Nanotechnology

Approaches to Safe Nanotechnology:
An Information Exchange with NIOSH

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Exposure Assessment and Characterization

There are currently no national or international consensus standards on measurement techniques for nanoparticles in the workplace.  However, information and guidance for monitoring nanoparticle exposures in workplace atmospheres has recently been developed by the International Organization for Standardization and is in press [ISO 2006].  If the qualitative assessment of a process has identified potential exposure points and leads to the decision to measure nanoparticles, several factors must be kept in mind. Current research indicates that mass and bulk chemistry may be less important than particle size, surface area, and surface chemistry (or activity) for nanostructured materials [Oberdörster et al. 1992, 1994a,b; Duffin et al. 2002]. Research is ongoing into the relative importance of these different exposure metrics, and how to best characterize exposures to nanoparticles in the workplace. In addition, the unique shape and properties of some nanomaterials may pose additional challenges. For example, the techniques used to measure fiber concentrations in the workplace (e.g., phase contrast microscopy) would not be able to detect individual carbon nanotubes (diameter <100 nm), nor bundles of carbon nanotubes with diameters less than 250 nm [Donaldson et al. 2006].

A. Monitoring workplace exposures

While research continues to address questions of nanoparticle toxicity, a number of exposure assessment approaches can be initiated to help determine worker exposures. These assessments can be performed using traditional industrial hygiene sampling methods that include the use of samplers placed at static locations (area sampling), samples collected in the breathing zone of the worker (personal sampling), or real-time measurements of exposure that can be personal or static. In general, personal sampling is preferred to ensure an accurate representation of the worker’s exposure, whereas area samples (e.g., size-fractionated aerosol samples) and real-time (direct-reading) exposure measurements may be more useful for evaluating the need for improvement of engineering controls and work practices. 
Many of the sampling techniques that are available for measuring airborne nanoaerosols vary in complexity but can provide useful information for evaluating occupational exposures with respect to particle size, mass, surface area, number concentration, composition, and surface chemistry. Unfortunately, relatively few of these techniques are readily applicable to routine exposure monitoring. These measurement techniques are described below along with their applicability for monitoring nanometer aerosols.

For each measurement technique used, it is vital that the key parameters associated with the technique and sampling methodology be recorded when measuring exposure to nanoaerosols. This should include the response range of the instrumentation, whether personal or static measurements are made, and the location of all potential aerosol sources. Comprehensive documentation will facilitate comparison of exposure measurements using different instruments and exposure metrics and will aid the re-interpretation of historic data as further information is developed on appropriate exposure metrics. Regardless of the metric and method selected for exposure monitoring, it is critical that measurements be conducted before production or processing of a nanomaterial to obtain background exposure data.  Measurements made during production or processing can then be evaluated to determine if there has been an increase in exposure from background measurements. NIOSH is presently conducting research to evaluate various measurement techniques and will release those results on this site when they become available.

Size-fractionated aerosol sampling

Studies indicate that particle size plays an important role in determining the potential adverse effects of nanoparticles in the respiratory system, by influencing the physical, chemical, and biological nature of the material; by affecting the surface area dose of deposited particles, and by enabling deposited particles to more readily translocate to other parts of the body. Animal studies indicate that the toxicity of nanometer aerosols is more closely associated with the particle surface area and particle number than with the particle mass concentration when comparing aerosols with different particle size distributions. However, mass concentration measurements may be applicable for evaluating occupational exposure to nanometer aerosols where a good correlation between the surface area of the aerosol and mass concentration can be determined or if toxicity data based on mass dose are available for a specific nanometer aerosol associated with a known process (e.g., diesel exhaust particulate). 

Aerosol samples can be collected using inhalable, thoracic, or respirable samplers, depending on the region of the respiratory system most susceptible to the inhaled particles. Current information suggests that a large fraction of inhaled nanoparticles will deposit in the gas-exchange region of the lungs [ICRP 1994], suggesting the use of respirable samplers. Respirable fraction samplers will also collect a nominal amount of nanometer-diameter particles that can deposit in the upper airways and ultimately be cleared or transported to other parts of the body.

Respirable fraction samplers allow mass-based exposure measurements to be made using gravimetric and/or chemical analysis [NIOSH 1994a]. However, they do not provide information on aerosol number, size, or surface area concentration, unless the relationship between different exposure metrics for the aerosol (e.g., density, particle shape) has been previously characterized. Currently, no commercially available personal samplers are designed to measure the particle number, surface area, or mass concentration of nanometer aerosols. However, several methods are available that can be used to estimate surface area, number, or mass concentration for particles smaller than 100 nm.

In the absence of specific exposure limits or guidelines for engineered nanoparticles, exposure data gathered from the use of respirable samplers [NIOSH 1994b] can be used to determine the need for engineering controls or work practices and for routine exposure monitoring of processes and job tasks. When chemical components of the sample need to be identified, chemical analysis of the filter samples can permit smaller quantities of material to be quantified, with the limits of quantification depending on the technique selected [NIOSH 1994a]. The use of conventional impactor samplers to assess nanoparticle exposure is limited to a lower efficiency of 200 to 300 nm. Low-pressure cascade impactors that can measure particles to ³ 50 nm may be used for static sampling, since their size and complexity preclude their use as personal samplers [Marple et al. 2001, Hinds 1999]. A personal cascade impactor is available with a lower aerosol cut point of 250 nm [Misra et al. 2002], allowing an approximation of nanometer particle mass concentration in the worker’s breathing zone. For each method, the detection limits are of the order of a few micrograms of material on a filter or collection substrate [Vaughan et al. 1989]. Cascade impactor exposure data gathered from worksites where nanomaterials are being processed or handled can be used to make assessments as to the efficacy of exposure control measures.  

Real-time aerosol sampling

The real-time (direct-reading) measurement of nanometer aerosol concentrations is limited by the sensitivity of the instrument to detect small particles. Many real-time aerosol mass monitors used in the workplace rely on light scattering from groups of particles (photometers). This methodology is generally insensitive to particles smaller than 300 nm [Hinds 1999]. Optical instruments that size individual particles and convert the measured distribution to a mass concentration are similarly limited to particles larger than 100 to 300 nm. 
The Scanning Mobility Particle Sizer (SMPS) is widely used as a research tool for characterizing nanometer aerosols, although its applicability for use in the workplace may be limited because of its size, cost, and the inclusion of a radioactive source. The Electrical Low Pressure Impactor (ELPI) is an alternative instrument that combines a cascade impactor with real-time aerosol charge measurements to measure size distributions [Keskinen et al. 1992]. 

Surface area measurements

Relatively few techniques exist to monitor exposures with respect to aerosol surface area. Isothermal adsorption is a standard off-line technique used to measure the specific surface area of powders that can be adapted to measure the specific surface area of collected aerosol samples. For example, the surface area of particulate material (e.g., using either a bulk or an aerosol sample) can be measured in the laboratory using a gas adsorption method (e.g., Brunauer, Emmett, and Teller, BET) [Brunauer et al. 1938]. However, the BET method requires relatively large quantities of material, and measurements are influenced by particle porosity and adsorption gas characteristics. 
The first instrument designed to measure aerosol surface-area was the epiphaniometer [Baltensperger et al. 1988]. This device measures the Fuchs or active surface-area of the aerosols by measuring the attachment rate of radioactive ions. For aerosols less than approximately 100 nm in size, measurement of the Fuchs surface area is probably a good indicator of external surface-area (or geometric surface area). However, for aerosols greater than approximately 1 µm the relationship with geometric particle surface-area is lost [Fuchs 1964]. Measurements of active surface-area are generally insensitive to particle porosity. The epiphaniometer is not well suited to widespread use in the workplace because of the inclusion of a radioactive source and the lack of effective temporal resolution. 
This same measurement principle can be applied with the use of a portable aerosol diffusion charger. Studies have shown that these devices provide a good estimate of aerosol surface area when airborne particles are smaller than 100 nm in diameter. For larger particles, diffusion chargers underestimate aerosol surface area. However, further research is needed to evaluate the degree of underestimation. Extensive field evaluations of commercial instruments are yet to be reported. However, laboratory evaluations with monodisperse silver particles have shown that 2 commercially available diffusion chargers can provide good measurement data on aerosol surface area for particles smaller than 100 nm in diameter but underestimate the aerosol surface area for particles larger than 100 nm in diameter [Ku and Maynard 2005, 2006].

Particle number concentration measurement

Particle number concentration has been associated with adverse responses to air pollution in some human studies [Timonen et al. 2004; Ruckerl et al. 2005], while in toxicological studies, particle surface area has generally been shown to be a better predictor than either particle number, mass, or volume concentration alone [Oberdörster and Yu 1990; Tran et al. 1999; Duffin et al. 2002]. A two-variable dose metric of particle size and volume was shown to be the best predictor of lung cancer in rats from various types of particles [Borm et al. 2004; Pott and Roller 2005].  This illustrates some of the complexity of interpreting the existing data on particle dose metric and response.  While adverse health effects appear to be more closely related with particle surface area the number of particles depositing in the respiratory tract or other organ systems may also play an important role.  

Aerosol particle number concentration can be measured relatively easily using Condensation Particle Counters (CPCs). These are available as hand-held static instruments, and they are generally sensitive to particles greater than 10 to 20 nm in diameter. CPCs designed for the workplace do not have discrete size-selective inputs, and so they are typically sensitive to particles up to micrometers in diameter.  Commercial size-selective inlets are not available to restrict CPCs to the nanoparticle size range; however, the technology exists to construct size-selective inlets based on particle mobility, or possibly inertial pre-separation. An alternative approach to estimating nanoparticle concentrations using a CPC is to use the instrument in parallel with an optical particle counter. The difference in particle count between the instruments will provide an indication of particle number concentration between the lower CPC detectable particle diameter and the lower optical particle diameter (typically 300 to 500 nm).

A critical issue when characterizing exposure using particle number concentration is selectivity. Nanoparticles are ubiquitous in many workplaces, from sources such as combustion, vehicle emissions, and infiltration of outside air. Particle counters are generally insensitive to particle source or composition making it difficult to differentiate between incidental and process-related nanoparticles using number concentration alone. In a study of aerosol exposures while bagging carbon black, Kuhlbusch et al. [2004] found that peaks in number concentration measurements were associated with emissions from fork lift trucks and gas burners in the vicinity, rather than the process under investigation. Although this issue is not unique to particle number concentration measurements, orders of magnitude difference can exist in aerosol number concentrations depending on concomitant sources of particle emissions.

Although using nanoparticle number concentration as an exposure measurement may not be consistent with exposure metrics being used in animal toxicity studies, such measurements may be a useful indicator for identifying nanoparticle emissions and determining the efficacy of control measures. Portable CPCs are capable of measuring localized aerosol concentrations, allowing the assessment of particle releases occurring at various processes and job tasks [Brouwer et al. 2004].

Surface Area Estimation

Information about the relationship between different measurement metrics can be used for estimating aerosol surface area. If the size distribution of an aerosol remains consistent, the relationship between number, surface area, and mass metrics will be constant. In particular, mass concentration measurements can be used for deriving surface area concentrations, assuming the constant of proportionality is known. This constant is the specific surface area (surface to mass ratio). 

Size distribution measurements obtained through sample analysis by transmission electron microscopy may also be used to estimate aerosol surface area. If the measurements are weighted by particle number, information about particle geometry will be needed to estimate the surface area of particles with a given diameter. If the measurements are weighted by mass, additional information about particle density will be required.

If the airborne aerosol has a lognormal size distribution, the surface-area concentration can be derived using three independent measurements. An approach has been proposed using three simultaneous measurements of aerosol that included mass concentration, number concentration, and charge [Woo et al. 2001]. With knowledge of the response function of each instrument, minimization techniques can be used to estimate the parameters of the lognormal distribution leading to the three measurements used in estimating the aerosol surface area. 

An alternative approach has been proposed whereby independent measurements of aerosol number and mass concentration are made, and the surface area is estimated by assuming the geometric standard deviation of the (assumed) lognormal distribution [Maynard 2003]. This method has the advantage of simplicity by relying on portable instruments that can be used in the workplace. Theoretical calculations have shown that estimates may be up to a factor of ten different from the actual aerosol surface-area, particularly when the aerosol has a bimodal distribution.  Field measurements indicate that estimates are within a factor of three of the active surface-area, particularly at higher concentrations. In workplace environments, aerosol surface-area concentrations can be expected to span up to 5 orders of magnitude; thus, surface-area estimates may be suited for initial or preliminary appraisals of occupational exposure concentrations.

Although such estimation methods are unlikely to become a long-term alternative to more accurate methods, they may provide a viable interim approach to estimating the surface area of nanometer aerosols in the absence of precise measurement data. Additional research is needed on comparing methods used for estimating aerosol surface area with a more accurate aerosol surface area measurement method. NIOSH is conducting research in this area and will communicate results as they become available. In the interim, NIOSH welcomes additional information and input on this topic.

B. Proposed Sampling Strategy

Currently, there is not one sampling method that can be used to characterize exposure to nanosized aerosols. Therefore, any attempt to characterize workplace exposure to nanoparticles must involve a multifaceted approach incorporating many of the sampling techniques mentioned above. Brouwer et al. [2004] recommend that all relevant characteristics of nanoparticle exposure be measured, and a sampling strategy similar to theirs would provide a reasonable approach to characterizing workplace exposure.
The first step would involve identifying the source of nanoparticle emissions. A CPC provides acceptable capability for this purpose. It is critical to determine ambient or background particle counts before measuring particle counts during the manufacture or processing of the nanoparticles involved. If a specific nanoparticle is of interest (e.g. TiO2), then area sampling with a filter suitable for analysis by electron microscopy should also be employed. Transmission electron microscopy (TEM) can identify specific particles and can estimate the size distribution of the particles.
Once the source of emissions is identified, aerosol surface area measurements should be conducted with a portable diffusion charger and aerosol size distributions should be determined with an SMPS or ELPI using static (area) monitoring. A small portable surface area instrument could be adapted to be worn by a worker, although depending on the nature of the work, this may be cumbersome. Further, losses of aerosol with the addition of a sampling tube would need to be calculated. The location of these instruments should be considered carefully. Ideally they should be placed close to the work areas of the workers, but other factors such as size of the instrumentation, power source, etc. will need to be considered.

Lastly, personal sampling using filters or grids suitable for analysis by electron microscopy or chemical identification should be employed, particularly if measuring exposures to specific nanoparticles is of interest. Electron microscopy can be used to identify the particles, and can provide an estimate of the size distribution of the particle of interest. The use of a personal cascade impactor or a respirable cyclone sampler with a filter, though limited, will help to remove larger particles that may be of limited interest and allow a more definitive determination of particle size. Analysis of these filters for air contaminants of interest can help identify the source of the respirable particles. Standard analytical chemical methodologies should be employed [NIOSH 1994a].

By using a combination of these techniques, an assessment of worker exposure to nanoparticles can be conducted. This approach will allow a determination of the presence and identification of nanoparticles and the characterization of the important aerosol metrics. However, since this approach relies primarily on static or area sampling some uncertainty will exist in estimating worker exposures.

Approaches to Safe Nanotechnology:
Working With Engineered Nanomaterials	Exposure Control Procedures