High Aspect Ratio Nanomaterials - Aerosols: Measurement, Dosimetry, and Health Effects - page 237

dose (Tran et al., 1999). This is increasingly important when considering the different aerodynamic
characteristics and deposition patterns dictating the dosimetry of nano-sized materials in the lung.
10.3.2.1.1 Lung Deposition
Based on the understanding of the role of particle size in dictating the respirability of a particle, it
seems unlikely that a particle of >5 μm could be respirable, let alone a iber reaching upward of 50 μm.
However, ibers that are in excess of the 3 μm diameter cutoff for respirability do reach the periphery
of the lung due to a peculiarity of iber aerodynamics. Aerodynamic diameter (D ae ) is proportional
to the iber diameter and not the length. In a laminar low of air, a iber aligns itself axially due to
airlow across the iber surface, allowing it to travel along, aligned with the airways (Morgan, 1995),
presenting a small D ae . Because of this, small D ae ibers many times longer than the cutoff diameter
for a spherical particle can deposit in various zones of the respiratory system, including the alveolar
region. Using the theory of Cox (Cox, 1970) to establish the aerodynamic diameter of a cylindrical
iber, Jones calculated that the ratio of aerodynamic diameter to geometric diameter is approximately
2.5-3 over a wide range of aspect ratios based on a iber settling perpendicular to its axis (Jones, 1993).
More simply put, the D ae of a iber is 2.5-3 times the actual diameter largely irrespective of length.
As the aerodynamic diameter of a iber is approximately three times the actual diameter, it is
dificult to know how this may relate to the deposition of ibrous nanoparticles in the respiratory
tract. For particles <0.5 μm in diameter, the appropriate metric relating to deposition is the diffusion
equivalent diameter rather than aerodynamic diameter. However, nanoibers can aggregate to form
nanoropes (Donaldson et al., 2006), so it remains to be elucidated whether aerodynamic diameter or
diffusion equivalent diameter dictates the particle behavior in the airlow of the lung.
10.3.2.1.2 Measuring Dose
The metric by which dose is measured is also an important concept. Ideally, we would measure
the biologically effective dose (BED), which is the quantity that drives the adverse (biological)
effect. The BED refers to the fraction of a total dose that may cause an adverse effect. In particle
toxicology, the difference between the total dose and the effective dose can be stark. In the case of
asbestos ibers (and a hypothesis for HARN), this would be the proportion of the total dose which
is both biopersistent and suficiently long to cause problems with clearance mechanisms. While a
measure of the BED would be the preferred metric for measuring dose, most often mass is used
as a surrogate due to the relative ease of its measurement. Other metrics have been put forward as
more closely approaching the BED. In the case of nano-sized particles that may have a low mass,
surface area is often seen as a driving factor and is suggested to be the BED and so the preferred
metric (Brown et al., 2001; Dufin et al., 2002; Maynard and Maynard, 2002). This requires further
study and method development but, needless to say, the low-density, high surface area, and high
iber number of nanoibers means that as a dose metric, mass is actually likely to be the least useful.
10.3.2.2 Dimension
The issue of dimension relates not only to the ability of a iber to penetrate the distal lung and
deposit in the alveolar region, it also dictates the ease with which alveolar macrophages can clear
material from this region of the lung. The origins of the importance of length again lie in the com-
parison of pathogenic and nonpathogenic ibers.
In 1981, Stanton published a seminal paper in the world of iber toxicology dealing with the
relationship between particle dimension and the development of mesothelioma, a rare tumor of
the chest wall, which is almost always associated with exposure to asbestos (Stanton et al., 1981).
A range of 72 experiments were conducted using a wide variety of respirable and durable minerals
ranging in size and chemical and structural attributes, which were introduced to the chest (pleural)
cavity of rats. Following this, they observed that the formation of tumors correlated most closely
with iber attributes based on length and diameter. Speciically, they found that ibers that measured
<0.25 μm in diameter and >8 μm in length correlated well with the formation of malignant