3.11. Reproductive and Developmental Toxicity

Reproductive toxicity refers to the adverse effects of a substance on any aspect of the reproductive cycle, including the impairment of reproductive function, and the induction of adverse effects in the embryo, such as growth retardation, malformations, and death. All these events and interactions are controlled to a large extent by the body’s endocrine system. Due to the complexity of the mammalian reproductive cycle, it is not possible to model the whole cycle in one in vitro system, in order to detect the effects of a chemical on mammalian reproduction. However, the cycle can be broken down into biological components that can be studied individually or in combination. This has the enormous advantage that the target cell/tissue/organ of an agent can be identified. In certain areas of reproductive toxicity testing, a number of useful and promising in vitro models are already available, which now need to be converted into individual tests with predictive power for safety testing. However, it should be clear that most of the single tests cannot be a replacement, since only in combination with other tests will detailed hazard identification be possible. The individual tests can then be used as building blocks to compose a tiered testing strategy. It should be noted that, until now, most attention has been devoted to developing and validating assays on some components of reproductive toxicology, and in particular, the organogenesis of the embryo, reflecting concerns about teratogenic chemicals, and the interaction of chemicals with steroid receptors, in order to detect endocrine disruptors. In these areas, the building blocks for a testing strategy exist and have been implemented in several laboratories. Other areas (for example, fertility, implantation, and placental and fetal toxicity) have received less attention. A number of the existing in vitro models need to be further developed and their protocols must be optimised before their relevance and reliability can be judged. Nevertheless, we must take care not to be too reductionist in our approach. Many of the processes that need to be modelled (for example gametogenesis) are dependent on cell–cell interactions, as well as on paracrine and endocrine signalling. It is not clear whether cultures of gametes would be useful in the absence of Sertoli cells, or that Sertoli/germ cell cultures would be useful in the absence of endocrine factors. These are questions that need to be explored and answered, if truly predictive models of reproduction are to be created. It should be noted that, unfortunately, many of the well-developed tests rely on tissues derived from intact mammals. This includes the micromass, whole-embryo culture, sliced testis, and ovarian follicle culture methods. In addition, the forthcoming revision of EU Directive 86/609/EEC on the protection of animals used for experimental and other scientific purposes, may mean that the protection of embryos and fetuses may be increased, which would have consequences, for example, for whole-embryo culture methods.