Food for Thought . . . Immunotoxicology : Challenges in the 21 st Century and In Vitro Opportunities

Do we need yet another review on alternative methods in immunotoxicology? the authors have contributed to many that have already been published (Gennari et al., 2005; Corsini, 2006; Carfì et al., 2007; Corsini and Roggen, 2009; Galbiati et al., 2010; lankveld et al., 2010; Pfaller et al., 2010). Immunotoxicology in general is also well covered in reviews and book chapters (Descotes, 2004, 2006; Kadow et al., 2009; Dietert, 2010; House, 2010; Rooney et al., 2012), and is even the subject of entire textbooks (Dean et al., 1994; House et al., 2006), though arguably the latter may no longer be entirely up to date. that is why this review is not another attempt to sum up the state of the art but to ask some fundamental but out of the box questions. Cambridge Advanced learner’s Dictionary & thesaurus defines “immunology” as “the study of how the body fights disease and infection”1. toxic immunomodulation would then mean either excess or deficiency in fighting disease and infection. Excess situations could be seen, for example, in cases of allergy and sensitization, where essentially harmless antigens trigger excessive defense. these are extensively covered in the abovementioned reviews; here, only autoimmunity and pyrogenicity/ inflammation will be touched on as examples of inappropriate immunoactivation. Defective situations could be seen for example in cases of primary and secondary immunodeficiency, which result in increased susceptibility to pathogenic infection and cancer (Gallagher et al., 2010; Riminton et al., 2011). this review will primarily focus on toxic immunosuppression. the only remark concerning hypersensitivity we want to make is that allergic contact dermatitis is to a considerable extent a preventable disease. there is a pressing need for alternative, non-animal methods to reduce and ultimately replace animal tests for this endpoint, as also required by some european regulations (i.e., Cosmetics Regulation and ReACH). the correct detection of skin sensitizers, the characterization Summary Over the last two decades, little has changed in the practice of immunotoxicity testing for regulatory purposes, especially for immunosuppression, and autoimmunity is still a challenge. Current guidelines still rely on animal tests, which include some immune endpoints in repeated dose tests and trigger dedicated tests only when certain alerts indicate a problem. At the same time, however, a wealth of in vitro approaches has been developed, but few have been adopted for routine testing. The extent to which immunotoxicity of chemicals represents a health problem for the human population at low levels of exposure is unclear: it appears that responses of healthy individuals to immunological challenges differ widely and most immunomodulators have few adverse effects except when they coincide with an infectious or malignant challenge or when early in life exposure is expected, in which cases the odds of progressing into infection, autoimmune diseases, or cancer can be changed. The enormous overcapacity of immune defense, the presence of compensatory mechanisms, and their fast restoration each contribute to limiting health threats for the individual, though on a population base also minor immunomodulation may result in increased morbidity. In vitro alternative approaches may allow screening for problematic substances and prioritize them for in vivo testing. New approaches are emerging from mapping pathways of immunotoxicity. Increasingly, the contribution of inflammatory and infectious components to the adverse outcome pathways of chemicals is recognized for various hazards, urging inclusion of tests for proinflammatory and immunomodulatory properties of chemicals into integrated testing strategies.