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! i j i i i <i :iety for obtained 5 Voiker j ' j i ;S in the evei and Id covered al probedicine, nds are imental criotion ase send tercam, j scribers ra cost. e of the contact 10017. The Science of the Total Environment, 32 (1983) 1--12 Elsevier Science Publishers B.V., Amsterdam -- Printed in The Netherlands 1 CHEMICALS WHICH CAUSE BIRTH DEFECTS - TERATOGENS: A SPECIAL CONCERN OF RESEARCH CHEMISTS VERA KOLB MEYERS Department of Chemistry and Biochemistry, Southern Illinois University, Carbondale, 11 62901 (U.S.A.) (Received January 25th, 1983; accepted April 17th, 1983) ABSTRACT Women who are research chemists suffer an unusually high risk of being exposed to teratogenic chemicals (chemicals which cause rirth defects) for the principal reason that they spend a good share of their lives in the laboratory in contact with wide variety of chemicals including new chemicals which may be unsuspected teratogens. Women research chemists therefore need to be able (a) to recognize known teratogens and (b) to predict teratogenicity of a compound that has not been tested. This article discusses these two points with an emphasis on the following topics: how to obtain infor mation on teratogenicity of chemicals; how to interpret teratogenicity data from the literature; and how to make an educated guess about the teratogenicity of chemical compounds. INTRODUCTION Teratology* is the scientific study of biological monstrosities and mal formations. A teratogen is an agent which acts during pregnancy to produce physical or functional defects in the embryo, fetus, or offspring [1]. The latter defects may be caused also by agents other than teratogens, such as agents which damage sperm. Since the latter agents act prior to pregnancy, technically they are not considered teratogens but are referred to as "birthdefect-via-sperm-damage" agents or sometimes broadly -s mutagens that cause damage to sperm [2]. This article deals mainly with teratogens, but some aspects of birth-defect-via-sperm-damage agents will also be discussed. Teratogenic agents may be chemicals, e.g. drugs, agricultural chemicals, common solvents and reagents, or physical factors, such as X-rays, or viruses. In this article only chemicals will be discussed. The identification of human teratogens poses a major problem. In most * Greek: teratos = monster; iogia = science. 0048-9697/83/S03.00 1983 Elsevier Science Publishers B.V. OLI 4704 lUllCfc IMS MATERIAL Mat. til PROTECTED BY COPYRIGHT LA* TITLE 17 U.S. CODE) .? ... : cases not enough statistically-vc'.id data are available. The use of a power ful scientific tool -- experiment -- is obviously precluded in humans. Even in rare unfortunate cases of the widespread use of a very potent human teratogen such as thalidomide, it may take a rather long time to discover their teratogenicity [3]. In several cases a drug has been classified as tera togenic based on only few observations of severe malformations in children exposed to drugs in utero [4]; the teratogenic effect of such drugs was not statistically proven beyond doubt. Existing statistics are complicated by the fact that information about the use of drugs in pregnancy obtained from mothers of teratogenic children is sometimes not very reliable. Thus, many of the mothers who took thalidomide during pregnancy have had strong feelings of guilt and this has, on occasion, led them, consciously or sub consciously, to deny that they had taken any drug [4]. Another serious problem in identifying human teratogens is that the prediction of teratogenicity of chemicals in humans based on studies on animals is often very poor. This is illustrated in Table 1 which shows com parison of doses required for teratogenic effects of thalidomide in various mammalian species. The data from Table 1 show that some animal species are much more sensitive to thalidomide than others, and that the human species happens to be among the most sensitive of mammals. The extra polation of animal data on humans is very difficult also because the most commonly used laboratory animals--mice and rabbits--have a very primitive placenta compared to humans [6a]. Another difficulty in identifying teratogens is the possibility that tera togenic effects may not be noticeable in the newborn, but may show up years later. For example, rats exposed to phenobarbital in utero suffered from delayed onset of puberty, disorders in the estrous cycle, and infer tility [7]. In another example, a single dose of ethylnitrosourea, a potent carcinogen, given to pregnant rats was found to produce in the offspring not only teratogenic but also carcinogenic effects, the latter being observed much later than the former [8]. An example of a well-studied "delayed" TABLE 1 COMPARISON OF DOSES REQUIRED FOR TERATOGENIC EFFECTS OF THALI DOMIDE IN VARIOUS MAMMALIAN SPECIES [5a] Species Human Cat Rabbit Monkey Rat Mouse Armadillo Dog Hamster Lowest dose (mg/kg) for detectable effects 0.5--1.0 0.5 2.5 10 10 31 100 100 350 OLI 4705 'er TABLE 2 ven DATA ON HUMAN "DES-DAUGHTERS" AS COMPARED TO CONTROL GROUP lan [9a] ver ira- Placebo-exposed DES- `en controls exposed lot ,he Number examined im Irregular menses ny Married History of pregnancy 319 10% 48% 31% ng Live births 22% ib- Vaginal adenosis 1.3% Ridges of vagina and cervix 0% 346 15% 54% 21% 13% 63% 38% he an teratogen in humans is that of DES (diethylstilbestrol), an artificial estrogen Tl- given in the past as a drug to many pregnant women. DES causes abnor US malities such as vaginal adenosis, ridges of the vagina, and other defects in es the daughters of the mothers who took this drug during pregnancy [9a]. an This is illustrated in Table 2. ra- In the males exposed to DES in utero (Table 3), various functional ist abnormalities such as testicular hypoplasia and abnormal semen were ob ve served. Also, the average sperm density was somewhat decreased as com pared to the placebo-exposed control [9a]. `cl* The identification of teratogens is further impeded by the occurrence of Ip the spontaneous abortions of the teratogenic embryo/fetus. If a spontaneous ad abortion occurs before a woman knows that she is pregnant, it is left un ;r- noticed and the teratogenic effect is reflected as a decreased fertility. In nt cases when a woman knew that she was pregnant, the teratogenic effect ig would be observed as an increase in the miscarriage rate. Well known examples d of such teratogens are anesthetic gases [9b, 10] and lead [9c]. Teratogenic effects in the latter two examples may occur also when only males are TABLE 3 DATA ON HUMAN "DES-SONS" AS COMPARED TO CONTROL GROUP [9a] *" ** ii Eliasson scores* of semen analysis Placebo-exposed controls DES* exposed Average Ellasson score Eliasson score ^ 5 (pathological semen) Eliasson score > 10 (severely pathological semen) 2.5 16% 8% 4.9 32% 18% Combines the sperm count, the sperm mobility, the mobility grade, and the sperm morphology into one quantitative number. OLI 4706 * 1 1 i 4 TABLE 4 EFFECTS OF LEAD ON HUMAN REPRODUCTION [9c] Effect a Decrease the fertility of a male by causing teratospermia, hypospermia, and asthenospermia (abnormal, deficient, and weak sperm, respectively). b Lead to miscarriage, stillbirth, and increased perinatal mortality if female ,s exposed. c Cause high abortion rate amongst the wives of lead workers (cf. a), d Cause birth defects (convulsions, macrocephally) if female is exposed during preg nancy. directly exposed to these teratogens. Table 4 illustrates multiple damaging effects of lead on human reproduction [9c]. Lead is thus an example of a teratogen which is also a "birth-defect-via-sperm-damage" agent. Difficulties in identifying human teratogens outlined above prevent scientists in many cases from labeling teratogens as "proven" human tera togens. This, coupled with the difficulties encountered in attempts to deter mine safe levels of exposure of embryo/fetus to teratogens, leaves the door open for many legal disputes concerning the use of teratogens. Examples of such disputes are the Bendectine Case about the use of the suspected tera togenic drug, bendectine, [11, 12] and cases related to the exposure to teratogenic chemicals in the work place (e.g. the lead pigments case) [13] or in the environment (e.g. the case of the pesticide 2,4,5-T) [14]. Con frontations over issues of female as well as male reproductive hazards in the work place and related court cases are described in details in reference 13 which also examines how government, chemical companies, and unions are approaching the problem of protection of workers and their unborn children from injury at the work place. Teratogens represent a potential danger to almost any woman in modern society, sinca teratogens such as drugs, agricultural chemicals, and environ mental pollutants may be difficult to avoid. Women who are exposed to teratogens in their work place, such as nurses exposed to anesthetic gases, workers in the chemical industries, etc., have an additional risk. However, women who are research chemists suffer an unusually high risk of being ex posed to teratogens, for the principal reason that they are very often ex posed to new chemicals which may be unsuspected teratogens. Since women research chemists spend a good share of their lives in the laboratory in con tact with wide variety of chemicals, they need to be able to do the fol lowing: (a) recognize known teratogens; (b) predict teratogenicity of a com pound that has not been tested; and (c) protect themselves from proven or suspected teratogens. The objective of this article is to briefly discuss the points (a) and (bh OLI 4707 5 How to obtain information on teratogenicity of chemicals Probably the most concise source of data on teratogens is a reference book by T. H. Shepard [1], This book provides information about terato genicity of chemicals and other teratogenic agents. The type of malfor mations and malfunctions observed as the effect of particular teratogens is also given, as well as the pharmacological procedures and animal species used in the teratogenicity tests. The 1980 edition of this book has over one thousand entries. Women working in the medicinal chemistry field will appreciate compre hensive treatment of teratogenic drugs given by Nishimura and Tanimura [15] and by Schardein [16]. However, the most comprehensive source of data on known or suspected teratogenic chemicals is the "Registry of Toxic Effects of Chemical Sub stances" (RTECS) [17]. RTECS is a compendium of toxicity data abstracted from the scientific literature and published by the National Institute of Occupational Safety and Health (NIOSH). For example, the 1978 edition of RTECS includes toxicity data, such as type of toxicity, toxic dose levels, route of exposure or administration, as well as species exposed, for nearly 34,000 different substances. Out of these only about 500 are teratogens (ca. 1.4%). An average of about 1500 new toxic compounds are added to RTECS every quarter, about 30 of which are teratogens. A list of 527 teratogenic substances obtained by computer search of RTECS has been published [18]. The subfile of the RTECS "Tumorigenic, Teratogenic, and Mutagenic Citations" is available in a microfiche form [19]. Information about teratogens may be also obtained from The Environ mental Teratology Information Center (ETIC), which was established in 1975 at Oak Ridge National Laboratory with the objective to collect, organize, and disseminate information on the evaluation of chemical, bio logical, and physical agents for teratogenic activity. Interpretation of teratogenicity data from the literature In general, the interpretation of data on teratogenicity of chemicals is very difficult for numerous reasons which were discussed in the Introduction. A chemist who attempts to interpret teratogenicity data from RTECS .nay experience special difficulties, namely, the evidence for teratogenicity of substances listed in RTECS is unevaluated. In addition, many of the com pounds on the teratogen list have been so identified on the basis of animal data. As pointed out in the Introduction, the prediction of teratogenicity of chemicals in humans which is based only on animal studies is often very poor. Data in RTECS are of uneven quality: in some instances a teratogen has been so identified cn the basis of a single study performed on just one animal species, in some other cases teratogenicity might have been based on the epidemiological studies in humans. Therefore, a teratogen list per se is not sufficient. One should study the original research reports and attempt to evaluate them. Chemists may find the following three references helpful in accomplishing the latter task, since these references renresep* critical OLI 4708 TABLE 5 INDUSTRIAL CHEMICALS WHOSE REPRODUCTIVE HAZARDS ARE REVIEWED BY BARLOW AND SULLIVAN [20] Chemical Acrylonitrile Aniline Arsenic and its compounds Benzene Benzo[a]pyrene Beryllium Boric acid (boron) Cadmium and its compounds Carbon monoxide Carbon tetrachloride Chlordecone (Kepone) Chloroform Chloroprene Dibromochloropropane (DBCP) Dichlorobenzene 1,1 -Dichloroethane Dichloromethane Dioxane Epichlorohydrin Ethylene dibromide Ethylene dichlcride Ethylene oxide Fluorocarbons Formaldehyde Chemical Formamides Lead (organic) Manganese and its compounds Mercury and its compounds (inorganic) Methyl n-butyl ketone (MBK) Methyl chloroform Methyl ethyl ketone (MEK) Nitrogen dioxide Ozone Platinum and its compounds Polybrominated biphenyls (PBB) Polychlorinated biphenyls (PCB) Selenium and its compounds Styrene Tellurium and its compounds Tetrachloroethylene Thallium and its compounds Toluene Toluene-2,4-diisocyanate (TDI) o-Toluidine Trichloroethylene Vinyl chloride Vinylidine chloride Xylene evaluation of numerous animal and human data on teratogens. First is the book by Barlow and Sullivan titled "Reproductive Hazards of Industrial Chemicals. An Evaluation of Animal and Human Data'' [20]. This book reviews the world-wide medical and scientific literature on reproductive hazards in animals and man of about 50 of the most commonly used indus trial chemicals. These compounds are listed in Table 5. Where no adequate human data is available, an attempt is made to evaluate the animal data to predict human hazard. In addition to teratogenicity, a wide variety of other effects is considered, such as sex differences in toxicity, placental transfer, effects on hormone secretion, sperm counts and morphology, estrous cycles, menstrual cycles, and postnatal development. The second reference is a review article by Strobino, et al., titled "Chem ical and Physical Exposure of Parents: Effects on Human Reproduction and Offspring" [21]. The authors present a critical evaluation of the reports published up to 1976 of detrimental effects of various drugs and other chemicals on reproduction or offspring of exposed parents. The effects resulting from maternal exposure before conception, maternal exposure during pregnancy, and paternal exposure are evaluated separately. Teratogenic OLI 4709 7 chemicals, other than drugs whose effects are reviewed by Strobino et al. [21], are: anesthetic gases, vinyl chloride, mercury, lead, polychlorinated biphenyls (PCB), dioxin, and alcohol. The third reference is the bool: by Nisbet and Karch titled "Chemical Hazards to Human Reproduction" [5]. This book is a critical evaluation and documentation of the current evidence of the reproductive hazards of various drugs and chemicals. Examples of teratogenic chemicals, other than drugs whose effects are reviewed in the reference 5 are: lead, selenium, cadmium, anesthetic gases, carbon monoxide, phthalate esters, formaldehyde, carbon disulfide, and laboratory solvents. The number of chemicals whose teratogenicity is critically evaluated in the reference 5, 20 and 21 is roughly one tenth of the number of chemicals listed as teratogenic in RTECo. When a compound is identified as a teratogen, its dose effects need to be considered. Unfortunately, very little has been published on dose--response relationships for human teratogens, and there is no systematic compilation of dose--response relationships for animal teratogens [5b], The available animal data show that usually the dose--response relationships rise steeply after the dose required to produce the first effect is exceeded [5b], This empirical observation has been used as a basis for the claim that threshold (safe) doses usually exist for teratogens in animals [5b, 20a], However, it is not clear that the assumption of thresholds can be extrapolated to humans [5b], More research is needed to establish the characteristics of dose--response relationships in humans, and to establish under what circum stances thresholds can be assumed to exist [5b], More than half of the 527 teratogens listed as such in RTECS show biological activity, most often as drugs for human or animal use or as agri cultural chemicals [22] (Table 6). Comprehensive reviews of the terato genicity hazard to humans from drugs are provided in references 15a and 16. Reference 15b also evaluates teratogenicity of pesticides. How to make an "educated guess" about the teratogenicity of chemical compounds From the previous section it is clear that finding the information about the teratogenicity of chemical compounds and interpreting it is often a difficult and time-consuming task with the results which are. more often than not, unsatisfactory. An even more difficult task is posed when one wishes to predict the teratogenicity of a compound which has not been tested for teratogenicity. Research chemists need tc make such predictions since they typically work with a variety of new chemicals or previously reported chemicals which have not been tested for teratogenicity. Many of the research chemi cals are only of the "academic interest" and there is a very little hope that they will be routinely tested for teratogenicity in the near future. Ideally, a scientist should be able to make a scientifically sound prediction about the teratogenicity of a chemical just by looking at its structure. Such predictions would be based on a thorough understanding of the mechanism OLI 4710 8 of action [23] and structure--activity relationships of teratogens [6b, c]. In reality, however, this is not possible, because at this time we have only a limited knowledge of these [23, 6b, cj. Well known teratologists-Shepard, Miller, and Marois wrote in 1975 [6dj: "Ideally, at some time in the future (1990?), it should be possible to predict teratogenic activity based on chemical structure of a compound and how it is metabolized". At this time it seems that the 1990 time mark is overly optimistic. What scientists can do at the present time, however, is to make an "educated guess" about the teratogenicity of a new compound based on the chemical structures and the biological activities displayed most often by the known teratogens [22], This "educated guess" method is described in details in the reference 22. We shall summarize here only its main features. Careful investigation of chemical structures and biological activities of 527 TABLE 6 CLASSIFICATION OF TERATOGENS BY BIOLOGICAL ACTIVITY [22] Classification Anticoagulants Anticonvulsants Antineoplastics Cardiovascular agents Carcinogenics Chelating agents Chemotherapeutic agents CNS affecting agents Diuretics Hormones and antihormones Neuropharmacological agents Pesticides Psychotomimetics Vitamins Compound e.g. Coumarins Barbiturates, hydantoins, oxazolidines, and succinimides e.g. Nitrogen mustards and others alkylating agents, antimetabolites such as purine, pyrimi dine, and folic acid antagonists, antibiotics such as actinomycin D, mitomycin C, alkaloids such as colchicine and vincristine e.g. Vasoconstrictors and vasodilators Azo dyes, nitrosamines, polynuclear hydro carbons, chlorinated ..vdrocarbons d-Penicillamine, EDTA, BAL e.g. Antibiotics, sulfonamides, quinine, and related substances Some anaesthetics, hypnotics, narcotics, seda tives, tranquilizers, analgesics Xanthines, thiadiazoles Corticosteroids, androgens, progestogens, estro gens, antithyroid drugs, ACTH, epinephrine, insulin and oral hypoglycemics such as sulfonylureas e.g. Organophosphorus anticholinesterases like parathion; amphetamines, atropines, ganglionblocking agents such as tetraethylammonium chloride Herbicides like 2,4-P and 2,4,5-T; insecticides like carbamates, chlorinated hydrocarbons, thiophosphates; fungicides LSD and mescaline Vitamins A and D in high dossage OLI 4711 teratogens revealed that most teratogens display the chemical structures presented in Table 7 and the biological activities shown in Table 6 [22]. The contents of these tables demonstrate that terratogens display a great variety of chemical structures and biological activities in which no simple pattern is obvious, The "educated guess" procedure suggests that if the compound has or is expected to have the type of biological activity displayed in Table 6, one should assume that it is teratogenic, despite the fact that we may not under stand the mechanism of its teratogenic action, even to the point that we do not know if the compound is a structurally specific or a nonspecific tera togen. For example, medicinal chemists working on the development of antineoplastic agents for cancer chemotherapy, or alkaloid chemists working with derivatives of vincristine, which happens to be an antineoplastic, should assume that such compounds are teratogenic. This procedure is likely to produce false positives, since not all estrogen derivatives are estrogenic, for example, or not all diuretics, for example, will be teratogenic. If the compound in question is a derivative of a known teratogen (consult RTECS [17] or the teratogen list in the references 18,19 or 22), or it has a structure displayed by known teratogens (Table 7j, the "educated guess" would be that such compound is teratogenic. Thus, if a compound is an imide, one should assume that it is teratogenic, since many imides, including thalidomide, are teratogens. This guess is likely to produce false positives, probably more in structurally specific than in nonspecific teratogens. If the compound in question has both the chemical structure shown in Table 7 and the biological activity displayed in Table 6, one should oe even more suspicious that the compound is a teratogen. TABLE 7 CLASSIFICATION 07 TERATOGENS BY CHEMICAL STRUCTURES [22] Teratogen Acrylates Alkaloids Amides Amines and ammonium salts Azo compounds Barbituric acid derivatives Benzodiazepines Carbamates Chlorinated hydrocarbons Folic acid derivatives Glutamic acid derivatives Hydrazines Hydantoins Imides Indandiones Metals fPb, Hg, Cd, As, etc.) Nitroso compounds t.- Teratogen Phenethylamines Fhenothiazines Phthalimides Piperazines Polynuclear hydrocarbons Purines Pyrimidines Salicylates Steroids Sulfonamides Tetracyclines Thiadiazoles Thiocarbamates Thiophosphates Triazenes Triazines Ureas OLI 4712 1 10 Examples of the predictive power of this method are given in the refer ence 22. The contentr of Table 6 and 7 are analyzed in much detail in the reference 2 which also gives some easy-to-understand explanations of the fact that some particular chemical structures are often found in teratogens. In summary of this section, it is possible to make an "educated guess" about the teratogenicity of the chemicals which have not been tested. This procedure is not very exact and it may produce false positives. However, at the present time we do not have a better way to predict teratogenicity. A note on teratogenic chemicals common in the research laboratories Many commonly used laboratory solvents such as CC14, CHC13, CT^Clj, CHC12CH3, dioxane, xylene, MEK, etc represent reproductive hazards [20], Central nervous system defects were observed in children bom to mothers exposed to organic solvents during pregnancy [24], It is possible that some of the malformations observed in infants of women who worked in the university laboratories [25] or other laboratories [26, 27] are also due to the organic solvents. Extra caution should be taken when working with the organic solvents, otherwise the exposure to these solvents may be quite significant since they are volatile and typically used often and in large quantities. Chemists working with any of the chemicals presented in Table 5, all of which are commonly found in the research laboratories, should consult reference 20 which contains detailed information about exposure levels and routes, pharmacological effects, and various other useful data. CONCLUSIONS Teratogenic chemicals are a special concern of women research chemists. In this paper various aspects of teratogenicity of chemicals are presented which we believe will be useful to women research chemists. Various sources of information on teratogenicity of chemicals are discussed. Due to the numerous difficulties in identifying and studying human teratogens, the teratogenicity data reported in the literature are often unevaluated, incom plete, and inconclusive. Therefore, a caution must be excercised in inter preting the teratogenicity data. Classification of teratogens by biological activity and by chemical structures is discussed as a useful tool in predicting teratogenicity of the compounds which have not been tested. ACKNOWLEDGEMENTS The author is grateful to Dr. Augusta R. Auerbach for editorial help and to Ms. Cindy L. A. Shepard for typing several versions of the manuscript. This work has been partially supported by a grant from the University Research Foundation, La Jolla, California. OLX 4713 UWMIUWUJ 11 references 1 T. H. Shepard, Catalog of Teratogenic Agents, The Johns Hopkins University Press, Baltimore, MD, 1973, PP. xiv--xvi. 2 R. E. Beyler and V. Kolb Meyers, What every chemist should know about teratogens -- Chemicals that cause birth defects, J. Chem. Ed., 59 (1982) 759--763, 3 The Insight Team of The Sunday Times, Suffer the Children: The Story of Thalido mide, Andre Deutsch, London, England, 1979, pp. 25--41. 4 R. W. Smithells, Drugs and human malformations in D. H. M. Woollam (Ed.), Ad vances in Teratology, Vol. 1, Academic Press, New York, NY, 1966, pp. 251--274. 5 I. C. T. Nisbet and N. J. Karch, Chemical Hazards to Human Reproduction, Noyes Publ., Park Ridge, NJ, 1983, (a) p. 100, (b) pp. 6, 99,110. 6 T. H. Shepard, J. R. Miller, and M. Marois (Eds.), Methods for Detection of Environ mental Agents that Produce Congenital Defects, Elsevier, Amsterdam, 1975. (a) J. G. Wilson, Critique of current methods for teratogenicity testing in animals and suggestions for their improvement, pp. 29--48. (b) H. J. Schumacher, Chemical structure and teratogenic properties, pp. 65--77. (c) E. F. Zimmerman, Chemical structure and teratogenic mechanism of action, pp. 79-88. (d) Editorial comment, p. 93. 7 C. Gupta, B. R. Sonawane and S. J. Yaffe, Phenobarbital exposure in utero: Alter ations in female reproductive function in rats, Science, 208 (1980) 508--510. 8 H. Druckrey, S. Ivankovicand R. Preussmann, Teratogenic and carcinogenic effects in the offspring after single injection of ethylnitrosourea to pregnant rats, Nature, 210(1966)1378--1379. 9 P. F, Infante and M. S. Legator (Eds.), Proceedings of a Workshop on Methodology for Assessing Reproductive Hazards in the Workplace, April 19--22, 1978, NIOSH Publication No. 81--100. (a) W.B. Gill, G. F. B, Schumacher and M. Bibbo, Effects of in utero DES-exposure on human adults: Testicular hypoplasia and abnormal semen in males; Vaginal adenosis and ridges in females, pp, 19--32. (b) E. N. Cohen, Waste anesthetic gases and reproductive health in operating room personnel, pp. 69--86. (c) W. N. Rom, Effects of lead on reproduction, pp. 33--42, 10 V. R. Hunt, Occupational health problems of pregnant women, A Report and Recom mendation for the Office of the Secretary, Department of HEW, April 30, 1975, Order No. SA-5304-75, pp. 64--66, and references. 11 A. A. Mitchell, L. Rosenberg, S. Shapiro and D. Slone, Birth defects related to Bendectin use in pregnancy, J. Amer. Med. Assoc., 245 (1981) 2311--2314. 12 J. F. Cordero, G, P. Oakley, F. Greenberg and L. M. James, Is Bendectin a teratogen, J. Amer. Med. Assoc., 245 (1981) 2307-2310. 13 Reproductive Hazards in the Workplace, Chem. Eng. News, Feb. 18, 1980, pp. 35-37; ibid, Feb. 11,1980, pp. 28-31. 14 C. Norwood, At Highest Risk, Protecting Children from Environmental Injury, Penguin Books, New York, 1981, PP. 245--246. 15 H. Nishimura and T. Tanimura, Clinical Aspects of the Teratogenicity of Drugs, Elsevier, New York, NY, 1976, (a) pp.92--270 and (b) pp. 271-287. 16 J. L. Schardein, Drugs as Teratogens, CRC Press, Inc,, Boca Raton, Florida, 1976. 17 National Institute for Occupational Safety and Health, Registry of Toxic Effects of Chemical Substances, Available as printed edn. (updated annually), microfiche issue (updated quarterly), and on-line computer data base (updated quarterly). Printed edn: Superintendent of Documents, U. S. Government Printing Office, Washington, DC. 18 V, Kolb Meyers and C. Y. Meyers, Chemicals Which Cause Birth Defects -- Tera togens. A Brief Guide, paperback printed at Southern Illinois University, Carbondale, IL 1980, 37 pp. (Available from the authors at cost: S3.00). OLI 4714 12 19 NIOSH, Tumorigenic, Teratogenic, and Mutagenic Citations: Subfiles of the Registry of Toxic Effects of Chemical Substances, NIOSH, GPO Stock 017-033-00352-1, 1979 (microfiche). 20 S. M. Barlow and F. M. Sullivan, Reproductive Hazards of Industrial Chemicals. An Evaluation of Animal and Human Data, Academic Press, New York, 1982,640 pp. (a) pp. 19--20. 21 B. R. Strobino, J. Kline, and Z. Stein, Chemicals and physical exposures of parents: Effects on human reproduction and offspring, Early Human Development, 1 :4 (1978) 371-399. 22 V. Kolb Meyers and R. E. Beyler, How to make an "educated guess" about the teratogenicity of chemical compounds, in S. M. Somani and F. L, Cavender (Eds.), Environmental Toxicology, Charles C. Thomas, Publ., Springfield, IL, 1981, pp. 124--161, 23 M. R. Juchau (Ed.), The Biochemical Basis of Chemical Teratogenesis, Elsevier, New York, NY, 1981. 24 P. C. Holmberg, Central-nervous-system defects in children born to mothers exposed to organic solvents during pregnancy, Lancet, 2 (1979) 177-179. 25 O. Meirik, B. Kallen, U. Gauffin and A. Erikson, Major malformations in infants born of women who worked in laboratories while pregnant, Lancet, 2 (1979) 91. 26 E. Hansson, S, Jansa, H. Wande, B. Kallen and E. Ostlund, Pregnancy outcome for women working in laboratorj.s in some of the pharmaceutical industries in Sweden, Scand. J. Work Environ. Health, 6 (1980) 131--134. 27 U. Blomqvist, A. Ericson, B. Kallen and P. Westerholm, Delivery outcome for women working in the pulp and paper industry, Scan. J. Work Environ. Health, 7 (1981) 114-118. OLI 4715