NIOSH Risk Assessment of Engineered Nanomaterials

Nanotechnology as we know it today did not exist at the time of the Occupational Safety and Health Act of 1970. Yet, its provisions to “assure safe and healthful working conditions” apply to nanotechnology workplaces and other workplaces where engineered nanomaterials are produced or used.

Engineered nanomaterials are used in a variety of products and applications, including in energy, electronics, transportation, environmental remediation, and medicine. The small size of engineered nanomaterials (at least one dimension smaller than 100 nanometers) gives them unique and useful properties. However, engineered nanomaterials could also pose a health risk to workers who produce or use these materials.[1]

NIOSH conducts risk assessments to estimate the likelihood and severity of adverse health effects in workers exposed to chemical substances including nanomaterials. NIOSH risk assessments support the development of occupational safety and health recommendations.

As we celebrate the 20th anniversary of the NIOSH Nanotechnology Research Center (NTRC), we highlight NTRC activities in risk assessment of engineered nanomaterials.

Early Assessments

In the early years of nanotechnology, health effects data were sparse for most nanomaterials.[2] Initial guidance was based on our understanding of the toxicology of ultrafine (nanoscale) particles, aerosol science, and industrial hygiene practice.[1] Prudent occupational safety and health practices were designed to reduce exposures to engineered nanomaterials in the workplace. In 2004, NIOSH launched the NTRC research program to better understand the exposures and potential health risks to workers.

Advancing Risk Assessment Methods

The NTRC played an early role in advancing occupational health risk assessment for engineered nanomaterials. NTRC researchers examined the risk assessment options for nanomaterials including quantitative methods using the limited data.[3]^,[4] They expanded on these concepts to describe an evidence-based approach to developing exposure control guidance for engineered nanomaterials.[5] They also created a framework to group materials according to their hazardous properties.[6]

As nanotoxicology data became more available, occupational exposure limits were established for several nanomaterials.[7],[8] NTRC risk assessments were used in developing NIOSH recommended exposure limits (RELs) for three different classes of nanomaterials—titanium dioxide, carbon nanotubes and nanofibers, and silver. The evidence for these risk assessments supports the occupational exposure limits that account for nanoscale particle size.

A challenge has been to identify relevant and reliable data, especially chronic exposure data of engineered nanomaterials.[9],[10] Dose estimation is an important source of uncertainty for nanomaterials,[11] where particle size may affect biological processes and internal dose.

Dosimetry Modeling

Disease risk depends on the internal dose (amount) of a hazardous substance that reaches the target tissue. Dosimetry models are used to estimate the amount of an agent taken up or absorbed in the body or specific organs (e.g., lungs).[12] Physiologically based pharmacokinetic (PBPK) models incorporate physiological information that influences the fate of chemicals in the body following exposure.[11]

The NTRC has collaborated with other researchers in developing and evaluating dosimetry and PBPK models to estimate the internal dose of nanoparticles.[13]^,[14]^,[15]^,[16] NIOSH has also supported some extensions of the Multiple-Path Particle Dosimetry model, including to estimate the respiratory tract deposition of non-spherical particles. NIOSH has used some of these models in its risk assessments of engineered nanomaterials.

Alternative Methods

Many nanomaterials do not have enough data to develop occupational exposure limits. For some nanomaterials, occupational exposure banding may be an option to determine provisionary guidance for risk management. NTRC researchers derived occupational exposure bands for several engineered nanomaterials in an evaluation of available approaches. Occupational exposure bands can be used in control banding tools for exposure control decisions when occupational exposure limits are not available.[17] NTRC researchers have also used data from published toxicology studies to group nanomaterials by their hazard potency and to predict the hazard group for a new material based on its physicochemical properties.[18],[19]

The NTRC has contributed to several collaborative efforts to advance the data and methods to support nanomaterials risk assessment. These efforts include proposing a tiered toxicology testing approach,[20] refining our understanding of the biological pathways associated with disease,[21] and extending the evidence basis for grouping nanomaterials for occupational exposure control decisions.[22] NTRC has also provided review and input on other grouping and testing strategies to evaluate the evidence for risk assessment and management of nanomaterials.[23],[24],[25]

Next Steps

Building an evidence base has been the biggest challenge to risk assessment of engineered nanomaterials. Recent efforts are encouraging, including a multi-center program in the European Union to develop the NanoInformaTIX database and the U.S. Environmental Protection Agency’s NaKnowBase database. In addition, NTRC researchers are developing a literature-based dataset as part of its evaluation of approaches to nanomaterials risk assessment.

For twenty years, the NTRC has contributed to the data and tools available to assess the risk of exposure to nanomaterials in the workplace and support risk management guidance. NTRC and other researchers continue to extend the databases, test models, and update guidance to protect workers.

Eileen D. Kuempel, Ph.D., is a Senior Research Health Scientist with the Emerging Technologies Branch in the NIOSH Division of Science Integration and Coordinator of the Risk Assessment Critical Topic Area in the NTRC.

This blog is part of a series to commemorate the 20th anniversary of the Nanotechnology Research Center. Click here for additional blogs in the series and on other nanotechnology topics. 

References

[1] NIOSH [2009]. Approaches to safe nanotechnology: managing the health and safety concerns associated with engineered nanomaterials. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2009–125, https://www.cdc.gov/niosh/docs/2009-125/pdfs/2009-125.pdf. [Draft documents for public comment: October 2005, July 2006].

[2] Maynard AM, Kuempel ED [2005]. Airborne nanostructured particles and occupational health. J Nanopart Res 7:587–614, https://link.springer.com/content/pdf/10.1007/s11051-005-6770-9.pdf.

[3] Kuempel ED, Geraci CL, Schulte PA [2007]. Risk assessment approaches and research needs for nanoparticles: an examination of data and information from current studies. Proceedings of the NATO Advanced Research Workshop on Nanotechnology: Toxicological Issues and Environmental Safety, Varna, Bulgaria, August 12–17, 2006. In: Simeonova P, Opopol N, Luster M, eds. Nanotechnology: toxicological issues and environmental safety. New York: Springer pp 119–145, https://archive.org/details/nanotechnologyto0000nato.

[4] Kuempel ED, Tran CL, Castranova V, Bailer AJ [2006]. Lung dosimetry and risk assessment of nanoparticles: evaluating and extending current models in rats and humans. Inhal Toxicol 18(10):717–724, https://www.tandfonline.com/doi/full/10.1080/08958370600747887.

[5] Schulte PA, Murashov V, Zumwalde R, Kuempel ED, Geraci CL [2010]. Occupational exposure limits for nanomaterials: state of the art. J Nanopart Res 12(6):1971–1987, https://link.springer.com/content/pdf/10.1007/s11051-010-0008-1.pdf

[6] Kuempel ED, Castranova V, Geraci CL, Schulte PA [2012]. Development of risk-based nanomaterial groups for occupational exposure control. J Nanopart Res 14:1029, https://doi.org/10.1007/s11051-012-1029-8.

[7] Mihalache R, Verbeek J, Graczyk H, Murashov V, van Broekhuizen P [2017]. Occupational exposure limits for manufactured nanomaterials, a systematic review. Nanotoxicology 9:1–13, https://www.tandfonline.com/doi/full/10.1080/17435390.2016.1262920.

[8] Schulte PA, Kuempel ED, Drew NM [2018]. Characterizing risk assessments for the development of occupational exposure limits for engineered nanomaterials. Regul Toxicol Pharmacol 95:207–219, https://doi.org/10.1016/j.yrtph.2018.03.018.

[9] ISO [2016]. ISO/TR 18637. Nanotechnologies—overview of available frameworks for the development of occupational exposure limits and bands for nano-objects and their aggregates and agglomerates (NOAAs). Published Nov. 21. Geneva, Switzerland: International Organization for Standardization, https://www.iso.org/standard/63096.html.

[10] OECD [2022]. Important issues on risk assessment of manufactured nanomaterials. Series on the safety of manufactured nanomaterials. No. 103. Paris, France: Organization for Economic Cooperation and Development, ENV/CBC/MONO(2022)3, https://search.oecd.org/chemicalsafety/publications-series-safety-manufactured-nanomaterials.htm.

[11] NIOSH [2020]. NIOSH practices in occupational risk assessment. By Daniels RD, Gilbert SJ, Kuppusamy SP, Kuempel ED, Park RM, Pandalai SP, Smith RJ, Wheeler MW, Whittaker C, Schulte PA. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. DHHS (NIOSH) Publication No. 2020-106 (revised 03/2020), https://doi.org/10.26616/NIOSHPUB2020106revised032020.

[12] Kuempel ED, Sweeney LM, Morris JB, Jarabek AM [2015]. Advances in inhalation dosimetry models and methods for occupational risk assessment and exposure limit derivation. J Occup Environ Hyg 12 (Suppl 1):S18-40, https://www.tandfonline.com/doi/full/10.1080/15459624.2015.1060328. Erratum in: J Occup Environ Hyg 2018, 15(4):D31.

[13] Garcia GJ, Schroeter JD, Kimbell JS [2015]. Olfactory deposition of inhaled nanoparticles in humans. Inhal Toxicol 27(8):394–403, https://www.tandfonline.com/doi/full/10.3109/08958378.2015.1066904.

[14] Su W-C, Cheng YS [2015]. Estimation of carbon nanotubes deposition in a human respiratory tract replica. J Aerosol Sci 79:72–85, https://www.sciencedirect.com/science/article/pii/S0021850214001669.

[15] MacCalman L, Tran CL, Kuempel E [2009]. Development of a bio-mathematical model in rats to describe clearance, retention and translocation of inhaled nano particles throughout the body. J Phys: 2009 Conf. Ser. 151 012028, https://iopscience.iop.org/article/10.1088/1742-6596/151/1/012028.

[16] Sweeney LM, MacCalman L, Haber LT, Kuempel ED, Tran CL [2015]. Bayesian evaluation of a physiologically based pharmacokinetic (PBPK) model of long-term kinetics of metal nanoparticles in rats. Regul Toxicol Pharmacol 73(1):151–163, https://dx.doi.org/10.1016/j.yrtph.2015.06.019.

[17] Dunn KH, Eastlake AC, Story M, Kuempel ED [2018]. Control banding tools for engineered nanoparticles: what the practitioner needs to know. Ann Work Expo Health 62(3):362–388, https://doi.org/10.1093/annweh/wxy002.

[18] Drew N, Kuempel E, Pei Y, Yang F [2017]. A quantitative framework to group nanoscale and microscale particles by hazard potency to derive occupational exposure limits: proof of concept evaluation. Regul Toxicol Pharmacol 89:253–267, https://doi.org/10.1016/j.yrtph.2017.08.003.

[19] Boots TE, Kogel A, Drew NM, Kuempel ED [2021]. Utilizing literature-based rodent toxicology data to derive potency estimates for quantitative risk assessment. Nanotoxicology 15(6):740–760, https://doi.org/10.1080/17435390.2021.1918278.

[20] Nel AE, Nasser E, Godwin H, Avery D, Bahadori T, Bergeson L, Beryt E, Bonner JC, Boverhof D, Carter J, Castranova V, Deshazo JR, Hussain SM, Kane AB, Klaessig F, Kuempel E, Lafranconi M, Landsiedel R, Malloy T, Miller MB, Morris J, Moss K, Oberdörster G, Pinkerton K, Pleus RC, Shatkin JA, Thomas R, Tolaymat T, Wang A, Wong J [2013]. A multi-stakeholder perspective on the use of alternative test strategies for nanomaterial safety assessment. ACS Nano 7(8):6422–6433, https://doi.org/10.1021/nn4037927.

[21] Halappanavar S, Ede JD, Mahapatra I, Krug HF, Kuempel ED, Lynch I, Vandebriel RJ, Shatkin JA [2021]. A methodology for developing key events to advance nanomaterial-relevant adverse outcome pathways to inform risk assessment. Nanotoxicology 15(3):289–310, https://doi.org/10.1080/17435390.2020.1851419.

[22] Visser M, Gosens I, Bard D, van Broekhuizen P, Janer G, Kuempel E, Riediker M, Vogel U, Dekkers S [2022]. Towards health-based nano reference values (HNRVs) for occupational exposure: Recommendations from an expert panel. NanoImpact 26:100396, http://dx.doi.org/10.1016/j.impact.2022.100396.

[23] OECD [2014]. Guidance on grouping of chemicals, second edition. Series on testing and assessment. No. 194. Paris, France: Organization for Economic Cooperation and Development, ENV/JM/MONO(2014)4, https://read.oecd-ilibrary.org/environment/guidance-on-grouping-of-chemicals-second-edition_9789264274679-en.

[24] OECD [2016]. Guidance document on the reporting of defined approaches to be used with integrated approaches to testing and assessment. Series on Testing and Assessment. Paris, France: Organization for Economic Cooperation and Development, No. 255. ENV/JM/MONO(2016)28.

[25] Grouping, Read-Across, CharacterIsation and classificatiOn framework for regUlatory risk assessment of manufactured nanomaterials and Safer design of nano-enabled products (GRACIOUS), https://www.h2020gracious.eu/].