Important issues in developmental toxicity testing

Correspondence address: Assoc Prof. Eduard Ujházy, PhD. Department of Reproductive Toxicology, Institute of Experimental Pharmacology, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovakia, e-mail: [email protected] Studies of individual development and its possible deterioration have been the concern since the 19th century, when Etienne Geoffroy de Saint-Hilaire (1772–1844) with his pioneer experiments opened the door for future experimental teratologists. Later scientists, focused on environmental agents which can alter embryonic and fetal development, such hyperthermia, malnutrition, pharmaceuticals, microbial toxins etc. Although the history of teratology involves many notable scientists, it has gained prominence after the big thalidomide tragedy in 1961. Principles of teratology were proposed later by James Wilson in his monograph Environment and Birth Defects (Wilson, 1973). From the relative safety assessment point of view, it is essential to identify adverse agents, which can be harmful, related also to the development of the organism. The critical embryofetal developmental stages, when the agents are potentially most dangerous, require careful consideration as to maternal dosing regiments. Much of our present knowledge concerning the adverse effects of chemicals on mammalian development and particularly on human brain development relates to events during the early stages of gestation. Gestation is divided into two major periods, the embryonic and the fetal period. In humans the embryonic period constitutes 20% and the fetal 80% of the whole gestation period. In animals used frequently in research, such as mouse and rat, the opposite is seen: the embryonic period constitutes 80% and the fetal period 20% of the gestation. In 1963, Werboff and Gottlieb came with the notion that chemical substances acting during sensitive prenatal brain development may cause behavioral alterations manifested in the postnatal period. They were the first to introduced the concept of behavioral teratology (Werboff and Gottlieb, 1963). Epidemiological as well as experimental studies in later periods showed that exposure of the developing organism to physical factors and/or chemical substances can cause not only structural but also functional anomalies. Functional maldevelopment of the brain can manifest as behavioral, emotional and/or cognitive disorders (Grandjean and Landrigan, 2006). Moreover, recent studies confirmed that any imbalance in the proper development of individual organs may result in their malfunctioning at various levels and in turn can result in chronic diseases in adulthood, such as diabetes, hypertension, etc.). (Barker, 2003). Not only chemical substances but also physical and environmental factors, such as insufficient nutrition, hypoxia, and stress, represent a serious risk factor for structural and functional development of the organism. In many cases, impairment of intrauterine development may cause the birth of a seemingly healthy individual with invisible stigma of future health problems.