Contents

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DHHS (NIOSH) Publication No. 2009-116

February 2009

Safer • Healthier • People™

Foreword

"Do occupational exposures to engineered nanoparticles pose an unintended risk of adverse health effects?" This is not an abstract or theoretical question that practitioners have the luxury of debating for years before it becomes a reality. Nanotechnology is a reality, with potential for great growth in the 21st Century. Workers are already engaged in processes in which they may be exposed to materials that never existed before in nature. We do not fully know how these engineered nanoparticles may enter the body, where they may travel once inside, or what effects they may have on the body's systems. We do not fully know whether or how effects may differ for chemically or structurally different particles at the nanoscale. Diverse stakeholders have agreed that research to address these questions is essential for the responsible development of nanotechnology.

As research progresses to answer those questions, the National Institute for Occupational Safety and Health (NIOSH) has recommended prudent precautionary interim measures for reducing work-related exposures and assessing potential risk. In the hierarchy of prevention, it is important to consider where it may be of value to provide medical screening of workers who may be exposed to a potential health hazard, but who may be asymptomatic-that is, who have no identifiable symptom of an occupational disease. On the frontiers of nanotechnology, where as yet little data exist for assessing risk with confidence, it is difficult to recommend specific screening tests. NIOSH has sought a wide range of opinions on the matter and along with its own review of the scientific literature presents this interim guidance for medical screening and hazard surveillance. The evidence base on the health effects of engineered nanoparticles is rapidly growing and NIOSH will continue to monitor and assess it and will update those recommendations as more definitive information becomes available.

Christine M. Branche, Ph.D.
Acting Director
National Institute for Occupational
Safety and Health
Centers for Disease Control
and Prevention

Executive Summary

Concerns have been raised about whether workers exposed to engineered nanoparticles are at increased risk of adverse health effects. The current body of evidence about the possible health risks of occupational exposure to engineered nanoparticles is quite small. While there is increasing evidence to indicate that exposure to some engineered nanoparticles can cause adverse health effects in laboratory animals, no health studies of workers exposed to the few engineered nanoparticles tested in animals have been published. The purpose of this document from the National Institute for Occupational Safety and Health (NIOSH) is to provide interim guidance about whether specific medical screening, including performing medical tests on asymptomatic workers, is appropriate for these workers.

Medical screening is only one part of what should be considered a complete safety and health management program. An ideal safety and health management program follows a hierarchy of controls and involves various occupational health surveillance measures. Since specific medical screening of asymptomatic workers exposed to engineered nanoparticles has not been extensively discussed in the scientific literature, this document makes recommendations based upon what is known until more rigorous research can be performed.

Currently there is insufficient scientific and medical evidence to recommend the specific medical screening of workers potentially exposed to engineered nanoparticles. Nonetheless, this lack of evidence does not preclude specific medical screening by employers interested in taking precautions beyond existing industrial hygiene measures. If nanoparticles are composed of a chemical or bulk material for which medical screening recommendations exist, these same screening recommendations would be applicable for workers exposed to engineered nanoparticles as well.

As research into the hazards of engineered nanoparticles continues, vigilant reassessment of available data is critical to determine whether specific medical screening is warranted for workers. In the interim, the following recommendations are provided for workplaces where workers may be exposed to engineered nanoparticles in the course of their work:

• Take prudent measures to control exposures to engineered nanoparticles.
• Conduct hazard surveillance as the basis for implementing controls.
• Continue use of established medical surveillance approaches.

NIOSH will continue to collect and evaluate new research findings and update its recommendations about medical screening programs for workers exposed to nanoparticles. NIOSH will also continue to consider the strengths and weaknesses of establishing exposure registries for workers potentially exposed to engineered nanoparticles for future health surveillance and epidemiological studies.

Acknowledgements

This Current Intelligence Bulletin (CIB) was developed by the staff of the National Institute for Occupational Safety and Health (NIOSH) who participate in the NIOSH Nanotechnology Research Center (NTRC). Special thanks go to Paul S. Schulte, Director, Education and Information Division, NIOSH and manager of the NTRC, Douglas Trout, and Ralph D. Zumwalde for writing and organizing the report. The NIOSH NTRC also acknowledges the contributions of Vanessa Becks and Gino Fazio for desktop publishing and graphic design, and Douglas Platt for editing the document.

NIOSH greatly appreciates the time and efforts of expert peer reviewers and NTRC staff who provided comments on a draft of this CIB.

Peer Reviewers

• Michael Kosnett, MD, MPH University of Colorado at Denver and Health Sciences Center
• Ken Donaldson, BSc, PhD, DSc, CBiol, FRCPath, FFOM University of Edinburgh Centre for Inflammation Research, ELEGI Colt Laboratory
• James Lockey, MD, Professor of Occupational, Environmental and Pulmonary Medicine, University of Cincinnati

Attendees and Participants: Workshop on occupational health surveillance and nanotechnology workers. April 17-18, 2007, Arlington, VA.

Interim Guidance for the Medical Screening and Hazard Surveillance for Workers Potentially Exposed to Engineered Nanoparticles

Introduction

Nanotechnology is a system of innovative methods for controlling and manipulating matter at the near-atomic scale to produce engineered materials, structures, and devices. Engineered nanoparticles are generally considered to include a class or subset of these manufactured materials with at least one dimension of approximately 1 to 100 nanometers (www.nano.gov/html/facts/whatIsNano.html). At these scales, materials often exhibit unique properties beyond those expected at the chemical or bulk level that affect their physical, chemical, and biological behavior. The term "ultrafine" is also frequently used in the literature to describe particles with dimensions less than 100 nanometers that have not been intentionally produced (e.g., manufactured) but are the incidental products of processes involving combustion, welding, or diesel engines. It is currently unclear whether a distinction in particle terminology is justified from a safety and health perspective if the particles have the same physicochemical characteristics.

The potential occupational health risks associated with the manufacture and use of nanomaterials are not yet clearly understood. Many engineered nanomaterials and devices are formed from nanometer-scale particles (i.e., nanoparticles) that are initially produced as aerosols or colloidal suspensions. Exposure to these materials during manufacturing and use may occur through inhalation, dermal contact, or ingestion; however, inhalation exposure is the main route of concern [ASCC 2006]. There is very limited information available about dominant exposure routes, the potential for exposure, and material toxicity.

At this time, society in general and companies in particular are faced with the dilemma of balancing a desire to expand a potentially bountiful technology against the potential hazards that may result. The real risks from the technology are not known, and the perceived risks are undetermined. In this regard, nanotechnology is no different from any other emerging technology. One of the first areas where exposures to engineered nanoparticles will occur is in the workplace. In the face of uncertainty about the hazards of nanoparticles, a corporate or societal response (such as implementing appropriate occupational health surveillance measures) may assure the public that appropriate efforts are being taken to identify and control potential hazards in a timely fashion.

Concerned individuals from government, industry, labor, and academia, together with occupational health professionals and medical personnel, have raised questions about whether workers exposed to engineered nanoparticles should be provided some type of medical surveillance. The purpose of this document is to provide interim guidance concerning specific medical screening for these workers - that is, medical tests for asymptomatic workers - until additional research either supports or negates the need for this type of screening. The type and degree of screening recommended here is in addition to any medical surveillance taking place as part of existing occupational health surveillance efforts.

Background: A Brief Review of the Literature

Effects of Exposure to Ultrafine Particles

Results from epidemiological studies in the general population have shown associations between fine particulate air pollution and increased morbidity and mortality from respiratory and cardiopulmonary disease [Dockery et al. 1993; Ibald-Mulli et al. 2002; Pope et al. 2004]. Other studies have investigated specific markers of effect associated with exposure to the ultrafine particulate fraction of air pollution [Ruckerl et al. 2006]. Studies of workers exposed to ultrafine particles (e.g., diesel exhaust and welding fume) have reported elevated lung cancer risks [Steenland et al. 1998; Garshick et al. 2004; Antonini 2003] while results from some animal studies have shown that many types of poorly soluble ultrafine particles can elicit a greater pulmonary inflammatory response than larger particles of the same composition on a mass for mass basis [Oberdörster et al. 1994; Lison et al 1997; Zhang et al. 2000, 2003; Brown et al. 2001; Höhr et al. 2002; Duffin et al. 2007]. Toxicological studies indicate that the chemical and physical properties that influence the toxicity of ultrafine particles may also be relevant to mechanisms that influence the toxicological response to engineered nanoparticles [Castranova et al. 2000; Aitken et al. 2004; Donaldson et al. 2005, 2006; Maynard and Kuempel 2005; Oberdörster et al. 2005a, b; Kreyling et al. 2006; Gwinn and Vallyathan 2006; Borm et al. 2006; Helland et al. 2007]. Studies have also shown that physicochemical properties such as surface reactivity, chemical composition, crystal structure, and shape also influence the toxicity of nanoscale particles [Zhang et al. 1998; Dick et al. 2003; Warheit et al. 2007a, b]. Adverse effects reported from exposure to ultrafine particles have raised concerns about workers exposed to engineered nanoparticles [Royal Society and Academy of Engineering 2004; Maynard and Kuempel 2005; IRRST 2006; Nel et al. 2006; Schulte and Salmanca-Buentello 2007; Maynard 2007; Lam et al. 2006; Kuempel et al. 2007; Aitken et al. 2004; ASCC 2006]

Effects of Exposure to Engineered Nanoparticles

Animal studies with some types of engineered nanoparticles have caused adverse lung effects (e.g., pulmonary inflammation and progressive fibrosis) [Lam et al. 2004, 2006; Shvedova et al. 2005; Takagi et al. 2008; Poland et al. 2008] and cardiovascular effects (e.g., inflammation, blood platelet activation, plaque formation, and thrombosis) [Radomski et al. 2005; Donaldson et al. 2006; Li et al. 2007]. Other studies have demonstrated that discrete nanoparticles may enter the bloodstream from the lungs and translocate to other organs [Oberdörster et al. 2002] while other studies have shown that discrete nanoparticles (35-37 nm count median diameter) that deposit in the nasal region may be able to enter the brain by translocation along the olfactory nerve [Oberdörster et al. 2005(b); Elder et al. 2006]. A broader review of the human and animal data can be found in the NIOSH document Approaches to Safe Nanotechnology: An Information Exchange with NIOSH [NIOSH 2006a].

Occupational Health Surveillance

NIOSH has historically recommended implementing occupational health surveillance programs when workers are exposed to potentially hazardous materials. Occupational health surveillance involves the ongoing systematic collection, analysis, and dissemination of exposure and health data on groups of workers for the purpose of preventing illness and injury. This information is frequently used for establishing and evaluating the hierarchy of preventive actions [Halperin 1996]. The general term occupational health surveillance includes medical and hazard surveillance. Occupational health surveillance is an essential component of an effective occupational safety and health program [Harber et al. 2003; NIOSH 2006b; Wagner and Fine 2008; Baker and Matte 2005]. While this document supports that concept, the main focus is whether a typical medical surveillance program that includes additional medical screening is warranted for workers potentially exposed to engineered nanoparticles.

Medical Surveillance

Medical surveillance targets actual health events or a change in a biologic function of an exposed person or persons. Medical surveillance is a second line of defense behind the implementation of engineering, administrative, and work practice controls including the use of personal protective equipment. NIOSH recommends the medical surveillance of workers when they are exposed to hazardous materials. The elements of a medical surveillance program generally include the following:

1. An initial medical examination and collec1tion of medical and occupational histories.
2. Periodic medical examinations at regularly scheduled intervals, including specific medical screening tests when warranted.
3. More frequent and detailed medical examinations as indicated on the basis of findings from these examinations.
4. Post-incident examinations and medical screening following uncontrolled or non-routine increases in exposures such as spills.
5. Worker training to recognize symptoms of exposure to a given hazard.
6. A written report of medical findings.
7. Employer actions in response to identification of potential hazards.

When the purpose of a medical surveillance program is to detect early signs of work-related illness and disease, it is considered a type of medical screening, also referred to as medical monitoring and includes medical testing to detect preclinical changes in organ function or changes before a person would normally seek medical care and when intervention is beneficial [Ashford et al. 1990; Baker and Matte 2005; Halperin et al. 1986; Harber et al. 2003; ILO 1998]. The establishment of a medical screening program should follow established criteria [Halperin et al. 1986; Borak et al. 2006; Baker and Matte 2005; Harber 2003] and that specific disease endpoints must be able to be determined by the test selected (see Appendix A).

Frequent Uses for Medical Surveillance

Medical examinations and tests are used in many workplaces to determine whether an employee is able to perform the essential functions of the job, with or without reasonable accommodation, without posing a direct and imminent threat to the safety or health of the worker or others. Workplace medical examinations must be conducted in compliance with the Americans with Disabilities Act of 1990 (ADA) (Public Law No. 101-336). For example, this law prohibits making a job offer contingent upon the applicant's submission to a medical examination. Still, medical examinations and examinations conducted before placing a worker in a given job could potentially provide useful baseline information in a variety of ways. For example, even if there appears to be no reason for immediate concern about exposure to engineered nanoparticles in a particular workplace setting, this type of baseline data may benefit employers and workers alike if questions come up later regarding potential worker health problems associated with the specific engineered nanoparticle.

Medical surveillance of workers is also required by law when there is exposure to a specific workplace hazard. Although OSHA does not have a standard that specifically addresses occupational exposure to engineered nanoparticles, OSHA has a number of standards that require medical surveillance of workers. Workplaces with engineered nanoparticles comprised of chemicals addressed by current OSHA standards (Appendix B) are subject to the requirements of those standards, including the requirements for medical surveillance. In addition, medical surveillance of workers handling engineered nanoparticles may also be triggered when workers are exposed to other hazardous substances (e.g., those listed in Appendix B) present in nanoparticle operations.

In addition to substance-specific standards, OSHA has standards with broader applicability. For example, employers must follow the medical evaluation requirements of OSHA's respiratory protection standard [29 CFR 1910.134] when respirators are necessary to protect worker health. This standard includes elements of medical surveillance. Likewise, the OSHA standard for occupational exposure to hazardous chemicals in laboratories [29 CFR 1910.1450] requires medical consultation following the accidental release of hazardous chemicals.

NIOSH also recommends medical surveillance (including screening) of workers when there is exposure to certain occupational hazards (Appendix C). None of the hazards noted in Appendix C are identified as engineered nanoparticles, but medical surveillance would apply to workers exposed to nanoparticles comprised of chemicals for which NIOSH has a recommendation. The medical surveillance of these workers may provide useful information if questions arise in the future about the health effects of their exposure to nanoparticles.

Hazard Surveillance and Risk Management

Hazard surveillance involves identifying potentially hazardous practices or exposures in the workplace and assessing the extent to which they can be linked to workers, the effectiveness of controls, and the reliability of exposure measures [Sundin and Frazier 1989; Froines et al. 1989]. Hazard surveillance for engineered nanoparticles is an essential component of any occupational health surveillance effort and is used for defining the elements of the risk management program. One component of a risk management program involves taking action to minimize exposure to potential hazards. In the case of engineered nanoparticles, even in the absence of adequate health information, an understanding of potential worker exposures can form the basis for ongoing risk management. Other critical elements of a risk management program include recognizing potential exposures and determining appropriate actions to minimize them (e.g., implementing engineering controls, employing good work practices, and using personal protective equipment) [NIOSH 2006a]. Hazard surveillance should include the identification of work tasks and processes that involve the production and use of engineered nanoparticles, and should be viewed as one of the most critical components of any risk management program.

Discussion and Conclusions

Assessing the potential toxicity of engineered nanoparticles is at an early stage. A body of scientific evidence has accrued from toxicology studies on selected engineered nanoparticles and from epidemiology studies of individuals exposed to ultrafine nanoparticles suggests that some nanoscale particles may pose a health concern [Kuempel et al. 2007; Gwinn and Vallyathan 2006; Donaldson et al. 2006]. This evidence suggests that safety and health professionals should consider precautionary management approaches in workplaces where there is exposure to engineered nanoparticles [Schulte and Salamanca-Buentello 2007; NIOSH 2006a; Royal Society and Royal Academy of Engineering 2004; Borm et al. 2006; Holman et al. 2006; IRSST 2006] such as the implementation of occupational risk management programs. Such approaches are described in the NIOSH document Approaches to Safe Nanotechnology: An Information Exchange with NIOSH [NIOSH 2006a].

The current body of evidence about the possible health risks of occupational exposures to engineered nanoparticles is not sufficient to support the determination of specific medical screening to identify preclinical changes associated with exposure to engineered nanoparticles. No substantial link has been established between occupational exposure to engineered nanoparticles and adverse health effects. In addition, the toxicological research to date is insufficient to recommend such monitoring, the appropriate triggers for it, or components of it. As the volume of research on the potential health effects from exposure to engineered nanoparticles increases, continual reassessment will be needed to determine whether medical screening is warranted for workers who are producing or using engineered nanoparticles. NIOSH will continue to examine new research findings and update its recommendations on medical screening programs for workers exposed to nanoparticles. Appendix D provides a brief discussion concerning occupational health programs that include medical screening and might serve as a model for future reference for one or more engineered nanoparticles. Appendix E provides discussion highlighting details of instances where sufficient evidence to support recommendations for specific medical screening for workers exposed to engineered nanoparticles is lacking.

At this time, only a few types of engineered nanoparticles have been studied, and a clear and consistent picture of the relevant endpoints for workers has not yet emerged. Various physicochemical parameters of nanoparticles (e.g., composition, size, shape, surface characteristics, charge, functional groups, crystal structure, and solubility) appear to affect toxicity [Oberdörster et al. 2005a; Borm et al. 2006; Warheit et al. 2007b; IRSST 2006]. It is not known whether size is the overriding parameter, though most studies show that size appears to be the major factor in enhancing the toxicity of engineered nanoparticles compared with the toxicity of larger particles of the same composition. Results from a limited number of experimental animal studies with engineered nanoparticles indicate the potential for respiratory and circulatory effects [Aitken et al. 2004; Borm et al. 2006; ASCC 2006; IRRST 2006]; however, it is not clear which effects are most critical, whether they are dose-dependent, and whether these effects are relevant to human exposure. Additional studies are needed to determine the biological significance of different physicochemical parameters and whether these parameters can be used to predict the potential toxicity of other untested engineered nanoparticles.

When occupational health surveillance is being established, it is necessary to understand the relative, absolute, and population-attributable risks to workers who are handling engineered nanomaterials. This includes understanding the hazard as well as the extent of exposure and ultimately the risk. Limited information is available on these topics, but exposures may be generally low relative to the airborne exposures of the same material in larger but respirable particle sizes. The level of risk resulting from lower exposures to nanomaterials is unknown. Ultimately, epidemiological studies of exposed workers will be needed to help assess exposure-response relationships. Although such studies are difficult to conduct, they are more likely than medical screening to clarify the relationship between exposure and adverse effects at this time.

Finally, there is not yet enough research to make categorical determinations of the hazards based on combinations of physicochemical factors [ASCC 2006; Aitken et al. 2004]. Although preliminary studies indicate that while specific medical screening may be warranted in the future, insufficient information is now available to make any recommendations beyond hazard surveillance. NIOSH will continue to assess the scientific evidence and periodically update the guidance on medical screening.

Recommendations

Continued in vivo and in vitro toxicological research is needed to identify potential health endpoints related to occupational exposure to engineered nanoparticles. Epidemiological studies of exposed workers will be needed to establish associations between exposures to engineered nanoparticles and adverse health effects and to assess other potential exposure-response relationships. Research is needed to assess various candidate biological markers that may ultimately be used in medical screening, including molecular markers [Schulte 2005]. This research is needed to assess sensitivity, specificity, and predictive value of biomarkers and clinical tests that might be developed and used to screen workers' health. Determining sufficient positive predictive value of a screening modality to detect adverse health effects early enough in the course of the disease to enable secondary prevention, is an important factor when considering medical screening efforts.

The following recommendations are provided for workplaces where workers may be exposed to engineered nanoparticles during the course of their work.

Take prudent measures to control exposures to engineered nanoparticles.

A prudent approach to controlling exposures to engineered nanoparticles has been described in the NIOSH draft document Approaches to Safe Nanotechnology: An Information Exchange with NIOSH [NIOSH 2006a].

Conduct hazard surveillance as the basis for implementing controls

To establish prudent measures for controlling exposure to engineered nanoparticles, it is important to identify which jobs or processes involve the production or use of engineered nanoparticles. Employers should identify and document the presence of engineered nanoparticles in their workplaces and the work tasks associated with them. This information will serve as the basis for applying various control measures [NIOSH 2006a]. Hazard surveillance programs should be designed to address some or all of the following questions:

1. What exposure agents are found in the workplace?
2. Are standardized, reliable, and practical methods available for measuring workers' exposures to the agents?
3. What exposure metrics (e.g., mass, particle count, particle surface area) are most relevant to the most important health concerns?
4. To what extent can specific exposures (e.g., nanoparticles) be linked to people?
5. What actions have been taken to control potentially hazardous exposures?
6. How effective are the controls (e.g., engineering)?
7. Which agents affect the most workers?
8. What jobs or industries are most likely to cause exposures to workers?
9. What health effects are most likely related to these exposures?
10. How are specific occupational exposures changing over time?

Continue use of established medical surveillance approaches

Currently, there are many established uses for medical surveillance by employers and occupational health practitioners (see Section 3.3). These may pertain to workers exposed to engineered nanoparticles, but they are not specifically focused on them. Employers should continue using these established approaches to collect data that may be informative in the future about whether there is an increase in the frequency of adverse health effects related to exposure to engineered nanoparticles. NIOSH continues to recommend occupational health surveillance as an important part of an effective risk management program. Lack of evidence for recommending medical screening for workers potentially exposed to engineered nanoparticles should not stop employers who want to take additional precautions, including medical screening, beyond those already established. However, it is important to note that nonspecific medical testing can have negative consequences such as adverse effects resulting from tests (e.g., radiation from chest radiographs), creating unnecessary anxiety in workers and employers from false-positive screening tests, and the economic ramifications of additional diagnostic evaluations [Nasterlack et al. 2007; Schulte 2005; Marcus et al. 2006].

NIOSH will continue to evaluate the usefulness of establishing exposure registries in workplaces were there is potential exposure to engineered nanoparticles. As the understanding of occupational exposure to engineered nanoparticles increases, the development of exposure registries may be needed to form the basis for future epidemiologic research (Appendix F). Such registries probably need to cover workers from numerous companies to reflect the diversity of exposures, to account for the small number of workers exposed at a given site, and to assess chronic health effects.

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APPENDIX A • Critical Aspects of an Occupational Medical Screening Program

APPENDIX B • OSHA Standards That Include Requirements for Medical Surveillance

APPENDIX C • Hazards for Which NIOSH Has Recommended the Use of Medical Surveillance

*Denotes the absence of a publication number or that recommendations were provided in testimony by NIOSH to the U.S. Department of Labor.
NTIS [National Technical Information Service] Web site: http://www.ntis.gov

APPENDIX D • Discussion of Occupational Health Surveillance Programs with Medical Screening

Occupational health surveillance programs exist that may be useful as models on which to base future efforts in the management of occupational exposures to one or more engineered nanoparticles together with any potential health risk(s) related to those exposures.

Occupational exposures to metalworking fluids (MWF) have been implicated in health problems including a variety of dermatologic and respiratory health conditions. In the NIOSH Criteria for a Recommended Standard: Occupational Exposure to Metal Working Fluids [NIOSH 1998], medical monitoring (screening) is recommended by NIOSH as part of a complete MWF safety and health program. Similarly, in the Safety and Health Best Practices Manual for Metalworking Fluids [OSHA, 2008], OSHA recommends a model for a medical monitoring (screening) program and provides information on implementation. These recommended programs provide examples of how appropriate occupational health surveillance principles may be applied toward prevention and control of occupational exposures and associated health risks. Although there are still scientific uncertainties related to occupational exposures to MWF that require further research, the recommendations for these medical monitoring programs are based on evaluation of extensive data concerning exposures, health effects, and exposure-health effect relationships. As noted in the NIOSH Criteria Document for a Recommended Standard, these recommendations concerning MWF are made with the expectation that they will prevent or greatly reduce the risk of adverse health effects in exposed workers. Gathering exposure and health effect data related to occupational exposure to engineered nanoparticles will be essential when formulating medical screening programs for workers exposed to engineered nanoparticles.

APPENDIX E • Examples of Limitations in the Evidence Base for Specific Medical Screening of Workers Exposed to Engineered Nanoparticles

Key among the criteria for recommending specific medical screening of workers exposed to engineered nanoparticles include determining whether the substance in question is a hazard and whether the disease to be averted is sufficiently common in the worker population to justify routine screening [Nasterlack et al. 2007; Borak et al. 2006; Halperin et al. 1986]. For engineered nanoparticles, there is insufficient evidence for a definitive hazard determination. Only a small number of the myriad types of engineered nanoparticles have undergone experimental animal inhalation testing, and no broad categories of physicochemical risk factors have been identified to allow for projecting hazards across particle types. No chronic inhalation studies of engineered nanoparticles have been conducted to date. The existence of a few short-term inhalation studies on carbon nanotubes and nanoscale metal oxides is not adequate to identify what disease endpoints to assess in medical screening. There is also insufficient information available regarding the absolute, relative or population-attributable risks associated with nanoparticle exposures [Nasterlack et al. 2007].

Examples of the issues in determining the rationale for recommending medical screening for workers potentially exposed to engineered nanoparticles are described as follows.

Single-Walled Carbon Nanotubes (SWCNTs)

Intratracheal (IT) exposure to SWCNTs has been associated with interstitial fibrosis in the rat (Lam et al. 2004]. Aspiration of purified SWCNTs caused rapid and progressive interstitial fibrosis in mice [Shvedova et al. 2005]. NIOSH has also shown that inhalation of SWCNTs cause interstitial fibrosis [Shvedova et al. 2008]. The problem is that purified SWCNTs are not redox reactive and the interstitial fibrosis is not driven by oxidant generation and inflammation. Therefore, measurement of markers of oxidant stress or inflammation in humans would not be predictive. If interstitial lung disease was considered the health endpoint of concern, monitoring of the carbon monoxide diffusion capacity of the lung could be performed noninvasively. A significant decline in diffusion would indicate a loss of alveolar-capillary gas exchange and suggest early signs of pre-clinical disease. Unfortunately, virtually no published data exist on occupational exposure concentrations for working in SWCNT operations. Consequently, there is too little information available at this time to verify disease endpoints. There is also too little information available on exposure in general and ultimately the risk to workers who handle these materials.

Nanoscale Metal Oxides

Pulmonary exposure to nanoscale metal oxides such as titanium dioxide (TiO2) have been shown in rat models to cause pulmonary inflammation [Oberdörster et al. 2005] and to inhibit the ability of the systemic microvasculature to respond to dilators [Nurkiewicz et al.2006; Nurkiewicz et al. in press] after IT or inhalation exposures. Ultrafine (nanoscale) TiO2 has been shown to be more potent in causing these effects than fine TiO2 on an equivalent mass basis. These effects have been associated with oxidant stress and induction of inflammatory mediators. Therefore, markers of oxidant stress and inflammation could be considered as early indicators of human exposure or response. Oxidant stress markers have been suggested as markers of toxicity to metal oxide nanoparticles as a class [Nel et al. 2006]. Examples of such markers would be nitrous oxide or isoprostanes in exhaled breath or blood markers of oxidant stress. However, the utility of these markers for screening workers exposed to engineered nanoparticles has not been demonstrated. In addition, some research shows that nanoscale TiO2 is linked to cancer of the lung and the International Agency for Research on Cancer (IARC) has categorized titanium dioxide as a possible carcinogen to humans [IARC 2006]. Nonetheless, no evidence clearly demonstrates that medical screening of asymptomatic workers exposed to lung carcinogens decreases the chance of dying from cancer (NCI 2007; Marcus et al. 2006).

Nanoscale Cadmium

Cadmium is a substance that has medical screening recommendations for workers exposed in order to prevent or assess lung and kidney toxicity (see Appendices B and C). At a minimum, these recommendations should pertain to nanoscale cadmium (e.g., such as that used in the production of quantum dots). Medical screening is typically triggered by the airborne concentration of the substance in the workplace (e.g., the "action level" concentration). An action level is some fraction, usually 50%, of an occupational exposure limit (OEL). Whether the action level concentration recommended for nonnanoscale cadmium particles is adequate for nanoscale cadmium is unknown. Workplaces with engineered nanoparticles of materials addressed by current OSHA standards are subject to the requirements of those standards, including the requirements for medical surveillance.

APPENDIX F • Exposure Registries

Exposure registries are useful tools for surveillance of new or perceived hazards. A registry provides a structured and orderly approach to handling the problem of identifying and maintaining communication with workers exposed to hazardous substances [Schulte and Kaye 1988]. An exposure registry is the enrollment of persons exposed or likely to have been exposed to occupational or environmental hazards; the registry may include how these groups are managed with regard to primary or secondary preventive efforts. In occupational situations, company employee rosters are de facto registries; however, they may not address employees who leave a company. Moreover, for a new cross-cutting technology such as nanotechnology, the registry could enroll persons from various companies. Generally, exposure registries are developed and maintained by government entities, but there are examples of private-sector registries related to exposure to commercial products.

The purposes and functions of exposure registries may be summarized as follows:

• Delineate a population at risk
• Follow cohort to ascertain exposure-disease associations
• Follow cohort to ensure the institution of appropriate primary and secondary prevention and medical surveillance
• Follow cohort to allow for appropriate social, legal, and economic support
• Demonstrate societal concern for the cohort and provide a base for political action relevant to the exposure
• Notify a cohort of an exposure, preventive measures, or therapeutic advances that were not understood or known at the time the registry was established

Various issues should be addressed when considering development of exposure registries. These include the term of the registry, needs of registrants, confidentially of information, cost of maintaining the registry, and the potential impact of the registry on workers and companies.

Registries are essentially a collection of individual worker information over time with at least a preliminary plan for analysis. Data collected in registries may be subject to limitations. Exposure registries are not always useful in etiologic research. For diseases with low prevalence following low-level exposures, exposure registries are not very effective tools because (1) exposure classification is often difficult, (2) the statistical power of prospective studies is low, and (3) the time period of the study may be impractically long. Moreover, changes in exposures experienced by registry participants over time may complicate the ability to establish clear exposure-disease relationships.

Exposure registries may provide opportunities to determine the exposure-disease association and risk. Also, when practical prospective studies can be designed, registries can be used to establish hypotheses. Many questions arise when considering an exposure registry for etiologic research, including:

• How can exposed persons be adequately differentiated from nonexposed persons?
• What group could serve as a comparison group so that the disease experience of the exposed group can be evaluated?
• How long should the group be followed?

Although exposure registries are useful tools to assist populations potentially at risk, their utility for workers exposed to engineered nanoparticles needs further evaluation.