Since the thalidomide disaster in 1958-1962, numerous hypotheses have been suggested on the possible mode of action of this most notorious human teratogen [1]. Until recently, all of these attempts have turned out to be failures [2].
Published in this issue is another hypothesis of McBride and co-workers on this matter [3]. Unfortunately, this attempt of an explanation of thalidomide's teratogenic potential is neither new nor convincing. Association of radioactivity of thalidomide with DNA (contaminated with acidic proteins) was already reported in 1968 [4], but not appreciated by the scientific community. Since there seems to be no end to speculations on the possible mode of the teratogenic action of thalidomide, it may be helpful to recall the criteria that should be fulfilled when seriously attempting to explain the teratogenicity of this type of compound. These criteria are essential to provide an explanation of the pronounced species and phase specificity, as well as the malformation pattern associated with the teratogenic action of thalidomide, and they imply that the investigations should be performed [2]:
β’ in a thalidomide-sensitive species (primates or possibly rabbits)
β’ at the thalidomide-susceptible stage of embryonic development (a short but welldefined period) β’ in cells of thalidomide-susceptible primordia (e.g., of the limbs or the heart) β’ under conditions inducing a close to 100% teratogenic effect β’ at doses not inducing embryomortality or a pronounced growth retardation β’ to demonstrate that the effect is confined to thalidomide and its teratogenic derivatives and not inducible with non-teratogenic derivatives with a very similar chemical structure (e.g., thalidomide isomers or enantiomers). While all of these criteria were fulfilled in some of the recent studies on the probable mechanism of the teratogenic action of thalidomide [5], these aspects were not adequately taken into account in the study of Huang and McBride [3]. The paper, actually to be considered a preliminary note, contains so many inadequacies that it is impossible to draw any conclusions. Some of the open questions are the following:
β’ It is difficult to understand why only single samples of DNA from pooled (27-45) embryos were measured per group. With the extremely small effect (a few counts above background), the evaluation of a larger number of samples (including more than one control) is essential.
β’ The authors pretend that the rat responds under their experimental conditions with a high percentage of typical malformations to a single i.v.-injection of 45 mg thalidomide/kg body weight, but they do not give any proof of this assumption. This opinion is strongly opposed by all experts in this field, according to a data pile from numerous laboratories, and the rat has long been considered an unsuitable species for studying thalidomide-induced teratogenicity [6]. With the rather odd model used (i.v.-injection of thalidomide in an organic solvent) no limb defects were observed by other authors, but only some eye abnormalities, and about 50% of the fetuses had rib defects [7], which are quite atypical for thalidomide teratogenicity.
β’ The authors postulate that thalidomide is metabolically activated to some electrophilic radical in the nucleus. From the data provided there is neither evidence for metabolic activation nor that such a process may proceed in the cell nucleus.