Asbestos Fibers and Other Elongate Mineral Particles: State of the ...

fiber length, width, and aspect ratio on carcinogenicity
were addressed in a seminal study
using a pleural surface implantation method
of challenge in the rat [Stanton et al. 1977,
1981]. Tests were performed on 72 durable
EPs: 13 crocidolites; 22 glasses; 8 aluminum oxide
sapphire whiskers; 7 talcs; 7 dawsonites; 4
wollastonites; 2 asbestos tremolites; 1 amosite;
2 attapulgites; 2 halloysites; 1 silicon carbide
whisker; and 3 titanates. The incidence of malignant
mesenchymal neoplasms a year after
implantation correlated best with EPs that were
longer than 8 µm and no wider than 0.25 µm,
with relatively high correlations with EPs longer
than 4 µm and no wider than 1.5 µm. This
suggested that carcinogenicity of durable EPs
depends on dimension and durability, rather
than physicochemical properties. This is sometimes
referred to as the Stanton hypothesis and
has been the subject of continuing research.
Reanalysis of the dimensions of seven of the
crocidolite samples used in the 1981 study
found that tumor probability was significantly
correlated with the number of index particles
(defined as particles longer than 8 µm and
no wider than 0.25 µm), but the coefficient was
low enough to suggest that factors other than
size and shape play a role in carcinogenic effects
of durable EPs [Wylie et al. 1987]. Further
analysis confirmed the number of such index
particles as the primary dimensional predictor
of tumor incidence, but the correlation was increased
when the data were analyzed by separate
mineral types [Oehlert 1991]. These analyses
suggested that mineral type is important,
which is counter to the Stanton hypothesis.
Lippmann [1988] reviewed data from animal
models exposed by instillation or inhalation of
EMPs of defined size distributions, along with
data on human lung fiber burden and associated
effects, and concluded that (1) asbestosis
is most closely associated with the surface area
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of retained EMPs; (2) mesothelioma is most
closely associated with numbers of EMPs longer
than about 5 µm and thinner than about
0.1 µm; and (3) lung cancer is most closely associated
with EMPs longer than about 10 µm
and thicker than about 0.15 µm. Lippmann
[1988] also stated that the risk of lung cancer is
associated with a substantial number of fibers
longer than 10 µm with widths between 0.3 µm
and 0.8 µm. A more recent review of the response
to asbestos fibers of various lengths in
animal models, along with data from studies of
human materials, concluded that asbestos fibers
of all lengths induce pathological responses;
it suggested caution when attempting to exclude
any subpopulation of inhaled asbestos
fibers, on the basis of length, from being considered
contributors to the development of asbestos-related
diseases [Dodson et al. 2003].
2.9.4.3 Initiation of Toxic Interactions
A first question in seeking a full understanding
of EMP properties and mechanisms responsible
for fibrosis, lung cancer, or mesothelioma
risks is the identity of initiating toxic interactions
and the morphological, physical, and/or
chemical properties of EMPs controlling them.
Among proposed initiating mechanisms are
these: (1) EMP surfaces generate ROS (even in
vitro in the absence of cells), which are the primary
toxicants to cells; (2) EMP surfaces are
directly membranolytic or otherwise directly
cytotoxic or genotoxic to components of the
cell, as are some nonelongate mineral particles,
and that damage can cause necrosis, apoptosis,
mutation, or transformation directly or by responsive
cellular production of secondary reactive
intermediates; and (3) EMP morphology
itself can result in frustrated phagocytosis
with an anomalous stimulation or release of
ROS or other toxic reactive species.
NIOSH CIB 62 • Asbestos