Embryo-foetal development

Reproductive toxicology, usually embryo/ foetal development studies in two species, is required in Europe and Japan if women of childbearing potential are included. Not required in the United States for some early trials... 

Embryo-foetal development (rat and rabbit). This is a standard Segment II, teratogenicity study. 

The FDA allows women to enter carefully controlled and monitored trials in which adequate contraceptive measures and pregnancy testing are performed without requiring results from animal reproductive toxicity tests. In Japan and Europe, because of the high level of concern regarding imintentional exposure of the developing embryo or foetus, an assessment of fertility in a rodent, and embryo/foetal development in a rodent or non-rodent are required if women of childbearing potential are to be included in a Phase I trial. The FDA would expect such results to support Phase II and Phase III studies. 

Frieling WJAM, Heijink E, Tesh SA, et al. Embryo-foetal development toxicity of propylene glycol in NZW rabbits. Repro Tox 2000 14 562. 

Segment II the embryo-foetal development (embryo during major organ development i.e. organogenesis, the foetus in the post-embryonic period) and... 

Teratogenic effect - animal testing showed effects on embryo-foetal development at levels equal to or above those causing maternal toxicity ... 

Before administration of a NME to man, a mutagenicity test in bacterial cells (Ames test), with and without metabolic activation, and tests for chromosomal aberrations in mammalian cells should be negative. Any positive or equivocal results will require additional tests to be performed before proceeding to man. Studies of embryo-foetal toxicity should be performed before administration of a NME to women of reproductive potential. Studies of fertility, early embryonic development and pre- and post-natal development are not required at this stage of development neither are carcinogenicity studies. 

In doses of 1.2 mg Ni/kg and up to 20 mg Ni/kg, nickel chloride caused increased resorption rates and a number of malformations in murine foetuses, specific to the foetal skeletal system, as shown by atomic absorption [425]. It was believed that nickel chloride might influence embryos during the passage through the oviduct, with subsequent effect on the development after implantation [426]. Preimplantation mouse embryos have also been used to investigate toxic effects of nickel chloride on early embryo development in vitro, and a dose-dependent effect has been found [427]. 

There are a number of media available which are not based on a detailed investigation of growth requirements, but rather include crude mixtures of nutrients added to promote cell growth. These include lactalbumin hydrolysate (Appendix 1 Table 9) or yeast extract (Appendix 4) to provide an inexpensive source of amino acids or vitamins. Thus Melnick s monkey kidney media A and B (Melnick, 1955) contain lactalbumin hydrolysate and calf serum in Hanks and Earle s BSS, respectively. Chick embryo extract and tryptose phosphate broth (Appendix 1, Tables 11 and 12) are also used occasionally and their use is referred to where appropriate throughout the book. Mitsuhashi and Maramorosch mosquito cell medium contains lactalbumin hydrolysate, yeast extract and foetal calf serum in a specially developed saline (Mitsuhashi and Maramorosch, 1964 Singh, 1967). 

Adverse effects of cannabinoids, and in particular of THC, on reproductive functions include retarded embryo development, foetal loss and pregnancy failure. They have been known for a long time (Geber and Schramm 1969 Kolodney et al. 1974 Das et al. 1995 Ness et al. 1999), and were recently reviewed (Paria and Dey 2000 Maccarrone et al. 2002). 

There is clear evidence from many different sources that the metabolism of compounds may be involved in their teratogenic effects, as will be seen in the final chapter in the discussion of thalidomide and diphenylhydantoin teratogenicity. The embryo and foetus of some species clearly have metabolic activity towards foreign compounds which may be inducible by other foreign compounds. Thus, foetal liver from primates has a more well-developed metabolic system for xenobiotics than does that from rodents and rabbits for example. This may be due to the late development of the smooth endoplasmic... 

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