The International Collaborative Immunotoxicity Study (ICICIS) was esta
blished in 1986 as a joint activity of the International Programme on
Chemical Safety (a cooperative programme of the United Nations Environ
ment Programme, the International Labour Office and the World Health O
rganization), the Commission of the European Union and the United King
dom Department of Health. The objectives were to examine whether vario
us experimental techniques could be used in the rat to indicate toxic
effects on the immune system, and so to suggest their possible value a
s general indicators of immunotoxicity. For this purpose scientists in
a number of laboratories in different countries agreed to do joint st
udies, first of azathioprine (AZA) and then of cyclosporin A (CYA), as
potent immunosuppressive compounds. The general experimental procedur
es and the detailed techniques employed were selected to explore wheth
er the limited pathological investigations in the conventional 28-day
subacute toxicity test in the rat (OECD, 1995), or 'Enhanced Pathology
' tests (weight determination and examination of additional lymphoid o
rgans and application of structured assessment and semiquantitative gr
ading of changes in the principal compartments of lymphoid tissues) wo
uld suffice to indicate ('flag') the occurrence of immunotoxicity due
to a chemical, or whether specific tests of immune function would be r
equired. When the second chemical, CYA, was studied, standardisation o
f the protocol for the test, and of all the investigations, and prior
training of the toxicological pathologists in the structured assessmen
t scheme, were shown to greatly reduce interlaboratory variation in th
e results. The initial investigation of AZA had shown that the indicat
ive power of the experiments had been diminished by the use of diverse
experimental procedures. The studies were done as toxicity tests, in
which three dose levels, including the maximum tolerated dose, and a v
ehicle control group were employed. The prime objective was to detect
any immunotoxic effect of the test compound. It was shown that the lim
ited, basic 'Pathology' investigations specified in Guideline 407 (OEC
D, 1981) were not able to reveal the effects on the immune system of A
ZA and CYA, but that several of the additional 'Enhanced Pathology' in
vestigations did so(3). Of the immune function assays, the most reliab
le and useful was the 'Antibody Forming Cell' technique. Other immunol
ogical evaluations, such as examination of proliferation induced by se
lected mitogens and NK cell assay, showed promise. The methods employe
d have the potential to reveal an 'immunotoxic' effect, without necess
arily indicating its mechanism, although the changes in different lymp
hoid compartments can afford a valuable guide to the detailed nature o
f the toxic action on the immune system. Function tests, being inheren
tly quantitative in nature may well suggest the nature or mechanism of
any effect seen, in addition to indicating the occurrence of the effe
ct. However, they may be less convenient to do as part of a routine to
xicity test. Overall, the work in ICICIS has shown that the immunotoxi
c actions of two chemicals were detectable within a 28-day subacute or
al toxicity test in the rat, provided that the conventional laboratory
procedures were extended to include extra investigations. Both additi
onal selected pathology investigations and immune function tests 'flag
ged' the immunotoxicity. (C) 1998 Elsevier Science Ireland Ltd. All ri
ghts reserved.