Congrès Annuel de la SFT - Nancy, 19-20 octobre 2009

Toxicité Juvénile des Xénobiotiques et Toxicologie de la Reproduction

Modèles Expérimentaux en Toxicologie de la Reproduction
Experimental models in reproductive toxicology

Paul Barrow

MDS Pharma Services, St Germain sur L'Arbresle, France

The thalidomide tragedy illustrated the need for reliable animal or alternative models for the assessment of reproductive hazards in the human. The research needs in this respect have barely changed over the last 40 years. The animal models and methods currently in use for the safety testing of pharmaceuticals and chemicals have successfully detected the reproductive toxicity of hundreds, if not thousands, of potentially harmful substances and prevented exposure of the human population. Nevertheless, there is still a risk of failing to detect a toxic agent, such as thalidomide, that is only teratogenic in primate species.

Monkeys are occasionally used for reproductive toxicity safety testing, but their routine use for this purpose would be ethically unacceptable. Rodents and rabbits are by far the preferred species for routine teratogenicity testing. Effects on fertility or on post-natal development are nearly always assessed in rodents.

The minipig has become more popular in biomedical research over recent years and is now a feasible model for reproductive toxicity studies. The recent regulatory requirements for the reproductive testing of vaccines have lead to an increased use of rabbits for post-natal evaluations.

Many biopharmaceuticals cannot be tested in non-primate species, due either to a lack of pharmacological action in lower species or to the induction of neutralising antibodies. A single-segment study design in the monkey has been proposed for this purpose.

Alternative or in-vitro methods are unlikely to replace in-vivo reproductive toxicology studies in mammalian species for the purposes of safety testing in the near future. Such methods are proving useful, however, for initial early-stage high-throughput screening of pharmaceuticals for teratogenicity. It is also hoped that these alternative methods will be used to select and prioritise the thousands of chemicals that will need to be tested for reproductive toxicity according to the new REACH regulations. Three alternative tests have been validated by ECVAM: the embryo stem cell test (EST), whole embryo culture (WEC) and the zebrafish (ZF) assay. According to the validation studies performed, a combination of any two of these alternative tests would allow the detection of up to 90% of human teratogens. It should be noted, however, that the list of substances assessed in the validation studies excluded known teratogenic agents that require metabolic activation in order to cause dysmorphogenesis. A false positive result was obtained for 10 to 20% of non-teratogens tested.

Finally, genomic innovations hold great promise for improving the reliability and precision of both in-vivo and alternative tests for the detection of developmental toxicity. Hopefully, the undergoing efforts in bioinformatics will succeed in identifying specific patterns of gene activation that characterise dysmorphogenic events in the human. The structure and function of many genes involved in organogenesis are largely conserved across the animal phyla, so it should be possible to detect warning signals in lower species (ZF for instance), even when the observed genomic activation does not progress to dysmorphogenesis in the model species.