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Home , Teratology

=urrsnt Eommsnts” EUGENE GARFIELD INSTITUTE FOR SCIENTIFIC INFORMATION” 3501 MARKET ST PHILADELPHIA PA 19104

Teratology Literature and the Controversy

Number 50 December 15, 1986

The prospect of bearing an abnormal or studies the action, detection, and treatment deformed child has long been a chilling fear of toxins. Although interrelated, each of of all expectant mothers. Of the estimated these disciplines has its own language. In 130 million children born each year world- the near future we will study the develop- wide, ] at least 2 to 3 percent are born with mental journals. some type of .z It has only been A major challenge to teratologists, there- within the last 150 years that doctors have fore, is to establish and expand links with attempted to interpret birth defects, or the varied disciplines contributing to the congenital malformations, in a scientific field. The multidisciplimry aspect of tera- manner. The term “” was first tology makes it an excellent field to dem- coined in 1832 by the French physician onstrate the value of citation analysis. The Isidore Geoffroy Saint-Hilaire to define a cognitive and social ties between scientific field of science dedicated to studying devel- papers and authors can be determined by opmental anomalies. The term is derived analyzing direct citation links, co-citation, from the Greek term ‘‘terato, ” meaning or bibliographic coupling. The relationships monster. He also described and classified between teratology and other areas carsthen the known abnormalities of his day. 3 be ascertained. ISI@is using similar proce- While teratology had its origins in the de- dures in a project concerning for scriptive of congenital malforma- the National Library of Medicine. We are tions, Richard W. Smithells, Department of using bibliometric methods to determine Pediatrics and Child Health, University of how well the current TOXLINE database Leeds, UK, points out that today teratolo- covers the relevant literature. gy includes any birth defect—morphologi- Figure 1 is a map showing how research cal, biochemical, or behavioral-induced by fronts from the various fields of teratology an embryotoxic agent at any stage of gesta- are related. The higher-level front on’ ‘Ter- tion.’$This wider definition inevitably in- atogenic activity of various chemicals” cludes the involvement of many disciplines. (#85-0540) shows the links between smaller For example, teratology is considered an fronts on environmental medicine, the ef- offshoot of . While fects of chemicals on fetal development, and developmental biology is the study of the the neurological effats of chemicals. Table overall development of the individual dur- 1 is a list of six 1985 research fronts direct- ing gestation, teratology is primarily con- ly concerning teratology. We will review cerned with factors that interfere with de- some of these research fronts, pointing out velopmental differentiation. These factors those areas that have made the most impact are often considered embryotoxins requir- in the science community. We will also dis- ing the expertise of a toxicologist who cuss some of the established principles of

404 Figure 1: Higher-1evel map for C2 research front #r?5-0540, ‘‘Teratogenic activity of varioua chemicals, ” showing li between Cl research fronts. The numbers of core/citing items are given in parentis foUowingthereaearch- from name on the map.

8482 Teratogeniceffncts to monomathylether, Chemicalfactorsaffecting mouse of chemicalagents ether, , sperm-headmorphology(2/21 ) on embryonic and other chemicalson development(2/19) reproductivesystemsin I male mrimels(2/20) 7 / 136!

Male reproductive dysfunction (2/1 7)

Neurologicalmanifestationsof chlordnconein humens(3/26) \

Evaluationof teratogenicectivity of variousagentsand their effects on fetal developmmt (2/28)

teratology as well as the obstacles prevent- A preliminary journal list was developed ing certain quegtions from being answered. using keywords, concepts, and prominent In addition, to show the complexities in- authors in an online and manual literature volved in the mechanisms of teratogenesis, search. We also examined the Journal Cita- we will discuss the drug thalidomide. This tion Reports@ for journal titles. The jour- dmg was taken off the market 25 years ago nals that appeared most often from these after it was established as a cause of congen- sources were added to the preliminary list. ital malformations. Controversy still exists The final list was reviewed by subject spe- concerning this tragedy-which allegedly cialists to provide an inclusive representa- caused over 10,000 children to be born with tion of all facets of teratogenesis. severe physical defects—and whether it The earliest teratology studies began ap- could have been averted. @g ~ the late1800s, when the emphasis shifted from classifying malformations to experimentally inducing them in animals. In Early Teratology Studies 1855 Camille Dareste applied heat, cold, The earliest scientific teratology shaking, and chemicals to chicken eggs. studies are found in a wide range of jour- These treatments artificially induced devel- nals, such as the American Journal of Oph- opmental abnormalities in chicks and pro- dsaimdogy, the American Joumul of Roent- vided the first proof that extrinsic factors gendogy, and the Biochenskal Journal. This could cauge abnormal embryonic develop- is an indication of the diverse fields contrib- ment. $ uting to the origin of modem teratology. The first report of experimentally induced Table 2 is a selected list of the current jour- congenital malformations in was nals publishing articles on teratology. These in 1921. Sylvester S. Zilva, Biochemical journals cover many disciplines, including Department, Lister Institute, London, UK, gynecology, , , and and colleagues fed a pregnant sow a fat- mutagenesis. deficient diet. Eight piglets were stillborn

405 TaMe 1: Tk 1985 SCf9SSCPrcrearch fronts on teratology and thalidomide. A= research-front number. B= reacarch- front name. C= numk of core items. D= number of citing items.

A B CD 85-1 S03 Uac of thalidomide therapy in leprosy 2 14 85-2250 Teratogenicity of retinoic acid and analogs 4 35 85-4632 Evaluation of teratogenic activity of various agents and their effects on fetal development 2 28 85-6306 Maternal drug use in early snd bkth defects 9 75 85-7692 Intrauterine factors affecting normaf fetal growth and development 2 18 85-8348 Teratogenic effects of chemical agents on 2 19

Tabte 2: Sekted tiatof journals reporting on teratology Etiology of Congenital Malformations and embryology. A=titfe and first yea of publication, B= 1985 impact factor. Wilson estimated that about 20 to 25 per- A B American JLNJmzdof Obstetrics and 1.78 cent of all birth defects are the result of ge- Gynecology ( 1920) netic transmission and chromosomal abnor- Anatomy and Embryology (1892) 1.62 malities, while 5 to 10 percent have been Arzneimittel-Forachung/Dmg Research (195 l) 0.87 Cell Differentiation (1972) 1,39 attributed to known environmental factors. Development, Growth & Differentiation 0.98 The remaining 65 to 75 percent of birth de- (1950) fects arise from unknown causes but may Developmental Biology (1959) 3.58 Differentiation (1973) 1.79 be caused by an interplay of multiple envi- Journal of Embryology and Experimental 2.46 ronmental agents with genetic factors. 10 Morphology ( 1953) Mutation R-ch (1964) 2.28 is an example of an environmen- Teratogenesis, Carcirrogenesis, and 0.99 tal factor acting as a teratogen. There is evi- Mutagenesis (1980) dence that habitual or even occasional drink- Teratology (1%8) 1,76 Toxicology (1973) 1.03 ing by an expectant mother can endanger the Toxicology and A@ied f%SITIMCOlOgy ( 1959) 1.93 health of the . A baby of a heavy drirtk- Toxicology Mters (1977) 0.76 er may be born with fetal alcohol Rouxs Archives of Developmental Biology 1.93 (1894) (FAS), characterized by a small head, defec- tive joints in the hands and feet, a cleft or died very soon afler birth. Four of these palate, heart abnormalities, or mental im- piglets were born with rudimentary liibs.h pairment. 11There is a large literature on In 1929 Leopold Goldstein and Douglas P. FAS that will not be reviewed here, but the Murphy, Gynecean Hospital Institute of research fronts have been identified in the Gyne.cologic Research, University of Penn- historiograph (see Figure 2). sylvania, Philadelphia, showed that X rays can affect human embryonic development.T Determinants of Drug Teratogenicity And in 1941 Sir Norman M. Gregg, Royal Alexandra Hospital, Sydney, Australia, de- Our review focuses on the mechanisms in- termined that the dreaded virus of , volved in drug-inducd malformations since or German measles, is a teratogen. BJames this is the topic involved with thalidomide. G. Wilson, Children’s Hospital Research The potential for drug teratogenicity is de- Foundation and Department of Pediatrics, pendent upon at least four variables, accord- University of Cincinnati, Ohio, observed ing to Marcus A. Khngberg and colleagues, that an interest in the teratogenic potential Department of Preventive and Social of drugs and other biologically active chem- Medicine, Saclder school of Medicine, Tel- icals virtually exploded during the 1950s. Aviv University, Israel. The first of these But despite the notoriety associated with the is the of the drug. Some embryonic thalidomide experience, Wilson noted that tissues are more sensitive to specific chem- teratology research continued to grow at a ical structures, modes of action, or biochem- steady, rather than startling, rate after 1960 ical peculiarities of certain compounds. A and 1961.9 second factor concerns dosage, timing, and

406 79-0958 Adverse effects m *“= of alcohol con- sumption during npregnancy (2/3B)

79.1292 80-1704 Teratogenic Influence of potential of drugs drugson malfor- in pregnancy mations (6/58) (3/41) b Figure 2: Historiograph of drug teratogenesis research. The numbers given in parentheses following the research- front titles refer to the numbers of corelciting items for each research front. If the same core documents are cited at the required thresholds year after year, linkages develop between research fronts and a historiograph is established, mode of drug administration. The critical uation is often unreliable for many reasons. teratogenic period in is between the One problem is that the structure and func- 3d and 12th weeks of pregnancy. Some tion of the placenta differ in anirnrdsand hu- drugs are teratogenic if given in low doses mans. Therefore a drug may affect an ani- over an extended pericd of time, while mal differently than humans. 1s others are damaging at higher doses for a In a recent article in Nature, Heinz Nau, short period of time; certain drugs, like tha- Institute for Toxicology and Embryophar- lidomide, have produced malformations macology, Free University of Berlin, Fed- after only a single exposure.12 eral Republic of Germany (FRG), and Wil- A third determinant in drug teratogenic- liam J. Scott, Division of Basic Science Re- ity is the interaction resulting when more search, Children’s Hospital Research Foun- than one drug is taken at a time. This inter- dation, Cincinnati, Ohio, have found that the play may cause four possible effects rang- acidic property of drugs may also be an im- ing from antagonistic, to additive, to syn- portant determinant of teratogenicity. Nau ergistic, to no effect at all. Klingberg and and Scott tested 11 drugs that have been colleagues state that a fourth factor deals shown to be teratogenic. Eight of these are with genetic susceptibility. Not all weak acids, whereas none is a weak base. exposed to a specific drug develop malfor- The authors also studied the pH level inside mations. This implies that there is an inher- the cells of mouse and rat at various ent, or genetic, susceptibility to drugs. 12 stages of gestation. Embryos are consider- These four determinants have made it dif- ably more basic than their mothers, suggest- ficult to identify more than a few drugs as ing that the lower acidity of the teratogenic. 1ssaddition, a major obstacle in causes acids to accumulate there. 14 identi&ing a teratogen is tinding a suitable experimental animal. Robert L. Brent, De- Thalidomide partment of Pediatrics, Jefferson Medical College, Philadelphia, states that transfer- The drug thalidomide provides an exam- ring animal teratologic data to the human sit- de of the umeliabili~ of transferring animal .

407 83-4319 854125 82.1543 84-0047 Effects of matar. Fetal exposure Characteristics Effects of fetal nal alcohol con- to ethanol and of fatal alcohol exposure to sumption during effects on fetal syndrome alcohol development (313fJ) n (20/1921 m n L&&E--l (12/150)

83-7044 1 85.6306 Anti-epileptic 84.0634 Maternal drug use drugsduring preg- Teratogenicity in early preg. nancy and their L of arrticonvul. nancy and birth role in terato- defects gerresis (4/45) l.-?3!-z(9/75)

teratogenic ec. tivity of various .cgentsand their effacts on fetal 84.3613 development Teratogenic (2/28) effects of expo- sure to drugsand m chemicals 65-8346 (26/266) Teratogenic affects of chemi- cal agentson em. bryonic develop- 2 ment m (2/19)

results to humans. Synthesized by Chemie In 1959 D.M. Burley, Medical Registrar, Griinenthal, Stolberg, FRG, thalidomide Westminster Hospital, London, and col- was first marketed in 1957 as a hypnotic leagues confirmed that thalidomide was an causing a deep sleep with no hangover ef- effective hypnotic with few side effects, fects. Before Griinenthal put thalidomide on comparing well with a barbiturate as a the market, Wilhelm Ktmz, then head of means for inducing sleep in 83 hospital inpa- chemical research at the firm, and colleagues tients. lb produced a study in 1956 showing that in- The drug was subsequently sold in 46 creased doses of thalidomide depressed the countries, including the UK, Japan, Sweden, central nervous system in animals but did Australia, and Canada. Soon, however, it not produce any toxic effects. The animals, became apparent that some patients who although sleeping or sedated, could easily used thrdidontide regularly for six months be roused. Kttnz and his coworkers were un- or more developed a neurological disorder able to determine a minimum lethal dose. 15 called peripheral neuropathy, which causes

408 numbness, cramps, and weakness in the Chemist~, Institute of Health, Rome, Italy, limbs. It was also later discovered that some were finally able to prove that rats were sen- pregnant mothers who took the drug in the sitive to thalidomide after all, but only at the first trimester, the time when limb buds of 12th day of gestation.zs the fetus are formed, produced children with Fortunately, thalidomide was never sold distinctive deformities. These types of de- in the US, due to a combination of the strict formities are called phocomelia, derived US drug laws and the diligence of pharma- from the Greek words phokos, meaning cologist-physician Frances O. Kelsey, the “seal,” and rnelos, meaning’ ‘extremities. ” medical officer at the Food and Drug Ad- Some children with phocomelia are born ministration who was in charge of the tha- without arms and have just flippers attached lidomide application. Kelsey received the at the shoulders; others have no legs, just Distinguished Federal Civilian Service toes sprouting from the hips; some simply Award in 1962 from President Kennedy for have no limbs at all. IT (p. 88) her efforts in preventing the marketing of Evidence for the of thalidomide thalidomide by the Richardson-Merrell began to accumulate. In December 1961, pharmaceutical company. 17 (p. 81) Al- Australian physician W.G. McBride wrote though Kelsey successfully kept the dmg off a letter to Luncet describing ‘‘the incidence the US market, thalidomide was distribut- of multiple severe abnormalities in babies ed to over 1,000 US physicians under an delivered of women who were given the “investigational program” by Richard- drug thalidomide during pregnancy. ” 1g son-Merrell. 21 About a month later, in January 1962, W. Lenz, Pediatric Clinic, University of Ham- burg, FRG, wrote of his own ex~riences with women who had taken thalidomide dur- Controversy ing pregnancy. 19The drug was soon taken off the world market. (These letters have be- Many people consider the thrdidomide come classics; there are over 180 cites to tragedy as inevitable because they believe McBride’s letter and about 140 to Lenz’s. that the drug was tested to the best standards In the near future I intend to examine the of the time. This opinion is considered a impact of letters in the scientific and medical poptdar fallacy by a team of journalists from literature.) the Sun&y i“imes of .Lmdora, M by Phillip It had become obvious that Knightley. In Suffer the Children: Zhe Story needed to be reconsidered. Animal studies of TMidomide, these reporters argue that performed after thalidomide was removed “the knowledge and scientific procedures from the market showed that thalidomide is to give protection [from thalidomide] were very species specific. While G. Pliess, available. The disaster might well have been Pathological Institute, University of Ham- averted every where.” 17 (p. 4) Knightley burg,zo and G-F. Somers, Distillers Com- and his coauthors chtim that although the an- pany, Liverpool, UK,Z1 failed to produce imal tests necessary to prove thalidomide malformations with thrdidomide in pregnant teratogenic were not in general practice be- rats, pharmacologist Vrddemar Larsen, fore the disaster, it was not unusual for drug Dumex Ltd., Copenhagen, Denmark, found reproductive studies to be performed in the that thalidomide given to selected strains of days before thalidomide. The authors de- white rabbits between the 8th and 16th days scribe how the drug Daraprim, developed of gestation caused typical limb malforma- in 1950 as an antimalarial, underwent ex- tions in the offspring. 22 Giorgio Bignami tensive reproductive studies in many animals and colleagues, Department of Therapeutic before it was marketed. Yet in the studies

409 by Ksmz and Burley, no mention was made the effects on the mammalian fetus. Paget as to the effects of thrdidomide on the fetus, contends that “the thalidomide tragedy did In the 1972 book Thalidomide and the not occur because a known risk was ignored, Power of the Drug Companies, Henning It occurred because an unknown risk was Sjostrom, a Swedish attorney, and Robert not deduced.’ ’29 Nilsson, a Swedish physician, argue that there was substantial literature available on the subject of the effect of drugs on the fetus Literature Study prior to the development of thalidomide. They quote John B. Thiersch, Department The scientific literature on thalidomide of , University of Washington dates back to 1956, when Kunz and his Medical School, Seattle, who stated, “in the coworkers first published on their newly ten years preceding the appearance of tha- synthesized compound in the journal lidomide, that is by 1959, not less than 25 Arzneimittel-Forschung/Drug Research. 15 compounds were shown by investigators By now, over 2,000 papers and books con- ranging from Japan to the US, to England cerning thalidomide have been indexed since and France to affect the foetus in utero, 1955. These include technical studies of the either killing many foetuses or inducing mal- teratology and metabolism of thalidomide as formations. ... The findings by the various well as editorial comment in medical jour- investigators were published in scientific nals. journals and distributed internationally.’ ’25 A current area of thalidomide literature Thiersch published a paper studying the concerns its use in dermatological clinical effect of the drug aminopterin on the investigations. Raymond L. Bamhill and A. fetus.zG Cited over 230 times since 1955, Colin McDougall, Department of Derma- this paper was the subject of a 1984 Cira- tology, Slade Hospital, Oxford, UK, have tion Ckzssic@ commentary published origi- found that thalidomide is effective in treat- nally in Current Contents@ and more recertt- ing patients with lepromatous Ieprosy.30 iy in Contemporary Classics in Clinical (See my earlier discussion of Ieprosy.sl) Medicine.27 Thiersch wrote, “I believe this Barnhill and McDougall’s paper, published publication is so highly cited because it in the Journal of the American Academy of opened up a new field-the effect of drugs Dermatology in 1982, is one of two core pa- on the fetus in utero.’ ’27 pers in the research front entitled “Use of In an April 1968 letter in New Scientist, thalidomide therapy in leprosy” (#85-1803), M. A. Phillips, a pharmacologist from Up- which includes 14 citing papers published minster, UK, also argued that before tha- in 1985 alone, lidomide was marketed, the knowledge was Those who are not familiar with its history available that many drugs may cause fetal frequently believe that modem teratology malformations if administered to pregnant had its inception as a consequence of the women. PhMips cited many studies show- thalidomide tragedy. However, as we have ing the adverse effects of drugs on the mam- indicated, there have been experimental ter- malian fetus published prior to 1958.28 atology studies since the turn of the century. G.E. Paget, of Smith, Kline and French, This is confirmed in a paper describing the Hertsford, UK, criticized the argument pre- organization of the Teratology Society by sented by Phillips as misleading. Paget noted Wilson, mentioned earlier, and Josef Wark- that one of the articles Phillips cited dealt any, Department of Pediatrics, University with a diet deficiency study as opposed to of Cincinnati College of Medicine. The a drug teratogenic study. Another article authors state that “it is incorrect to say that Phillips cited studied chick embryos and not thalidomide was the impetus that gave tera-

410 Table 3: Selected list of aaamiations engaged in research teratology literature. 33 Cited in about 700 or providing information on teratology. papers since its publication, chapters of this Citation Ckssic are core to two fronts from Table 1: “Evaluation of teratogenic activi- American College of Toxicology ty of various agents and their effects on fetal 9650 Rnckvifle Pke Bethesda, MD 20814 development” (#85-4632) and “Teratogenic effects of chemical agents on embryonic de- American Etnard of Obstetrics and Gynecology velopment” (#85-8348). Both of these re- 4507 University Way, NE Seattfe, WA 98105 search fronts are included in Figure 2, a his- toriograph showing the development of the European Teratology Sodery field of teratology from 1976 to 1985. CIO Laboratory of Teratology Karolinska Institute S-104 01 Stnckbolm 60 Sweden Conclusion Japaneae Teratology Society Kinki University Sched of Medicine It is not pmsible to determine whether the Sayama-Cho, Osaka 589 fhrdidomide tragedy cotdd have been avoid- Japan ed using the concepts and technologies avail- Iatin American Association of Environmental able in the late 1950s. My purpose is not , and Teratngen .%cieties to report allegations of blame, but to focus do Jntematiomd Association of Environmental Mutagen Sncieties on learning from experience. As Paget not- Institute of General ed in 1968, “The important thing is to re- University of 0s10 mind ourselves that there may be other un- PO, Box 1031 Blindem, Oslo 3 known risks. We must be constantly vigi- Norway lant in our efforts to deduce their existence

Teratology Society and to detect them before they do harm.’ ’29 c/o Carol Kimmel As a personal footnote to thk study, I can Reproductive Effects Assessment Group well recall the complacent attitude of many US Environmental Protection Agency RD-689 organizations toward the literature problem. 401 M Street, SW I was asked to testify on this by Senator Washington, DC 2t34@ Hubert Humphrey.sA Whether literature searching would have prevented the tragedy is debatable. But in those days, it was often tological science its begiming, but it is cer- cavalierly assumed that we had little to learn tainly equally incorrect to deny that thalid- from the literature. Sometimes in our rush omide was a strong stimulus to both the ex- to find new solutions, we forget that we have perimental and clinical aspects of the much to learn from the past, field. “32 Wilson and Warkany are two of the founders of the Teratology Society, orga- nized in 1960. This association established the journal Teratology in 1968. Table 3 lists ***** other organizations that engage in research or provide information on teratology. Both Wilson and Warkany have had a sig- nificant impact on the field of teratology. My thanks to C.J. Fiscus and Lisa Holland Their 1%5 book Teratology: Principles and for theirhelj in the preparation of this essay. Techniques is considered a cornerstone of Owaalsl

411 REFERENCES

1. Population and population movementx, 1986 IMannica book of the year. Chicago, IL: Encyclopedia Britannica, 1986. p. 347-8. 2. Kurzel R B & Cetrulo C L. The effect of environmental pollutants on human reproduction, including birth defects. Environ. Sci. Techrd. 15:626-40, 1981. 3. Geoffroy Saint-HifrdreI. Hisroire gMrafe c1 poniculi?re des anomalies de 1‘organisation chez I‘homme et les unimaru (A comprehensive de(aikd historical approach to human and animal teratology). Paris: Bailli2rc, 1832- 1836.3 vols. 4. Sndthells R W. The cbalfenges of teratology, Teratology 22:77-85, 1980. 5, Datwte C. M.4moire sur l’intkence qu’exerce sur le d4ve10ppement du pdet (The effect of varnish aPPl@f to chick egg-shells on embryonic developmenI). Ann. Nofur, Sci, 4:119-28, 1855. 6. zilva S S, Gelding J, Drunrmorrd J C & Coward K H. The relatien of the fat-soluble factor to rickets and growth in pigs. Biochem. J. 15:427-37, 1921. 7. Goldateim L & Murphy D P. Etiology of the ifl-heakh in children born atler maternal pelvic irradiation. Arwr. J. Roentgenol. 22:322-31, 1929. 8. Gregg N M. Congenital cataract folfowing German measles in the mother. Trrms. Ophtholtnol, Sot. AWL 3:35-46, 1941. 9. Wtin J G. The evolution of taatological testing. Temfofogy 20:205-12, 1979. 10.---—---- Embryotoxicity of drugs in man. (Wilson J G & Fraxer F C, cds. ) Hondboo& of ferutology. Vol. 1. New York Plenum Press, 1977. p. 31YJ-55. 11. Mi3fer M W. Effects of alcohol on the generation and migration of cerebral cortical neurons. Science 233(4770): 1308-10, 1986. 12. Klfngberg M A, Papier C M & Hart J. Birth defects monitoring. Amer. J, htd. Med. 4:309-28, 1983. 13. Brent R L. Protecting the public from teratogenic and mutagenic hazards. J. Clin. PhammcoL 12:61-70, 1972. 14. Nars H & Scott W J. Weak acids may act m teratogens by accumulating in the basic milieu of the early mammalian embryo. Noture 323(6085):276-8, 1986. 15. Kmu W, Keller H & Mfkkter H. N-pbtfralyl-ghrtaminsiiure-imid(N-phtha.lyl-glutaminicimide). Arzneim. -Forsch. -Drug Res. 6:426-30, 1956. 16. Burley D M, DerrrrfaonT C & Harrison W. Clinical exprience with a new sedative drug. Practitioner 183:57-61, 1959. 17. Knightley P, Evans H, Potter E & Waff&ee M. Suffer the chi/dren: rhe story of thalidomide. New York Viking Press, 1979, 309 p. 18. MeBride W G. Letter to editor. (Thalidomide and congenital abnormalities.) Lancer 2:1358, 1961. 19. Law W. Letter to editor. (Thalidomide and congenital abnormalities. ) f.ancet 1:45, 1%2. 20. P3iess G. Letter to editor, (Thalidomide and congenital abnorm?dities.) Lancei 1:1128-9, 1%2, 21. Somers G F. Letter to editor. (Thalidomide and congenital abnormalities. ) Lancer 2:912-3, 1%2. 22. Larsen V. The teratogenic effects of thalidomide, imipramine HCI and imipramine-N-oxide HC1 on white Danish rabbits. Acts Pharmacol. Toxiccd. 20:186-203, 1963. 23. Bfgnarrd G, Bovet D, Bovet-Nitti F & Rmmti V. Letter to editor. (Drugs and congenital abnormalities.) Lacet 2:1333, 1%2. 24. Kekiey F O. Personal communication. 29 October 19g6. 25. Sj&str6m H & Nilaatm R. 7halidomi& and the power of the drug companies. Hanrwrdsworth, UK: Penguin, 1972. p. 171. 26. Thkmelr J B. Therapeutic with a folic acid antagonist, 4arninopteroylghrtamic acid (4-mnino P. G. A.) administered by the oral route. Amer. J. Obstet. Gynecol. 63:1298-304, 1952, 27. —------Citation Classic. Commentary on Amer. J. Obster. GynecoL 63:1298-304, 1952. Current Contents/Clinical Practice 12(7): 14, 13 February 1984. (Reprinted in: Barrett J T, ed. Contemporary clrr.rsics in clinical medicine. Philadelphia: ISI Press, 1986. p. 2%.) 28. Philtipa M A. Letter to editor. (Thalidomide.) New Sci. 38:45, 1%8. 29. Paget G E. Letter to editor. (Thalidomide. ) New Sci, 38:362, 1968. 30. Barnfdlf R L & McDougafl A C. Thrdidomide: use and possible mode of action in reactional Iepromatous leprosy and in various other conditions. J. Amer. Acad. DermotoL 7:317-23, 1982. 31. Garfield E. hprosy: down but not out. E$says of an in@nwtion scientist. Philadelphia: 1S1 Press, 1981. Vol. 4. p. 601-8. 32. Wkmr J G & Warkany J. The history of organized teratology in North America. Teratology 31 ;285-96, 1985. 33. ---—---- Teratology: pn’nciples and techniques. Chicago, IL. University of Chicago Press, 1965.279 p. 34. US Congres House. Subcommittee of the Cnrrrmittee on Government Operations. Federal infommtion systems and pkm.s-implications and issues. Statement of Dr. Eugene Gogleld, President, Institute for Scientific Information. 93rd Congr., 2nd Sess. 29, 31 January; 5 February 1974. Washington, DC: Govemnrent Printing Office, 1974. p. 883-901.

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