Toxicology of Industrial Compounds

198 EVALUATION OF TOXICITY TO THE IMMUNE SYSTEM
The next problem is to find which tests can suitably be used—simply and
without having to treat additional animals—for reliable identification of
interactions with the immune system. Another question which has not yet
been solved is relating to the dosages and the changes in immunological
parameters which are still tolerable and at which times these should be
determined.
National and international collaborative studies
Most of the guideline drafts favour a two-tiered to three-tiered approach
for the screening of immunotoxic side effects, with the greatest disparities
in respect of the proposals for tier I tests, ranging from just organ weights
and a little more emphasis on the histology of the lymphatic organs, to a
series of elaborate, supplementary function tests including, in some cases,
satellite groups.
Any discussion about basic tests is hampered by a lack of data from
routine toxicological and/or epidemiological studies although a few years
ago a number of collaborative studies were initiated, namely: ICICIS
(international), US-NTP (international, USA (two)), BGA (Federal German
Health Office, Germany), GEVI (France). The aim of all these studies is to
check on different histological parameters and functional tests for their
possibility to flag an immunotoxic potential of a compound in a routine 14
or 28 day study (rats) in an interlaboratory trial. Two immunosuppressive
standards (azathioprine and/or cyclosporin A) have been used so far.
Although the experimental phase is finished the evaluation of the data is
still underway.
Table 15.1 summarises the immunotoxicological experiments and
collaborative studies currently in progress. With a few exceptions all
investigations are based on a 28-day gavage study in rats. These basic tests
were supplemented by extended histopathology and functional tests.
ICICIS
The first substance to be investigated in the international collaborative
study was azathioprine. However this first attempt suffered from lack of
harmonisation between the models used by the 28 participants world-wide.
This made the comparability and the evaluation of the results particularly
problematic.
The second substance which was tested by ICICIS in a more restrictive
design with slightly fewer participants was cyclosporin A. The
experimental section as well as the first evaluation of the results has now
been completed.
As the final evaluation—including statistics—of ICICIS is likely to take
some time (years?) it will not be discussed further at this point.