Adverse immune effect

Immunotoxicity. Limited information is available regarding the effects of endosulfan on the human immune system. However, specially designed studies using rats indicate that both humoral and cellular immune responses are depressed by ingested endosulfan at doses that do not induce any overt signs of toxicity (Banerjee and Hussain 1986,1987). In vitro studies support the possibility that endosulfan affects immune system function (Das et al. 1988). These results demonstrate that immunotoxicity may be a more sensitive end point of endosulfan-induced toxicity than other end points, and humans may be at risk for adverse immune effects following exposure to endosulfan. An intermediate-duration oral MRL was derived based on the observation of depressed immune responses (Banerjee and Hussain 1987). 

Ezendam, J., Vos, J., and Pieters, R., Mechanisms of Hexachlorobenzene-induced adverse immune effects in Brown Norway rats. J. Immunotoxicol., 1, 167, 2004. 

Ezendam, J. et al., Macrophages are involved in hexachlorobenzene-induced adverse immune effects. Toxicol. Appl. Pharmacol., 209, 19, 2005. 

Generally accepted 28 consecutive daily doses in rodents. Adaptations of immunotoxicity assays have been described using non-rodent species. The species, strain, dose, duration, and route of administration used in immune function assays should be consistent, where possible, with the non-clinical toxicology study in which an adverse immune effect was observed. 

Fig. 2. Proposed mode of action of hexachlorobenzene-induced adverse immune effects (HCB = hexachlorobenzene ROS = reactive oxygen species NO = nitric oxide DC = dendritic cells) (from Ezendam, 2004).

Chemicals may exacerbate autoimmunity in genetically predisposed animals or in induced animal models (Kammuller et al., 1989a). The rationale behind using autoimmune-prone animal strains for the purpose of studying and predicting the autoim-munogenic potential of chemicals is that, apart from being probably very sensitive for adverse immune effects, exacerbation of disease is considered one of the possibilities by which chemicals may elicit autoimmune phenomena (Pollard et al., 1999). As mentioned also, the Brown Norway rat is a sensitive rat strain for Th2-dependent phenomena, as is the Lewis rat for cyclosporin-induced autoimmunity. 

Ezendam J (2004) Mechanisms of hexachlorobenzene-induced adverse immune effects [thesis], Utrecht, Utrecht University. 

An even more complex situation has been observed with recombinant proteins (biotherapeutic drugs, biopharmaceuticals). ICFI S8 does not apply to these drugs, but increasingly adverse immune effects are being observed with biopharmaceuticals. Probably the best-known example involved recombinant erythropoietin (EPO), indicated for patients with anemia associated with cancer chemotherapy. For reasons that are not been completely understood, reformulated recombinant EPO, when administered to patients, was associated with pure red cell aplastic anemia. These patients developed neutralizing antibodies to EPO, resulting in ablation of both endogenous and recombinant molecule activity (Schellekens and Jiskoot, 2006). 

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