Paul A. Schulte

Mechanisms of pulmonary toxicity and medical applications of carbon nanotubes: Two faces of Janus? ☆

Nanotechnology is an emerging science involving manipulation of materials at the nanometer scale. There are several exciting prospects for the application of engineered nanomaterials in medicine. However, concerns over adverse and unanticipated effects on human health have also been raised. In fact, the same properties that make engineered nanomaterials attractive from a technological and biomedical perspective could also make these novel materials harmful to human health and the environment. Carbon nanotubes are cylinders of one or several coaxial graphite layer(s) with a diameter in the order of nanometers, and serve as an instructive example of the Janus-like properties of nanomaterials. Numerous in vitro and in vivo studies have shown that carbon nanotubes and/or associated contaminants or catalytic materials that arise during the production process may induce oxidative stress and prominent pulmonary inflammation. Recent studies also suggest some similarities between the pathogenic properties of multi-walled carbon nanotubes and those of asbestos fibers. On the other hand, carbon nanotubes can be readily functionalized and several studies on the use of carbon nanotubes as versatile excipients for drug delivery and imaging of disease processes have been reported, suggesting that carbon nanotubes may have a place in the armamentarium for treatment and monitoring of cancer, infection, and other disease conditions. Nanomedicine is an emerging field that holds great promise; however, close attention to safety issues is required to ensure that the opportunities that carbon nanotubes and other engineered nanoparticles offer can be translated into feasible and safe constructs for the treatment of human disease.

Work, Obesity, and Occupational Safety and Health

There is increasing evidence that obesity and overweight may be related, in part, to adverse work conditions. In particular, the risk of obesity may increase in high-demand, low-control work environments, and for those who work long hours. In addition, obesity may modify the risk for vibration-induced injury and certain occupational musculoskeletal disorders. We hypothesized that obesity may also be a co-risk factor for the development of occupational asthma and cardiovascular disease that and it may modify the workers response to occupational stress, immune response to chemical exposures, and risk of disease from occupational neurotoxins. We developed 5 conceptual models of the interrelationship of work, obesity, and occupational safety and health and highlighted the ethical, legal, and social issues related to fuller consideration of obesitys role in occupational health and safety.

Occupational Risk Management of Engineered Nanoparticles

The earliest and most extensive societal exposures to engineered nanoparticles are likely to occur in the workplace. Until toxicologic and health effects research moves forward to characterize more broadly the potential hazards of nanoparticles and to provide a scientific basis for appropriate control of nanomaterials in the workplace, current and future workers may be at risk from occupational exposures. This article reviews a conceptual framework for occupational risk management as applied to engineered nanomaterials and describes an associated approach for controlling exposures in the presence of uncertainty. The framework takes into account the potential routes of exposure and factors that may influence biological activity and potential toxicity of nanomaterials; incorporates primary approaches based on the traditional industrial hygiene hierarchy of controls involving elimination or substitution, engineering controls, administrative controls, and use of personal protective equipment; and includes valuable secondary approaches involving health surveillance and medical monitoring.

Occupational Nanosafety Considerations for Carbon Nanotubes and Carbon Nanofibers

Carbon nanotubes (CNTs) are carbon atoms arranged in a crystalline graphene lattice with a tubular morphology. CNTs exhibit high tensile strength, possess unique electrical properties, are durable, and can be functionalized. These properties allow applications as structural materials, in electronics, as heating elements, in batteries, in the production of stain-resistant fabric, for bone grafting and dental implants, and for targeted drug delivery. Carbon nanofibers (CNFs) are strong, flexible fibers that are currently used to produce composite materials. Agitation can lead to aerosolized CNTs and CNFs, and peak airborne particulate concentrations are associated with workplace activities such as weighing, transferring, mixing, blending, or sonication. Most airborne CNTs or CNFs found in workplaces are loose agglomerates of micrometer diameter. However, due to their low density, they linger in workplace air for a considerable time, and a large fraction of these structures are respirable. In rat and mouse models, pulmonary exposure to single-walled carbon nanotubes (SWCNTs), multi-walled carbon nanotubes (MWCNTs), or CNFs causes the following pulmonary reactions: acute pulmonary inflammation and injury, rapid and persistent formation of granulomatous lesions at deposition sites of large CNT agglomerates, and rapid and progressive alveolar interstitial fibrosis at deposition sites of more dispersed CNT or CNF structures. Pulmonary exposure to SWCNTs can induce oxidant stress in aortic tissue and increases plaque formation in an atherosclerotic mouse model. Pulmonary exposure to MWCNTs depresses the ability of coronary arterioles to respond to dilators. These cardiovascular effects may result from neurogenic signals from sensory irritant receptors in the lung. Pulmonary exposure to MWCNTs also upregulates mRNA for inflammatory mediators in selected brain regions, and pulmonary exposure to SWCNTs upregulates the baroreceptor reflex. In addition, pulmonary exposure to MWCNTs may induce levels of inflammatory mediators in the blood, which may affect the cardiovascular system. Intraperitoneal instillation of MWCNTs in mice has been associated with abdominal mesothelioma. MWCNTs deposited in the distal alveoli can migrate to the intrapleural space, and MWCNTs injected in the intrapleural space can cause lesions at the parietal pleura. However, further studies are required to determine whether pulmonary exposure to MWCNTs can induce pleural lesions or mesothelioma. In light of the anticipated growth in the production and use of CNTs and CNFs, worker exposure is possible. Because pulmonary exposure to CNTs and CNFs causes inflammatory and fibrotic reactions in the rodent lung, adverse health effects in workers represent a concern. NIOSH has conducted a risk assessment using available animal exposure-response data and is developing a recommended exposure limit for CNTs and CNFs. Evidence indicates that engineering controls and personal protective equipment can significantly decrease workplace exposure to CNTs and CNFs. Considering the available data on health risks, it appears prudent to develop prevention strategies to minimize workplace exposure. These strategies would include engineering controls (enclosure, exhaust ventilation), worker training, administrative controls, implementation of good handling practices, and the use of personal protective equipment (such as respirators) when necessary. NIOSH has published a document containing recommendations for the safe handling of nanomaterials.

A systematic review of the effectiveness of occupational health and safety training

OBJECTIVES Training is regarded as an important component of occupational health and safety (OHS) programs. This paper primarily addresses whether OHS training has a beneficial effect on workers. The paper also examines whether higher engagement OHS training has a greater effect than lower engagement training. METHODS Ten bibliographic databases were searched for pre-post randomized trial studies published in journals between 1996 and November 2007. Training interventions were included if they were delivered to workers and were concerned with primary prevention of occupational illness or injury. The methodological quality of each relevant study was assessed and data was extracted. The impacts of OHS training in each study were summarized by calculating the standardized mean differences. The strength of the evidence on trainings effectiveness was assessed for (i) knowledge, (ii) attitudes and beliefs, (iIi) behaviors, and (iv) health using the US Centers for Disease Control and Preventions Guide to Community Preventive Services, a qualitative evidence synthesis method. RESULTS Twenty-two studies met the relevance criteria of the review. They involved a variety of study populations, occupational hazards, and types of training. Strong evidence was found for the effectiveness of training on worker OHS behaviors, but insufficient evidence was found of its effectiveness on health (ie, symptoms, injuries, illnesses). CONCLUSIONS The review team recommends that workplaces continue to deliver OHS training to employees because training positively affects worker practices. However, large impacts of training on health cannot be expected, based on research evidence.

Characterizing the burden of occupational injury and disease.

Objectives: To review the literature on the burden of occupational disease and injury and to provide a comprehensive characterization of the burden. Methods: The scientific and governmental literature from 1990 to the present was searched and evaluated. Thirty-eight studies illustrative of the burden of occupational disease were reviewed for findings, methodology, strengths, and limitations. Results: Recent U.S. estimates of occupational mortality and morbidity include approximately 55,000 deaths (eighth leading cause) and 3.8 million disabling injuries per year, respectively. Comprehensive estimates of U.S. costs related to these burdens range between

Ethical and scientific issues of nanotechnology in the workplace.

128 billion and

Quantification of epithelial cell micronuclei by fluorescence in situ hybridization (FISH) in mortuary science students exposed to formaldehyde.

155 billion per year. Despite these significant indicators, occupational morbidity, mortality, and risks are not well characterized in comparative burden assessments. Conclusions: The magnitude of occupational disease and injury burden is significant but underestimated. There is a need for an integrated approach to address these underestimates.

A conceptual framework for the validation and use of biologic markers

In the absence of scientific clarity about the potential health effects of occupational exposure to nanoparticles, a need exists for guidance in decisionmaking about hazards, risks, and controls. An identification of the ethical issues involved may be useful to decision makers, particularly employers, workers, investors, and health authorities. Because the goal of occupational safety and health is the prevention of disease in workers, the situations that have ethical implications that most affect workers have been identified. These situations include the a) identification and communication of hazards and risks by scientists, authorities, and employers; b) workers’ acceptance of risk; c) selection and implementation of controls; d) establishment of medical screening programs; and e) investment in toxicologic and control research. The ethical issues involve the unbiased determination of hazards and risks, nonmaleficence (doing no harm), autonomy, justice, privacy, and promoting respect for persons. As the ethical issues are identified and explored, options for decision makers can be developed. Additionally, societal deliberations about workplace risks of nanotechnologies may be enhanced by special emphasis on small businesses and adoption of a global perspective.

Issues in the development of epidemiologic studies of workers exposed to engineered nanoparticles.

A micronucleus assay employing fluorescence in situ hybridization (FISH) with a centromeric probe was used on specimens of exfoliated buccal and nasal cells collected from mortuary science students exposed to embalming fluid containing formaldehyde. FISH labeling allowed micronuclei (MN) containing a whole chromosome (centromere-positive, MN+) to be differentiated from those containing only chromosomal fragments (centromere-negative, MN-). Each student was sampled before and after the 90 day embalming class. We determined if an increase in MN frequency could be attributed to formaldehyde exposure and was specific to either MN+ or MN-. In buccal cells, total MN frequency was significantly increased from 0.6/1000 to 2/1000 (p = 0.007) following the course, whereas in nasal cells it was not (2 and 2.5/1000, respectively, p = 0.2). Cells with multiple MN were present only in samples taken after exposure to embalming fluid. Although the baseline frequency was higher for MN+ in both buccal (0.4/1000 for MN+ and 0.1/1000 for MN-) and nasal cells (1.2/1000 for MN+ and 0.5/1000 for MN-), the increase in MN frequency was greater for MN-, (9-fold, p = 0.005 for buccal cells; 2-fold, p = 0.03 for nasal cells) than for MN+ (> 2-fold, p = 0.08 for buccal cells; no change, p = 0.31 for nasal cells) in both tissues. Thus, the primary mechanism of micronucleus formation appeared to be chromosome breakage. This finding is consistent with known clastogenic properties of formaldehyde, the component of embalming fluid most likely responsible for micronucleus induction.