issue of applicability of experimental study findings of lung neoplasms in rats for lifetime-exposed production workers to PSPs. A full consensus view was not reached by the Workshop participants, although it was generally acknowledged that the findings of lung tumors in rats following chronic inhalation, particle-overload PSP exposures occurred only in rats and no other tested species; and that there was an absence of lung cancers in PSP-exposed production workers. Since the publication of the ILSI Workshop report in 2000, there have been important new data published on the human relevance issue. A thorough and comprehensive review of the health effects literature on poorly soluble particles/lung overload was undertaken and published by an ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals) Task Force in 2013. One of the significant conclusions derived from that technical report was that the rat is unique amongst all species in developing lung tumors under chronic inhalation overload exposures to PSPs. Accordingly, the objective of this review is to provide important insights on the fundamental differences in pulmonary responses between experimentally-exposed rats, other experimental species and occupationally-exposed humans. Briefly, five central factors are described by the following issues. • Interspecies differences in lung responses of rats vs. other rodents, triggering different adverse outcome pathways (AOPs); • Interspecies differences in inhaled particle kinetics in rats vs nonhuman primates and humans triggering differential particle-related pulmonary responses. • Advanced and updated human respiratory tract deposition and retention models allowing more realistic particle translocation/retention estimates. • Differences in morphologies and characterizations of rat vs. human pulmonary tumor types and locations within the respiratory tract. • Comprehensive in-depth analysis of available epidemiological data from PSP production workers that demonstrate no correlation between particle exposures and lung cancers or other non-malignant respiratory diseases. Focusing on these five interrelated/convergent factors clearly demonstrate an inappropriateness in concluding that the findings of lung tumors in rats exposed chronically to high concentrations of PSPs are accurate representations of the risks of lung cancer in PSP-exposed production workers. The most plausible conclusion that can be reached is that results from chronic particle-overload inhalation studies with PSPs in rats have no relevance for determining lung cancer risks in production workers exposed for a working lifetime to these poorly soluble particulate-types

Assessment of the potential in vivo ecotoxicity of Double-Walled Carbon Nanotubes (DWNTs) in water, using the amphibian Ambystoma mexicanum

Because of their specific properties (mechanical, electrical, etc), carbon nanotubes (CNTs) are being assessed for inclusion in many manufactured products. Due to their massive production and number of potential applications, the impact of CNTs on the environment must be taken into consideration. The present investigation evaluates the ecotoxic potential of CNTs in the amphibian larvae (Ambystoma mexicanum). Acute toxicity and genotoxicity were analysed after 12 days of exposure in laboratory conditions. The genotoxic effects were analysed by scoring the micronucleated erythrocytes in the circulating blood of the larvae according to the French standard micronucleus assay. The results obtained in the present study demonstrated that CNTs are neither acutely toxic nor genotoxic to larvae whatever the CNTs concentration in the water, although black masses of CNTs were observed inside the gut. In the increasing economical context of CNTs, complementary studies must be undertaken, especially including mechanistic and environmental investigations

Engineered nanomaterials: toward effective safety management in research laboratories

It is still unknown which types of nanomaterials and associated doses represent an actual danger to humans and environment. Meanwhile, there is consensus on applying the precautionary principle to these novel materials until more information is available. To deal with the rapid evolution of research, including the fast turnover of collaborators, a user-friendly and easy-to-apply risk assessment tool offering adequate preventive and protective measures has to be provided.Results: Based on new information concerning the hazards of engineered nanomaterials, we improved a previously developed risk assessment tool by following a simple scheme to gain in efficiency. In the first step, using a logical decision tree, one of the three hazard levels, from H1 to H3, is assigned to the nanomaterial. Using a combination of decision trees and matrices, the second step links the hazard with the emission and exposure potential to assign one of the three nanorisk levels (Nano 3 highest risk; Nano 1 lowest risk) to the activity. These operations are repeated at each process step, leading to the laboratory classification. The third step provides detailed preventive and protective measures for the determined level of nanorisk.Conclusions: We developed an adapted simple and intuitive method for nanomaterial risk management in research laboratories. It allows classifying the nanoactivities into three levels, additionally proposing concrete preventive and protective measures and associated actions. This method is a valuable tool for all the participants in nanomaterial safety. The users experience an essential learning opportunity and increase their safety awareness. Laboratory managers have a reliable tool to obtain an overview of the operations involving nanomaterials in their laboratories; this is essential, as they are responsible for the employee safety, but are sometimes unaware of the works performed. Bringing this risk to a three-band scale (like other types of risks such as biological, radiation, chemical, etc.) facilitates the management for occupational health and safety specialists. Institutes and school managers can obtain the necessary information to implement an adequate safety management system. Having an easy-to-use tool enables a dialog between all these partners, whose semantic and priorities in terms of safety are often different

Subspecific Identification of Sharp-Tailed Grouse Samples from Montana

Columbian sharp-tailed grouse (Tympanuchus phasianellus columbianus) historically occupied much of the shrub-steppe habitat of the intermountain west, ranging from interior British Columbia south to California and Colorado. The subspecies has been extirpated from most of its range and currently exists in only scattered isolated populations. The last remnant populations in western Montana were located in the Tobacco Valley near Eureka and the Blackfoot Valley near Helmville. However, those populations were extirpated during the previous decade and the subspecies can no longer be confirmed in the state. A rangewide genetic analysis of sharp-tailed grouse in 2006 documented restricted gene flow based on an analysis of 45 tissue samples taken from Montana birds east of the continental divide. We extended that earlier analysis with a total of 133 tissue samples, including samples from western Montana birds extracted from museum skins collected in 1897, and compared these samples to other genetic profiles reported from across the species range. We compared these samples to test for genetic differences in an area where the reported distribution of the Columbian subspecies is geographically near populations from the plains subspecies (T. p. jamesi). We were able to assign subspecies classification to 126 of the 133 Montana samples, including all samples from west of the Continental Divide. All Montana samples conclusively typed out to the Plains subspecies. Our analysis identified 3 similar genetic clusters across sharptail populations: (1) Alberta, Colorado, Montana, North Dakota, South Dakota and Nebraska, (2) Washington, British Columbia and western Idaho, and (3) Utah and southern Idaho. Both microsatellite and control region sequence data indicate that sharp-tailed grouse from all localities in Montana are molecularly most similar to populations from the plains regions of Alberta to Nebraska, indicating that Montana birds share a relatively recent molecular history. It does not appear that the Continental Divide is a current or historical barrier to gene flow in sharp-tailed grouse

How should the completeness and quality of curated nanomaterial data be evaluated?

Nanotechnology is of increasing significance. Curation of nanomaterial data into electronic databases offers opportunities to better understand and predict nanomaterials' behaviour. This supports innovation in, and regulation of, nanotechnology. It is commonly understood that curated data need to be sufficiently complete and of sufficient quality to serve their intended purpose. However, assessing data completeness and quality is non-trivial in general and is arguably especially difficult in the nanoscience area, given its highly multidisciplinary nature. The current article, part of the Nanomaterial Data Curation Initiative series, addresses how to assess the completeness and quality of (curated) nanomaterial data. In order to address this key challenge, a variety of related issues are discussed: the meaning and importance of data completeness and quality, existing approaches to their assessment and the key challenges associated with evaluating the completeness and quality of curated nanomaterial data. Considerations which are specific to the nanoscience area and lessons which can be learned from other relevant scientific disciplines are considered. Hence, the scope of this discussion ranges from physicochemical characterisation requirements for nanomaterials and interference of nanomaterials with nanotoxicology assays to broader issues such as minimum information checklists, toxicology data quality schemes and computational approaches that facilitate evaluation of the completeness and quality of (curated) data. This discussion is informed by a literature review and a survey of key nanomaterial data curation stakeholders. Finally, drawing upon this discussion, recommendations are presented concerning the central question: how should the completeness and quality of curated nanomaterial data be evaluated

Impact of pulmonary exposure to gold core silver nanoparticles of different size and capping agents on cardiovascular injury

Background:The uses of engineered nanomaterials have expanded in biomedical technology and consumer manufacturing. Furthermore, pulmonary exposure to various engineered nanomaterials has, likewise, demonstrated the ability to exacerbate cardiac ischemia reperfusion (I/R) injury. However, the influence of particle size or capping agent remains unclear. In an effort to address these influences we explored response to 2 different size gold core nanosilver particles (AgNP) with two different capping agents at 2 different time points. We hypothesized that a pulmonary exposure to AgNP induces cardiovascular toxicity influenced by inflammation and vascular dysfunction resulting in expansion of cardiac I/R Injury that is sensitive to particle size and the capping agent. Methods: Male Sprague–Dawley rats were exposed to 200 μg of 20 or 110 nm polyvinylprryolidone (PVP) or citrate capped AgNP. One and 7 days following intratracheal instillation serum was analyzed for concentrations of selected cytokines; cardiac I/R injury and isolated coronary artery and aorta segment were assessed for constrictor responses and endothelial dependent relaxation and endothelial independent nitric oxide dependent relaxation. Results: AgNP instillation resulted in modest increase in selected serum cytokines with elevations in IL-2, IL-18, and IL-6. Instillation resulted in a derangement of vascular responses to constrictors serotonin or phenylephrine, as well as endothelial dependent relaxations with acetylcholine or endothelial independent relaxations by sodium nitroprusside in a capping and size dependent manner. Exposure to both 20 and 110 nm AgNP resulted in exacerbation cardiac I/R injury 1 day following IT instillation independent of capping agent with 20 nm AgNP inducing marginally greater injury. Seven days following IT instillation the expansion of I/R injury persisted but the greatest injury was associated with exposure to 110 nm PVP capped AgNP resulted in nearly a two-fold larger infarct size compared to naïve. Conclusions: Exposure to AgNP may result in vascular dysfunction, a potentially maladaptive sensitization of the immune system to respond to a secondary insult (e.g., cardiac I/R) which may drive expansion of I/R injury at 1 and 7 days following IT instillation where the extent of injury could be correlated with capping agents and AgNP size.This work was supported by the National Institute of Environmental Health Sciences U19ES019525, U01ES020127, U19ES019544 and East Carolina Universit

Genotoxicity of metal oxide nanomaterials: review of recent data and discussion of possible mechanisms

Nanotechnology has rapidly entered into human society, revolutionized many areas, including technology, medicine and cosmetics. This progress is due to the many valuable and unique properties that nanomaterials possess. In turn, these properties might become an issue of concern when considering potentially uncontrolled release to the environment. The rapid development of new nanomaterials thus raises questions about their impact on the environment and human health. This review focuses on the potential of nanomaterials to cause genotoxicity and summarizes recent genotoxicity studies on metal oxide/silica nanomaterials. Though the number of genotoxicity studies on metal oxide/silica nanomaterials is still limited, this endpoint has recently received more attention for nanomaterials, and the number of related publications has increased. An analysis of these peer reviewed publications over nearly two decades shows that the test most employed to evaluate the genotoxicity of these nanomaterials is the comet assay, followed by micronucleus, Ames and chromosome aberration tests. Based on the data studied, we concluded that in the majority of the publications analysed in this review, the metal oxide (or silica) nanoparticles of the same core chemical composition did not show different genotoxicity study calls (i.e. positive or negative) in the same test, although some results are inconsistent and need to be confirmed by additional experiments. Where the results are conflicting, it may be due to the following reasons: (1) variation in size of the nanoparticles; (2) variations in size distribution; (3) various purities of nanomaterials; (4) variation in surface areas for nanomaterials with the same average size; (5) differences in coatings; (6) differences in crystal structures of the same types of nanomaterials; (7) differences in size of aggregates in solution/media; (8) differences in assays; (9) different concentrations of nanomaterials in assay tests. Indeed, due to the observed inconsistencies in the recent literature and the lack of adherence to appropriate, standardized test methods, reliable genotoxicity assessment of nanomaterials is still challenging

Review of nanomaterials in dentistry: interactions with the oral microenvironment, clinical applications, hazards, and benefits.

Interest in the use of engineered nanomaterials (ENMs) as either nanomedicines or dental materials/devices in clinical dentistry is growing. This review aims to detail the ultrafine structure, chemical composition, and reactivity of dental tissues in the context of interactions with ENMs, including the saliva, pellicle layer, and oral biofilm; then describes the applications of ENMs in dentistry in context with beneficial clinical outcomes versus potential risks. The flow rate and quality of saliva are likely to influence the behavior of ENMs in the oral cavity, but how the protein corona formed on the ENMs will alter bioavailability, or interact with the structure and proteins of the pellicle layer, as well as microbes in the biofilm, remains unclear. The tooth enamel is a dense crystalline structure that is likely to act as a barrier to ENM penetration, but underlying dentinal tubules are not. Consequently, ENMs may be used to strengthen dentine or regenerate pulp tissue. ENMs have dental applications as antibacterials for infection control, as nanofillers to improve the mechanical and bioactive properties of restoration materials, and as novel coatings on dental implants. Dentifrices and some related personal care products are already available for oral health applications. Overall, the clinical benefits generally outweigh the hazards of using ENMs in the oral cavity, and the latter should not prevent the responsible innovation of nanotechnology in dentistry. However, the clinical safety regulations for dental materials have not been specifically updated for ENMs, and some guidance on occupational health for practitioners is also needed. Knowledge gaps for future research include the formation of protein corona in the oral cavity, ENM diffusion through clinically relevant biofilms, and mechanistic investigations on how ENMs strengthen the tooth structure