drug testing

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The Way Forward in Reproductive/Developmental Toxicity Testing

Horst Spielmann

The use of experimental animals in reproductive toxicity testing is critically reviewed on the occasion of the 50th anniversary of the publication of the Three Rs concept by Russell and Burch, since there is major concern that reproductive toxicity testing will significantly increase due to the requirements of the EU Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) system. A comparison of the test guidelines for drugs, agrochemicals and industrial chemicals shows that, for historical reasons, significantly different testing strategies are applied. The current status of development and validation of in vitro tests in reproductive toxicology is also critically evaluated. The mouse embryonic stem cell test (mEST) is the most advanced and promising of the in vitro tests. Although it has not yet been accepted for regulatory purposes, its use in preclinical drug development is well established. Moreover, promising molecular endpoints have been established in the mEST, including proteomic and toxicogenomic endpoints. Preliminary results have been obtained with a human EST (hEST). In addition, an overview is given on new in vitro reproductive toxicity tests that are currently being developed in the EU FP6 project, ReProTect, since the ReProTect test battery, which covers the essential steps of female and male fertility, implantation and embryotoxicity, holds promise for use as a screening assay for reproductive toxicity testing according to the EU REACH legislation. However, since validated in vitro methods will not be available in the short term, opportunities for the refinement of the standard in vivo tests are discussed, in order to reduce the numbers of animal used in reproductive toxicity testing. Finally, recommendations for toxicity testing in the 21st century call for the harmonisation of test methods across all areas of regulatory testing as a first step. Since the REACH system testing framework for industrial chemicals is driven by the reproductive safety testing requirements of agrochemicals, a shift is proposed to exposure-driven testing of industrial chemicals. In particular, the implementation of a new ‘extended one-generation reproductive toxicity study’ (EOGRTS), which includes triggers for additional testing for fertility, developmental neurotoxicity and immunotoxicity, would significantly reduce test animal numbers. It is concluded that in vitro methods hold great promise for reproductive toxicity testing in the 21st century, e.g. the ReProTect in vitro battery and the embryonic stem cell (ESC) technology focusing on molecular endpoints in both the mEST and the hEST.
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An Immunologic Model for Rapid Vaccine Assessment — A Clinical Trial in a Test Tube

Russell G. Higbee, Anthony M. Byers, Vipra Dhir, Donald Drake, Heather G. Fahlenkamp, Jyoti Gangur, Anatoly Kachurin, Olga Kachurina, Del Leistritz, Yifan Ma, Riyaz Mehta, Eric Mishkin, Janice Moser, Luis Mosquera, Mike Nguyen, Robert Parkhill, Santosh Pawar, Louis Poisson, Guzman Sanchez-Schmitz, Brian Schanen, Inderpal Singh, Haifeng Song, Tenekua Tapia,
William Warren and Vaughan Wittman

While the duration and size of human clinical trials may be difficult to reduce, there are several parameters in pre-clinical vaccine development that may be possible to further optimise. By increasing the accuracy of the models used for pre-clinical vaccine testing, it should be possible to increase the probability that any particular vaccine candidate will be successful in human trials. In addition, an improved model will allow the collection of increasingly more-informative data in pre-clinical tests, thus aiding the rational design and formulation of candidates entered into clinical evaluation. An acceleration and increase in sophistication of pre-clinical vaccine development will thus require the advent of more physiologically-accurate models of the human immune system, coupled with substantial advances in the mechanistic understanding of vaccine efficacy, achieved by using this model. We believe the best viable option available is to use human cells and/or tissues in a functional in vitro model of human physiology. Not only will this more accurately model human diseases, it will also eliminate any ethical, moral and scientific issues involved with use of live humans and animals. An in vitro model, termed “MIMIC” (Modular IMmune In vitro Construct), was designed and developed to reflect the human immune system in a well-based format. The MIMIC® System is a laboratory-based methodology that replicates the human immune system response. It is highly automated, and can be used to simulate a clinical trial for a diverse population, without putting human subjects at risk. The MIMIC System uses the circulating immune cells of individual donors to recapitulate each individual human immune response by maintaining the autonomy of the donor. Thus, an in vitro test system has been created that is functionally equivalent to the donor’s own immune system and is designed to respond in a similar manner to the in vivo response.
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Integrated Testing Strategies for Toxicity Employing New and Existing Technologies

Robert D. Combes and Michael Balls

We have developed individual, integrated testing strategies (ITS) for predicting the toxicity of general chemicals, cosmetics, pharmaceuticals, inhaled chemicals, and nanoparticles. These ITS are based on published schemes developed previously for the risk assessment of chemicals to fulfil the requirements of REACH, which have been updated to take account of the latest developments in advanced in chemico modelling and in vitro technologies. In addition, we propose an ITS for neurotoxicity, based on the same principles, for incorporation in the other ITS. The technologies are deployed in a step-wise manner, as a basis for decision-tree approaches, incorporating weight-of-evidence stages. This means that testing can be stopped at the point where a risk assessment and/or classification can be performed, with labelling in accordance with the requirements of the regulatory authority concerned, rather than following a checklist approach to hazard identification. In addition, the strategies are intelligent, in that they are based on the fundamental premise that there is no hazard in the absence of exposure — which is why pharmacokinetic modelling plays a key role in each ITS. The new technologies include the use of complex, three-dimensional human cell tissue culture systems with in vivolike structural, physiological and biochemical features, as well as dosing conditions. In this way, problems of inter-species extrapolation and in vitro/in vivo extrapolation are minimised. This is reflected in the ITS placing more emphasis on the use of volunteers at the whole organism testing stage, rather than on existing animal testing, which is the current situation.
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