Abnormalities of craniofacial development: discussion report.

(i) Retinoids and embryopathy Comments focussed primarily on the differential teratogenicity of the various retinoids used experimentally and on the dose levels concerned. Dr Johnston raised the issue of retinoid blood levels following application of retinol to embryos. Studies by Kochhar in the seventies using radiolabelled retinol showed that the blood levels went up to a high peak following administration and then came down a certain extent and levelled off because of retinol coming out of the fat in the liver where it had been stored (Kochar, 1977). In more recent studies in Newcastle, UK, Vitamin A apparently seemed to concentrate within the cartilages. Different retinoids have been used in the various experimental studies making comparisons difficult sometimes. For instance, Dr Poswillo had used retinol in his studies whereas Dr Sulik reported the effects of retinoic acid. The timing of exposure and pharmokinetics can be rather important when using these different forms of vitamin A. Dr Johnston pointed out that retinol may act over a longer period than retinoic acid and possible differences in the results may be related to which retinoid is used. In response, Dr Sulik said that both she and Dr Poswillo saw analogues of the Treacher Collins syndrome. A more significant difference in their studies was that she analysed the treated embryos at an earlier stage during pathogenesis. However, as Dr Poswillo agreed, ultimately the same conclusions were reached. With regard to the effects of retinoic acid on the secondary palate, Dr Sulik reported that she had occasionally seen clefts and these were very large. It appears that the palatal shelves do not form and a portion of the maxillary prominence is wiped out. The question was raised of how the doses of retinoic acid and Accutane® used by Dr Sulik and colleagues compared with the accumulative doses in humans. In reply, Dr Webster explained that the Accutane® levels in serum that are teratogenic in humans are well below the level achieved in the pregnant mouse. However, the whole embryo culture studies indicated that the 4-oxy-metabolite has roughly equal teratogenicity and that the combined human serum levels of both compounds are teratogenic to the rat embryo in culture. Only trace amounts of the 4oxy-metabolite are found in the mouse serum. With regard to excess intake of Vitamin A in humans the chief concern is when people are taking 'mega' doses between 50000 and 100000 international units per day.