Andrew D. Maynard

Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study

Carbon nanotubes have distinctive characteristics, but their needle-like fibre shape has been compared to asbestos, raising concerns that widespread use of carbon nanotubes may lead to mesothelioma, cancer of the lining of the lungs caused by exposure to asbestos. Here we show that exposing the mesothelial lining of the body cavity of mice, as a surrogate for the mesothelial lining of the chest cavity, to long multiwalled carbon nanotubes results in asbestos-like, length-dependent, pathogenic behaviour. This includes inflammation and the formation of lesions known as granulomas. This is of considerable importance, because research and business communities continue to invest heavily in carbon nanotubes for a wide range of products under the assumption that they are no more hazardous than graphite. Our results suggest the need for further research and great caution before introducing such products into the market if long-term harm is to be avoided.

Principles for characterizing the potential human health effects from exposure to nanomaterials: Elements of a screening strategy

AbstractThe rapid proliferation of many different engineered nanomaterials (defined as materials designed and produced to have structural features with at least one dimension of 100 nanometers or less) presents a dilemma to regulators regarding hazard identification. The International Life Sciences Institute Research Foundation/Risk Science Institute convened an expert working group to develop a screening strategy for the hazard identification of engineered nanomaterials. The working group report presents the elements of a screening strategy rather than a detailed testing protocol. Based on an evaluation of the limited data currently available, the report presents a broad data gathering strategy applicable to this early stage in the development of a risk assessment process for nanomaterials. Oral, dermal, inhalation, and injection routes of exposure are included recognizing that, depending on use patterns, exposure to nanomaterials may occur by any of these routes. The three key elements of the toxicity screening strategy are: Physicochemical Characteristics, In Vitro Assays (cellular and non-cellular), and In Vivo Assays.There is a strong likelihood that biological activity of nanoparticles will depend on physicochemical parameters not routinely considered in toxicity screening studies. Physicochemical properties that may be important in understanding the toxic effects of test materials include particle size and size distribution, agglomeration state, shape, crystal structure, chemical composition, surface area, surface chemistry, surface charge, and porosity. In vitro techniques allow specific biological and mechanistic pathways to be isolated and tested under controlled conditions, in ways that are not feasible in in vivo tests. Tests are suggested for portal-of-entry toxicity for lungs, skin, and the mucosal membranes, and target organ toxicity for endothelium, blood, spleen, liver, nervous system, heart, and kidney. Non-cellular assessment of nanoparticle durability, protein interactions, complement activation, and pro-oxidant activity is also considered.Tier 1 in vivo assays are proposed for pulmonary, oral, skin and injection exposures, and Tier 2 evaluations for pulmonary exposures are also proposed. Tier 1 evaluations include markers of inflammation, oxidant stress, and cell proliferation in portal-of-entry and selected remote organs and tissues. Tier 2 evaluations for pulmonary exposures could include deposition, translocation, and toxicokinetics and biopersistence studies; effects of multiple exposures; potential effects on the reproductive system, placenta, and fetus; alternative animal models; and mechanistic studies.

Safe handling of nanotechnology

The pursuit of responsible nanotechnologies can be tackled through a series of grand challenges, argue Andrew D. Maynard and his co-authors.Take fiveThe spectre of possible harm — real or imagined — is threatening to slow the development of nanotechnology. In a Commentary this week a group of nanotechnologists outlines a series of five “grand challenges”. If they and their colleagues can rise to these challenges — which include development of new ways of measuring exposure to nanomaterials and assessing the health and environmental impact of that exposure — the true extent of any risks involved should become clear.

Exposure to Carbon Nanotube Material: Assessment of Nanotube Cytotoxicity Using Human Keratinocyte Cells

Carbon nanotubes are new members of carbon allotropes similar to fullerenes and graphite. Because of their unique electrical, mechanical, and thermal properties, carbon nanotubes are important for novel applications in the electronics, aerospace, and computer industries. Exposure to graphite and carbon materials has been associated with increased incidence of skin diseases, such as carbon fiber dermatitis, hyperkeratosis, and naevi. We investigated adverse effects of single-wall carbon nanotubes (SWCNT) using a cell culture of immortalized human epidermal keratinocytes (HaCaT). After 18 h of exposure of HaCaT to SWCNT, oxidative stress and cellular toxicity were indicated by formation of free radicals, accumulation of peroxidative products, antioxidant depletion, and loss of cell viability. Exposure to SWCNT also resulted in ultrastructural and morphological changes in cultured skin cells. These data indicate that dermal exposure to unrefined SWCNT may lead to dermal toxicity due to accelerated oxidative stress in the skin of exposed workers.

Translocation of inhaled ultrafine manganese oxide particles to the central nervous system

Background Studies in monkeys with intranasally instilled gold ultrafine particles (UFPs; < 100 nm) and in rats with inhaled carbon UFPs suggested that solid UFPs deposited in the nose travel along the olfactory nerve to the olfactory bulb. Methods To determine if olfactory translocation occurs for other solid metal UFPs and assess potential health effects, we exposed groups of rats to manganese (Mn) oxide UFPs (30 nm; ~ 500 μg/m3) with either both nostrils patent or the right nostril occluded. We analyzed Mn in lung, liver, olfactory bulb, and other brain regions, and we performed gene and protein analyses. Results After 12 days of exposure with both nostrils patent, Mn concentrations in the olfactory bulb increased 3.5-fold, whereas lung Mn concentrations doubled; there were also increases in striatum, frontal cortex, and cerebellum. Lung lavage analysis showed no indications of lung inflammation, whereas increases in olfactory bulb tumor necrosis factor-α mRNA (~ 8-fold) and protein (~ 30-fold) were found after 11 days of exposure and, to a lesser degree, in other brain regions with increased Mn levels. Macrophage inflammatory protein-2, glial fibrillary acidic protein, and neuronal cell adhesion molecule mRNA were also increased in olfactory bulb. With the right nostril occluded for a 2-day exposure, Mn accumulated only in the left olfactory bulb. Solubilization of the Mn oxide UFPs was < 1.5% per day. Conclusions We conclude that the olfactory neuronal pathway is efficient for translocating inhaled Mn oxide as solid UFPs to the central nervous system and that this can result in inflammatory changes. We suggest that despite differences between human and rodent olfactory systems, this pathway is relevant in humans.

Exposure to Carbon Nanotube Material: Aerosol Release During the Handling of Unrefined Single-Walled Carbon Nanotube Material

Carbon nanotubes represent a relatively recently discovered allotrope of carbon that exhibits unique properties. While commercial interest in the material is leading to the development of mass production and handling facilities, little is known of the risk associated with exposure. In a two-part study, preliminary investigations have been carried out into the potential exposure routes and toxicity of single-walled carbon nanotube material (SWCNT)—a specific form of the allotrope. The material is characterized by bundles of fibrous carbon molecules that may be a few nanometers in diameter, but micrometers in length. The two production processes investi-gated use-transition metal catalysts, leading to the inclusion of nanometer-scale metallic particles within unrefined SWCNT material. A laboratory-based study was undertaken to evaluate the physical nature of the aerosol formed from SWCNT during mechanical agitation. This was complemented by a field study in which airborne and dermal exposure to SWCNT was investigated while handling unrefined material. Although laboratory studies indicated that with sufficient agitation, unrefined SWCNT material can release fine particles into the air, concentrations generated while handling material in the field were very low. Estimates of the airborne concen-tration of nanotube material generated during handling suggest that concentrations were lower than 53μg/m3 in all cases. Glove deposits of SWCNT during handling were estimated at between 0.2 mg and 6 mg per hand.

Inhalation vs. aspiration of single-walled carbon nanotubes in C57BL/6 mice: inflammation, fibrosis, oxidative stress, and mutagenesis

Nanomaterials are frontier technological products used in different manufactured goods. Because of their unique physicochemical, electrical, mechanical, and thermal properties, single-walled carbon nanotubes (SWCNT) are finding numerous applications in electronics, aerospace devices, computers, and chemical, polymer, and pharmaceutical industries. SWCNT are relatively recently discovered members of the carbon allotropes that are similar in structure to fullerenes and graphite. Previously, we (47) have reported that pharyngeal aspiration of purified SWCNT by C57BL/6 mice caused dose-dependent granulomatous pneumonia, oxidative stress, acute inflammatory/cytokine responses, fibrosis, and decrease in pulmonary function. To avoid potential artifactual effects due to instillation/agglomeration associated with SWCNT, we conducted inhalation exposures using stable and uniform SWCNT dispersions obtained by a newly developed aerosolization technique (2). The inhalation of nonpurified SWCNT (iron content of 17.7% by weight) at 5 mg/m(3), 5 h/day for 4 days was compared with pharyngeal aspiration of varying doses (5-20 microg per mouse) of the same SWCNT. The chain of pathological events in both exposure routes was realized through synergized interactions of early inflammatory response and oxidative stress culminating in the development of multifocal granulomatous pneumonia and interstitial fibrosis. SWCNT inhalation was more effective than aspiration in causing inflammatory response, oxidative stress, collagen deposition, and fibrosis as well as mutations of K-ras gene locus in the lung of C57BL/6 mice.

Assessing exposure to airborne nanomaterials: Current abilities and future requirements

For over half a century, health-related aerosol exposure measurements have been characterized in terms of the mass of material present per unit volume of air. Yet recent research has challenged the applicability of this paradigm to airborne nanometer-scale particles (nanoparticles) and nanometer-structured particles (nanostructured particles). By classifying engineered nanoparticles into categories based on physical/chemical structure, and relating these categories to health impact-relevant attributes, we have explored the applicability of different physical exposure metrics to a range of particle class/attribute combinations. Using this approach, it is clear that no single method for monitoring nanoaerosol exposure will suit all nanomaterials. Rather, there will be occasions where particle number, surface area and even mass concentration measurements will play an important role in evaluating potential impact. Correspondingly, currently available techniques to measure exposure against these three metrics are reviewed. While current methods enable aerosol concentration to be evaluated against all three metrics, most techniques are inappropriate for making routine personal exposure measurements on a regular basis. We therefore explore the idea of a universal aerosol monitor, which would enable personal exposure measurements to be collected for all three metrics simultaneously, while being inexpensive enough to encourage widespread use. Such a device would provide an economical and adaptable solution to monitoring exposure to nanostructured aerosols, as both the materials and information on the potential risks they present are developed.

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.

Nanotechnology: assessing the risks

Nanotechnology is seen as a transformative technology, which has the potential to stimulate scientific innovation while greatly benefiting society. However, the enthusiasm with which the scientific and technical communities are embracing the technology is being tempered by concerns over possible downsides, including risks to human health. “Are these concerns valid?” is a question being asked by many, but frequently from differing perspectives. Given the increasingly complex interface between nanotechnology and society, relevant answers will be built on solid science and framed within a societal context.