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consequences of an immunostimulation resulting from exposure to environmental chemi-
cals are yet not well defined and are poorly understood.
In ecotoxicology, a tier approach is used to evaluate the immunotoxicity of environmen-
tal pollutants. Tier 1 addresses the
in vitro
effects of chemicals on immune cells from the
investigated species.
In vitro
exposures to a single compound or to cocktails can be con-
sidered, and effects on phagocytic activity, lymphocyte proliferation, and oxidative burst,
in parallel with a cytotoxicity assay, are generally tested as immunomarkers. This first tier
not only allows the identification of potential immunotoxic compounds in the targeted
species, it also provides a range of concentrations within which compound(s) are immu-
notoxic but not cytotoxic. This represents essential information as the second tier aims
to investigate
in vivo
laboratory exposure to doses inducing immunotoxic effects without
systemic toxicity. In this second tier of the approach, efforts have to be made to design
experiment settings that reproduce environmentally relevant doses and ways of exposure.
As in the first tier, exposures to a single compound or cocktails can be considered. Three
or more doses have to be tested in order to establish dose-response curves for the differ-
ent immunomarkers. These provide essential information to adequately select the panel
of markers used in the third tier. In most cases, NK cells cytotoxic activity, phenotyping,
specific antibody production, and phagocytosis are selected (Luster et al. 1992a, 1992b;
FDA 1993; Fournier et al. 2000a). Additional immunomarkers such as the synthesis of pro-
inflammatory cytokines can also be investigated, depending on whether the xenobiotic(s)
present in the environment is suspected to act on inflammation processes. The third tier
addresses the detection of immunotoxic effects in the field in relation to exposure to envi-
ronmental pollutants and the potential consequences on health status.
The integration of immunotoxicology as part of a risk assessment analysis is relatively
new. The few studies that address the link between the effects on immunomarkers and
the consequences on host susceptibility to pathogens and cancers provide large databases
underpinning the identification of highly predictive immune assays (Luster et al. 1993).
Ongoing studies are presently addressing the dose-effect and dose-response curves
of different immunomarkers and xenobiotics in order to determine the “no observable
adverse effect level” (NOAEL). The establishment of this NOAEL is complicated by the
existence of confounding factors and the different sensitivity of the immunological assays
(Luster et al. 1993). When these values have been determined for a large number of xenobi-
otics in different species, the next challenge will be the use of these models in field studies
to support the risk assessment analysis. Therefore, the development of models of exposure
that clearly identify the dose, the method of exposure, the metabolism, and the bioavail-
ability of chemicals in the environment for key species is strongly needed.
Effects of xenobiotics on the immune response can vary from immunodepression to immu-
nostimulation. Moreover, the same chemical can actually decrease specific immunomark-
ers while stimulating others, and a single compound can stimulate an immune function at
lower doses while acting as a strong inhibitor at higher doses. The method and duration of
exposure, gender, age, stress, nutritional status, and the relative complexity of the immune
system of the investigated organism have been highlighted as important confounding fac-
tors that can modulate the immunotoxic effects of toxicants. In this regard, stress induction
during sampling requires particular attention since it has been demonstrated to strongly
affect immune functions. Accordingly, noninvasive sampling methods have to be empha-
sized in order to minimize as much as possible any stress during sampling. Additionally,
efforts have to be made to standardize protocols including interlaboratory exercises in order
to establish reference values with standard toxics in specific animal models.
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