480) you printed a reply from Dr. A. T. ... Miss Mary Seller4 gave thalidomide in doses of 50 mg. per kg. to ... has not already been done.-I am, etc.,. Lowestoft ...
544 AUG. 25, 1962
CORRESPONDENCE
Correspondence Becauise of heavy press-ure on our space, correspondents are asked to keep their letters short.
Drugs and Foetal Abnormalities SIR,-Dr. D. H. M. Woollam's well-reasoned letter (August 11, p. 406) will be read with great interest by all those concerned with the experimental study of congenital malformations. The mouse and rat have been extensively used in this field because they breed well and produce large litters. Pure-bred strains are available and pregnancy is easily timed. The first demonstrable response to a teratogenic agent may well be a reduction in litter size. This can then be investigated by killing the experimental animals before term and examining the uterine contents. The presence of foetal resorptions (easily demonstrable in these animals) even in the absence of the embryos a few days after the application of the noxious agent often makes it possible to demonstrate abnormalities which would present as foetal resorptions later on in pregnancy. In searching for an effective screening procedure it would seem unwise at the onset to restrict investigations to one or two animal species. Many teratogenic agents have been shown to be effective in the chick and the incubation of large numbers of treated eggs would be a relatively simple undertaking which may well produce quick results. Another point, perhaps of some importance, is that almost all mammalian teratological studies have been carried out in the rodentia, which have a unique placental structure and physiology and therefore a peculiar maternal-foetal relationship. It would seem reasonable that work with known teratogenic agents should be carried out on some other mammalian order to see what differences in response occur. Finally, I should like to echo Dr. Woollam's warning that under appropriate experimental conditions many relatively innocuous drugs can be demonstrated as having teratogenic properties (aspirin, for instance) and that the ultimate experimental animal must always be man.-I am, etc., FELIX BECK. Department of Anatomy, University College, Cardiff.
Tetracycline and Congenital Limb Abnormalities SIR,-In your issue of August 18 (p. 480) you printed a reply from Dr. A. T. Mennie to a letter from Dr. F. Wilson and myself on this subject (August 11, p. 407). As Dr. Wilson is away on holiday, may I reply to Dr. Mennie ? I understand that Dr. Mennie did not have an opportunity before writing to study the article in Nature' to which Dr. Moynahan2 and Dr. Wilson and I referred. If he does so he will find that the authors injected tetracycline into the yolk sacs of chick embryos eight days old in amounts varying from 0.1 mg. to 2.5 mg.; 2.5 mg. produced limb deformities in the chick embryos. Assuming, as a rough approximation, a weight of about 10 g. for embryo plus yolk sac, this is a dose of about 250 mg. per kg., which is of the same order as the doses of thalidomide used in recent experiments: Giroud et al., for example,3 gave mice and rabbits 125250 mg. per kg. of thalidomide daily, and one of their
BRITISH
MEDICAL JOU'RNAI.
findings was malformations in 30%/, of the surviving rabbits. Miss Mary Seller4 gave thalidomide in doses of 50 mg. per kg. to pregnant rats, mice, and rabbits; there were no malformations in the rats, mice, and silver-grey rabbits, but some of the New Zealand white rabbit foetuses had flexion of the fore-paws. Mr. K. E. V. Spencer' gave two Himalayan doe rabbits, 2.3 and 2.1 kg. in weight, 500 mg. of thalidomide each day from day 8 to day 14 of pregnancy. These does produced offspring with deformed limbs. Perhaps one of the most significant findings in the paper by Bevelander et al.1 is that the tetracycline, administered as a single dose, was concentrated in the skeleton of the chick embryo ; this part of the embryo appeared to have some special affinity for the antibiotic. If a woman in early pregnancy is given 250 mg. of tetracycline four times a day for, say, five days it is conceivable that with each dose the drug is concentrated in increasing amounts in the limbs of the human embryo. The woman will certainly have received, over a five-day period, a total dose of about 70 mg. per kg., which is not all that much lower than the dose (of the order of 250 mg. per kg.) which causes malformations in the chick embryo. It should be noted also that the human embryo has been thought by some more susceptible to teratogens than other species. It is, one must confess, a little disturbing to learn from Dr. Mennie that experiments designed to detect any teratogenic effect from tetracycline administration have been confined to one species, the rat. Dr. G. F. Somers6 has found that in his experience thalidomide has no very significant teratogenic effects in chickens' eggs, mice, rats, hamsters, and cats, even at enormous dose levels. The rabbit, however, proved sensitive. It would be advisable to test for possible teratogenic effects of the tetracycline group in more than one species of animal. I am aware that the letter from Dr. Wilson and myself has been reported in the lay press, but surely it is more likely that certain occurrences (I am reliably informed, for example, that the tetracyclines have been " banned " in Mexico and Brazil) were due not so much to our letter as to a report (see the Daily Telegraph, August 9, 1962) that Dr. Bevelander in America "had linked the antibiotic drug aureomycin with deformities in babies," and that publication of a paper by him on this subject was awaited. Finally Dr. J. J. Coghlan has suggested7 that the feeding of tetracyclines to farm animals (to make them gain weight faster) might conceivably be associated with the reported great increase in births of malformed animals. On the face of it this interesting suggestion would appear to deserve further investigation, if this has not already been done.-I am, etc., M. P. CARTER. Lowestoft, Suffolk.
REFERENCES l Bevelander, G., Nakahara, H., and Rolle, G. K., Nature (Lond.), 1959, 184 (Suppl. 10), 728. 2 Moynahan, E. J., Lancet, 1962, 1, 970. Giroud, A., Tuchmann-Duplessis, H., and Mercier-Parot, L., ibid., 1962, 2, 298. Seller, M. J., ibid., 1962, 2, 249. Spencer, K. E. V., ibid., 1962, 2, 100. Somers, G. F., personal communication. Coghlan, J. J., Daily Telegraph, August 17, 1962.
SIR,-The uncritical accusation concerning the dangers of tetracycline therapy during the early months of pregnancy calls for comment. At home and abroad the warning contained in the letter by Drs. Wilson and Carter' has caused concern
