what every chemistry should know about teratogens

What Every Chemist Should Know About ~eratogens-chemicals that Cause Birth Defects Roger E. Beyler and Vera Kolb Meyers Department of Chemistry and Biochemistry, Southern Illinois University, Carbondale, IL 62901

Between 2% and 3% of all babies horn in this country (and in other countries where data are available) have serious malformations requiring medical attention ( I ) . Society in general and chemists in particular are becoming aware that chemicals cause some of these malformations in the newborn human. About one third of these conditions are life threat- ening. More than twice as manv defects are detected with increasing age of the child as arbrecognized at hirth. The result is that prenatal mnlformations account for nearly half of the patients in pediatric wards in our hospital* (2). Thus, there is need ior impnwement uf the initial health of our uffspring. - -

I t is a major problem and deserves a high priority in any pro- gram to improve the nation's health.

Only a small proportion of these hirth defects can he traced to known and certain causes. About 5% and 10% respectively, of the defects are known to he due to chromosomal aberrations and gene mutations. However, since recognition of gene mutations and minor chromosome aberrations in humans is exceedingly difficult, it is possible that a far greater proportion of hirth defects are due to genetic causes. Less than 3% of malformations are known to he caused by chemicals suh- stances (3). That leaves a large percentage of defects unaccounted for a t present.'

Some of the unaccounted for defects are undouhtedlv due to so-called environmental (and mostly chemical) hazards. Thev prohahlv include things found so commonly in our environment that we overlook them: ethyl alcohol, carbon monoxide from cigarettes, or caffeine from excessively used stimulant drinks. Or for some they could h e d m toa parent's chemical exposure on the job. A few hirth (lefects are probably

Data on birth defects are not very reliable. Percentages cited above are conservatively low. A very recent publication gives reproductive abnormality and impairment data that are substantially greater than in references 1, 2, and 3: "Chemical Hazards to Human Reproduction," Council on Environmental Quality, January 1981. pp. 111-5 and 111-24 to 26. This book (284 pp.. including references and appendix) is for sale from the Superintendent of Documents, U.S. Government Printing Of- fice, Washington, DC 20402.

due to over-the-counter and prescription drugs. I t is ohvious in the latter example that a large percentage of pregnant women take one or more drugs early in pregnancy, even if it is onlv for a minor health orohlem. Some of these d r w s mav ~ ~ . - . not yet he recognized as hazardous to the embryo, as was true for DES thirtv vears ago. The general class of chemical suh- . - stanccs considered here is called teratogens, and knowledge- ahle chemists should lrrcome informed on this subject.

What Is a Teratoaen? - The field known as terarology may be defined as the sci-

entific studv of hiolwical monstrosities and malfunctions. The word "teraiogen2' i i derived from the Greek word teratos meaning monster and the Latin word cenus meaning hirth. A teratogen, then, is an agent which a& during pregnancy to oroduce a ~hvsical or functional defect in the embryo, fetus, or iffspring i4 j.

Physical defects, such as those found in Siamese twins, douhie-headed humans, dwarfs, etc., are overt and have been observed and recorded on stone and wood since time imme- morial. The history of ancient (5) and of more recent (6) teratology is rather interesting. Maternal impressions in early times (for examnle. a mother friehtened hv a rabbit had a child ~ - - ~ - ~ ~ . ~ ~ ~~

with a harelip) br the not-so-ancient use bf x-ray therapy for pregnant women are historical facts that put our present state of knowledge into perspective.

Functional defects, such as the impaired mental ability that is a risk in offspring of women who use excessive amounts of drugs or alcohol during pregnancy, are more covert than are physical defects. Establishing cause for various functional defects will continue to challenge teratologists for years to come. An impaired function, in contrast to an ohvious structural malformation, is often not detected at hirth. Eventually, parental recognition of the defect occurs with the child's increasing age.

Teratogens versus Other Reproductive Hazards in the Workplace

Much of our recent teratogen concern has been devoted to

Volume 59 Number 9 September 1982 759

so-called "reproductive hazards in the workplace," the subject of several recent articles in Chemical and Engineering News (7,8). The focus of attention is most often on the reproductive hazards for women of child-bearing aee workine in the chemical industry. Most would agree ihs an extra iegree of nrotection is needed for these women because of increased susceptibility of the embryo/fetus to chemicals as compared to adults in general.

~ e r a t o l o ~ k s and epidemiologists are becoming increasingly convinced that birth defects can result from occupational exposure of males to chemicals that cause sperm damage. These "birth defect via sperm damage chemicals" may best be classified as mutagens, rather than teratogens.

I t is of interest to examine chemicals that are teratogens and those that are mutagens. In a recent listing there a substantial duplication of chemicals cited as teratogenic and those cited as carcinogenic (156 out of 527 teratogens are carcinogenic) (9). I t is a generally accepted view that mutagens and carcinogens have substantial overlap as well (lo), as evidenced by use of the Ames (mutagen) test for screening potential carcinogens. Therefore, one might expect the list of teratogens and that of mutagens to have many identical entries; some overlap between teratogens and mutagens has already been reported (11). I t may he primarily a question of whether the agent has its effect on ova, spermatazoa, the embryo, or the fetus.

Good safetv nractices will include nrotection from aU three . . of the hazards: carcinogens, teratogens, and mutagens. Therefore, protection of both male and female employees to identical levels of air contamination may be justified. Stan- dards that are set bv safetv eneineers. industrial hvgienists. - . - and toxicologists need to pay attentionto such considerations in the immediate future.

Teratogens in the Academic Laboratory What ahout smaller amountsofa terntogen than what one

might he exposed to in manufncturing, formulating, or pnck- aging processes? A resrarch chemist must take extra precnu- tiuns. because safe levels of exposure have not t m n estahlished for most teratogens. Greater Eare must he exercised when one is working with new compounds, since they may be teratogenic. Even a small exposure of short duration to a potent (new and untested) teratogen might present a great risk. However, one should not underestimate the risk from pro- longed exposure to a weakly teratogenic compound, particularly one that is among our "common" reagents and solvents. Obviously, any academic lab may have some teratogenic risk.

The motivation for our search of the literature for a list of teratogens was an inquiry from a pregnant student who was concerned about working in our undergraduate teaching lab. Such inquiries by our students, as more information about teratogenic hazaards becomes available, will become more frequent. When use of teratogens in lahoratories cannot be avoided, the same safety procedures must be used for teratogens that are used for any very toxic material. A recent, two-volume publication on the handling of teratogens, carcinogens, and mutagens underlines the fact that safety methods are essentially the same for all three of them (12). Teratogen precautions are also included in the ACS safety publication for use in academic lahoratories (13). A very recent book on hazardous laboratory chemicals, bearing Na- tional Research Council sponsorship and review, deals with health hazards in the laboratory as distinct from those in pilot plant or manufacturing operations (14). One health hazard briefly covered is that of emhryotoxins. Academic teaching laboratories are also specifically considered in this useful book.

Literature on Teratogens Information about what compounds are teratogens has not

been readily available to the average chemist. Most people

have heard about the effects of thalidomide, but what other compounds are in that category? When the booklet of Meyers a n d ~ e y e r s 14) brcame a\.ailnhle, requests for copies came from chemists and their spuuses, from pharmacologists, toxicologists, government scientists, and management personnel in industry. Thr list of over five hundred teratogens the lxx~klet contained seemed to fill a minor void on the subjwr. Xlutivated by that response, this paper isdesigned toadd to the hooklet bv inforniine chemists in teaching lahoratories - about a few basic facts and where to turn for more complete information on the suhject of teratogens.

Probably the most concise source of data on chemicals which are teratoeenic is a reference book (neriodicallv updated) by the whknown teratologist, ~ h o m & ~ . shepard (3). I t is the place to ao for information on teratogenicitv of chemicals and other t&atogenic agents; the phar~acolog&al procedures and animal species used to test these are given, as svell as a concise description of'the type uimalfi,rmativnsmd malfunctions ubserved. 'i'he most recentlv updnted rdition of this mtalog (1980) has w r r one thousand &irs.

'I'he Kn\,ironmenrd Trrntolwy Information Center (ETICJ was established a t Oak Ridge National Laboratory in 1975 to "collect, organize, and disseminate information on the eval- uation of chemical, biological, and physical agents for teratogenic activity" (15). Its files of information are very com- . prehensive.

Information on human teratogens, primarily from the viewpoint of drugs used in the mid-sixties, is covered by Smithells (16). More recent coverage, with some emphasis on environmental teratogens and how to deal with the problem, is provided by Miller (17). The most comprehensive treatment of teratogenic drugs from the clinical perspective is a book by Nishimura and Tanimura (18). I t also covers environmental teratogenic compounds.

There is also one very down-to-earth reference on teratogens that is worthy of mention. I t is written for the public- at-large and would be suitable reading for students in non- majors chemistry courses or for high school students. I t is a chapter titled "Drugs in Pregnancy" found in a paperback hook published by Consumers Union (19).

The National Institute for Occupational Safety and Health (NIOSH) has published annually a Registry of ToxicEffects of Chemical Substances (RTECS), a compendium of toxicity data abstracted from the scientific literature. The 1978 edition of RTECS includes toxicity data (type of toxicity, toxic dose levels, route of exposure or administration, species exposed, description of exposure, etc.) for nearly 34,000 different substances (20). An average of about 1500 new toxic compounds are added every quarter; 85 new teratogen listings were added during approximately 9 months in 1979 (21 ).

~ e - h & e looked f i r chemical features and biological activities that 527 teratogens (4,22) from an RTECS computer search had in common. It was not our desire to use a descriptor approach (23) for a few functional groups we might choose, as we endeavored to oreanize the data. This mav be more ef- "

fective a t a later stage of structure-activity analysis. As de- scribed below, we have looked for biological activity classes (or groupings) and for structural classes that are multiplicated in the teratogen list. Others have also been looking for biological classes of teratogens, notahly the types of drugs, hormones, etc. (24). Functional group considerations for teratogenicity, found in the literature prior to our search (4,221 are limited to a few classes: sulfonamides. polvhaloaenated biphenyls, phthalimides, and several others. -

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Precautions for Interpretation of the Teratogen Llst from RTECS

The obligation of chemists and especially of chemical ed- ucators to inform people about the hazards from teratogen exposure is obvious. some of the chemicals on the list we obtained are very common in everyday life; others are found in our environment in low concentration. Most (like aspirin,

760 Journal of Chemical Education

caffeine. nicotine. alcohol) nrobablv reauire larger doses than . . are usually taken by the average person in oraer to become hazardous. That is why responsible interpretation of the data . . is so important and why chemists share with physicians, toxicologists, and others the task of giving cautious and well-considered information to the public. Radiation, nutri- tional factors (251, genetic susceptibility (26), immunogenic factors (27,281, and viral infection should also be identified as causing birth defects.

One must hear in mind that manv of the com~ounds on the teratogen list have been so identiffed on the basis of a single study performed on just one animal species. The data obtained are not evaluated and represent in such instances no more than a preliminary screening test. With few exceptions to the known human teratogens (such as thalidomide, lead compounds, vinyl chloride, etc.) teratogens are not classified into "proven" and "suspected" (as with carcinogens), or "strong," "medium," "weak," or similar categories; not enough data are available to permit such classification.

Then too, the animal data in this areaunfortunately donot transfer well to the human. Mice, rats, and rabbits, which are the most commonly used laboratory animals, have a different, more primitive placenta than humans. Primates, which are similar to humans in that resect , are not used routinelvdue . . to their high cost.

In addition, the dose levels for m a w of the animal tests are huge in comparison with what a women might re- ceive. Also, the method of administration of compounds to animals is often different from those that are most frequent in human exposure (oral, or inhaled, as for volatile materials in the envirohment). Concentration of chemicals in an animal embryo after intravenous or intraperitoneal injection, for example, may he considerably higher than from other routes of administration.

A good correlation in animallhuman teratogenicity data is by no means routine. However, the extrapolation of animal data to humans seems reasonable for many chemicals such as: chemicals which affect cell division or cell growth (antibiotics, pesticides, antineoplastic agents); compounds that affect or control the growth of particular organs or components of the hodv (sex hormones. insulin. and antidiabetic aeents): and cheki'cals which could affect'major systems (circ;ltor;; nervous. eastrointestinal. etc.) of the develonine emhrvo.

~ l ' s z , it is reasonable topredict that general celipoisons, such as CO. alkvlmercurv comnounds. and heaw metals. will have an ad;erse effect on an ~mbryoffetus wheh the mdther is exwsed at sublethal doses. There are teratoloeists. however. .. . whoho not include '.fetotoxic" or..fetopathogmir" agents in the teratogen classification (291, claiming that u hile r,irt~lally

Table 1. Classliication of Teraioaens bv Chemical Structures

Acrylater and Methacrylater Alkaloids Amldes and Sullonamldes Amlnes and Ammonium Salts Am Comwunds and Hvdradnes Cmbamates and Thiocarbamaiw Chlorinated and Polynuclear Hydrocarbons Heavy Metals Indandiones Imldes Nitroso Compounds Phenethylamlner Piperazlnes Polypeptides Purines and Pyrimidines Salicylates Steroids Sulfur Heterocycles (wch as Thladlaroles and Phenolhlarlnes) Thiophosphates Triazenes and Trlazlneo Ureas

all chemical agents at a high enough dose can result in embryo or fetal lethality, not all chemicals are capable of causing a specific teratogenic defect. The distinction is not so simple. Minamata disease from methylmercury poisoning, first identified in Minamata Bay, Japan, caused a congenital palsy which sometimes was not noticed until children reached grammar school age. The mercury compounds certainly are lethal in animal tests a t sufficientlv high dosaee hut clearlv give functional abnormalities (teratogenicity) in humans a t the appropriate dose (30).

A few teratogens on the list are unexpected, such as lactose, galactose, and fat soluble vitamins such as A and D (31.32). The latter two vitamins are also known to cause hypervi- taminosis svm~toms after vroloneed. excessive dosaee in - . adults. ~er&ogenic effect ofthese is of concern, since many women take self-prescribed massive doses of all kinds of vitamins, believing that vitamins are harmless. Further work is obviouslv needed tolearn whv the two milk-related sugars are on the iist.

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Classes of Teratogenic Compounds It hecame obvious during the writing of structural formulas

from the RTECS computer-produced names that two useful groupings of the compounds were possible: a chemical structure or functional group classification and a biological activity classification. Previous literature sources (particularly 1,18) have identified a number of teratogenic classes. However, none has produced such a comprehensive listing as we are giving in the tables that follow.

Tahle 1 illustrates the clas&fication of teratogens by chemical structure. Some, like the indandiones, have only three or four specific teratogen examples; others, like imides, include dozens of teratoeenic comnounds.

It is norrworthy that a numl)er 1)1 nitrogen classes of rorn- oounds anuenr: nmides. imides ~includinr rhalidurnide. the . . hos t notorious teratogen), carbamates, ;reas, and suifon- amides. Many specific examples of these functions, with N bonded to C=O or S=O, are on the list. Other N-containing groupings, including amines, quaternary ammonium salts, several polypeptides (angiotensin, hradykinin, insulin) and a few amino acids, are usually rather special structures. Pos- sibly their teratogenicity is due to their hormonal, ganglion blocking, alkaloidal toxic, etc. effects. Azo compounds, hy- drazines, triazenes, and nitrosamines are generally carcinogens, expected to give abnormal cell division (and thus teratogenic) effects. Nitrogen heterocycles such as piperazines, hydantoins (which could also be considered to be imides), tiiazines, purines, and pyrimidines may each have their teratogenicity explained for a variety of biological reasons (uide infra). The alkaloids in the list are most often those that are known to have antineoplastic activity. They are generally quite toxic to animals and humans.

Sulfur-containing teratogens usually have phosphorus (thiophosphates) or nitrogen also present: thiadiazoles, sulfonamides, thiocarbamates, and phenothiazines (chlorpromazine, etc.).

The chlorinated hydrocarbons (including 2,4-D, CCla, CHC18, penta-, and hexachlorohenzene, etc.) and the polynuclear hydrocarhons (methylcholanthrene, benzanthracene, henzvnvrene) have carcinogenic vroverties, so their terato-

is not unexpected (oide &&a). One mieht hone that there would be relativelv few surnrises

when the teratogens were examined from the standptint of their hiolwical acti\itv. Thtu vmved ro he rhe case, vud Tahle 2 gives the-most obvious biological activities we found on ex- amination of the list of teratogens.

'I\) begin with, artivities knwm t#,ntf~ct wII growth and reU division are widen( in Tahle 2. Cnrcinogens, some mentioned before, include the full complement: nit~osamines, chlorinated hydrocarhons, sex hormones, azo dyes, and polynuclear hydrocarbons. Teratogenic antineoplastics include: nitrogen mustards and alkylating agents of all varieties, purine and


Table 2. Classification ol Teratogens by Biological Actlvltles

Anllblotlu Anticoagulants Antlepileptlw Antihistamines (and the reldsd antl-nau~aa d r w ) AntineOplastlCs Antlpsychotlw Blood Pramre Rsgulatm (VaMeonnrlctors and Vasodilators) Cardnogerm CNS D e ~ r e ~ a n l s iAnaNthdlcL Analasslcs. Hvmotlw. Narcotics. . -

Sedatives, and Tranqdllz.rs) CNS Stimulants and Antid.pr..un(s Dlruetics Gangllon Blocking Agents Hormones, Antlhormones (and hnlratlvea) Pestlsldes (Herbicides. Funglcldss, Inrectlcldes) Pshychotmimetlcs (or Haltuclnog-) Vltaminr lfat sotublab

pyrimidine antagonists (such as 5-fluorouracil and 6-mer- caotoourine). antifolic acid aeents (methotrexate). antibiotics (s;chLas adinomycin D and kitom$cin C), and alkaloids used for cancer treatment (like vincristine and vinblastine). A few antibiotics not used for cancer, such as several from the strentomvces eroun. and some of the tetracvcline varieties. . . .. are on the list.

A number of aeents that affect the circulatorv svstem. in- - . . cluding w ~ n e that affect blood pressure (such as angiotensin, bmdvkinir~. and reser~ine) are found in'l'sble 2. Anticoaau- ~ a n t ~ e x h i b i t hemorrhagic hazards for the fetus or embryo: coumarins are quite dangerous; heparin would be safer.

A very large group of activities in Table 2 relate to an effect on the nervous system. A number of barbiturates are listed, which are generally considered to be general CNS depressants or hypnotic-sedatives. Tranquilizers and antipsychotics include meprobamate and chlorpromazine. The antiepileptics one finds include hydantoins, barbiturates, succinimides, and oxazolidines. Hallucinogenic agents like LSD and mescaline are listed, as are representatives of two other major drug abuse categories: narcotics and CNS stimulants. Debate continues in some quarters about the hazard of marijuana use by preg- ~- . nant women. Both cannabis and tetrahydrocannabinol appear on our list. Anti-depressants and ganglionic blocking agents (like tetraethylammonium chloride) have representatives among the teratogens.

Diuretics are frequently taken by women and may be prescribed during pregnancy to counteract fluid retention. Sev- eral diuretics, including thiadiazoles and xanthines (caffeine and theophyline) are on the list.

Many teratogens in the list are lethal to plants or lower animal forms. One finds the complete gamut of pesticides: herbicides (2.4.5-T and 2.4-D. for examole) and a t least one . . plant growthregulator (indoleacetic acid) are included. The maior insecticide classes of carhamates. chlorinated hvdro- c&ons, and thiophospbates are on thelist. They shoild be used with ereat care, not sprayed in large auantities in POD- ulated areis hecause of thiir possihle t&atoyenicity. ~ " n i i - rides, thouah nor as broadlv svrawd, are noticeablv on the list and merit caution in thei;aipl&ation.

Compounds having general chemical structures presented in Table 1 andlor having general biological activities presented in Tahle 2 are very often synthesized in the laboratory for a variety of reasons, ranging from applied bio-medicinal research to pure mechanistic studies. Often, chemists work with the same type of compound for years. In many cases, more often than not, chemists are not even aware of a teratogenic hazard! Unfortunately, many very common chemicals, such as solvents and simple reagents, are on the list. Some of these are presented in Tahle 3.

Conclusion: How to Use Teratogen Data

How should chemists use the RTECS data on teratogenicity

Table 3. Some Common Chemicals which are Teratogenlc (4 )

AcryIIc Acid Glyclnonltrlle Anlllne Herachlorobenrene Benzene lodoacetic Acid 2-Butanone Lead Cadmium Mercury Carbon Monoxide Nltrobenzene Carbon Tetrachloride Nltrous Oxide Chlorolorm Phenol Diphenylamine Polychlorbated and Polybromlnated DMF biphenyls (PCB and PBB) OMSO Salicyclb Acid Ethanol Toluene Formaldehyde

of chemicals? A partial answer is presented in our publication (22). which deals with makine an educated euess about the . .. "

teratogenicity of chemical compounds. I t indicates how one may use good judgement about teratogenicity for any new chemical that fits into either (or both) of the categories found in Table 1 or 2.

When one works with such chemicals, or with chemicals which are listed in RTECS as teratogens, safety measures equivalent to those for handling carcinogens (33) should be followed. The application of these safety measures means that minor inconveniences (like a hood or glove box for volatiles, or rubber gloves, and care in disposal) will he introduced. superficialiy it may appear that these inconveniences are not justified since most of the teratogens from the list are of a "suspected"or "vaguely suspectedk type as far as humans are concerned. However, the benefit from diminishing the risk in cases where the teratogen hazard is real more than compen- sates for any minor inconvenience in instances where the teratogen hazard is small or does not exist. A few predicted "positives" that prove to he "false" as teratogens are better than having a family live through many years with a child having a birth defect.

Those of us in the education orofession orobablv have a greater obligation than chemistsin general to deal with tera- toeen data. because our students are novices in the field. As with carcinogens in the teaching laboratory, we must delete reaeents. solvents (benzene and DMF are on the list), and " . preparations that involve teratogens. This is an area in which we can set an example of good practice for both our students and the chemical profession in general.

In our academic research laboratories we must inform all personnel of teratogen hazards and enforce safety procedures. The obligation to judge the risks and establish needed procedures obviously lies with the faculty member directing the research. Our microbiologist associates have long dealt with similar problems in working with viruses and more recently in carrying out recombinant DNA research. Research with teratogens and potential teratogens deserves similar consid- eration.

Our obligation in the classroom to inform students about teratogens is perhaps even greater. Only a few faculty mem- bers will be involved in research that has maior t e r a h e n risk: however, many are likely to teach a class that deals with some aspect of the suhject. Often we have taught more about environmental chemical hazards in our non-majors courses than in the standard courses for majors. That ought to change. Chemical companies are increasingly showing concern that candidates for emnlovment are well informed about safe handling of chemic&"(34,35).

Responsibility of those in the teaching profession also ex- tends to informing the public-at-large. Lack of knowledge is one of the main reasons for fears about chemicals, whether they are listed on food labels or on a prescription drug from the doctor. Many people worry about anything that has a chemical name. We cannot ban salicylates, caffeine, or etha-

,762 Journal of Chemical Education

nol, but we can warn people about the possible danger from excessive use of these during pregnancy.

We should teach people to follow instructions carefully when using any pesticide, or when taking any drug. It is our responsibility to set the example of protecting future offspring by teaching and enforcing good safety practices for any and all individuals (students, technicians, or others) working in our academic laboratories.

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Pres,New York, I966,Vol. I.p.254. (2) Shepard. T. H., Miller. J. R., and Mamis, M., (Editoral. "Methods for Detection of

Environmental Agent* that Produce Congenital Defeds." Ameriean Elsevier PuhL Co..Inc..N~w York. 1975 ,~ . 13.

(3) Shepard, T. H., "Catalog of TerafgenieAgent*."The Johns Hopklm U n i v ~ i t y Press. Bdtimare, 1973, p. XI.

(4) Meyors, V.K.and Mpyen.C.Y.,"Chemi& Which Caus~BirthDefecta-T~atogtapntap. A BriefGuide."paperback prinVd at Southern nlinok Uniwsity. Carbondale, 1980, 37 pp., evailabla from the suthore at cost ($3.W1.

(5) Wsrkany, J., in "Birth Defectp: Fishbein, M., (Editor), J. 9. LippinmUCo.. Phila- delphia, 1963, pp. l a 2 4 See also Warkany. J.."Congenital Malfomstions." Year Book Medical Publishers, Chicago. 197I.p~. 6-16.

(6) Miller, R. W.,in "Chemical Mutagens. Principles and Methods lor Their DFtection: Hollaender. A , and do Serres. F. J.. (Editors]. PlenumPr~ae, New York, 1978.Voi. 5. pp. 101-108.

(1) Rswls, R. L.,Chrm. E w . Nsws,58.(8) 28(19801. (8) Rawls, R. L., Chem. E n 8 Nems,58. (7) 35 (1980). (9) Ref. (41,pp. 21-37,

(101 Dagsni. R.. Chom. Eng Newa, 68.9 (1980). (11) Ref. (61.p. 119. (12) Walters, D. 8.. (Editor), "Safe Handling ofChemiea1 Csreinogena. Mutagem. Tera-

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"Safety in Academic Chemistry Laboratories: A Puhlieafian of the ACS Committee on ChemicalSafety. 3rd Ed.. 1979,~. 10.

"Prudent Practices for Handling Hslsrdovn Chemicals in Labonrtories." National Academu Pres. Washineton. DC. 1981.277 no. . .

ReL (13),;. 303. ReL (11, pp. 251-'278. Ref. (6). pp. 101-108 and 119-126. ~ i ~ h i ~ ~ ~ ~ . H. and Tanimura, T., "Clinical Aspem of the Teratogenieity olDrue."

American Elsicvier Pub1 Co., New York, 1976,453 pp. "The Medicine Show: Consumers Union'sPraetieal Guideto Some Everyday Health

Problemsand Health Ploducts." 5th Ed.. Consumer Unin.Mount Vsmon,NY, 1960, ~ ~

pp. 241-263. "Registry of Toxic Effect. of Chemical Subtanees," by National Institute for Oeeu-

pafionsl Safety and Health (NIOSH). Available a.printededition (updated ennu- dly), miaofiehe issue (updated quarterly), and on-line mmputerdata base (updated quarterly). Printed edition: Superinfendent of Document*. U. S. Government Printing Offire. Washington, DC.

"Tmorigenie, Teratgenic, and Mutasenic Citations: Subfilea of the Registry ofToxic Effects of Chemical Substances." NIOSH GPO Stack 017-033.W352~1. 1979 (mi- crofiche).

Meyerr. V. K. and Beyler, R E., in "Envimnmental Toxicology. Principles aod Policies," Sameni. S. M., and Cevender. F. L. (Editors). Charlea C. Thomas, Springfield. IL,

Ref. (181, pp. 99-270. Wilson. J. G. and Warkany, J., "T~atolagy Principlesand T&igue~:'The Uniwrsiry

of Chieseo P r e . Chicaeo. 1965. no. 113-130. Ref. (25),ip. 21-56. Ref (251. w. 21&250 . . . . . , . . , , ?. . . . . . . . Ret (21, pp. 25. Rsbenstein. D. L.. J. CHBM. EDUC., 55.292 (1978). Gal, I., Shaman, I. M.,snd Pryae-Davies, J., in "Advances inTeratolom." Wwllam,

D.H. M.. IEdifor1.AeademicPrpas.NewYork. 1972.Vol.S.rr~. 113-160. Ref. (18). ip . 251-253. Ref (121 pp. 129-152. Fischbeck,B. C., J. C ~ M . EouC.,56.A7 (1979). Keufman. 3. A,. J. CHEM. EDUC., 55. A337 (1976)
