Combined Actions and Interactions of Chemicals in Mixtures

7.7.1.3 Mechanisms of immunotoxicity
A variety of mechanisms can be involved in immunotoxicity. Ultraviolet radiation
and 7,12-dimethylbenz[a]anthracene can cause the disappearance of Langerhans
cells from the skin (or the loss of their function), with consequent disturbance or
dysregulation of the skins immune function. Cyclosporin A blocks the synthesis of
lymphokines. The thymus toxicity of 2,3,7,8-TCDD is due to an effect on the
epithelial cells of the thymus mediated by Ah-receptor. Bis(tri-N-butyltin)oxide is
also toxic to the thymus but primarily because it induces cortical thymocyte cell
death (De Wall et al. 1997). PCBs are mainly toxic to B-cells. Ozone modulates
the non-specific defence mechanisms suppressing phagocytic activity in alveolar
machropages. The immunotoxic effect of aflatoxin and maybe trichothecenes is
probably linked to inhibition of protein synthesis (IPCS 1996a).
7.7.1.4 Combined action and interactions in immunotoxicity
Mixtures of chemicals such as tobacco smoke, engine exhaust and air pollutants
may have an effect on the immune system (rewieved in Germolec and Luster
1994). There are few genuine immunotoxicology studies performed on chemical
mixtures.
A mixture of 25 groundwater contaminants was studied in B6C3F1 mice in a 14
days and 90 days study. The mixture was found to be myelotoxic, suppressing the
granulocyte-macrophage progenitor cells. In addition a decreased cellularity was
observed in the bone marrow. Antibody formation to sheep red blood cells was
decreased. An infection model showed an increased number of parasitised red
blood cells in mice challenged with the malaria parasite P. yoelli. Several of the
components of the mixture, including Aroclor, benzene, and heavy metals, had
previously been shown to cause similar immmunological effects in laboratory
animals. However, the authors conclude, that none of the individual contaminants
were present at sufficient concentration in the chemical mixture to be solely
responsible for the observed effects on the immune system (Germolec et al. 1989).
Although all chemicals were administered in sub-immunotoxic doses the total dose
in the highest dose groups was relatively high, i.e. 756 ppm in drinking water in the
14 days study and 378 ppm in the 90 days study, because of the many chemicals in
the mixture. The result of this study indicates some kind of additive immunotoxic
effect.
Hsieh et al. (1990) exposed mice to a mixture of benzene and toluene in drinking
water. Benzene alone produced the well-characterised profile of anaemia and
alterations in immune function. The mixture of benzene and toluene was
completely devoid of these adverse effects probably because the two chemicals
compete for the same metabolising enzymes and thus the bioavailability of toxic
metabolites was decreased.
Omara et al. (1997, 1998) exposed rat splenocytes, thymocytes and peripheral
blood lymphocytes in vitro for 24 or 72 h to methylmercury (MeHg), mixtures of
PCDDs and PCDFs, and mixtures of PCBs alone and in combination. A variety of
immmunological parameters were measured. The only immunotoxic effect found
was a decreased response to T and B cell mitogens induced by MeHg. All
combinations of MeHg/PCBs/PCDDs/PCDFs decreased the mitogenic response to
levels similar to those of MeHg alone. In these studies no additive effect was
found. The in vitro exposure of lymphocytes to these chemicals is not optimal for
assessing immunotoxicity and may possibly explain the meagre results of the
study.
The immunotoxic effects of TCDD are mediated by binding to a soluble cytosolic
protein, the aryl hydrocarbon receptor, present in the thymus in the epithelial cells.
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