Immunotoxicity testing approaches

Induced models are often used to the study the pathogenesis of, and therapeutic venues for relevant autoimmune diseases. Some of these models, in particular EAE and AA models, have also been proposed as means to evaluate the immunomodulatory effects of chemicals on established autoimmune diseases in the Tiered Approach of immunotoxicity testing. 

The ICH guidance on immunotoxicity testing suggests a weight-of-evidence decision making approach. The general principles that apply to this guideline are as follows ... 

One of the obvious and most important goals of an experimental immunotoxicity testing strategy is to enable the best extrapolations between the results generated in the animal models and the potential risk of immunotoxicity in humans. One of the recent fallouts of this goal has been the recognition that the historic approaches that have been used in clinical... 

Guidance for testing compounds for immunotoxicity is relatively few. The earliest guidelines were developed for pesticides in 1996 by US EPA (OPPTS 880.3550 followed by 880.3800 and 870.7800). The studies were taken from the National Toxicology Program (NTP) tier-testing approach. They typically request tests in rodents and most immunotoxicology is done in vivo [12]. 

Methods such as the TDAR assay have been shown to predict immunotoxicity in humans (Vos and Van Loveren, 1998). The factors to consider for conducting a TDAR assay are defined in the ICH S8 guidance (2006). This assay should be used along with standard immunotoxicity end points, results of other specialized immunotoxicity tests, and clinical data, when available, in a weight-of-evidence approach (see Chapter 2). 

Toxic equivalency factors (TEFs) are estimated relative to 2,3,7,8-TCDD, which is assigned a value of 1. They are measures of the toxicity of individual compounds relative to that of 2,3,7,8-TCDD. A variety of toxic indices, measured in vivo or in vitro, have been used to estimate TEFs, including reproductive effects (e.g., embryo toxicity in birds), immunotoxicity, and effects on organ weights. The degree of induction of P450 lAl is another measure from which estimations of TEF values have been made. The usual approach is to compare a dose-response curve for a test compound with that of the reference compound, 2,3,7,8-TCDD, and thereby establish the concentrations (or doses) that are required to elicit a standard response. The ratio of concentration of 2,3,7,8-TCDD to concentration of test chemical when both compounds produce the same degree of response is the TEF. Once determined, a TEF can be used to convert a concentration of a dioxin-like chemical found in an environmental sample to a toxic equivalent (TEQ). 

The basis of the recommended approach to a hazard assessment of the potential immunotoxicity of a substance is that many immunotoxic substances can be identified via the standard tests for systemic toxicity. Special smdies to characterize effects of concern for immunotoxicity are used only when necessary for adequate hazard assessment. The nature of special smdies, and when they should be conducted, need to be decided on a case-by-case basis. A tiered approach to the identification of immunotoxic hazard in routine toxicology is described in WHO/IPCS (1996). 

In Vitro Approaches to Test Various Aspects of Immunotoxicity 18.2.2.1 Introduction... 

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