Toxicology of Industrial Compounds

standard techniques for chronic toxicity/carcinogenicity studies, including
dose and latency considerations. Rats were exposed for 2 years and
hamsters for 18 months. The animals were observed for their lifetime or until
20% survival of the test group was reached. Positive and shamexposed
negative controls were included in the protocol.
Fiber aerosols
In designing these animal inhalation studies, the techniques of fiber
preparation, aerosolization, exposures, measurement, quantification and
determination of actual target organ dose were critical factors. Fiber
dimensions that permitted deposition into the distal lung regions (i.e.
respirable fibers) for the model used were selected. The characteristics of the
fiber aerosol in actual work areas for man was an important consideration
in determining experimental exposure. For example, an average fiber size
of 1×20 µm has been measured during simulated RCF work practices. The
critical need to use fibers pre-selected for their size and to verify the actual
size distributions of the fiber exposure aerosol was met throughout the
study. Non-fibrous particles (shot) in the aerosol were reduced to the
maximum extent possible. Furthermore, fiber preparation, handling and
aerosolization did not alter the physical-chemical characteristics of the
fiber, since as will be discussed later, these are known to be critical
determinants of fiber toxicity.
Nose-only rather than whole-body exposure was used for several
reasons, including the impossibility of preparing the huge quantities of
specially sized fibers that would be required for 2 years of whole-body
exposure. Additionally, nose-only exposure levels permitted better control
of exposure levels and host entry.
Selection of exposure concentrations
It was important that at least three exposure concentrations be used in the
chronic inhalation study in order to assess the dose-response relationships
of any induced changes. The highest concentration selected was the
‘Maximum tolerated dose’ (MTD), while lower concentrations were 50 per
cent of the MTD and multiples of the projected occupational and
environmental exposure levels.
Experimental design, time lines
T.W.HESTERBERG ET AL. 97
Groups of three or six randomly selected animals from each exposure
group were killed at 3, 6, 12, 18 and 24 (rats only) months to follow the
progression of histopathological changes and to determine lung fiber
burdens. An additional six ‘recovery’ animals were removed from each