Reproductive Toxicology and InVitro Tests

Despite a broad range of alternative methods, substantial numbers of animals are still required for the in-vivo testing of toxicity of drugs, chemicals, and cosmetics [37, 38]. In particular, efforts for the development of alternative tests for reproductive toxicity hazard [5] are unfolding, including the use of mESC and hESC [39-41]. For toxicity testing in general - but reproductive toxicity in particular - current regulatory data requirements vary considerably, being most stringent for pharmaceuticals, food additives and pesticides/biocides. For a number of reproductive key phases, which for these regulatory purposes to date are covered in standardized animal tests, no validated alternatives exist. These in-vivo tests have a disadvantage in that molecular information on functional deficits in terms of biomarkers appears difficult [39, 42]. As outlined above, alternative in-vitro tests have the potential to provide this urgently needed, more specific molecular and functional information about toxicological mechanisms on the respective target tissues and, moreover, have the chance to translate subsequently to devices for fast and efficient HTS [21].

The complexity of events involved in reproductive and systemic toxicology, organ or tissue interactions, barriers and metabolic activation, is generally inade quately addressed in vitro. This limitation can be compensated, for instance, by the addition of metabolizing systems or co-culture of various cell types. On the other hand, the use of hESC provides the unique opportunity to approach the human target species by ruling out variances between species which are one of the major disadvantages of in-vivo tests in animals. The current contribution is set in a framework of developing concepts for the validation of innovative alternative systems, namely mESC and hESC or reporter gene-based tests using genetically engineered cells [5].

Due to the current policy for testing chemicals in the European Community (REACH) [1] and elsewhere (EPA-HPV program in the US, TTREC in Japan) [3, 4], animal consumption for toxicity safety testing is expected to increase substantially, and the time lines foreseen are narrow. Reproductive toxicity is one of the crucial endpoints, and so there is an urgent need for the rapid development of alternative methods for at least partial replacement. In this regard, the subtle - but nonetheless potentially severe - impairment of endocrine homeostasis by endocrine disruptors has prompted the development of corresponding in-vitro methods. Their respective reliability and relevance needs to be explored, in particular in combination with further in-vitro methods and novel sensor technologies, computer-based quantitative structure-activity relationship (QSAR), and methods based on patterns or signatures of surrogate biomarkers. Beyond development and prevalidation, the integration into a conceptual framework for safety toxicology (tiered testing strategy with decision points and various branches) is the ambitious goal of related projects such as ReProTect [5, 24].

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