Boutou-Kempf, Odile PharmD, MPH; Marchand, Jean-Luc PhD; Radauceanu, Anca MD; Witschger, Olivier PhD; Imbernon, Ellen MD; the group Health Risks of Nanotechnologies
Nanomaterials have unique physical and chemical properties, which make them highly attractive for industrial applications but also modify their interaction with biological systems, with the potential to generate toxicity.1 Alerted by the possible impact of nanomaterials exposure on human health, the French Ministries of Health and of Labour have given the French Institute for Public Health Surveillance responsibility for designing the protocol of an epidemiological surveillance system of workers likely to be exposed to engineered nanomaterials. The Institute for Public Health Surveillance has benefited from the scientific support of a multidisciplinary working group held by the French Institute for Public Health Research. The protocol has been developed in close collaboration with the Institut National de Recherche et de Sécurité in particular for the inhalation exposure assessment.
Four major goals are commonly assigned to epidemiological surveillance: (1) to detect timely unusual health situations, (2) to assess the magnitude of a health problem to make decisions affecting public health policy and allocation of resources, (3) to contribute to further research, and (4) to evaluate the effects of prevention and intervention efforts.2
Designing the protocol of an epidemiological surveillance system in the field of occupational exposure to nanomaterials needs to face numerous issues such as the wide range of nanomaterials, the identification of health outcomes that need to be followed-up, the quantitative assessment of exposure, the identification and cooperation of companies involved in the manufacture and incorporation of nanomaterials, and the registration of workers producing or handling nanomaterials.
THE WIDE RANGE OF NANOMATERIALS
The International Organization for Standardization defined nano-objects as materials with one, two, or three external dimensions in the nanoscale (from approximately 1 nm to 100 nm).3 Engineered nanomaterials are commonly described as materials designed and produced to have structural features with at least one dimension of 100 nanometers or less.4 This definition encompasses many forms of materials: nano-objects themselves (powder of nano-objects, aerosol of nano-objects), materials incorporating nano-objects (nano-objects in liquid suspension, nano-objects incorporated in solid materials, nano-objects linked to the surface of solid materials), mass or surface nanostructured materials. At this broad range of nanomaterials correspond different circumstances of exposure on the workplace. The exposure to aerosol of nano-objects occurring during the handling of powder is today the best documented situation.5
According to toxicological studies, chemical characteristics (such as composition, added functional group, surface coating, impurities), physical features (such as size, surface, shape, charge) as well as physicochemical properties (such as crystallinity and aggregation/agglomeration state) influence the toxicity of nano-objects. The combination of these different features adds to the great diversity of nanomaterials.1 Therefore, it seems relevant to focus on epidemiological surveillance of workers likely to be exposed to a few nanomaterials of interest.
REGISTRATION AND COLLABORATION OF COMPANIES AND WORKERS PRODUCING OR HANDLING NANOMATERIALS
In France, companies producing the main sorts of nano-objects are well known; however, registration of companies incorporating nano-objects is not complete.6 To collect critical information such as the number of workers likely to be exposed to nanomaterials, conditions of exposure, medical follow-up, and collaboration issues, an exploratory study was performed from 2008 to 2010 and several companies producing or incorporating carbon nanotubes, carbon black, titanium dioxide, or amorphous silica were contacted to be visited (Table 1). In each facility, the number of workers likely to be exposed to nanomaterials was quite low.
Three kinds of companies could be distinguished:
* Research and development facilities producing and incorporating emerging nano-objects like carbon nanotubes: three of them have been visited and are ready to collaborate in an epidemiological surveillance system. The probability of individual occupational exposure was low because of extensive engineering control measures implementation and the use of appropriate personal protective equipment. Nevertheless, accidental exposure could not be excluded.
* Chemical companies producing materials for decades such as amorphous silica, carbon black, or titanium dioxide: four companies were visited among seven existing in France. The workers were likely to be exposed to aggregated and agglomerated forms of nanometer-sized primary particles (existence of dust deposit on the work environment).
* Companies incorporating nanomaterials: the total number operating in France is not known at the moment. Three of the companies working in the fields of cosmetics and tire production were contacted, and one was visited. Cooperation issues could be anticipated from this experience. In this group of industries, the lack of standardized definition for nanomaterials was a matter of concern. Some of the companies refuted the word nanomaterial to describe agglomerated and aggregated forms of primary nanometer-sized particles.
In France, for all workers, occupational medical surveillance is mandatory by law (French labour code, articles R4624-10 to R4624-20). As all other workers, those producing or handling nanomaterials have a health follow-up, which is not specific to their exposure to nanomaterials but rather determined by their exposure to other nuisance materials. Visits to industrial sites showed that all workers concerned about nanomaterials had annual clinical examinations that in some cases included lung function tests, blood withdrawal (blood cell counts, creatinine, transaminase, C Reactive Protein), or chest radiography. This confirms that, for workers dealing with nanomaterials, health data already exists in companies through occupational medicine.
IDENTIFICATION OF HEALTH OUTCOMES THAT NEED TO BE FOLLOWED-UP
A comprehensive review of the scientific literature has been conducted. Toxicological studies gave some relevant information on toxicokinetic, short-term, and long-term effects on animal health and biological mechanism of action. These studies could be helpful to identify potential biological markers of effect. Human experimental studies provided an insight into toxicokinetic and short-term health effects. Epidemiological studies on the effects of particulate air pollution were also consulted as a parallel can be drawn between nano-objects and ultrafine particles. Epidemiological studies conducted among workers exposed to bulk materials produced for decades such as carbon black and amorphous silica constituted the last source of information.7,8 Although none of them considered specifically the exposure to aerosol of nano-objects, some of the results seemed to be relevant.
An increased risk of adverse malignant and nonmalignant respiratory effects has been found in a number of toxicological studies and epidemiological studies on the effects of particulate air pollution and nanomaterials produced for a long time.7–12 Different outcomes should then be monitored in an epidemiological surveillance system of workers likely to be exposed to nanomaterials such as pulmonary and systemic inflammation, occurrence and worsening of chronic respiratory illness (asthma, obstructive lung disease), increased susceptibility to infectious diseases, pulmonary fibrosis, and lung cancer. Concerning carbon nanotubes, toxicological studies drew special attention to the possible risk of fibrotic respiratory disease and mesothelioma.13–15 Spirometry, chest radiography, exhaled nitric oxide, or exercise oxymetry could be implemented in the occupational medical surveillance. Although a promising tool for noninvasive assessment of lung inflammation, biomarkers analysis in exhaled breath condensate is still pending validation studies.16
Inference from findings in epidemiological studies of particulate air pollution suggests that cardiovascular effects should be a matter of concern for workers exposed to nanomaterials.12 Ischemic heart disease especially myocardial infarction, ischemic strokes, thrombosis, arrhythmias, heart failure, and cardiac arrest are different health outcomes that should be followed-up.12 Validated surrogate markers such as heart rate variability, measures of vascular function and atherosclerosis, or blood markers of cardiovascular risk might be candidate components of a medical surveillance collected by means of electrocardiogram, cardiac holter, cardiovascular imaging, exercise test, or phlebotomy.17
As described in experimental studies, inhaled nano-objects could cross the alveolar-capillar barrier into the bloodstream and gain access to various organs of the cardiovascular system and eventually to other organs.18,19 Moreover, a direct access to the central nervous system via the olfactory pathway has been described for some nanoparticles.20,21 Thus, the follow-up of workers likely to be exposed to nanomaterials needs to focus on health outcomes affecting respiratory and cardiovascular systems. Nevertheless, it should keep a nonspecific feature to be able to register health outcomes affecting other organs or systems.22
QUANTITATIVE ASSESSMENT OF EXPOSURE
Although current knowledge is far from conclusive, it is apparent that characterizing exposures to nanoaerosols in terms of mass concentration and chemical composition does not seem appropriate under all circumstances.11,23 In addition to the two other major physical exposure metrics (ie, number and surface area concentrations), additional nano-object/nanoaerosol characteristics such as size fraction, shape, degree of agglomeration/aggregation, crystallinity, charge, surface chemistry, and solubility are thought to be relevant in determining the potential health impact. Such a full characterization cannot be carried out on a routine basis within an epidemiological study, and an adequate sampling strategy needs therefore to be developed.24 This strategy could employ a combination of direct-reading instruments measuring different metrics coupled with specific aerosol samplers for subsequent characterization by chemical and/or electron microscopic analysis. The Nanoparticle Emission Assessment Technique approach, recently proposed by the National Institute for Occupational Safety and Health, could be used as a basis of this specific sampling strategy.25
A DOUBLE EPIDEMIOLOGICAL SURVEILLANCE DESIGN
A double epidemiological surveillance design is about to be proposed to the French ministries, consisting of a prospective cohort study and repeated cross-sectional studies (Figure 1). The two parts of the surveillance system should complement each other. Because of the costs of the prospective follow-up, the cohort will be limited to a few nanomaterials of interest, while all nanomaterials produced or handled in France will be in the scope of the repeated cross-sectional studies.
THE PROSPECTIVE COHORT STUDY
The objectives of the prospective cohort study will be to monitor medium- and long-term possible health effects of nanomaterials exposure and to allow for further research. It could also provide guidance for public health policy and be helpful to assess prevention efforts such as the control of exposure.
The protocol of the prospective cohort study needs to be simple and easy to implement, with a step-by-step approach and a nonspecific health follow-up but special focus on respiratory and cardiovascular conditions. The scope will be initially restricted to the production or incorporation of powder of nano-objects, including their aggregated or agglomerated forms.
Carbon nanotubes, titanium dioxide, carbon black, and amorphous silica are considered to be of high priority. Indeed, the greatest amount of available information related to hazards of nanomaterials includes titanium dioxide and carbon-based nanomaterials.16 Moreover, titanium dioxide, carbon black, and amorphous silica are produced in large amounts in France, whereas carbon nanotubes production could increase in the coming years.6 This selection of high-priority nanomaterials will be reexamined subsequently at regular time-intervals.
To deal with numerous scientific uncertainties inherent to the field of engineered nanomaterials, a step-by-step approach is necessary to implement an epidemiological surveillance system of workers likely to be exposed (Figure 2).
The first step will be to set up an exposure registry, which will keep record of workers using or handling powder of nano-objects on the workplace. The exposure registry is thought to be the initial step of the prospective cohort study. This step should be clearly identified in the protocol because of the small number of workers likely to be exposed in each single company and the need to incorporate workers from numerous industrial sites. In 2009, National Institute for Occupational Safety and Health has recommended consideration of the establishment of nanomaterials exposure registry as a preparatory step for epidemiological studies.16,22 Critical data will arise from this first step like the description of geographical scattering of industrial sites and number of workers likely to be exposed to each nano-object. This information will be useful for finalizing the subsequent steps of the protocol such as the health follow-up and the exposure assessment strategy.
Developing an exposure registry requires identifying companies concerned about nano-objects, gaining management cooperation, defining inclusion criteria, addressing issues relating to the personal confidentiality, enrolling workers, and collecting exposure data.16,22 Included workers will be those likely to be exposed to powder of nano-objects. In each site, a highly sensitive but nonspecific definition will be used for inclusion purposes. It will rely on job titles or work tasks but not on metrological data. It can be anticipated that inclusion criteria will be different in each plant although coherence between sites should be a matter of concern. In this first step, exposure will be assessed in a qualitative or semiquantitative way (job title, work tasks, duration of employment, etc). Inclusion and exposure data will be updated prospectively.
Data available in the registry will make it possible to design a mortality follow-up, through a linkage with French deaths and causes of deaths registries. Thus, this initial step will provide a first basic and nonspecific surveillance system.
In a second step, an additional nonspecific health follow-up will be implemented for workers registered in the exposure registry and accepting to be included in the prospective cohort. Two different components could be identified with a passive health monitoring system using already existing medical data and an active health follow-up.
For passive health follow-up, medical records collected for administrative purposes will be gathered. These will include data from health insurance organizations (such as doctor's consultations, drug deliveries, and costly chronic diseases) and from hospitals (mainly medical diagnosis following hospital discharge). Medical data recorded on a regular basis by occupational health physicians will be collected as well. The active health follow-up will be based on annual self-administered questionnaire. Beyond the collection of health data, the annual self-administered questionnaire will be useful to update contact details of workers, to keep in touch with them and to forward feedback information.
Besides the health follow-up, a quantitative assessment of exposure will be conducted. It will combine epidemiological tools such as job or task-exposure matrix and measurement strategies of the ambient aerosol on the workplace.
Among numerous parameters, which are known to influence the biological toxicity of nanomaterials, six could be chosen for measurement strategies: chemical composition, size, shape, aggregated/agglomerated state, mass, and number (Table 2). Using simultaneously different sampling techniques could help to overcome nonspecificity of instrumentation. Among the available techniques, condensation and optical particle counters and size-distributive particle concentrations devices should be part of the sampling strategy. Measurement campaigns could be repeated at regular time interval and after the introduction of significant improvements in the industrial process. Bulk samples of the nano-objects produced or handled on the workplace could be collected for future analysis as well. Among the possible analysis is the nanodustiness analysis, which is thought to be relevant for emission of particles from nano-objects in the form of powders.5
Subsequently, optional modules could be implemented like standardized clinical examinations, diagnostic testing, and biobank for research purposes. Implementation of these modules will depend on serious health effects hypotheses identification, critical information arising from exposure registry, and the availability of economic resources.
The exposure registry will be implemented within the next 3 years while finalizing the protocol of the health follow-up and the quantitative exposure assessment. It requires first to gain the authorization from the French authority in charge of privacy and personal data protection. Strong support from the government would be helpful to ensure companies collaboration.
REPEATED CROSS-SECTIONAL STUDIES
The objectives of the repeated cross-sectional studies will be to document the circumstances of exposure and to raise hypotheses on possible health effects. The protocol has not been finalized yet. Nevertheless, it will be implemented through a system of tracking workers exposed to nanomaterials, which is constituted at the moment by the Federation of Occupational Health Services in small and medium companies. Only qualitative assessment of the exposure will be available.
In response to concern about potential impact of nanomaterials exposure on human health, France has wished to develop in a timely manner an epidemiological surveillance tool that could accompany the development of nanotechnologies. In the meantime, there are not many workers producing or handling nanomaterials but the number could increase rapidly in near future.
Establishing exposure registries appears to be a valuable first step to prepare epidemiological surveillance and to implement further epidemiological research studies in this field of nanomaterials.16,22 Working at an international scale with standardized protocols will increase the power of epidemiological studies when they are pooled. Finalizing the quantitative exposure assessment strategy will be a major issue in the coming years.
The general protocol of the health surveillance design is about to be submitted for approval and financing to the Ministries of Health and of Labour. Besides the protocol itself, the report provides some recommendations about further epidemiological research. Thus, cross-sectional studies using biological markers of effects (eg, biomarkers of pulmonary and systemic inflammation, response to oxidative stress, endothelial dysfunction, coagulation, blood viscosity, immunological effects) could be rapidly implemented on the workplace. In existing retrospective epidemiological studies of workers exposed to nanomaterials produced for decades, especially carbon black, the assessment of exposure should be reexamined in the light of what is known today about metrics likely to explain biological effects.
While scientific and social concerns have grown over the possible human health risks of nanomaterials, the development of an exposure registry of workers producing or handling nanomaterials will be a great advance for surveillance and research. Such a challenging project will require the support of all stakeholders.
1. Nel A, Xia T, Madler L, Li N. Toxic potential of materials at the nanolevel. Science. 2006;311:622–627.
2. Thacker SB, Stroup DF, Parrish RG, Anderson HA. Surveillance in environmental public health: issues, systems, and sources. Am J Public Health. 1996;86:633–638.
3. International Organization for Standardization. ISO/TS 27687: Nanotechnologies—terminology and definition for nano-objects—nanoparticle, nanofibre and nanoplate. Geneva: ISO; 2008:1–7.
4. Oberdorster G, Maynard A, Donaldson K, et al. Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy. Part Fibre Toxicol. 2005;2:8.
5. Brouwer D. Exposure to manufactured nanoparticles in different workplaces. Toxicology. 2010;269:120–127.
6. Honnert B, Vincent R. Production et utilisation industrielle des particules nanostructurées. Hygiène et sécurité du travail—Cahiers de notes documentaires. 2007;209:5–21.
7. Sorahan T, Hamilton L, van TM, Gardiner K, Harrington JM. A cohort mortality study of U.K. carbon black workers, 1951–1996. Am J Ind Med. 2001;39:158–170.
8. Wellmann J, Weiland SK, Neiteler G, Klein G, Straif K. Cancer mortality in German carbon black workers 1976–98. Occup Environ Med. 2006;63:513–521.
9. Boffetta P, Soutar A, Cherrie JW, et al. Mortality among workers employed in the titanium dioxide production industry in Europe. Cancer Causes Control. 2004;15:697–706.
10. Heinrich U, Fuhst R, Rittinghausen R, et al. Chronic inhalation exposure of Wistar rats and two different strains of mice to diesel exhaust, carbon black, and titanium dioxide. Inhal Toxicol. 1995;7:533–556.
11. Oberdorster G, Oberdorster E, Oberdorster J. Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect. 2005;113:823–839.
12. Pope CA III, Dockery DW. Health effects of fine particulate air pollution: lines that connect. J Air Waste Manag Assoc. 2006;56:709–742.
13. Poland CA, Duffin R, Kinloch I, et al. Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat Nanotechnol. 2008;3:423–428.
14. Ryman-Rasmussen JP, Cesta MF, Brody AR, et al. Inhaled carbon nanotubes reach the subpleural tissue in mice. Nat Nanotechnol. 2009;4:747–751.
15. Takagi A, Hirose A, Nishimura T, et al. Induction of mesothelioma in p53+/− mouse by intraperitoneal application of multi-wall carbon nanotube. J Toxicol Sci. 2008;33:105–116.
16. Trout DB, Schulte PA. Medical surveillance, exposure registries, and epidemiologic research for workers exposed to nanomaterials. Toxicology. 2010;269:128–135.
17. Brook RD, Rajagopalan S, Pope CA III, et al. Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. Circulation. 2010;121:2331–2378.
18. Kreyling WG, Semmler M, Erbe F, et al. Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low. J Toxicol Environ Health A. 2002;65:1513–1530.
19. Oberdorster G, Sharp Z, Atudorei V, et al. Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. J Toxicol Environ Health A. 2002;65:1531–1543.
20. Elder A, Gelein R, Silva V, et al. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health Perspect. 2006;114:1172–1178.
21. Oberdorster G, Sharp Z, Atudorei V, et al. Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol. 2004;16:437–445.
22. Schulte PA, Schubauer-Berigan MK, Mayweather C, Geraci CL, Zumwalde R, McKernan JL. Issues in the development of epidemiologic studies of workers exposed to engineered nanoparticles. J Occup Environ Med. 2009;51:323–335.
23. Oberdorster G, Oberdorster E, Oberdorster J. Concepts of nanoparticle dose metric and response metric. Environ Health Perspect. 2007;115:A290.
24. Witschger O. Nanoparticules: quelles possibilités métrologiques pour caractériser l'exposition des personnes? Spectra analyse. 2008;264:17–30.
25. Methner M, Hodson L, Geraci C. Nanoparticle emission assessment technique (NEAT) for the identification and measurement of potential inhalation exposure to engineered nanomaterials—part A. J Occup Environ Hyg. 2010;7:127–132.
This article has been cited 3 time(s).
Nanosafe 2012: International Conferences on Safe Production and Use of NanomaterialsOverview of Risk Management for Engineered NanomaterialsNanosafe 2012: International Conferences on Safe Production and Use of Nanomaterials
Nanosafe 2012: International Conferences on Safe Production and Use of NanomaterialsFrench registry of workers handling engineered nanomaterials as an instrument of integrated system for surveillance and researchNanosafe 2012: International Conferences on Safe Production and Use of Nanomaterials
Journal of Occupational and Environmental MedicineNanomaterials and Worker Health: Medical Surveillance, Exposure Registries, and Epidemiologic ResearchJournal of Occupational and Environmental Medicine
©2011The American College of Occupational and Environmental Medicine