Assessing the first wave of epidemiological studies of nanomaterial workers

  • Saou-Hsing LiouEmail author
  • Candace S. J. Tsai
  • Daniela Pelclova
  • Mary K. Schubauer-Berigan
  • Paul A. Schulte


The results of early animal studies of engineered nanomaterials (ENMs) and air pollution epidemiology suggest that it is important to assess the health of ENM workers. Initial epidemiological studies of workers’ exposure to ENMs (<100 nm) are reviewed and characterized for their study designs, findings, and limitations. Of the 15 studies, 11 were cross-sectional, 4 were longitudinal (1 was both cross-sectional and longitudinal in design), and 1 was a descriptive pilot study. Generally, the studies used biologic markers as the dependent variables. All 11 cross-sectional studies showed a positive relationship between various biomarkers and ENM exposures. Three of the four longitudinal studies showed a negative relationship; the fourth showed positive findings after a 1-year follow-up. Each study considered exposure to ENMs as the independent variable. Exposure was assessed by mass concentration in 10 studies and by particle count in six studies. Six of them assessed both mass and particle concentrations. Some of the studies had limited exposure data because of inadequate exposure assessment. Generally, exposure levels were not very high in comparison to those in human inhalation chamber studies, but there were some exceptions. Most studies involved a small sample size, from 2 to 258 exposed workers. These studies represent the first wave of epidemiological studies of ENM workers. They are limited by small numbers of participants, inconsistent (and in some cases inadequate) exposure assessments, generally low exposures, and short intervals between exposure and effect. Still, these studies are a foundation for future work; they provide insight into where ENM workers are experiencing potentially adverse effects that might be related to ENM exposures.


Epidemiological studies Nanomaterial workers Biological markers Cross-sectional study Longitudinal panel study Sample size Nanoparticle exposure 


Antioxidant markers


Superoxide dismutase


Glutathione peroxidase

Oxidative stress markers






5-Hydroxymethyl uracil


8-Iso-prostaglandin F2α

















Pulmonary effect markers


Clara cell protein


Fractional exhaled nitric oxide


Krebs Von den Lungen 6


Macrophage inflammatory protein-1β


Pulmonary function test


Forced vital capacity


Forced expiratory volume at 1 s


Maximal mid-expiratory flow


Peak expiratory flow rate

FEF25 %

Forced expiratory flow at 25 %

FEF50 %

Forced expiratory flow at 50 %

FEF75 %

Forced expiratory flow at 75 %


Transforming growth factor beta-1

Systemic inflammation markers


Highly sensitive C-reactive protein








Interleukin-6 soluble receptor


Nuclear factor-kappaβ


Tumor necrosis factor α

Vascular or endothelial function biomarkers


Highly sensitive C-reactive protein


Intercellular adhesion molecule




Interleukin-6 soluble receptor




Vascular cell adhesion molecule


Heart rate variability


Standard deviation of all normal to normal R–R intervals


The root mean square of successive differences between adjacent normal cycles


Low frequency/high frequency ratio


Low frequency


High frequency


Very low frequency


Carbon nanotube/carbon nanofiber


Exhaled breath condensate


Engineered nanomaterials


Engineered nanoparticles




Nano-objects, their aggregates and agglomerates


Ultrafine particles



This study was partly supported by the National Health Research Institutes of Taiwan (Grants 01A1-EOSP03-014) and the Institute of Occupational Safety and Health, Taiwan (Grants IOSH101-M323). The authors also thank project teams P25/1LF/2 and P28/1LF/6, of the Charles University in Prague, Czech Republic, which supported this work.


SHL and CSJT conceived the study. SHL, CSJT, DP, and MKSB searched and checked the databases according to the inclusion and exclusion criteria. PAS helped to develop search strategies. SHL, CSJT, DP, MKSB, and PAS extracted the data and assessed their quality. SHL wrote the draft of the paper. All authors contributed to writing, reviewing, or revising the paper and read and approved the final manuscript.


The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the U.S. National Institute for Occupational Safety and Health and Taiwan National Health Research Institutes.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. Bekker C, Brouwer DH, Tielemans E, Pronk A (2013) Industrial production and professional application of manufactured nanomaterials-enabled end products in Dutch Industries: potential for exposure. Ann Occup Hyg 57:314–327CrossRefGoogle Scholar
  2. Bergamaschi E, Poland C, Canu IG, Prina-Mello A (2015) The role of biological monitoring in nano-safety. NanoToday 10:274–277CrossRefGoogle Scholar
  3. Borm PJ, Robbins D, Haubold S, Kuhlbusch T, Fissan H, Donaldson K, Schins R, Stone V, Kreyling W, Lademann J, Krutmann J, Warheit D, Oberdörster E (2006) The potential risks of nanomaterials: a review carried out for ECETOC. Part Fibre Toxicol 3:11–45CrossRefGoogle Scholar
  4. Chang CC, Kuo CC, Liou SH, Yang CY (2013) Fine particulate air pollution and hospital admissions for myocardial infarction in a subtropical city: Taipei, Taiwan. J Toxicol Environ Health A 76:440–448CrossRefGoogle Scholar
  5. Cui L (2013) Exposure assessment and inflammatory response among workers producing calcium carbonate nanomaterials. Ph D. Dissertation. University of WashingtonGoogle Scholar
  6. Dahm MM, Evans DE, Schubauer-Berigan MK, Birch ME, Fernback J (2012) Occupational exposure assessment in carbon nanotube and nanofiber primary and secondary manufacturers. Ann Occup Hyg 56:542–556Google Scholar
  7. Dahm MM, Evans DE, Schubauer-Berigan MK, Birch ME, Deddens JA (2013) Occupational exposure assessment in carbon nanotube and nanofiber primary and secondary manufacturers: mobile direct-reading sampling. Ann Occup Hyg 57:328–344CrossRefGoogle Scholar
  8. Dahm MM, Schubauer-Berigan MK, Evans DE, Birch ME, Fernback JE, Deddens JA (2015) Carbon nanotube and nanofiber exposure assessments: an analysis of 14 site visits. Ann Occup Hyg 59:705–723CrossRefGoogle Scholar
  9. Erdely A, Dahm M, Chen BT, Zeidler-Erdely PC, Fernback JE, Birch ME, Evans DE, Kashon ML, Deddens JA, Hulderman T, Bilgesu SA, Battelli L, Schwegler-Berry D, Leonard HD, McKinney W, Frazer DG, Antonini JM, Porter DW, Castranova V, Schubauer-Berigan MK (2013) Carbon nanotube dosimetry: from workplace exposure assessment to inhalation toxicology. Part Fibre Toxicol 10:53CrossRefGoogle Scholar
  10. Fatkhutdinova LM, Khaliullin TO, Zalyalov RR, Mustafin IG, Birch EM, Kisin ER, Shvedova AA (2013) Biological markers relevant to realistic occupational exposures to multiwalled carbon nanotubes. 2nd International School-conference on nanotechnology and nanotoxicology. Book of Abstract, pp 23–24Google Scholar
  11. Glass D, Sim M, Abramson M, Plebanski M, Priestly B, Dennekamp M, Mahzar M (2013) An investigation of the immunological and respiratory effects among workers exposed to engineered nanoparticles. Accessed at on Dec 15, 2013
  12. Guseva Canu I, Boutou-Kempf O, Delabre L, Ducamp S, Iwatsubo Y, Marchand JL, Imbernon E (2013) Medical surveillance and epidemiologic studies of engineered nanomaterials (enm) workers in France. Occup Environ Med 70(Suppl 1):A66Google Scholar
  13. Hesterberg TW, Long CM, Bunn WB, Sax SN, Lapin CA, Valberg PA (2009) Non-cancer health effects of diesel exhaust: a critical assessment of recent human and animal toxicological literature. Crit Rev Toxicol 39:195–227CrossRefGoogle Scholar
  14. Hesterberg TW, Long CM, Lapin CA, Hamade AK, Valberg PA (2010) Diesel exhaust particulate (DEP) and nanoparticle exposures: what do DEP human clinical studies tell us about potential human health hazards of nanoparticles? Inhal Toxicol 22:679–694CrossRefGoogle Scholar
  15. Huang CH, Tai CY, Huang CY, Tsai CJ, Chen CW, Chang CP, Shih TS (2010) Measurements of respirable dust and nanoparticle concentrations in a titanium dioxide pigment production factory. J Environ Sci Health A Tox Hazard Subst Environ Eng 45:1227–1233CrossRefGoogle Scholar
  16. IARC (1999) Cancer epidemiology: principles and methods. I. Dos Santos Silva (Ed). Chapter 5. Overview of study designs. International Agency for Research on Cancer, WHOGoogle Scholar
  17. Ichihara S, Li WH, Omura S, Fujitani Y, Liu Y, Wang QY, Hiraku Y, Hisanaga N, Ding XC, Kobayashi T, Ichihara G (2013) Effects on respiratory and cardiovascular systems in workers handling titanium dioxide particles. The 6th international symposium on nanotechnology, occupational and environmental health (NanOEH), Book of abstracts. O-30-B-36, pp 47Google Scholar
  18. Institute of Occupational Safety and Health (2012) Applications of the newly developed nanoparticles exposure assessment techniques to workplaces in nanoindustries (II). IOSH 101-H322Google Scholar
  19. International Agency for Research on Cancer (2012) IARC: Diesel engine exhaust carcinogenic. (Press Release No. 213). Accessed at Jan 15, 2013
  20. International Agency for Research on Cancer (2014) Volume 111: Fluoro-edenite, silicon carbide fibres and whiskers, and single-walled and multi-walled carbon nanotubes. IARC Working Group. Lyon. IARC Monogr Eval Carcinog Risk Chem Hum (in press)Google Scholar
  21. Koivisto AJ, Lyyränen J, Auvinen A, Vanhala E, Hämeri K, Tuomi T, Jokiniemi J (2012) Industrial worker exposure to airborne particles during the packing of pigment and nanoscale titanium dioxide. Inhal Toxicol 24:839–849CrossRefGoogle Scholar
  22. Lee JH, Kwon M, Ji JH, Kang CS, Ahn KH, Han JH, Yu IJ (2011) Exposure assessment of workplaces manufacturing nanosized TiO2 and silver. Inhal Toxicol 23:226–236CrossRefGoogle Scholar
  23. Lee JH, Mun J, Park JD, Yu IJ (2012) A health surveillance case study on workers who manufacture silver nanomaterials. Nanotoxicology 6:667–669CrossRefGoogle Scholar
  24. Lee JS, Choi YC, Shin JH, Lee JH, Lee Y, Park SY, Baik JE, Ahn K, Yu IJ (2015) Health surveillance study of workers who manufacture multi-walled carbon nanotubes. Nanotoxicology 9:802–811CrossRefGoogle Scholar
  25. Liao HY, Chung YT, Lai CH, Lin MH, Liou SH (2014a) Sneezing and allergic dermatitis were increased in engineered nanomaterial handling workers. Ind Health 52:199–215CrossRefGoogle Scholar
  26. Liao HY, Chung YT, Tsou TC, Wang SL, Li LA, Chiang HC, Li WF, Lai CH, Lee HL, Lin MH, Hsu JH, Ho JJ, Chen CJ, Shih TS, Lin CC, Liou SH (2014b) Six-month follow-up study of health markers of nanomaterials among workers handling engineered nanomaterials. Nanotoxicology 8(Suppl):100–110CrossRefGoogle Scholar
  27. Liou SH, Tsou TC, Wang SL, Li LA, Chiang HC, Li WF, Lin PP, Lai CH, Lee HL, Lin MH, Hsu JH, Chen CR, Shih TS, Liao HY, Chung YT (2012) Epidemiological study of health hazards among workers handling engineered nanomaterials. J Nanopart Res 14:878–892CrossRefGoogle Scholar
  28. Liou S, Liao H, Chung Y, Lai C, Wang S, Chiang H, Li L, Tsou T, Lin M, Lin C, Li W, Lee H (2013) Four-year follow-up study of health hazards among workers handling engineered nanomaterials. Occup Environ Med 70(Suppl 1):A62CrossRefGoogle Scholar
  29. McDonnell WF, Nishino-Ishikawa N, Petersen FF, Chen LH, Abbey DE (2000) Relationships of mortality with the fine and coarse fractions of long-term ambient PM10 concentrations in nonsmokers. J Expo Anal Environ Epidemiol 10:427–436CrossRefGoogle Scholar
  30. National Institute for Occupational Safety and Health (2011) NIOSH Current Intelligence Bulletin 63. Occupational exposure to titanium dioxide. DHHS (NIOSH) Publication No. 2011–160Google Scholar
  31. National Institute for Occupational Safety and Health (2013) NIOSH Current Intelligence Bulletin 65: Occupational Exposure to Carbon Nanotubes and Nanofibers. DHHS (NIOSH) Publication No. 2013–145Google Scholar
  32. Nowak D, Kalucka S, Białasiewicz P, Krl M (2001) Exhalation of H2O2 and thiobarbituric acid reactive substances (TBARs) by healthy subjects. Free Radic Biol Med 30:178–186CrossRefGoogle Scholar
  33. Oberdörster G, Oberdörster E, Oberdörster J (2005) Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113:823–839CrossRefGoogle Scholar
  34. Paik SY, Zalk DM, Swuste P (2008) Application of a pilot control banding tool for risk level assessment and control of nanoparticle exposures. Ann Occup Hyg 52:419–428CrossRefGoogle Scholar
  35. Pelclova, D, Fenclova Z, Vlckova Stepanka, Zdimal V, Schwarz J, Pusman J, Zikova N, Syslova K, Kuzma M, Navratil T, Zakharov S, Kacer P (2012) Markers of oxidative stress are elevated in workers exposed to nanoparticles. NANOCON 2012, Conference Proceedings, pp 654–658.
  36. Pelclova D, Fenclova Z, Navratil T, Vlckova S, Syslova K, Kuzma M, Zdimal V, Schwarz J, Pusman J, Zikova N, Zakharov S, Kacer P (2013) Urine and exhaled breath condensate markers of oxidative stress in workers exposed to aerosol containing TiO2 nanoparticles. 2nd QNano integrating conference. Abstract Book, pp 71Google Scholar
  37. Pelclova D, Fenclova Z, Navratil T, Vlckova S, Syslova K, Kuzma M, Zdimal V, Schwarz J, Makes O, Zikova N, Zakharov S, Machajova M, Kacer Petr (2014a) Markers of oxidative stress in exhaled breath of workers exposed to iron oxide (nano) particles are elevated. Abstracts from 19th Interdisciplinary Toxicological Conference TOXCON. Interdisciplinary Toxicology 7(Suppl 1):69–70Google Scholar
  38. Pelclova D, Fenclova Z, Navratil T, Vlckova S, Syslova K, Kuzma M, Zdimal V, Schwarz J, Pusman J, Zikova N, Zakharov S, Machajova M, Kacer P (2014b) Markers of oxidative stress in exhaled breath condensate are significantly increased in workers exposed to aerosol containing TiO2 nanoparticles. Abstracts of the 50th Congress on the European Society of Toxicology (EUROTOX) Edinburgh September 7–10, 2014. Toxicol Lett 229(Suppl):S12CrossRefGoogle Scholar
  39. Peters A, von Klot S, Heier M, Trentinaglia I, Hörmann A, Wichmann HE, Löwel H, Cooperative Health Research in the Region of Augsburg Study Group (2004) Exposure to traffic and the onset of myocardial infarction. N Engl J Med 351:1721–1730CrossRefGoogle Scholar
  40. Rudnicka AR, Rumley A, Lowe GDO, Strachan DP (2007) Diurnal, seasonal, and blood-processing patterns in levels of circulating fibrinogen, fibrin d-dimer, c-reactive protein, tissue plasminogen activator, and von Willebrand factor in a 45-year-old population. Circulation 115:996–1003CrossRefGoogle Scholar
  41. Schubauer-Berigan MK, Dahm MM, Yencken MS (2011) Engineered carbonaceous nanomaterials manufacturers in the United States: workforce size, characteristics, and feasibility of epidemiologic studies. J Occup Environ Med 53(Suppl):S62–S67CrossRefGoogle Scholar
  42. Schubauer-Berigan KM, Dahm MM, Deddens JA et al (2013) From the very small to the very large: challenges in conducting epidemiologic studies of U.S. workers exposed to carbon nanotubes. Occup Environ Med 70(Suppl 1):A64Google Scholar
  43. Schulte PA, Smith A (2011) Ethical issues in molecular epidemiologic research. In: Rothman N et al (eds) Molecular epidemiology: principles and practices. IARC, Lyon, pp 9–22Google Scholar
  44. Schulte PA, Trout D, Zumwalde RD, Kuempel E, Geraci CL, Castranova V, Mundt DJ, Mundt KA, Halperin WE (2008) Options for occupational health surveillance of workers potentially exposed to engineered nanoparticles: state of the science. J Occup Environ Med 50:517–526CrossRefGoogle Scholar
  45. Schulte PA, Schubauer-Berigan MK, Mayweather C, Geraci CL, Zumwalde R, McKernan JL (2009) Issues in the development of epidemiologic studies of workers exposed to engineered nanoparticles. J Occup Environ Med 51:323–335CrossRefGoogle Scholar
  46. Seal S, Karn B (2014) Safety aspects of nanotechnology based activity. Saf Sci 63:217–225CrossRefGoogle Scholar
  47. Stern ST, McNeil SE (2008) Nanotechnology safety concerns revisited. Toxicol Sci 101:4–21CrossRefGoogle Scholar
  48. Törner A, Duberg AS, Dickman P, Svensson A (2010) A proposed method to adjust for selection bias in cohort studies. Am J Epidemiol 171:602–608CrossRefGoogle Scholar
  49. Törner A, Dickman P, Duberg AS, Kristinsson S, Landgren O, Björkholm M, Svensson A (2011) A method to visualize and adjust for selection bias in prevalent cohort studies. Am J Epidemiol 174:969–976CrossRefGoogle Scholar
  50. Tsai CJ, Huang CY, Chen SC et al (2011) Exposure assessment of nano-sized and respirable particles at different workplaces. International Symposium of Occupational Safety and Health on Engineering Nanoparticles, pp 181–196Google Scholar
  51. Vermeulen R, Pronk A, Vlaanderen J, Hosgood D, Rothman N, Hildesheim A, Silverman D, Melis A, Spaan S, Voogd E, Hoet P, Godderis L, Lan Q (2014) A cross-sectional study of markers of early immunological and cardiovascular health effects among a population exposed to carbon nanotubes: the CANTES study. Occup Environ Med 71(Suppl 1):A35CrossRefGoogle Scholar
  52. Wu WT, Liao HY, Chung YT, Li WF, Tsou TC, Lin MH, Ho JJ, Wu TN, Liou SH (2014) Effect of nanoparticles exposure on fractional exhaled nitric oxide (FENO) in workers exposed to nanomaterials. Int J Mol Sci 15:878–894CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Saou-Hsing Liou
    • 1
    • 2
    Email author
  • Candace S. J. Tsai
    • 3
    • 4
  • Daniela Pelclova
    • 5
  • Mary K. Schubauer-Berigan
    • 6
  • Paul A. Schulte
    • 6
  1. 1.National Institute of Environmental Health SciencesNational Health Research InstitutesMiaoli CountyTaiwan, ROC
  2. 2.Graduate Institute of Life SciencesNational Defense Medical Center, Academia Sinica, and National Health Research InstitutesTaipeiTaiwan
  3. 3.Department of Environmental and Radiological Health ScienceColorado State UniversityFort CollinsUSA
  4. 4.Birck Nanotechnology CenterPurdue UniversityDiscovery ParkUSA
  5. 5.Department of Occupational Medicine, First Faculty of MedicineCharles University in PraguePragueCzech Republic
  6. 6.National Institute for Occupational Safety and HealthCincinnatiUSA

Personalised recommendations