Nanoparticles: State of the Science Paul A. Schulte, PhD Douglas Trout, MD Ralph D. Zumwalde, MS Eileen Kuempel, PhD Charles L. Geraci, PhD Vincent Castranova, PhD Diane J. Mundt, PhD Kenneth A. Mundt, PhD William E. Halperin, MD Objective: Health authorities, employers, and worker representatives are increasingly faced with making decisions about occupational health surveillance of workers potentially exposed to engineered nanoparticles. This article was developed to identify options that can be considered. Methods: The published scientific literature on health effects from engineered and incidental nanoparticles and the principles of occupa- tional health surveillance were reviewed to describe possible options and the evidence base for them. Results: Various options for occupational health surveillance were identified. The options ranged from no action targeted to nanotechnology workers to an approach that includes documentation of the presence of engineered nanoparticles, identifica- tion of potentially exposed workers, and general and targeted medical testing. Conclusions: Although the first priority should be to implement appropriate primary preventive measures, additional efforts to monitor employee health may be warranted. Continued research is needed, and the collection of such information for exposure registries may be useful for future epidemiologic studies. (J Occup Environ Med. 2008;50: 517526) T he question of what type of occupa- tional health surveillance is appropri- ate for workers potentially exposed to engineered nanoparticles is of in- creasing importance. This is because of a growing, but not definitive, body of evidence for potential health haz- ards of some types of engineered nano- particles and the fact that increasing numbers of workers are currently han- dling them. 19 These exposures can occur in research laboratories, and in operations where engineered nano- particles are manufactured, used, and disposed. 4 The development and pro- liferation of new engineered nano- particles can be expected to continue to outpace health researchers ability to evaluate the potential health con- sequences. Consequently, health au- thorities, employers, occupational health professionals, and workers are faced with determining appropriate strategies for occupational health surveillance in the face of uncer- tainty about the exposure and hazard from handling engineered nanopar- ticles. The current dearth of regula- tory clarity further contributes to the ambiguity surrounding what devel- opers and producers of engineered nanoparticles should consider doing to assure that their employees are protected. Although implementing appropriate engineering controls, us- ing effective personal protective equipment, and establishing safe handling procedures are paramount, additional efforts to monitor em- ployee health may be warranted in the near future. In this article, we characterize the range of action options From the National Institute for Occupational Safety and Health (Drs Schulte, Trout, Kuempel, Geraci, and Castranova, and Mr Zumwalde), Centers for Disease Control and Prevention, Cincinnati, Ohio; ENVIRON International Corporation (Dr Mundt), Amherst, Mass; and University of Medicine and Dentistry of New Jersey (Dr Halperin), NJ. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health. Address correspondence to: Paul A. Schulte, PhD, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, 4676 Columbia Parkway, MS-C14, Cincinnati, OH 45226-1998; E-mail: pas4@cdc.gov. Copyright 2008 by American College of Occupational and Environmental Medicine DOI: 10.1097/JOM.0b013e31816515f7 JOEM
Volume 50, Number 5, May 2008 517 on a continuum of hazard and medical surveillance. For each action, we de- scribe the scientific evidence base or rationale and implications. Because the body of evidence for potential hazard related to occupational expo- sure to engineered nanoparticles is continually changing, decisions about the need for and type of occu- pational health surveillance are likely to evolve over time. Occupational Health Surveillance Occupational health surveillance is the ongoing systematic collection, analysis, and dissemination of expo- sure and health data on groups of workers for the purpose of early detection of disease and injury as well as trends or patterns of occurrence presumably leading to prevention of subsequent disease. Occupational health surveillance can help define the magnitude and scope of occu- pational health issues among groups of workers and guide efforts to improve worker safety and health and monitor progress. The general term occupational health surveillance includes hazard and medical surveillance; integration of hazard and medical surveillance is key to an effective occupational health surveillance program. 1015 A substance may be defined as a hazard if it has the potential to cause harm under some set of circum- stances. Hazard surveillance consists of the periodic characterization of chemical/physical hazards in the workplace. Medical surveillance tar- gets actual health events or a change in a biologic function in an exposed person or persons. Medical screening (monitoring) is one form of medical surveillance that is designed to detect early signs of work-related illness by administering tests to apparently healthy persons to detect those with early stages of disease or risk of disease. 16 Occupational health surveillance is also conducted for the purpose of determining whether the hierarchy of techniques for injury and illness pre- vention are effective. These tech- niques can be ordered by primacy into primary, secondary, and tertiary prevention. 4,14 Within this hierarchy are a range of activities from premar- ket testing for potential toxicity to preclinical evaluation of exposed workers; all of which are intended to prevent long-term impairment and disability (see Fig. 1). Occupational health surveillance is the process by which information resulting from any one of these activities is col- lected and used to support or alter what is done at a step higher in the hierarchy. Critical in the discussion of occu- pational health surveillance for workers potentially exposed to engi- neered nanoparticles is what triggers the need or requirement for surveil- lance. The standard approach to oc- cupational health surveillance with known hazards, that is, ones with a documented evidence base and occu- pational exposure limits (OELs), is to utilize the concept of an action level. The action level represents some fraction of the OEL, usually 50%, which if exceeded will trigger various preventive actions including, in some cases, medical monitoring. This situation generally does not oc- cur with engineered nanoparticles since there is no government or pro- fessional association OELs specifi- cally for engineered nanoparticles. However, workers with airborne ex- posures to the nanoscale forms of bulk substances that have OELs will be subject to the same medical mon- itoring requirements as those ex- posed to the bulk form. This is in contrast to engineered nanoparticles that either have no established haz- ard database, OEL, or surveillance guidelines. In the absence of OELs and atten- dant action levels for engineered nanoparticles, occupational health surveillance may be considered in terms of qualitative job hazard expo- sure analyses. This type of health surveillance approach has been pio- neered in the pharmaceutical indus- try and in the United Kingdom. 17,18 Generally, these approaches are based on some knowledge of the degree of hazard. When this is not known, as with many engineered nanoparticles, various other approaches may need to be utilized, for example, by determin- ing whether toxicity information exists Fig. 1. The hierarchy of occupational health prevention with examples of surveillance feedback (Adapted from Am J Ind Med. 1996;29:321323). 518 Health Surveillance and Nanotechnology
Schulte et al for a similar type of nanoparticle that can be used as a surrogate for trigger- ing action. 19 Hazard Potential of Engineered Nanoparticles Various factors must be consid- ered to obtain perspective on the hazard potential of engineered nano- particles. First, the types and physi- cochemical properties of engineered nanoparticles are vast. The broad range and combination of parameters that can influence toxicity, such as composition, size, shape, surface coating, charge, attached functional groups, solubility, contaminants, and degree of agglomeration, may result in nanoparticles with large differ- ences in hazard potential. Second, much of the scientific evidence on the potential toxicity of engineered nanoparticles is based on toxicologi- cal and epidemiological studies of certain types of microscale (microme- ter-scale) and nanoscale (nanometer- scale) particles, including metal ox- ides, fumes, and combustion-derived nanoparticles. 2,8,2022 The term ul- trafine is frequently used in the context of nanometer-diameter parti- cles that have not been intentionally produced but are the incidental prod- ucts of processes involving combus- tion or hot processes. The extent to which these studies are predictive of the potential hazard of engineered nanoparticles will depend on the spe- cific physicochemical properties of the engineered particles and on the exposure conditions. Potential occupational health risks associated with manufacturing and using nanomaterials are not yet well defined. Many engineered nanomate- rials and devices are formed from nanoparticles that are initially pro- duced as aerosols or colloidal sus- pensions. Minimal information is currently available on the potential for exposure, dominant exposure routes, and material toxicity. Other exposures in the workplace where engineered nanoparticles are handled (including ambient particulates) may complicate the measurement of engi- neered nanoparticles and confound the association between exposures and health outcomes that might be reported. The epidemiological and toxicological literature on ultrafine or fine particles and fibers provides information on the organ systems and effects that may also be relevant to clinical evaluations or medical surveillance of workers exposed to engineered nanoparticles. However, engineered nanoparticles may differ in their physicochemical properties and may also exhibit enhanced or unique biological effects related to increased reactive surface area and quantum effects. 9,22 Inhalation is generally considered the primary route of occupational exposure to nanoparticles. Once in- haled, a substantial proportion of nanoparticles are likely to deposit in the human respiratory tract (30% 90%, depending on breathing rate and particle size). 23 Nanoparticles readily reach the deep lung, and the alveolar region is the primary site of deposition for nanoparticle sizes in the 10 to 100 nm range, whereas head and thoracic deposition pre- dominate for nanoparticles less than 10 nm. Deposition increases with exercise and in individuals with chronic obstructive pulmonary dis- ease. 2325 Other potential routes of exposure include passing through the skin and ingestion. Size and charge of particles appear to influence both dermal penetration and gastrointesti- nal absorption. 2631 Exposures to some types of nanoscale particles (eg, generated from combustion or hot processes) have been associated with adverse health effects in humans. For ex- ample, diesel exhaust has been as- sociated with eye and respiratory irritation, 32 endothelial dysfunction (impaired vasodilation) with mild systemic inflammation, 33 and lung cancer, 34 while welding fume ex- posure has been associated with metal fume fever, susceptibility to pulmonary infection, obstructive lung disease, and possible neurologic changes. 35,36 Cardiovascular system effects, including markers of blood coagulation and systemic inflamma- tion, have been observed in experi- mental studies of human volunteers inhaling a low concentration of car- bon nanoparticles. 24,25,37,38 In the general population, particulate air pollution (a mixture that includes combustion-derived ultrafine parti- cles) has been associated with in- creased morbidity and mortality from adverse respiratory and car- diovascular effects, primarily among susceptible populations such as the elderly or infirm. 3943 No epidemiological studies of oc- cupational cohorts exposed to engi- neered nanoparticles have been published. In experimental animal studies with ultrafine and nanoscale particles, the large surface area of the particles has been shown to play a key role in adverse lung effects, including inflam- mation and tumorigenesis, as does the surface reactivity, crystallinity, and biopersistence of the particles in the lung. 4449 Adverse lung responses ob- served in humans occupationally ex- posed to fine and ultrafine particles are similar to those observed in experi- mental studies with rodents. 34,50 Translocation is considered more likely for nanosized particles than for fine particles. In rodents, nanopar- ticles have been found to translocate from the respiratory tract to other organs, including brain, liver, kidney, and spleen, 5153 and the rate appears to depend on the physicochemical prop- erties of the nanoparticles (eg, size, chemical composition, shape, and charge). 5457 In experimental studies of human volunteers, low-dose, short-term inhalation of radiolabeled carbon nanoparticles (Technegas) showed that most of the deposited nanoparticles remained in the lungs up to 2 days after exposure. 58,59 These studies did not find evidence for the rapid translocation of nano- particles to the blood circulation or accumulation in the liver, as had been reported earlier (possibly due to JOEM
Volume 50, Number 5, May 2008 519 instability of the radiolabel-nanopar- ticle complex). 60 Studies of carbon nanotubes in rodents have shown early-onset of pulmonary fibrosis, granulomas, and oxidative stress in the lungs and car- diovascular system. 5,61 67 Metal nanoparticles, including cobalt and nickel caused greater lung inflamma- tion and injury in rats than microme- ter-sized particles. 68,69 Liver, kidney, and spleen were target organs of copper nanoparticles in mice ex- posed by oral gavage, causing acute toxicity, while micrometer-sized copper did not. 70 As observed in animal studies with various types of nanoparticles, contaminants associ- ated with specific nanoparticles (eg, metals used as catalysts) may pose a health risk to workers. 66,67 Continuum of Occupational Health Surveillance Like the techniques of prevention shown in Figure 1, occupational health surveillance efforts can also be ordered in a continuum. Because there is a lack of definitive evi- dence regarding specific health ef- fects associated with nanoparticle exposures, and because engineered nanoparticles are highly heteroge- neous, it is difficult to identify an appropriate evidence-based occupa- tional health surveillance strategy for workers handling nanomaterials. It may be that hazard surveillance rather than medical surveillance is more appropriate to initiate at this time, given the lack of knowledge regarding specific health outcomes in humans. A continuum of hazard and medical surveillance is shown in Figure 2, ranging from no targeted hazard or medical surveillance action to targeted medical surveillance of workers handling nanoparticles. Tar- geted medical surveillance refers to medical surveillance for specific bi- ologic changes known to be linked to exposure to specific engineered nanoparticles. Generally, each action in the continuum builds on the con- duct of the previous actions. No Targeted Action (ie, No Specific Occupational Surveillance Related to Engineered Nanoparticles) A decision to take no targeted action for workers potentially ex- posed to engineered nanoparticles may be influenced by whether or not there are other medical surveillance programs in place for these workers. These programs are established because of existing hazardous sub- stances in the workplace rather than exposure to engineered nanopar- ticles. Clearly, there is extensive medical surveillance conducted in various workplaces where known hazardous materials are manufac- tured or used. Over 30 Occupational Safety and Health Administration (OSHA) standards and hundreds of National Institute for Occupational Safety and Health (NIOSH) guid- ance documents recommend medical surveillance for various occupational hazards. Additionally, three types of medical surveillance that might also be occurring in a workplace pertain to the assessment of the workers abil- ity to wear or use required respiratory or other personal protective equip- ment, and medical examination per- taining to job placement and medical examination as part of emergency medical care after a work-related ex- posure or incident. So the option at one end of the continuum is no new action in addition to what already is occurring, or, if there is no other medical surveillance occurring in a given workplace, then nothing new related to medical surveillance would be implemented. Hazard surveillance may follow a similar logic as medical surveil- lance. 13 Employers, as part of their due diligence and in adherence to occupational safety and health and environmental laws, are obligated to make a determination as to whether regulated materials are present in the workplace. This is a rudimentary form of hazard surveillance. The no action option involves doing noth- ing beyond this rudimentary effort. Whether pertaining to hazard or health surveillance, a no action determination should be the product of active evaluation that is well doc- umented, and should not be equated with inaction. In most cases no action will pertain to no additional medical or hazard surveillance for workers potentially exposed to engi- neered nanoparticles. Document the Presence of Engineered Nanomaterials The presence of free (unbound) engineered nanomaterials in work- places where they are produced or purchased should be obvious to em- ployers since they are the result of intentional efforts. This second option for action on the continuum includes identifying and recording where in the Fig. 2. Continuum of hazard and medical surveillance and related research approaches for nanoparticle workers. 520 Health Surveillance and Nanotechnology
Schulte et al workplace and production process engineered nanomaterials are han- dled (eg, producing nanomaterials as powders or slurries/suspensions/ solutions), including storage and dis- posal. 71 The information that would be useful to record can be gathered based on existing management knowledge of processes and job tasks, including What nanomaterials are being manufactured or handled Where in the workplace exposure might occur When these nanomaterials are made or used How the nanomaterials are pro- duced or used. Special consideration should be given to processing equipment break- down and the need for and frequency of major routine maintenance. Less clear are situations where engineered nanoparticles are aggre- gated, agglomerated or even embed- ded in materials, such as composites, and hence are not free or unbound. 71 The question is whether these engi- neered nanoparticles can be released and inhaled or come into contact with the skin. The answer may be yes if the nanomaterial is subject to manipulation through kinetic pro- cesses that result in generating air- borne nanomaterial or free unbound engineered nanoparticles. There is limited information currently avail- able to evaluate the extent to which such release actually occurs. Identify Workers Potentially Exposed to Nanoparticles Identification of workers poten- tially exposed to engineered nano- particles is the next higher action option on the continuum. Given the uncertainty about the hazards of en- gineered nanoparticles it has been suggested that a broad definition ini- tially be used to identify workers potentially exposed to nanoparticles and that such a definition be refined as more reliable information on ex- posures and health effects become available. 72 The broad definition will, by intent, be overly broad in terms of identification of a group that is at risk of exposure. The Depart- ment of Energy, for example, defines a worker potentially exposed to en- gineered nanoparticles as one who handles engineered nanoscale par- ticles that have the potential to become dispersed in air; is routinely exposed (spends a sig- nificant amount of time in an area in which engineered nanoparticles have the potential to be dispersed in the air); works on equipment that might be contaminated with materials that could foreseeably release engi- neered nanoparticles during ser- vicing or maintenance. 72 The purpose for identifying and recording such information in a sys- tematic mannersuch as in a data- baseis 3-fold. First, such records can be used to determine whether or not workers with potential exposure will need to have appropriate train- ing in the safe handling and disposal of materials, proper maintenance of equipment, and use of personal pro- tective equipment. Second, such records will be available if there is a need to establish exposure regis- tries or participate in epidemiologic or health surveillance studies. 73,74 Third, should new information about health effects trigger the need for medical monitoring, a roster of po- tentially at risk workers will be available. As more information becomes available about appropriate metrics and instrumentation for airborne- engineered nanoparticles, there will be a need for quantitative rather than qualitative assessments of exposure to engineered nanoparticles for indi- vidual workers. Such information will allow for assessment of the ef- fectiveness of controls, adherence with exposure recommendations and standards, and could serve to help set action levels to trigger medical sur- veillance. At present it is not known what exposure metrics and particle characteristics (eg, mass, surface area, particle count, shape, aerody- namic diameters) are best for expo- sure assessment; however, particle count, surface area and mass are pres- ently considered to be most useful. 19 Whether monitoring biological markers of exposure will be useful to supplement exposure assessment is not known. Before such action would be warranted more information is needed on biotransformation of par- ticles and toxicokinetics, given the potential invasiveness and some- times complicated logistical issues surrounding biomonitoring. General Medical Monitoring Baseline and periodic routine non- specific medical monitoring is the next action in the occupational health continuum. It may take place apart from or in conjunction with one of the previous actions. If such medical monitoring is provided it would likely either be provided to all work- ers in a facility or to some subset of workers potentially exposed to engi- neered nanoparticles. The utility of nonspecific medical monitoring is limited because the health endpoints that may be linked to engineered nanoparticle are not well known or confirmed at this time. Nonetheless, general medical monitoring may serve as an early warning system for possible, yet to be determined, health effects linked to exposure. This de- termination will require that the data be continually analyzed on a group basis and if possible, linked to expo- sure and compared with appropriate comparison population rates. The limitation of this monitoring ap- proach is that it may identify health effects unrelated to exposure to en- gineered nanoparticles and in some cases false positives, all of which will require follow-up and diagnostic evaluation. It also may give moni- tored employees a false sense that such procedures would be sensitive to any health risk associated with exposure to engineered nanopar- ticles. This needs to be balanced against a reasonable assurance that periodic examination affords that no JOEM
Volume 50, Number 5, May 2008 521 obvious or easily detected health ef- fects are present. In some worksites, workers will be monitored through existing programs if they work in areas with both reg- ulated hazards (or hazards which may not be regulated but for which well-accepted medical monitoring procedures exist) and engineered nanoparticles. This medical monitor- ing, which is conducted due to the exposure to the regulated hazards, may have the effect of collecting baseline health information for workers. If medical data were in- cluded, medical history and lifestyle information (eg, tobacco and alcohol use, exercise frequency) would also be useful to record in such baseline data. Targeted Medical Testing for Workers Exposed to Engineered Nanoparticles If specific hazards of engineered nanoparticles are identified and characterized then it could be pos- sible to detect preclinical changes through medical testing and/or modify exposure potential through risk management interventions. Medical monitoring is not meant as the primary means for protecting workers but rather as a secondary prevention effort, after risk manage- ment efforts (eg, engineering con- trols and use of personal protection equipment) have been implement- ed. 75 The rationale for specific med- ical surveillance of workers exposed to nanoparticles is based on the re- sults of a needs assessment. 10 A primary determination from a needs assessment involves some assess- ment of risk, which is the potential or probability of a hazardous material under certain exposure scenarios to cause harm. Risk may be thought of as a com- bination of hazard and exposure. For example, workers producing a sub- stance with known toxicity but never exposed might be judged as not at risk from that substance. A compo- nent of determining this risk, how- ever, may involve the presence or absence of controls (engineering, ad- ministrative, personal protection) in the workplace and whether the expo- sure is being controlled successfully. Further, even if low, the probability of a process failure, operator error, or industrial accident could result in some potential risk. If the potential exists for residual riskthat is, the workers are at some risk of harm based on the hazard and exposure concentration, medical surveillance may be warranted. Targeted medical testing data, analyzed on a group basis, can assist in detecting patterns and trends, and linking with expo- sure. 14,16 If known or anticipated biological changes linked to expo- sure to engineered nanoparticles can be identified, then medical testing can serve to identify sentinel events. 76,77 On the basis of the toxicological studies summarized above, prelimi- nary findings of research on exposure to engineered nanoparticles and previ- ous research of ultrafine particles, the most likely target organ systems will include the respiratory and circula- tory systems, although skin exposure may also occur. 1,79,20,22 Medical tests that include an evaluation of the respiratory system could help to in- dicate changes in pulmonary func- tion or early indicators of fibrosis. Although not widely validated, ex- haled nitrous oxide or isoprostanes have been used as noninvasive mark- ers of pulmonary inflammation. 7880 Additionally, the National Institute of Occupational Health in South Af- rica is conducting a biomarker study of gold miners. 81 They are monitor- ing blood levels of several antioxi- dant enzymes, cytokines, and total antioxidant levels. They report that decreases in red cell glutathione and serum Clara cell proteins were associated with silica exposure. Also, tests that are indicative of inflammatory response in pulmo- nary and circulatory systems might be useful. 5,62,65 None of these tests are validated for use in asymptom- atic workers. Beyond the respiratory and circulatory systems, the impact of engineered nanoparticles is poorly understood. Nanoparticles in the blood circulatory system could reach many other organs and specific tests related to early changes in organ function may be warranted. 3 Trans- location to the brain by nanoparticles has been demonstrated but the sever- ity and clinical relevance is not known, nor is there enough informa- tion to suggest what type of testing could be useful to assess such ef- fects. Criteria for medical testing for workers have been published and would need to be met before imple- mentation of specific medical screening of workers potentially ex- posed to engineered nanopar- ticles. 10,12,16,8284 At the present time, it does not appear that there is scientific and medical evidence suf- ficient to recommend medical screening of workers potentially ex- posed to engineered nanoparticles. A medical surveillance plan, like all targeted medical surveillance plans, in- volves adherence to recognized basic elements that include interpretation of the findings for workers and manage- ment, implementation of follow-up ac- tion, and program evaluation. 10,82 Data Collection and Use Responsibilities Regardless of the level of occupa- tional health surveillance action that may be selected; the gathering, stor- age, and use of individual-level or individually identifiable data carry certain legal and ethical obligations. Various issues are outside the scope of this article; they include confiden- tiality, Health Insurance Portability and Accountability Act (HIPPA) re- quirements, understanding of origi- nal and intended use of surveillance data, informed consent, and report- ing test results, among others. 12,83,84 Less well appreciated are possible ethical responsibilities to properly analyze and report findings from constructed databases. 522 Health Surveillance and Nanotechnology
Schulte et al Future Research In Vitro and In Vivo Studies The basis for selecting among the options for occupational health sur- veillance of workers potentially ex- posed to engineered nanoparticles is based on knowledge of potential haz- ards. The results from in vivo studies involving various animal models and in vitro studies using various testing systems are frequently used as the basis for that determination. 1,9 Al- though such research has provided preliminary indications of hazards from some types of engineered nano- particles, the heterogeneity of these particles is large. Also, whether and the degree to which effects seen in various animal testing systems are relevant to humans (especially at lev- els to which humans are exposed) may not be known. Nevertheless, animal (rat) models of adverse lung effects from inhaled poorly soluble particles have been shown to be consistent with the findings of some epidemiological studies in- cluding occupational exposures to asbestos, silica, and diesel exhaust particulate. 8588 Ultimately for guidance and regu- latory purposes, it may be necessary to determine whether broad catego- ries of engineered nanoparticles can be identified that are based on simi- lar physicochemical parameters. It is not known if particle size will be the preeminent factor or various combi- nations of size and other physico- chemical parameters will be needed to help establish risk-based catego- ries on which to base future surveil- lance decisions. Epidemiologic Studies It will be important to know whether workers who have handled and been exposed to engineered nanoparticles develop adverse health effects and disease. 19 Chronic ef- fects, such as pulmonary malignant and nonmalignant disease, and circu- latory disease may take decades to assess in worker populations. This is because of the inherent nature of such effects as well as the fact that exposures, if they occur, are likely to be quite low given the initial societal concerns and precautions for control- ling workplace exposures to engi- neered nanoparticles. 1,79,75 Acute effects may be more easily assessed but the frequency also may be low given the wide prevalence of work- place exposure controls. Epidemiologic studies of worker populations potentially exposed to engineered nanoparticles will be dif- ficult to conduct for various reasons including 1. Heterogeneity of engineered nano- particles making it difficult to find a sufficiently large group of workers exposed to the same particles; 2. Dispersion of the contemporary workforce resulting from generally small numbers of potentially ex- posed workers in any given facility; 3. Difficulty in identifying and re- cruiting potentially exposed work- ers and employers; 4. Insufficient exposure to cause and/or latency to detect chronic diseases; 5. Lack of exposure data and stan- dardized exposure metrics needed to develop comparable exposure histories. Despite these limitations, the es- tablishment of formal national, or even an international, exposure and employee tracking registries might be warranted. Exposure registries are useful tools for surveillance of new or perceived hazards since they pro- vide documentation of who is work- ing with which materials, when, and where in the facility. A registry pro- vides a structured and orderly ap- proach to handling the problem of identifying and maintaining commu- nication with workers exposed to hazardous substances, 72 utilizing a common set of variables. 74 An expo- sure registry is the enrollment of persons exposed or likely to have been exposed to occupational or en- vironmental hazards that can serve as a means of identifying persons for primary or secondary preventive ef- forts. In occupational situations, company employee rosters are de facto registries; however, they may not address employees who leave a company. Moreover, for new tech- nologies, such as nanotechnology, registries could be developed and maintained by government entities; however, there are examples of pri- vate sector registries related to expo- sure to commercial products. Whether such registries would foster potential discriminatory actions or legal liabilities would need to be addressed. If sufficient numbers of workers can be recruited with exposure to the same engineered nanoparticles using similar exposure metrics, it may be useful to conduct studies to link ex- posures with various biological markers or other biological changes that may be precursors to more seri- ous health effects. 89 In the meantime, results from in vivo and in vitro research will continue to be the basis for decision-making concerning oc- cupational health surveillance. Companies currently involved with nanotechnology are faced with the dilemma of balancing a desire to expand a potentially bountiful tech- nology with limited knowledge about the potential hazards. 90 The potential health risks associated with nanotechnology are not well estab- lished, and the perceived risks are undetermined. As one commentator noted: Even if studies showed every commercially relevant nanoparticle to be harmless in every real world scenario, public skepticism about the safety of nanoparticles could still build and sharply limit their use in products. 91 One of the earliest areas where exposures to nanoparticles is occurring is in the workplace including universities and other non- manufacturing settings. 71 In the face of uncertainty about the hazards of nanoparticles, a corporate or societal response (such as implementing se- lected exposure registries in poten- tially high exposure sectors) may assure the public that appropriate efforts are being taken to identify JOEM
Volume 50, Number 5, May 2008 523 and control exposures in a timely and responsible manner. References 1. Department for the Environment, Food, and Rural Affairs (DEFRA). Character- izing the Potential Risks Posed by En- gineered Nanoparticles: A First UK Government Research Report. London: HM Government; 2006:157. Available at: http://ec.europa.eu/european_group_ ethics/docs/uk_report_nanoparticles_ en.pdf. Accessed October 23, 2007. 2. Maynard AD, Kuempel ED. Airborne nanostructural particles and occupational health. J Nanoparticles Res. 2005;7:587 614. 3. Oberdorster G, Oberdorster E, Oberdor- ster J. Nanotoxicologyan emerging discipline involving studies of ultrafine particles. Environ Health Perspect. 2005; 113:823839. 4. Borm PJA, Robbins D, Haubold S, et al. The potential risks of nanoparticles: a review carried out for ECETOC. Particle Fibre Toxicol. 2006;3:11. 5. Li Z, Hulderman T, Salmen R, et al. Cardiovascular effects of pulmonary ex- posure to single-wall carbon nanotubes. Environ Health Perspect. 2007;115:377 382. 6. Duffin R, Tran L, Brown D, et al. Proin- flammogenic effects of low-toxicity and metal nanoparticles in vivo and in vitro: highlighting the role of particle surface area and surface reactivity. Inhal Toxicol. 2007;19:849856. 7. Australian Safety and Compensation Coun- cil (ASCC). A review of the potential occupational safety and health implications of nanotechnology. 2000. Available at: http://www.ascc.gov.au/ascc/healthsafety/ emergingissues/nanotechnology. 8. Aitken RJ, Creely KS, Tran CL. Nanopar- ticles: an Occupational Hygiene Review. Health and Safety Executive. Research Re- port 274. Norwich UK; HSE Books; 2004. 9. Institut de Recherche Robert-Sauve en Sante du Travail (IRSST). Nanopar- ticles: Actual Knowledge about Occupa- tional Health and Safety Risks and Prevention Measures. Studies and Re- search Projects R-470. Montreal, Canada: IRSST;2006:100 pages. Available at: http://www.irsst.qc.ca/files/documents/ PubIRSST/R-470.pdf. Accessed October 23, 2007. 10. Harber P, Conlon C, McCunney RJ. Oc- cupational medical surveillance. In: Mc- Cunney RJ, ed. A Practical Approach to Occupational and Environmental Medi- cine. Philadelphia, PA: Lippincott, Wil- liams, and Wilkins; 2003;582599. 11. Baker EL, Matte TP. Occupational health surveillance. In: Rosenstock L, Cullen E, Brodkin R, et al, eds. Textbook of Clinical Occupational and Environ- mental Medicine. 2nd ed. Philadelphia, PA: Elsevier Saunders Company; 2005: 7682. 12. Ashford NA, Spadafor CJ, Hattis DB, et al. Monitoring the Worker for Exposure and Disease. Baltimore, MD: The Johns Hopkins University Press; 1990. 13. Wegman DH. Hazard surveillance. In Halperin W, Baker EL, Monson RR, eds. Public Health Surveillance. New York: VanNostrand Reinhold; 1992:4275. 14. Halperin WE. The role of surveillance in the hierarchy of prevention. Am J Ind Med. 1996;29:321323. 15. Wagner GR, Fine LJ. Surveillance and health screening in occupational health. In Wallace RB, ed. Maxcy-Rosenau-Last Public Health and Preventive Medicine. 15th ed. New York: McGraw-Hill Med- ical Publishing; 2008:759793. 16. Halperin WE, Ratcliffe JM, Frazier JM, et al. Medical screening in the workplace: proposed principles. J Occup Med. 1986; 28:522547. 17. Naumann BD, Sargent EV. Setting occu- pational exposure limits for pharmaceu- ticals. Occup Med. 1997;12:6780. 18. Health and Safety Executive. Foundry Control Guidance Sheet FD02: Engineer- ing Control for Foundry Fumes from Melting. London: HSE; 2006. 19. Kuempel ED, Geraci CL, Schulte PA. Risk assessment and research needs for nanomaterials: an examination of data and information from current studies. In: Simeonova PP, et al, eds. Nanotechnol- ogyToxicological Issues and Environ- mental Safety. Proceedings of the NATO Advanced Research Workshop on Nano- technologyToxicological Issues and Environmental Safety, Varna, Bulgaria, 1217 August, 2006. New York: Spring- er; 2007:119145. 20. Donaldson K, Tran L, Jimenez LA, et al. Combustion-derived nanoparticles: a re- view of their toxicology following inha- lation exposure. Part Fibre Toxicol. 2005;2:1014. 21. Oberdorster G, Maynard A, Donaldson K, et al. Principles for characterizing the potential human health effects from ex- posure to nanomaterials: elements of a screening strategy. Part Fibre Toxicol. 2005;35:28. 22. Gwinn MR, Vallyathan V. Nanoparticles: health effects-pro and cons. Env Health Perspect. 2006;114:18181825. 23. International Commission on Radiologi- cal Protection. Human Respiratory Tract Model for Radiological Protection. An- nals of the ICRP Publ. 66. New York: Pergamon; 1994. 24. Jaques PA, Kim CS. Measurement of total lung deposition of inhaled ultrafine particles in healthy men and women. Inhal Toxicol. 2000;12:715731. 25. Brown JS, Zeman KL, Bennett WD. Ul- trafine particle deposition and clearance in the healthy and obstructed lung. Am J Respir Crit Care Med. 2002;166:1240 1247. 26. Tinkle SS, Antonini JM, Rich BA, et al. Skin as a route of exposure and sensiti- zation in chronic beryllium disease. Environ Health Perspect. 2003;111: 12021208. 27. Kohli AK, Alpar HO. Potential use of nanoparticles for transcutaneous vaccine delivery: effect of particle size and charge. Int J Pharm. 2004;275:1317. 28. Ryman-Rasmussen JP, Riviere JE, Mon- teiro-Riviere NA. Penetration of intact skin by quantum dots with diverse phys- icochemical properties. Toxicol Sci. 2006;91:159165. 29. Jani P, Halbert GW, Langridge J, et al. Nanoparticle uptake by the rat gastroin- testinal mucosa: quantitation and particle size dependency. J Pharm Pharmacol. 1990;42:821826. 30. Desai MP, Labhasetwar V, Amidon GL, et al. Gastrointestinal uptake of biode- gradable microparticles: effect of particle size. Pharm Res. 1996;13:18381845. 31. Florence AT. The oral absorption of mi- cro- and nanoparticulates: neither excep- tional nor unusual. Pharm Res. 1997;14: 259266. 32. Sydbom A, Blomberg A, Parnia S, Sten- fors N, Sandstrom T, Dahlen SE. Health effects of diesel exhaust emissions. Eur Resp J. 2001;17:733746. 33. Tornqvist H, Mills NL, Gonzalez M, et al. Persistent endothelial dysfunction in humans after diesel exhaust inhalation. Am J Respir Crit Care Med. 2007;176: 395400. 34. Stayner L, Dankovic D, Smith R, et al. Predicted lung cancer risk among miners exposed to diesel exhaust particles. Am J Ind Med. 1998;34:207219. 35. Ambroise D, Wild P, Moulin JJ. Update of a meta-analysis on lung cancer and welding. Scand J Work Environ Health. 2006;32:2231. 36. Antonini JM, Santamaria AB, Jenkins NT, et al. Fate of manganese associated with the inhalation of welding fumes: potential neurological effects. Neuro Toxicol. 2006;27:304310. 37. Chalupa DC, Morrow PE, Oberdorster G, et al. Ultrafine particle deposition in sub- jects with asthma. Environ Health Per- spect. 2004;112:879882. 524 Health Surveillance and Nanotechnology
Schulte et al 38. Pietropaoli AP, Frampton MW, Oberdor- ster G, et al. Blood markers of coagula- tion and inflammation in healthy subjects exposed to carbon ultrafine particles. In: Heinrich U, ed. Effects of Air Contami- nant on the Respiratory TractInterpre- tations from Molecular to Meta Analysis. Stuttgart, Germany: INIS Monographs, Frauinhofer IRB Verlag; 2004;181194. 39. Wichmann H-E, Spix C, Tuch T, et al. Daily mortality and fine and ultrafine particles in Erfurt, Germany. Part I: role of particle number and particle mass. Res Rep Health Eff Inst. 2000;98:586. 40. Dockery DW, Pope CA, Xu X, et al. An association between air pollution and mortality in six U.S. cities. N Engl J Med. 1993;329:17531759. 41. Ibald-Mulli A, Wichmann HE, Kreyling W, et al. Epidemiological evidence on health effects of ultrafine particles. J Aerosol Med Depos. 2002;15:189201. 42. Pope CA, Burnett RT, Thun MJ, et al. Lung cancer, cardiopulmonary mortality and long term exposure to fine particulate air pollution. JAMA. 2002;287:1132 1141. 43. Pope CA, Burnett RT, Thurston GD, et al. Cardiovascular mortality and long- term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation. 2004;109:7174. 44. Oberdorster G, Yu CP. The carcinogenic potential of inhaled diesel exhaust: a particle effect? J Aerosol Sci. 1991;21: S397S401. 45. Driscoll KE. Role of inflammation in the development of rat lung tumors in re- sponse to chronic particle exposure. In: Mauderly JL, McCunney RJ, eds. Parti- cle Overload in the Rat Lung and Lung Cancer: Implications for Human Risk Assessment. Philadelphia, PA: Taylor & Francis; 1996;139152. 46. Tran CL, Buchanan D, Cullen RT, et al. Inhalation of poorly soluble particles. II. Influence of particle surface area on in- flammation and clearance. Inhal Toxicol. 2000;12:11131126. 47. Hohr D, Steinfartz Y, Schins RP, et al. The surface area rather than the surface coating determines the acute inflamma- tory response after instillation of fine and ultrafine TiO2 in the rat. Int J Hyg Environ Health. 2002;205:239244. 48. Warheit DB, Webb TR, Reed KL, et al. Pulmonary toxicity study in rats with three forms of ultrafine-TiO2 particles: differential response related to surface properties. Toxicology. 2007;230:90 104. 49. Elder A, Gelein R, Finkelstein JN, et al. Effects of Subchronically Inhaled Carbon Black in Three Species. I. Retention Ki- netics, Lung Inflammation, and Histopa- thology. Toxicol Sci. 2005;88:614629. 50. Castranova V. From coal mine dust to quartz: mechanisms of pulmonary patho- genicity. Inhal Toxicol. 2000;(Suppl 3): 714. 51. Elder A, Gelein R, Silva V, et al. Trans- location of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health Perspect. 2006; 114:11721178. 52. Geiser M, Rothen-Rutishauser B, Kapp N, et al. Ultrafine particles cross cellular membranes by nonphagocytic mecha- nisms in lungs and in cultured cells. Environ Health Perspect. 2005;113: 15551560. 53. Muhlfeld C, Geiser M, Kapp N, et al. Re-evaluation of pulmonary titanium di- oxide nanoparticle distribution using the relative deposition index: evidence for clearance through microvasculature. Part Fibre Toxicol 2007;29:47. Available at: http://www.particleandfibretoxicology. com/content/pdf/1743-8977-4-7.pdf. Ac- cessed October 23, 2007. 54. Oberdorster G, Sharp Z, Atudorei V, et al. Extrapulmonary translocation of ultrafine carbon particles following whole-body in- halation exposure of rats. J Toxicol Environ Health Part A. 2002;65:15311543. 55. Kreyling WG, Semmler M, Erbe F, et al. Translocation of ultrafine insoluble irid- ium particles from lung epithelium to extrapulmonary organs is size dependent but very low. J Toxicol Environ Health Part A. 2002;65:15131530. 56. Kreyling WG, Semmler-Behnke M, Moller W. Ultrafine particle-lung interac- tions: does size matter? J Aerosol Med. 2006;19:7483. 57. Hagens WI, Oomen AG, de Jong WH, et al. What do we (need to) know about the kinetic properties of nanoparticles in the body? Regul Toxicol Pharmacol. 2007; 49:217229. 58. Mills NL, Amin N, Robinson SD, et al. Do inhaled carbon nanoparticles translo- cate directly into the circulation in hu- mans? Am J Respir Crit Care Med. 2006; 173:425431. 59. Wiebert P, Sanchez-Crespo A, Seitze J, et al. Negligible clearance of ultrafine particles retained in healthy and affected human lungs. Eur Respir J. 2006;28: 286290. 60. Nemmar A, Hoet PHM, Vanquicken- borne B, et al. Passage of inhaled parti- cles into the blood circulation in humans. Circulation. 2002;105:411414. 61. Lam CW, James JT, McCluskey R, et al. Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation. Toxicol Sci. 2004;77:126134. 62. Shvedova AA, Kisin ER, Mercer R, et al. Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice. Am J Physiol Lung Cell Mol Physiol. 2005;289:L698 L708. 63. Donaldson K, Aitken R, Tran L, et al. Carbon nanotubes: a review of their prop- erties in relation to pulmonary toxicology and workplace safety. Toxicol Sci. 2006; 92:522. 64. Helland A, Wick P, Koehler A, et al. Reviewing the environmental and human health knowledge base of carbon nano- tubes. Environ Health Perspect. 2007; 115:11251131. 65. Radomski A, Juraz P, Alonso-Escolano D, et al. Nanoparticle-induced platelet aggregation and vascular thrombosis. Br J Pharmacol. 2005;146:882893. 66. Lam C-W, James JT, McCluskey R, et al. A review of carbon nanotube toxicity and assessment of potential occupational and environmental health risks. Crit Rev Toxicol. 2006;36:189217. 67. Mossman BT, Borm PJ, Castranova V, et al. Mechanisms of action of inhaled fi- bers, particles and nanoparticles in lung and cardiovascular diseases. Part Fibre Toxicol. 2007; 4:4. Available at: http:// www.particleandfibretoxicology.com/ content/pdf/1743-8977-4-4.pdf. Ac- cessed October 23, 2007. 68. Zhang Q, Kusaka Y, Donaldson K. Com- parative pulmonary responses caused by exposure to standard cobalt and ultrafine cobalt. J Occup Health. 2000;42:179 184. 69. Zhang Q, Kusaka Y, Zhu X, et al. Comparative toxicity of standard nickel and ultrafine nickel in lung after intra- tracheal instillation. J Occup Health. 2003;45:2330. 70. Chen Z, Meng H, Xing G, et al. Acute toxicological effects of copper nanopar- ticles in vivo. Toxicol Lett. 2006;163: 109120. 71. Schulte PA, Geraci C, Zumwalde R, Hoover M, Kuempel E. Occupational risk management of engineered nanoparticles. J Occup Environ Health. 2008;5:239249. 72. Department of Energy (DOE). Approach to Nanomaterial E S & H. Nanoscale Science Research Centers. Revision 2 June, 2007. Available at: http://www.sc. doe.gov/bes/DOE_NSRC_Approach_ to_Nanomaterial_ESH.pdf. 73. Nasterlack M, Zober A, Oberlinner C. Considerations on occupational medical surveillance in employees handling nano- particles. Int Arch Occup Environ Health. 2008;81:721726. JOEM
Volume 50, Number 5, May 2008 525 74. Schulte PA, Kaye WE. Exposure regis- tries. Arch Environ Health. 1988;43:155 161. 75. National Institute for Occupational Safety and Health (NIOSH). Approaches to safe nanotechnology: an information exchange with NIOSH. Available at: www.cdc.gov/niosh/topics/nanotech/ nano_exchange.html. 76. Mullan RJ, Murthy LI. Occupational senti- nel health events: an updated list for phy- sician recognition and public health surveil- lance. Am J Ind Med. 1999;19:775799. 77. Rutstein D, Mullan R, Frazier T, et al. Sentinel health events (occupational): a basis for physician recognition and public health surveillance. Am J Public Health. 1983;73:10541062. 78. Birrell MA, McCluskie K, Hardaker E, Knowles R, Belvisi MG. Utility of exhaled nitric oxide as a noninvasive biomarker of lung inflammation in a disease model. Eur Respir J. 2006;28: 12361244. 79. Beilman G. Exhaled nitric oxide in pathophysiologic states: the substance behind the gas. Chest. 2004;125:1113. 80. Makris D, Paraskakis E, Korakas P, et al. Exhaled breath condensate 8-isoprostane, clinical parameters, radiological indices and airway inflammation in COPD. Res- piration. 2008;75:138144. 81. Murray J, Girdler-Brown B. Validation of biomarkers for improved assessment of exposure and early effect from expo- sure to crystalline silica. Final report SIOM. 03-08-03 Phase 2. Johannesburg, South Africa: South African Institute of Occupational Medicine; 2007. 82. National Institute for Occupational Safety and Health (NIOSH). Criteria for a Recommended Standard: Occupational Exposure to Refractory Ceramic Fibers. Cincinnati, Ohio: DHHS, Centers for Disease Control and Prevention (NIOSH) Publication No. 2006-125; 2006. 83. International Labour Office. Technical and Ethical Guidelines for Workers Health Surveillance (Occupational Safety & Health Series No. 72). Geneva: Interna- tional Labour Office;1998:54. Available at: http://www.ilo.org/public/english/protection/ safework/cops/english/download/e000017. pdf. Accessed October 23, 2007. 84. American College of Occupational Envi- ronmental Medicine. Position statement: medical surveillance in the workplace. 2000. Available at: http://www.acoem. org/paprquid/papers/msurv.htm. 85. Mauderly JL. Relevance of particle- induced rat lung tumors for assessing lung carcinogenic hazard and human lung cancer risk. Environ Health Perspect. 1997;105(Suppl 5):13371346. 86. Stayner L, Dankovic D, Smith R, et al. Predicted lung cancer risk among miners exposed to diesel exhaust particles. Am J Ind Med. 1998;34:207219. 87. Kuempel ED, Smith RJ, Dankovic DA, et al. Concordance of rat and human based risk estimates for particle-related lung cancer. Ann Occup Hyg. 2002;46(Suppl 1):6266. 88. Kuempel ED, Tran CL, Bailer AJ, et al. Biological and statistical approaches to predicting human lung cancer risk from silica. J Environ Pathol Toxicol Oncol. 2001;20(Suppl 1):1532. 89. Schulte PA. The use of biomarkers in surveillance, medical screening and inter- vention. Mutat Res. 2005;592:155163. 90. Schulte PA, Salamanca-Buentello F. Eth- ical and scientific issues of nanotechnol- ogy in the workplace. Environ Health Perspect. 2007;115:512. 91. Holman MW. Nanotech environmental, health, and safety risks: action needed. In: Health and Nanotechnology: Eco- nomic, Societal, and Institutional Impact. Perspectives on the Future of Science and Technology. Report from conference convened with the cooperation of the United States Department of State and the European Commission. Varenna, It- aly, May 2123. 2006:7887. 526 Health Surveillance and Nanotechnology