Document DG38919w5vLa3j1xqZJLpGw0M

RECEIVED DEC 0 2 1985 J. T. BARR --7 '1 \^, Tcratogenusix, <.'an.iiinenc.*Ms, and Mutagenesis 5:251-JIX (1985) Extrapolation of the Evidence on Teratogenicity of Chemicals Between Humans and Experimental Animals: Chemicals Other Than Drugs K. Hemmlnkl and P. Vineis Institute of Occupational Health, Helsinki, Finland (K.H.) and Istituto di Anatomia 9 Istotogia Patologica, Torino, Italy (P.V.) Epidemiologic literature regarding the possible association between malformation.-, and 23 exposures or occupations other titan pharmaceutical products, was ana lysed- The qualitative level of scientific evidence was classified into four cate gories: high (ethanol, methylmcrcury, PCBs. laboratory work), limited (anesthetic gases, carbon monoxide), low (hexarfdorophene, LSD, nitrous oxide, smelter work, tobacco), and inadequate (ajTytKJr exposures). Human data for exposures belonging to 1 ill 11 ^1 >rji,,, ,liiplt"JTinTilnili<l~~ were quantitatively compared to resul^o>fumiiJ teratogenicity lasts of the relevant chemicals. Ethanol, methyl- ffercury, and PCBs have caused malformations in experimental animals, and the effective doses have ranged from 0.2 to E.O times the effective human doses. Ethanol and PCBs caused similar types of lesions in some animal species as have been observed in humans. Key words; chemical exposures, malformations, epidemiology, teratogenicity testing, ethanol, melhylmercury, PCBs FOREWORD This review was commissioned to the authors by the Advisory Subgroup in Toxicology of the European Medical Research Councils in 1981. The need was felt for a consideration, a posteriori, of the current practice of testing chemicals far teratogenicity and other embryotoxic effects in laboratory animals. This practice is based upon the belief that results of such tests will predict the ability (or lack of ability) of specific chemicals to induce similar effects in man. The financial support of the Finnish Medical Research Council and of (he Italian National Research Council is acknowledged. Address repriru requests to K Hcmminli, Institute of Occupational Health, Haartmaninkulu t, 00290 Helsinki 29. Finland. > 1985 Alan R. Lbs. Inc. AP00019894 t, r 252 HemminU And Vincis The aim of the review was to assess the correspondence between epidemiologi cal and experimental observations. The rationale was (hat an analysis restricted to those chemicals for which human data* are available would allow an estimation of the proportion of false positive and false negative results in experimental tests. It was soon apparent that this approach had several limitations: 1) The demonstration of lack of effects in man requires an amount and quality of epidemiological evidence which are very difficult to attain: Therefore, the identi fication of chemicals giving false positive findings in laboratory animals U problematic. 2) Reports of an association between exposures and embryotoxic effects in man are not equally convincing for the existence of a causal link. In fact, studies have covered a wide range of objectives, from hypothesis generation to hypothesis confir mation. Therefore, the epidemiological literature had to be thoroughly scrutinized in order lo identify those chemicals for which an effect on man could be considered us firmly established. In addition, in many studies observations could lead to more than one interpretation, so that a description was needed of the essential findings in each study. The criteria and the interpretation by the authors are stated. 3) Epidemiological observations (of any quality) regarding teratogenicity foU lowing chemical exposures which have been reported in the scientific literature are very numerous. It was therefore decided to exclude medicaments from the first phase of the exercise. 4) The review was restricted to structural malformations for two reasons. Inclusion in the epidemiological review of studies of other embryotoxic effects would have further increased the size of the review. In addition, the majority of analytical epidemiological studies (ic, those allowing for the recognition of causc-to-effect relationships) are of the case-control type, in which only one effect is taken into consideration. The original objective thus turned out to be loo ambitious. The review does not allow conclusions to be drawn about the usefulness of teratogenicity testing in terms of public health (ie, assessment of the prcdictivity of the results of tests in laboratory animals). However, it has two elements of interest. On the one hand* it provides a thorough analysis of epidemiological findings with explicit evaluations of their relia bility. In addition, it pinpoints some established (or almost established) causal associ ations with teratogenicity in the human species, which require investigation of their mechanism of action. -No conclusion can be drawn on the validity of the practice of testing chemicals for teratogenicity. The many different types of embryotoxicity and the variation of doses and responses in different mammalian species reinforces the view of the Advisory Subgroup in Toxicology that only an increase in knowledge of the mecha nism of action of embryotoxins will lead to sound methods for the prediction or this hazard of human exposure. Advisory Subgroup in Toxicology of the European Medical Research Councils (*) (^Composition of the Subgroup: W,N. AlUritl^e (C'urshsHon). E. Cohen (The Hague). 1). Hcnschlcr (Wurzburg). E. Schenk (Slrashurgl, B. HolmstcUt (Stockholm). K Jsgcr (Geneva), R. Lauwerys (Bruxelles). K Lembeck (Gru/i. N. Lcry (Lyon), 1 Purchase (Aldcrley Park). H. Tcrracim (Torino). AP00019895 Teratogenicity Data 253 INTRODUCTION Tests for teratogenicity and other cmbryotoxic effects in experimental animals are commonly used in the belief that they predict risks in humans. Yet. the validity of this approach has not been established; animals species vary considerably in their susceptibility to teratogenic agents 111- In principle, experimental and epidemiological data should be systematically compared so as to enable the identification--if any--of Mfa!se positive" and "false negative" chemicals in experimental tests and thus to estimate the sensitivity and specificity of these. In fact, for only a limited number of environmental chemicals is information on their effects on the human fetus available, and the validity or this information requires a thorough scrutiny. In addition, because of the intrinsic limitations of the epidemiological approach, the identification of "true negatives" is questionable. An alternative, albeit reductive, approach is the identifi* cation of "true positives" and the qualitative and quantitative comparison of epide miological and experimental data concerning these. Thus, the present review has two purposes; 1) to evaluate whether chemicals with evidence of teratogenicity in humans show, on a qualitative ground, similar effects in animals, and 2) to evaluate whether human and animal effective doses are comparable. A similar although qualitative approach regarding carcinogenicity of chemicals turned out to be rewarding (2,3), since it revealed that almost all human carcinogens are carcinogenic in experimental animals also (although quantitative comparability is still uncertain). The exercise required a preliminary evaluation of the epidemiological findings regarding the effects of specific exposures on the human fetus. In view of the relatively large number of exposures for which some epidemiological studies or observations on man were available and required scrutiny, some limitations have been introduced; l) The present review does not consider therapeutic agents; 2) only epidemiological studies regarding congenital anomaly (eg, structural malformations and neurological defects) as an end point arc considered (thus excluding birth weight alterations, abortions, still births, and behavioral effects). Yet in experimental studies all expressions of teratogenicity and embryoioxicity detected during pregnancy or at birth are recorded. The limitation of epidemiological data to congenital anomalies is technical rather than scientific; it is realized, however, that in terms of public health, ie, for predicting effects in humans, all cmbryotoxic effects should be considered H.4). METHODS Chemical exposures, other than drugs, for which there are human data on teratogenicity have been identified through Medline and Toxline data banks using key words such as teratogenicity, malformations, and birth defects. Additional sources of literature were some reviews [1,5,6), and files maintained by the authors. No new articles were included after the summer of 1982. The chemical exposures identified from the literature are reported in Table 1. It is obvious that for complex exposures and some mixtures comparison with animal data is problematic. The following criteria have been adopted in the evaluation of epidemiologic evidence for each chemical or exposure: A high level of evidence was achieved when information on malformations and exposures was reliable (ie, derived from objective sources), and 1) analytical <ic, controlled ) studies were available and no positive bias AP00019896 254 Hemminki and Vfneis TABLE I. Chemicals (Other Than Drugs) for Which Epidemiologic Data Have Been Evaluated___________ Individual chemicals Carbon mono* kie Fluoride (water fluoridation) Halo thane Hcxachlorophene LSD Lead Mcthylmercviry Nitrous oxide 2,3.5-T* TCDD Vinyl chloride Mixture*, complex exposures Anesthetic gases CnfTcc Ethanol Gitsolinc Cannabis PCBs (Kancchlor) Potato blight Smelting work Soft water Laboratory work (wttvewx) Spray adhesives Tobacco__________________ Contaminated by TCOD and other dioxins. was identifiable (ie, systematic errors in selection of subjects, collection of informa tion, or comparability of groups); no positive confounder was identifiable (ie, a factor which was predictive of the occurrence of the disease and was associated with the exposure being investigated); the association was strong (say, relative risk greater than two) or. if not strong, it was substantiated in two or more studies; the results were unlikely to be due to chance alone; ie, the statistical power of the study seemed to be sufficient as to detect the reported association; given the purpose of the review, wc arc not concerned with a low power as a cause of "fafse negative" results; in addition, several independent studies done under different circumstances make the cause-effect relationship more likely; or alternatively, 2) several case reports showed association between a very rare exposure and a very rare malformation. Limited evidence was achieved when several case reports or uncontrolled clini cal series were available: analytical studies were available and biases, if present, were unlikely to explain all of the reported association, and the association was weak and not shown to be reproducible. A low level of evidence was based on the following: few case reports or clinical studies, geographic and/or chronological correlation studies only, individual analytical studies showing a weak and biased and/or confounded association. Inadequate evidence was based on studies showing serious bias or serious confounding or on insufficient available information. These criteria are only to be considered as guidelines to make the comparison with animal data easier. The categories of high, limited, tow, and inadequate level of evidence do not indicate a different teratogenic potency of chemicals but different qualitative levels of available knowledge. The following criteria were applied while the original literature was reviewed: 1) Regardless of the terms used for the frequency of malformations in the original papers, we use the term prevalence rate (number of malformed children per 100 live births or deliveries). 2) The literature search considered only maternal exposure during pregnancy. Thus, maternal exposure before conception and paternal exposure were not considered. 3) With some exceptions, individual case reports and geographic or historical correlation studies have been mentioned but not discussed in detail. Case reports may AP00019897 Teratogenicity Data 255 reflea fortuitous observations, since defective children can be more easily reported than normal babies from mothers exposed to a chemical. Geographic correlation studies usually do not allow for the identification of the effect of the relevant agent separately from that of other exposures. 4) The design of some studies (eg, on anesthetic gases) is unusual in epidemiol ogy, since they are based on a cross-sectional selection of (exposed and unexposed) groups at the time of the study, and a retrospective ascertainment of pregnancy outcomes and previous exposures; they are reported as "exposure-selective retrospec tive studies'* 17]. 3) Consideration of the potential confounding factors in studies on malforma tions is limited. It is reasonable to think that at least maternal age, parity, and socio economic status may be potential confounders 18], since they predict the occurrence of at least some malformations and are associated with many exposures. Also, alcohol consumption could confound association measures in some studies. EPIDEMIOLOGIC STUDIES Anesthetic Gases Available analytical studies are summarised in Table II. These studies have been defined as "exposure selective studies'* |7j since they were based on cross-sectional selection ofexposed and unexposed groups from professional or employment records or similar flies. In general, groups were subsequently refined according to the information obtained in questionnaires. Exposure data were collected in most of the studies through mail questionnaires. Exceptions were the studies of Cohen el a! |9J, who directly interviewed nurses but not other groups, and of Ericson & Kallen 110] who used hospital records for ascertaining duration of exposure. In most studies, exposure wat> characterised by duration and period of pregnancy. In two studies, duration and levels of exposure to halotharte were respectively scored by the interviewed subjects 111,12], Cohen el al [13] report malformations of the offspring of chairstde assistants exposed to nitrous oxide alone and to mixtures containing nitrous oxide. Lauwery* et al [14] collected information on the different types of anesthetic gases to which physicians and nurses were exposed. Pregnancy outcome was identified through mail questionnaires in all studies but ones in which use was made of a national delivery register (10]. Response rates ranged from 40 to 92%. with 70% as a common value. Among those studies reporting the response rate separately for exposed and control subjects, in two the rate was lower for the unexposed group. Results. Considering only females exposed at least in early pregnancy, the studies of Knill-Jones et al |15|, Corbett et al [16], Cohen et al [17], KniU-Jones et al [18] (only when a 1:1 matching of unexposed to exposed subjects was introduced), Gdthc and Hoffman [19] (only when nonsmokers were considered), Pharoah ct al [20] (only for heart-great vessels defects) and Cohen et al [13] (only for light users of anesthetics) showed statistically significant differences of prevalence rates between exposed and unexposed subjects. Of these studies, four controlled for potential confounders. Rate ratios can be calculated from these studies and ranged from 1.6 to 3.6 [18] (however, when 1:2 matching was introduced, the rate ratio became 1.1, not l TABLE II. Epidemiologic Evidence on Teratogenicity tf Ancsthetk Gists* Authors) and 'car Avkrog and Harvald. 1970 M*M| Cohen ct al. 1971 (91 Knill-Jones et al. 1972 U5J Rosenberg and Kirves. 1973 111] Country Denmark U.S.A. U.K. Finland Type of study Retrospective exposure' selective study Retrospective exposureselective study Retrospective exposureselective study Retrospective exposure* selective study Subjects and sample size Source(i)of information-- exposure' Soured s) of information-- outcome Prevalence rales of defects at birth (per live births or pregnancies) Comments1 578 Nurses of anesthetic dept. + 174 anesthetists (respondents: 72*) 159 Nurses. 50 Interviews to nurses, female anesthetists. mail questionnaires 81 physicians to other groups (eoWols) (respondents: 77% of anesthetists and physicians) 1241 Women Mail questionnaire anesthetists + 1678 fall trimesters) women general physicians (controls) (respondents; exposed 82%, unexposed 80% 300 Married nurses (58 m anesthesiology) Mail questionnaire (duration and level of exposure to (respondents: hakxhanc scored) 709-75*1 Mail question naires Interviews to nurses, mail questionnaires toother groups Mail questionmirc Mail question naire Wives of male anesthetists: 3/137; female anesthetists: 0-26: anesthetists nurses: 1/229 Female anesthetists 2%: physicians 4.2* 46/893 (5.2%) among exposed: 89/1835 14.9%) among controls Exposed in t-ll j trimesters; 6.5%:lL <0-2 uncxpttsetl in l-tl j trimester: 2.5% ) No malformations Exposure to observed halothane APOOO19899 CMbcttdil, 1974 |16i I U.S.A. Cohen etal, 1974 |I7J U.S.A. Knill-Jones et al, 1975 118) U.K. Retrospective exposureselective study Retrospective exposureselective study Retrospective exposureselective study 621 Nurse Mail questionnaire anesthetists (respondents: 85%) All operating room personnel in U.S. A. (49,585) + 23.911 pediatricians and nurses (controls) (respondents: 4176%) 7,949 Male anesthetists (under 65) and controls (general doctors and anesthetists not working in first trimester of their wives* pregnancies) (respondents; 70%> Mail questionnaire (1 trimester and 1 year before conceptioa) Mail questionnaire on male and female exposure (1 trinwvucr) Mail 16.4% Among nurses p < 0.05 questionnaire practicing during Hemangiomas: pregnancy: 12 in the ex 5.7% among nurses posed group vs. 1 not practicing in the unexpnet) during pregnancy inguinal hernias: 14 vs. 2 Mail questionnaire (title Exposed females: | 9.6%: unexposed} females: 5.9%; j p 0.001 emphasizes wives of male I health risks of anesthetists: 5.4%;} p < 0.04 anesthetics) wives of male J pediatricians: 4.2% Cnrt/ cmtrnt Mail questionnaire 4.5% In children of Minor defects: c.m. exposed males; 3.09%'; e.f. 5.5% in children of 3.19%; u.d. exposed females; 2.35'T J.6% in children of a * p< 0.02 unexposed doctors When matchinx for Cor\f. cvntnA potential confounders: e.m. p < 0.01--minor 4.5%; unexposed 1 defects 3.1% vs. males 3.2%: e.f. 1 2,1% 5.5%; unexposed 1 p < 0.01-/;/ females 1.5% / matching 5.3% e.f.; 4.9% p. value n.s.-- u.f. 1:2 matching icomimtedl 257 TABLE H. Epidemiologic Evidence wi Teratogenicity of Anesthetic Cm* (Continued) Authorts) and year Country 1 Type of study Subjects and sample size Sourcc(i) of information--- exposure' Sourcc(s) of information-- outcome Prevalence rates of defects at birlh (per live births or pregnancies) Comments' Cohen etal, 1975 [211 U.S.A. Tomlin. 1976 U.K. [152] Spence el al. U.K. and 1977 |I53) U.S.A. Gikhe and Hoffman, 1977 f|9| Sweden Retrospective exposure selective study Case rcpoti Retrospective exposureselective study Retrospective exposureselective study 2,798 Male oral surgeons + 4,797 male dentists (exposed: subjects having worked at least 3 hours /week with anesthetists the year before their wives' pregnancy) (respondents: 396S*> Mail questionnaire Mail questionnaire (title emphasizes health effects of anesthetics) Combined analysis of Mail questionnaire Cohen (1974) and (only cxponirc in Knill-Jones (1972. early pregnancy 1975) studies considered) (response roe in U.S. male controls: 45*) All Swedish male Mail questionnaire anesthetists and female anesthetist nurses vs. internal physicians and surgical nurses; index group: 1,382 pregnancies: control group: 2.002 pregnancies (response rate: 89.7*) Mail questionnaire Mail questionnaire 4.7* in the exposed p - 0.26 Coif, group; 4.1* in the control unexposed group Three malformed children from "approximately'' 50 anesthetists 5.5* In female \ anesthetists 4.0* J In female controls] 5.0* In male 1 anesthetists 3-7*] In male controls J Male anesthetists; 1.7* among exposed 1.8* among uneaposed female nurses: 3.0* exposed I 3.2* unexposed) 5.9* exposed } 2.9* unexposed) Types of defects not reported p <0.04 p < 0.01 (Greatest difference in U-S. data = low response rate) Conf. tvnrrof smokers noosmokera-- p < 0.01 A P 0 0 0 I9 9 0 I (fwwnvajf '/WJ uuojirui IR p9pn]0IH wuuuiApupdg ^majsp Jaqw.. || *A Z ln9 *|0JJUO3 Olfi 1U MtOU sa -si${WDWUt u; iqujjq irotntui C pu diq jo wonrxni x;s IpModlMII M 4ZI*6I ("*** po*odv 9q> u 986 ppsd9Z sa swojap pMiMiqo ZZ USttMflfMK SI XpmiiMMdd> JO ll&ipillp (Cl Suoun spajap UPtflS STK1AJ9U JO |Kp|33|SO|nni(J 3AIJ ($661 P"* 061)*pJOMJ <J5AT|3p pazuamckiios (XauwSajd uj ajnsodxj jo uottunp) spjooaj |njdto|| 4*OM |KMpMU ui paXofdtua UMUOW ||* SA 'jauuouad uwoj fluimado a|BUj 699 ijp|np s| 1|1IM SISIIMItSXfV $6 sttMsuMnpad locualzs'Ol) sMOuniSsjd 99Z/KSuoui*(%9||) UjMmiSajd 8PZ/6Z [unodti* atm(tO{*t| ajiMMottoeb JO 3JOOS MIPafaBS) 1W jjituooiKanb |iew **9PU%S8 :saiu asuodm) SUBpUIEIpad 9Sf + nstiMpwuv ZII Xpro* Mipaja* ainsodva <Cpm* MP|9S -.TjnSOdXJ pAHOJJWWUfl (prt Aipapa .unsodxg (0 0 > d .*99 sp** miS>tJVM| .`/pni5 dop**Q H!3 ItoofUM :.*6'l **Min S|afS3A ijS u*m| tsutiMlijd j*j %*rs *l ',,4*11 S19KM VtOli |M| :SKcp3l||S9UV ajicuuotisanb |W <J5Z4 :J*iapood>J) SH*l3lsXl|d MitouoiHanb ne^ U9UKVA J666 4pflW AMI39|3I -lIModM oAiuxhojpy Ujp3S (Oil 6461 P* *U3 IKII '5171 W6I "UU"1. Izil 3461 `uatnnuvA juMtuy put lisquMojj I loll LL&l *n `p !* I TABLE II. iiptiiiiolo)jic Evidtnw on Teralugeniclty of Anesthetic Gatw* (Continued) Auihor(j) and year Country Type of study Subjects and sample size Sources) of information-- exposure" Source(s)of information-- outcome Prevalence rales of defects at birth (per live births or pregnancies) Comments" Tbmlia. 1979 U.K. J22| Cohen el al. 1980113| U.S.A. Retrospective exposureselective study Retrospective exposureselective study 340 Anesthetists: -exposed" were those spending at least 1/2 of their work time in anesthetic practice (respondents 92.4%) Mail questionnaire Mail questionnaire 9.3% For exposed in the last 20 years; 7.2% for exposed before; 4.3% for unexposed (children of male and female anesthetists not separately analysed) Excess due toCNS and musculoskeletal defects HenochSchdnlein purpura, muscular dystrophy and diabetes included as malformations 107.771 Dentists 130.000 chairside assistants (response rates: 70 and 73%) Mail questionnaire (ftoatiseni of anesthetics, light users ( = 1-8 hours/ week), heavy usen (=more than 8 h/ wk) in the same year and the year before concept) Mail questionnaire Wives or male Con/! amirxft demists: nonusers 4.9%.light users 4.6%. heavy users 4.8%. Female chairside assistants: nonusers 3.6%\ light users 5.7%*. a = p < 0.02 heavy users 52%. (nilrout oxide stone exposere = 5.5%) Exposed chairtide j assistants; 2.47%; I musculoskeletal unexposed c.a,: | defects--p < 0.01 I.IS% I Lauwerys JI..I98I w Belgium Retrospective exposureselective study 121 Male and 28 Mail questionnaire female anaesthetists (durstion of + 63 male and 176 exposure, hours/ female operating day of exposure. theatre nurses vs. types of 62 + 27 anaesthetics. dermatologisii, 290 ventilation system) + 22 occupational physicians. 14 + 33 intensive care noises. 20 female social nurses and 168 other doctors and nurses: Response rate: 47*. ranging from 41.5% (intensive care nurses) to 35.5* (social MKCS) Mail questionnaire Exposure of mothers in pregnancy: fellterm malformed 7/ 259 pregnancies: premature malformed 3/239: still-births. malformed 0/259. Never-exposed mothers: fell-term malformed 47/ 1.519 pregnancies: premature malformed 5/1.319: still-births. malformed 3/1519 Type of anesthetics was ascertained. No differences among group?, for suxAing habits and drug consumption. No difference among croups for birth defecis was statistiealk significant e.m., exposed miles; e.f., exposed females; u.m- unexpoaed males; u f.. unexpoaed females; n.i.. not significant "Level and trimester of exposure in brackets. bCocnments include: (^values. types of malformations, specific exposures, serious identifiable bias, and confounding--when confounding factors were controlled in the study this is reported as Cotif. comrot. i AP00019904 261 262 HemminUi and Vincis statistically significant) or 3.8 (only for heart-great vessels defects) (20]. Other studies (9.11,14,19,21, limited to smokers[ showed either no or not statistically significant differences. The negative result obtained by Ericson and Kitllen ] 10] is particularly relevant, since outcome was usscscd through an objective source. Types of malformations. Excesses of specific malformations were shown by Corbett et al 116, haemangiomas and inguinal hernias), Knill-Jones ct al {18. minor defects], Pharoah cl al |20, heart-great vessels defects], Rosenberg & Vanuinen {12. luxation of hip and inguinal hernias], Tomlin |22. CNS and musculoskeletal defects] and Cohen et al (13, musculoskeletal defects]. Minor malformations arc more prone to information bias (23|, ie. an apparent excess may be due to more accurate reporting by the exposed subjects. This is particularly suggested when unexposed controls show an excess of unspecified "other" defects (12], In addition, ependymoma, Hcnoch-Schbnlcin purpura, muscular dystro phy. diabetes, heart murmur, and malabsorption syndrome were included among malformations in single studies. In some studies, the purpose of the investigation was mentioned in the question naire title ("health effects of anesthetics"); this may have induced more accurate answers by the exposed groups. Evaluation of anesthetic gases. Due to the aforementioned shortcomings (in consistency of results, nonohjcctive sources of information, possible recall bias), the available evidence of teratogenicity of anesthetic gases is limited. Nitrous oxide has been associated with on excess of birth defects among female chairsitle assistants in one study only (13( {see Table U), and the evidence of teratogenicity is low for it. The evidence for /uilotliane is inadequate. Caffeine (Coffee) Ingestion of cafTeine, mainly from coffee, tea, and cola beverages averages al 190 mg/d per adult population in the US (24]. Five epidemiologic studies on the as sociation between coffee and caffeine consumption during pregnancy and malforma tions in the offspring have been reported and arc reviewed below; results arc sum marized in Table 111. Also, other types of reproductive effects have been studied (25|. In the prospective Boston Collaborative Perinatal Project, over 50,000 pregnant women were interviewed on their consumption of drugs (26]. Over 5,000 women reported use of caffeine, usually as an ingredient in medication. No specific type of malformation was related to caffeine intake. Yet. coffee drinking wus not controlled for and the authors recommend caution in interpretation of results. In a ease-control study reported by Borlee and co-workers |27], the parents of 202 case children and of 175 control children were interviewed on the types of beverages consumed. Proportions of mothers drinking more than 8 cups of coflee per day were 23% among eases and 13% among controls (p < 0.05). The association dill not involve specific tyjK's of malformations. The frequent coffee drinkers ap peared to be older than the women drinking less coffee. AP00019905 i Teratogenicity Data 263 TABI.K 111. Kfwdeminltmic Evidence on Teratogenicity nf Coffee Consumption* Information on coffee consumption Prospective 1 Retrospective 1 Rctnrspciiivc | RctfmpttJivc 1 Retrospective 1 Sample sire 50.31)0 Birth* 140 Caw* 2.030 Ca.se* 12.205 Women 4H2 Cases Malformation* All All 380 Inguinal hernia. 299 deft lip palaic, 277 cardiac. 144 pyloric stemvsis. 120 cleft palate. 101 CNS (O All 83 CNS. 150 skeleton. 45 cardiovascular. 154 oral cleft* Risk ralio (consumers v*. nonconsumers) - i (Use cif i-afTcrnc medication) Sipnificunec . JL_ . 1.5 (> Cups/ day) p < 0.05 Pyloric stenosis: 95* c,l.: 1.8 (? 200 mg 0.8-3.9 caUuinc/Jay) - 1.0 - t.O Reference Heinonen d al. 1977 1261 Bnrleect al. I97X I27| Rosenberg ct al. 1982 128] Linn ct al. 1482 |2Q| Kurppa cl al. 1982 |30I *1. interview; Qk inuil questionnaire; < l) Tor csich group of defctls, 712 other meNormalinn* were used a* u comparison gnmp. In a case-control study. 380 infants with inguinal hernia. 299 with deft lip with or without cleft palate (CL CP), 277 with cardiac defects, 194 with pyloric stenosis. 120 with Isolated deft palate, and 101 with neural tube defects were compared with 712 other malformed infants (control group). Maternal ingestion during pregnancy of tea. coffee, and cola was investigated through personal interviews. Relative risks ranged up to 1.8 (0.8-3.9) for pyloric stenosis (total daily caffeine intake greater than 200 mg vs. no ingestion). The corresponding estimates for inguinal hernia, CLCP. cardiac defect, deft palate, and neural lube defect were 1.4, 1.3, 1.3, 0.8, and 0.8. respectively. None of the point estimates of relative risks was significantly greater than unity and no dose-response relationship was apparent |28) (Table III). Linn and co-workers |29| carried out a retrospective study on 14.300 women, among which compliance was 90%. There was no association between malformations in the offspring and coffee consumption even in the highest exposure category (> 4 cups of coffee per day). Finally, the mothers of 482 children with central nervous system, skeletal, cardiovascular, and oral cleft malformations from the Finnish Reg ister of Congenita! Malformations were interviewed and compared in referent mothers of healthy-children. No difference was found in the consumption of coffee [301. The evidence on the teratogenicity of coffee or caffeine intake is low. The one study reporting an effect does not rule out the results of other negative studies. APOOOf9906 264 Henvninki and Vincis Carbon Monoxide Ai least ciy,!u cases of documented maternal intoxication from coal gas used for illumination were associated with retarded mental or psyehomntor development in the offspring (4,31.321. In three of these cases autopsies were performed and showed softening of basal ganglia, cerebral atrophy, hydrocephalus, and microecphalus [32|. In nine other case reports )4[, various types of brain pathology, including damage of the basal ganglia and microcephaly, were detected. The evidence is lintiU'd for a direct effect of carbon monoxide in inducing structural changes of the CNS in the offspring of exposed women. Ethanol Previous reviews indicated a causative role of alcohol in the "fetal alcohol syndrome, FAS" (33.34) (Table IV). The features of this syndrome are not unequiv* ocai |35-37[; Sokol [38| has proposed that a reliable diagnosis should include at (east one typical Icature of each of three groups of defects: growth returdution. CNS effects, and facial characteristics. The presence of FAS in live bom children in France, Sweden, and the US ranged between 1/600 and 1/1000 (37.39a,b.40]; it doubled when milder syndromes were included. Prevalence rates of 19% were reported among children born from mothers consuming 56 or more grams alcohol daily |37(; elsewhere, rates were in the order of 35% in children ofchronic alcoholics [40,41). In these studies, the quantity of alcohol consumption was estimated by interview and was probably subject to u reporting bias. In three series of FAS children the prevalence of microcephaly, oral clefts, and heart defects were respectively 40-90%. 1-25%, and 25-50% (42-44). ie. greatly in excess of the corresponding rates in the general population. When considering the studies including information about alcohol consumption and the presence of major structural malformations, the association is less clear. In a prospective study, there was an increase in the frequency of major malformations (32 vs. 9% in the control group) in the offspring of heavy drinkers consuming a mean daily dose of 2.2 g alcohol/kg (451. Microcephaly was the main type of malformation noted, and it explained most of the difference between the groups. Hypospadias and genito-urinary and oral malformations were more common in infants of alcohol abusers as compared to the controls [39a,bl, No excess oral clefts and cardiovascular defects have been noted in a study of Tennes and Bluekard |46|. -There is a hiah evidence of a teratogenic effect of alcoholism in humans in so far as it induces FAS. A eausut relationship between maternal alcohol consumption and other structural malformations in the offspring is less well established. Gasoline Mental retardation, scaphocephaly, prominent occiput, poor head growth, and minor anomalies were found in two children whose mothers reported inhalation of gasoline. Four children with a similar syndrome occurred in 1973-77 in Shamattarere, Canada, but gasoline sniffing could not be ascertained (47). The evidence is ituich-qiuin'. Hexachlorophene Hailing J4X] compared the occurrence of malformations in six groups of nurses using I % hcxachhirophcne soap and in six hospital-matched groups not using the Teratogenicity IHila 265 soap. Pregnancy outcomes were retrieved from the records of obstetric departments: the source of the exposure data was not staled. Kxposure consisted uf20-60 washings per day, both before and during the first trimester of pregnancy. U>ss to follow-up was 15% in three hospitals. Major malformations were 0/233 live births of the controls (vs. 4-5 expected) and 25/460 live births of exposed women. There was no adjustment for age and parity, but it is unlikely that confounding could explain such a difference. Bullzar ct al (49| reported two studies. In the first study. 63 hospitals were asked to provide lists of women in medical occupations who had left work because of childbirth in 1965-75. Only 31 hospitals replied and provided data on approximately 1,500 women. Ail women hud worked at least in the later pan of pregnancy. Malformed children were identified through the Swedish Register of Congenital Malformations in 1965-72. and from the Medical Birth Record Register (MBRR) thereafter. Results are given separately lor the 1965-72 period (5 malformed children born from 930 women, vs. 9- K) expected), ami for the 1973-75 period. In 1973-75. observations arc reported separately for 2(X) women from three hospitals in the Gothenburg area and for 260 women from other hospitals. Observed and expected malformations were respectively 13 vs. 4 in the former group and 3 vs. 5 in the latter (this observation of an excess in the Gothenburg area could not be referred to any particular exposure). The second study reported by Balt/jr ct al |49[ describes the outcome of 29.806 pregnancies among women employed in medical occupations in 1973-75. These women, identified from a register of medical personnel, were linked with the birth register through the personal identification number. Malformations were collected through die Medical Birth Record Register. Expected numbers were calculated from all deliveries in Sweden in 1973-75 (323.011 infunts). A total of 1.551 defective children were born in the study group, vs. 1.491 expected: an excess in Gothenburg was confirmed (42 observed. 29 expected: p < 0.01). A comparison between the use of hcxuchlomphcne soaps in "periods presenting possibilities for exposure during pregnancy" and malformations in the offspring revealed no apparent assx:iation. Some aspects in these two studies reported by Balt/ur ct al require comments: exposure was ill-defined: in the first study only 31/63 hospitals responded, and the quality of information from these hospitals was probably different: there ujs no information on individual exposures to hcxuchlorophcnc. There is a Unv level of evidence about hcxachlorophenc teratogenicity in man. Lead The data on the teratogenicity of lead to humans arc historical and cannot be evaluated critically [50). A ease report on the association of lead intake in moonshine whiskey and fetal anomalies has been published, but it may also be a result of alcohol intake {51). No epidemiological evidence is available to evaluate the possible terato genicity of lead to humans. LSD and Cannabis Several ease reports have been published regarding children bom to mothers taking LSD during or before pregnancy [52-55]. Most of them describe similar skeletal defects: a common feature was distal agenesis of limbs. In these reports the LSD doses were not estimated, but it is stated that they were sufficient for psychedelic TABLE IV, Epidemiological Evidence oy Teratogenicity of Ethanol (Alcoholic Beverages)* Minmaiinn i>n exposure Retrospective. 1 Retrospective, 1 (clinical nervations) Prospective. 1 Retrospective. 1 (clinical observations) Prospective. I Prospective, f Sample size 127 Cases from alco* hoik mothers 11 Cases with "fcttl alcohol syndrome" (FAS) 23 Chronic alcoholic women + 46 matched controls 6900 Births Malformations Facial characteristics, growth deficiency, psychomotor disturbances Short palpebral fissures (11). microcephaly (10), maxillary hypoplasia (7). limb anomalies (0). al tered palmar crease pat tern (8). cardiac anomalies (7) 6 Babies with FAS in the alcoholic group (includ ing short palpebral fis sures, prosis, strabismus, joint anomalies) Babies with FAS 633 Women "No specific pattern of anomalies" 70 Infants bom from "alcoholic'* moth ers + 93 "cofitroi" infants A priori definition of "fea tures compatible with FAS" Exposure level - Nondrinken: 326 women (1). <45 ml absolute alcohol daily: 249 (H>. > 45 ml daily average (ab solute alcohol); 58 (III) "Alcoholic" mothers: one nunee or more of absolute alcohol/ day or 5 + drinks on occasion Risk ratio and statistical significance -- Severe cases t/1000. less severe 1/400 9* Congenital anomalies in Group 1 11 % in Group II 32* in Group III (p < 0.001) 9/70 Infants with FAS from heavy thinkers (> 1.0 ounces/day) 0/31 from moderate drinkers (0.1-0.9] 2/62 in control infant* Reference Umoinec(a). 1967 J35| /ones and Smith. 1975 and 1973 J33.36] /ones et al. 1976 (41] Ochacne et al. 1977 (39a( Ouellette etal. 1977(45] Hanson etal. 1978 |37| Rftrospective for 2 infants, prospective for the other 2: 1 Prospective, I 4 Dead infants 23 Pregnancies. 21 live births Different features of brain malformation at neuropathology PAS aid other anomalies Retrospective 204 Abusers 11.923 controls All Prospective. Q 278 Births ATI Retrospective 109 Infants with FAS All Retrospective 71 Infants with FAS All *1. Interview; q, questionnaire; FAS. fetal alcohol syndrome. "Heavy ethanol in take" in pregnancy (2 women) + occa sional "binge" (2 women) "alcohol problem" Alcohol abuse was de fined "clinically" S Exposure categories during f and III trimester 7/21 FAS. other 7/21 thought to have al cohol-related problems FAS 12.5* in abu sers vs. 0* in con trol), hypospadias, genito-urinary and oral malformations increased No excess risk Anomalies in FAS infants: microcephalus 184*). var ious facial anomalies (1174*) Anomalies in FAS infants: microcephalus |44*). var ious facial anomalies (7-68*) Clarren et al. 1978 (42| Olcgard et ai. 1979 |40| Sokol ct al. 1980 Twine and Blackard. 1980 f46| Majcwski, 1981 |44| Nestleret at. 1981 |43| APOOOf9 9 1 0 267 268 Ilemminki and Vincis effects. LSD was either taken throughout pregnancy or in the first trimester. In at least three reports, there were multiple exposures (cannabis, drags, or other strong hallucinogens). A further report 156] describes a hnhy with multiple malformations, including absence of phalanges, born to a mother who had taken 3 doses 9 months prior to conception. Finally, another report describes the birth of a normal baby from a woman who had been a high-level consumer up to 2 months before pregnancy |57|. No malformations were described in a follow-up study on ten pregnant women with an intake of LSD which entailed hallucinatory phenomena 15K|. All women took LSD in the First trimester of pregnancy and some also later. Another uncontrolled follow-up study |59) included 247/300 women taking LSD and other drugs and responding to a questionnaire: during follow-up 148 of them had pregnancies (120 live births) and 14 malformations were detected, including six turned-in feet, two tibial rotations, and one unspecified bone deformity of legs. No birth detect was observed among the 12 women taking LSD during pregnancy. The median single dose for mothers of malformed babies was 100 fig (range 75-250 /xg). Overall, the level of evidence for LSD is low since the positive findings derive from case reports, most of which describe multiple drug intake. However, the evidence cannot he entirely disregarded, because distal limb agenesis, which has been described in the offspring of six mothers taking LSD. is otherwise observed rarely. The epidemiologic literature on teratogenic effects of cannabis is scanty and overlaps with that on LSD. In two ease reports ]53.54|, the mothers of tables with distal defects of limbs consumed both cannabis and LSD. In a further report [56] and in one follow-up study |59] concerning mainly LSD, cannahix is mentioned as one of several drugs concurrently consumed by the mothers. The level of evidence for cannabis is inadequate. Mtthylmercury Knowledge on the embryoioxieity of mcihylnwrcury derived front studies re^-v garding the ingestion of contaminated food |reviews by Kotte and Longo. ftO. Chang ~ chit, 6) |. These studies include the well-known epidemic A Minamata, Japan (621. In the latter population severe neurological disorders in adults ingesting methylmercury-contaminatcd fish were described as early as in 1953. However, only a few >*rs later children affected by symptoms resembling those of cerebral palsy were described. Between 1953 and 1971 at least 25 children were born whh brain damage. ' " After systematic research, a syndrome could be observed and this was also connected to ulkylmcrcury ingested in contaminated fish by the mothers. A comparable epidemic of microcephaly and other neurological disorders look place in Iraq in 1972. us a result of ingestion of gram treated with mcthytmcrcury {63.64J. Out of 32 infants exposed in utcru. ten showed cerebral palsy at the age of 1 year. In Iraq as well as in Minamata, mercury wax found is biological samples from the affected mothers and children. A dose-response relationship has been established (651 A loud maternal exposure to l- 1.2 mg/kg corresponded to a 5<>% frequency of neurological signs in the offspring |65|. In Iraq the total ingested doses were about 150 mg and the daily exposures ab.HH X(> ^xg/kg. with large variation*. Observations from Minamata ami Iraq have also been confirmed in other small series of cases from AP0001991f Tsratogenicity Data 269 U.S.S.R., Sweden, and the U.S. {60.61,661. Neuropathology of prenatal intoxication revealed the following in two cases from Mitisumoto cl al |67| and in two cases from Choi ct al {681: narrowing of gyri, hypoplasia of the basal ganglia and cerebellum, and hcteroiopic neurons in cerebral and cerebellar white matter. Mcthylmercury can be considered u teratogen with a high level of evidence, taking into account the morphologically detectable changes in the CNS. Kanechlor (PCBs) A "PCB-inducod fetopathy" (Yusho) has been described as a feature of an episode of intoxication occurring in 1968 in Japan, in which approximately 1.000 persons of different ages were accidentally intoxicated by rice oil contaminated with Kanechlor 400. a technical tctrachlornbiphcnyl product. The Yusho oil contained about 1,000 ppm of PCBs and 5 ppm of polychlorinated dibenzofurans (69j. The dialogic role of the ingestion of this oil was ascertained for intoxicated persons through the following: I) examination of oil containers, shipping records of the producing company, and records of oil dealers; 2) analysis of biological samples; 3} a case-control study on 121 adult patients and 121 adult controls concerning use of oil and fats 1701. A fetotoxic effect of Kanechlor was first recognised when a group pf intoxicated mothers delivered 13 babies with a syndrome which included dark brown pigmenta tion of the skin and mucous membranes, retardation of growth, gingival hyperplasia, spotted calcification of the skull (70-72|. Hyperkeratosis, atrophy or the skin, and cystic dilatation of hair follicles were described in stillborn babies delivered by exposed mothers 170.71 {. PCBs were detected in the skin by chromatography. One. five, and one females had been exposed respectively in the first, second, and third trimester only, two had been exposed throughout pregnancy, and the lime of exposure was unknown for four. Miller !7! j estimated an average exposure of 11 weeks. Intake was estimated to be 65-839 PCB/kgfday 173). There is a hixh level of evidence that tlie contaminants found in the food oil are human teratogens. Whether PCBs. dibenzofurans, or possibly dioxins were the causative agents cannot be resolved. Potato Blight Rcmvkk [74,75] reported a positive geographic correlation between potato blight and anencephuly-spina bifida (ASB). Subsequently to this, a number of geo graphical and temporal correlation studies have been undertaken; hy and large they failed to confirm Rcnwick's findings 176-85). Lorher ct al (86] reported two eases of ASB born to mothers on a potatoavoidance diet during pregnancy. A few analytical studies are available. Robert et al [87] interviewed mothers of 336 malformed babies (neural lube defects! and as many normal controls in Glamorghan, South Wales. Cases and controls were born in 1964-66 and their mothers were approached through a questionnaire several years later. One-third of both cases and controls did not reply nr were not traced. Home-grown potato consumption did not differ among eases and controls. In another case-control study on potato consumption in pregnancy [88], 83 children with spina bifida, collected retrospectively up to 12 years before the study, were compared with 85 children chosen from the general population and matched to 270 Hemmlnki and Vlneis the cases by sex, month, and year of birth, residence and -social class. Mothers were interviewed by health visitors. No difference in maternal potato consumption during pregnancy was found between cases and controls. Potential confoundcrx like maternal age and parity were not considered. In this study, a negative confounding may have been introduced by strictly matching for residence and date of birth, since blighted potato consumption varies according to social class, place, and time. In another case-control study in New York City |H9|, 265 mothers of babies with ASB diagnosed in 1970-72 and 549 control mothers agreed to be interviewed by telephone on their current potato consumption. Controls (2 per case) were chosen from birth certificate files and were matched to eases by parental residence and date of birth. No relative risks were reported, but they can be computed from the published figures. Most of them are lower than one. The study, however, had some shortcom ings: cases represented 70% of those who were eligible for interview, whereas the corresponding proportion for controls was 94%. In addition, although nonrespondent controls were replaced, the matched controls were not always dropped when the case refused the interview. Thus, a comparison bias (higher social class selection of respondent eases) cannot be excluded. Finally, the analysis did not take into account maternal age and parity. However, bias and confounding so strong as to mask a positive association are unlikely. Nevin and Merrett (90] reported on 8b pregnant women who had a previous infant with ASB and who were advised to avoid eating potatoes in subsequent pregnancies. The advice was followed by 27 women who were compared with the other 61. ASB occurred respectively in 2/27 (8.7%) and in 2/61 (3.6%) {p > 0.05). This study leaves some open questions: The 88 women derived from a larger group but mechanisms of selection arc not stated: inclusion of women in the groups (potatofree or not) was not random and confounding cannot be ruled out; numbers arc small. The available studies do not indicate a role of potato blight in the etiology of ASB. Correlation studies were negative. Analytical studies concern potato (and not specifically blighted potato) consumption or avoidance: none of them suggested any association with ASB. Shortcomings in the design of these studies cast some doubt on the acceptability of such negative results but do not provide any suggestion of u positive association. Smelter Work In a recent study (911. a list of women employed ax copper smelters in a company in 1955-1976 was compared with the records of pregnancies of the local hospital. ITic completeness of either company records or follow-up is not discussed. Malformations were 17/29! among the offspring ofwomen in the smelter as compared to 22/1.(XX) in controls (p < 0.005). Multiple malformations contributed to this difference. Sulphur dioxide. lead, arsenic, and cadmium have been suggested as the possible causative agents |92.93}, The results were not controlled for possible con founding factors. This individual study provides a low level of evidence on the teratogenic haiards of copper smelting. Soft Water Fedriek f94J reported a negative correlation between water hardness and prev alence rates of anencephuly in ten areas in the U.K. This contrasts with a similar correlation study [9S| in Liverpool and south-west Lancashire where the highest Teratogenicity ihit* 271 incidence rate of uncnccphalus (3.9/1,000/ycar) was found in a "hard water" area, and the lowest rate (2.9/l,000/ycar) in a "soft water" area. Lowe ci a] 196} correlated water hardness with a) CNS malformations (mortality data) in 48 South Wales areas and b) ancncopahlj in 38 country boroughs in England and Wales. Correlation coefficients were at! negative. Analogously, negative correla tion coefficients were found by Crawford ct al |97] comparing water hardness and anencephaly mortality in 5S English large towns (many comparisons were made and most correlation coefficients were statistically significant). Morton et al (98| carried out similar work in South Wales coasidcring CNS malformations. The correlation coefficients were negative but low and statistical significance was weak (p < 0.05). Multiple comparisons were made. A case-control investigation in Cardiff included 108 eases of neural tube defects and as many controls matched for sex. age, and social class. Determination of II elements in the drinking water yielded similar results for cases and controls J99). Another case-control study in Canada included 468 deaths from anencephalus and a random sample of 4,129 live births |]00|. Motltcrs lived in 142 localities for which the water concentration of 14 elements was available. No association was found for any of the 14 elements. Risk estimates were adjusted for potential confounding factors (parity, season and year ofbirth, maternal age. and others). However, samples were not collected from ease and control dwellings. Overall, these studies provide inadequate evidence on the teratogenicity of soft water. Laboratory Work (Solvents) Five studies suggest an association wiih teratogenicity (Table V). Kuccra (101} reported that five out of nine mothers of infants with sacral agenesis had been exposed to miscellaneous industrial solvents, as ascertained retro spectively. No control group was used. Other malformations were not analysed. A Swedish group has published three studies on laboratory personnel possibly exposed to solvents for whom other exposures have not been ruled out. Mcirik ct al 1102) identified from the university files the laboratory Matt who had been working during pregnancy. They had given birth to a total of 245 newborn children. Malfor mations were recognised both through interviews and from the Swedish Malformation Register. Eleven children with serious malformations were found vs. four expected on the basis of the rates among deliveries in the same hospital birth wards, adjusting for maternal age and parity. The 11 malformations included four anal or oesophageal atresias or stenosis, and two children with pcs cquino-varus. The second study was similar in design but regarded offspring of women working in chemical laboratories of the pharmaceutical industry 1103). In the exposed group, prevalence of major malformations was 6/106 (5.8%) vs. 2/297 (0.7%) in the referent group. The malformations included (wo oral clefts and one multiple gut atresia. The exposed-referent comparison was uncontrolled for the potential con founding factors. It is reported, however, that the age distribution was similar in the two groups. The third study was similarly designed and covered laboratory workers of pulp and paper industry. Major malformations were 6 vs. 2.9 expected, standardized for age. parity, and hospital [!04|. Malformations included two gut atresias, two heart defects, one anencephaly. and one cleft palate. AP00019915 i TABLE V. EpiJwninlotiic E*Meiw on Teratogenicity of Laboratory Work* Information on exposure Sample site MHllVrfTtWliofls Retrospective Q 9 Cases Sacral agenesis Retrospective fUmvcrsil> tiles f interview | 322 Wooten All Retrospective I. Q 44)5 Women All Retrospective. Q Retrospective. I 890 Women 120 Cases *1. interview; Q. null questionnaire. All CNS delects Risk rjiio and significance (p) 5 Mothers exposed h or ganic solvents J Cases of anal or oesopha geal atresia in women working vs. mm- in women mil working in a lahtmnorv during pre-gnurw A Major tnaUtirniiUkiRs out of 103 infants aiming "chemical laboratory workers" ts. 2-297 among the nonchomical workers, One multiple gut atresia in the former group 6 Major malformation* (vs. 2.Vetpectcdi among women working in labora tories (2 gut alruoa) RR = h.5 tp<0.IM> for ex posure lo organic solvents __ Reference Kuccru. I960 11011 Meirik dal. 1979 11021 Hanssonet al. I9H0 |I03| Blomqvlfl al. 1981 f 104] Hofmberg. 1979: Hoimberg and Nurminen 1105,106| A{ 9l66l000dV paijnaaoajnsodxa asm aim ui put? `uwouq inu srm amsodxo jo aajSap oqx `XaueuSaJd 3uunp 3u;Xuds X'S'^'Z oi posodxa uaaq ftujARq sjaqioui 01 tuoq 'epyiq muds qi|M sO|qeq umi poquasap [9111 ssqjoj pun ajt?s Xq uodoi r `puci^ waft uj [S|[| SuiXwds apianyaq Xxouaqd 01 pdin -qtJUB pus pupjdirj u; paquasap aja* siuejui uxiunq ui suoiiruuojicut jo sasra*oMX asn apiatqjaq ui pamqiJiiB aq p|noa Xitpiqjoui put! Xijjnijoiu aAnanpoJdai ui spuaii ou X|po3o|[n pun *oaup.33U hr ajaw spiny pun vanvsn ui siuauiairisraiii pMiiXjRuy paXwds X|oaisnriu uaaq pnq x*S`fr*Z ajaqw 'Ruozijy 'aqojj} jeau stojr aqi ui spjoaaj (njidsoq aqi u posnq Xpms 33oiiuiapido uir mo paiuca |vi \ | uttHiovS r*1 unoy 'paqaeaj aq p|tu>a suoisnpuco nu pun 'aienbapHut pojapjKuoa sew ]Buaietu sip jnq 'sfEjidsoq uoSies aajqi 111 |^| 11 aauaias jo Xiuapeay jbuoiibn STl 9qi.io aaimuuio^ c Xq paianpuon snw XdAjns v 'IZlll jjoiouoh pu* {ml astry pun asoy Xq paqsqqnd uaaq aARq mrujoi\ inoqe suoda.i jBaiiopaaue jaqio auiojpuXs s.uamiq qi;M uojpjiqa peq sjaqioiu oj tumuiot^ in sXtuds appiqiaq Xq )iq uaaq pcq oqw U3LUUM luruScud jno; paquasap [OilI j* la dunx 'lfOI t I i3 ffunox Xq moiAaj aqi uo posnq X[uirui si untirsw siqx suiqintftisaAii} jruuojui pus spodaj asvo pasodxo X|uicuj w3M ajduad qaiqw oj waSn aqi Xpnis qmta joj Xjpads 01 apmu uaaq SRq uojja uir J3AOMOH vuixnip qiiA\ paiminuRiuivi ** qans) t|Ka;iuaqa paiRuijojq.i jgqjo t1 cunsodx? luojj sumtip ui aansodxa Xpimndas asXjnur 01 a|qissod juu v| j[ aaOi. puex-S`fr,8 iwijiipqa aq ui spoou snMsaqpc Xuds ju uoiitsu<iuKK> itiaiuiaqa aqx .ambspiM s; soAjsnqpu Xwds jo sianjja aiuoSuiwai uo aauopjAa aqi snqx 'sjsXjrub 01 pau`lqn>i aq pjnua *uiRd psuiui aqi jo (% = nj %h Xjuo |soi ) MaiAjaju? irnsod aqi ui sujnjaj a>li[ Xjja jo asnnaaq paiiiu]| s\ 1; :s|ojiu(vi.jo asoqi 01 pajudium sn sasna jo saiuoq aqi ui uaijo aunti saAjsaqpr Xiuds jo asn syndai Xpms jaqio aqj, 'UoM uoimuijojui juaiaijinsui ssaiS put? laiuisqi? ui si auo `payixlaj saipnis owl aqt JO ssAjsaqpv Aejdg paqsiiqwisaun suibuioj jopitj |rsni?a aqi Sutaq siua|os jj aauapiAa aqx '1/.V11/ i ^jum Xjoinjoqt!| jo sadXi umuaa qqw paiutavtssn Xiiaiua3)Bjai aqi uo aauapiAa aqx MaiAjaiui |uosjad b ui X}aAt>aadsojiai paiaayoa srm sainsixixa uo uui|i!uiiojui xiuJiuoa jo jaquinu J8|iuns n pus suoiinuui>j]R^ I'niuoSuo^ jo jo)s]riay qsiuuij aqi oj payodaj suoijmujoj|rui moisXu sduajou [yj| popnpui Xpms aqL `P31J,'*^SJ osqr srw sisnp oi ajnsodxa jo ssaaxa uy 1901 *i>'OI \ i^!Jis!P ojrjpw Xjiujojcuj oums aqi uiaij uaqnu pjiuoa aqi 01 pajrduxta sr sjatpoui-asra aqi Suoum `sa p|) paiuasajdiOAO aq 01 siuaA|os atiinXiosnoijRA 01 sajnsodxa iwiijiiiapi srq Xpms |oj)U(asca qsiuujj y sjoqmR aqi Xq siuoa|os shuijba aq 01 lqtfmiqj ajn asaqj, sjoppi |Rsni;a aiji Xjjhia|)i ci ja|-ui> u; paudisap Km ajaw saipnis aqx `uoui?|ndtKl aqi jn isaj aqi j3ao snivaui! |i!u;isa|UMij|si!3 pm< syap |rjo jo ssaava ub joj aauapua dtmjis apuiud saipms pauiquioa aqi 'Xpms qara 111 papauoa aq pjooa suonnuuojimu jo sjaqiunu ||inus qflrmqi usajj `a|qiu|aj aiaw Riep uojiBiiiJiiJicui pun iuauiXo|diua qinq jo luatuuimjaasi! 'saipnis aajqi aqi u[ LZ Bltqi X)iajuaoiBJax > 274 Hemminki and Vincis after the neural tube closed [these comments were made by a subcommittee of the N.Z. Agricultural Chemicals Board: 117], Geographic pathology studies. Cutting et al 1118] surveyed retrospectively malformations occurring in 22 hospitals in South Vietnam, as reported on the daily summaries prepared by midwives. Private clinics were not surveyed, some hospital records had been destroyed, home deliveries were excluded, as was. the Chinese group of the population. Prevalence rates were 5.3/1.000 in 1960-63 (period of light spraying of Agent Orange) and 4.5/1,000 in 1966-69 (heavy spraying). Overall, 2,355 defects in 488.852 births were identified. Anencephaly. cleft lip/palate, club foot, and hydrocephaly accounted for 80% of all malformations. There was no nonexposed category and only a dose-response relationship could be measured. It has also been pointed out (1091 that heavily sprayed areas were underrepresented and there was no precise knowledge of exposure of pregnant women. Two geographic pathology studies on 2,4.5-T spraying in New Zealand have been reported. McQueen ct al |H9[ collected cases of anencephaly and spina bifida in three areas where clusters of cases were allegedly present. Cases were collected in 1974-76 fmm hospital records, and a comparison was mode between observed and expected numbers in each area. In Northland there were seven cases, which corre spond to the expected value. Five cases occurred in Taranaki, of which three were in the same street. In Waikato there were eight cases (one anencephaly, seven spina bifida), all diagnosed in 1 month. The mothers were interviewed about 2,4,5-T contacts in pregnancy: 3/7 mothers of cases in Northland. 3/4 mothers of cases in Taranaki (one is excluded because she conceived elsewhere) and possibly 4/8 mothers of cases in Waikato declared to have conceived during the period of 2,4.5-T use. However, the authors state that only in one or two cases was there "some exposure" to 2.4.5-T in the critical period, and (hey concluded chut there is no evidence. This is not to be considered an analytical study, since it lacks controls and standardized interviews. Hanify ct al 1120) compared prevalence rates of malformations in seven New Zealand areas in 1960-66 (when no exposure to 2,4.5-T occurred) and in 1972-76 (when 2,4.5-T spraying was common). Quantity, dates, and places of spraying were collected from the companies. No geographic or temporal correlation could be found, with the possible exceptions of talipes and hypospadias 4-epispadias (no mention is made of the changing attitudes In the registration of birth defects). Other correlation studies relating to 2.4,5-T spraying in agriculture have been reported in Australia |I2I|. Arkansas (122). and Hungary |I23{. These studies concentrated respectively on anencephaly and meningomyelocele in 1965-76, deft lip/palaie in 1943-74 and deft lip/palaic, cystic kidney, anencephaly. and spina bifida in 1970-76. They were all negative. A further study of geographic and time correla tions in Western Australia suggested a ride of "insecticides" and "herbicides" in the occurrence of cleft lip/palatc. but no firm conclusion could be reached (124]. A Birth Defect Registry has been established as a surveillance system in the Seveso area, which was highly polluted by 2,3,7.8-TCDD in 1976 (125]. It collects malformations (all types) in 11 towns (222.000 residents) from the lists of live and still-births: this is followed by home visits of paediatricians. From 1978 to 1980. oiuiw u| 'is'oiu in isopmu pajapisuai uq seq pojja aqi wq lKrttl'9Z) suopniu -jujtcui (SND) uiawXs snoAjau jRJiuaojo uuajjnaao oqi qi; paiEtaoss'* xbav Huiifuure Xaroq suotin3i)S9Aui awos uj `|9|} p9AJ9qo sn (p|oj-f| ucqj ssajj inojja {fcuis r noipnis aunts u| i|-Zr9Cl wipms jaqm iiuoaos Xq pouuyuoa jou 3i9M sSuipuy aqx'XoAjns ^!|nwi'M iRinujjaj qsiiug 34> J *puiu3wd OOO'Z.1 uo rOKP4 iRi-iawm ut sjaqouiK Suouib siaojap ynaq imtuafluoa uj DSBsj.'vui ur payodw 11 Cl i in Jpup^d '1A 3mRX u! pasijRuiums ojr soipms iu.iooj jo sqnsDJ pun suSisap oqx iOCI l uoisuqaf pun [ft3i | pnunuig put* jnXM<i*umiisapuri Xq po/AatAOJ se saipms pouSissp-qoM puoAM ui pwStis-OAin unnq snq flui-toi'is aitajitip jo Xipmotfoinjm aiqissod oqj. oooeqoj. 'AimthjpiHH vi oinsodxa p'ujoirui jo Xii.iiua3uiRj.il jo oauopiAg sainwtdxo |t?iu.ilir<J <n X|uo j.ij.u GClt")j, put: I.VfZ uo snipniv |Rnj]X|nun o|qiqii:.\r aqj tqfil ui lunpt.vn: ur 3uimo||oj 3u.iiuo|q;> flusdopAsp anqjo/* jo j.iqmnu patjiTOdsun ur joj Xpwjrdas vuottRAjasqo yod.u k>u saop Xpms siqj `pajapisuop si:m auiqn CJGOI 01 3Jnsi>dxa uaq* go'l Pun HI 'i W3M soiirni pniopivoo-i si?M utxoip Xur it) ojnsodxa uoqw, *X|3An.i3ds3J 'j'o pun %*o ojoav vonuj oirj poisnlpn-oiin pun opnj,* ,iqi `suimnuijojiruj icniuoSuo.i jjr joj '(%C9-t9) a\oj nJ3M *iiu .vnmqduio.t 3qj. dniuS puiuoa aqi paiujoj wnvodxa }oii.->qdojo|qn ou qijw iuc|d .mnrs .up ui qiuoiu j isb3| in tfuiqjo/tv uoiu jo jnqiunu .hubs aqj. 'Mnxoip m pasodx.i ..X[|i:iiuohkJ., pajapisuo.i ojoav asaqj, soss.THud |OU.X|d ojojqn uj u! qtuoiu j m:.i| it* 3ui>|jom '(uoisjAia URSupiyO [pdiiupiq aaoq jo sMXoidui? ot6 J" wa]m oo Xpms uoqoa r poquosnp |R3i| |n pupsu^oj. (lURPijjuSis X||i!.iiviiniv nm pjoa\ vppuojpjjip nip) sqyjq yst/t! pun *sqyiq fn/(, `|Ujq |0tV6 XpAipridsru ojo/a spapp inijuaSuo.1) jo sniRj aqx :XnuRuflpjd aqi 3uutip paXiuds oqw asoqi |nm U,UP Jnqio siipiuirq.') poXiuds oq asoqi 'sapunudaid .ssqu jisqi Suijnp SuiXcids iou ni3M oq*t umu o>ui dnojfl pavndxo aqi SuipiAip '[PsX|i:uroj cun nmp osnqi `[it] ] jadnd Joqnj n iq -posHKixaun nqi Aikhur | -s\ *dmu3 pnsodxn oqi u; punoj sirrajap ynoq jnqj <4l c-8'tl T %06) Sc*l ka\ m nqi -dmu3 pasodxoun dip joucuptiqaui (%9* l) i pun 'dnojS pasodxd oqi jo uojpjiq.'v u; punoj oiom (%0'Z) suoiiruijojirui jnoj-XiU3MX soaiav jpqi iuojj pr>uiciqi> sjo/a voiuo^ino X.iunuS.ud vROJsqw *aanv<xIxo inoqn pcMOiAjoiuj Xipisod run* Xnqx *PunlRfl/ M3(q ui ^uisn sjoirniiddR opirttisad ,i|Riu Suouir ssuiomno 3Ati.inpoid.ij jo uodoj XjRuuutpjd n psqvqqnd I931I |R 19 quius K9jnsixlx9 |niuatnd ujciuo-i soipms 9[qntpAR Xpo am 'S9]pn)S|ea|)X|euy SB3JR pajn||od X]q3iq ui Sutuixfoj pun Xarjnaac atpouSnip joircuif oi onp sttiq uotpapp e iuojj ijnsai ppo.i souo? g +V 9i|i ui ..saiinuouR joqio,. pur BtpRdsodXq jo ssaixa ur :Xisnnnnm pnpjdjoiui aq ismu sqnsaj Xjnujunpjd asoq.L `9`9 SR' >no+ H sa tl f V am>7 aqi ui ..saipuiouR jaqM.. jo| aqi *uoi|tpprt uj `UOflO`0 > J sRiprdsodXq pun (ro - d 'z rPU!4 ds joj 'spjoioj pqidsoq XpjRquuri qiiAv mtsijRduio.i ut 'punoj aja.w vojiuj aiiu qi?;n 'soiJivjflaj i.i.ijap qutq Jaqio pinr vpju.vj pnidsoq Xpji:qiu<n iptM pojirdiuoa .u.im v.inr>| qios aqi ut suoiiRjiu.iauai .lip nil Sni|Hi.Mbp ipaiuqod iou XipattaqR) mo pim >i `v :sviuo/ jnoj oiui pnpi.vip srav imjr Xjivi^ah .1*1.1 x,fb <u yx uiojj p.vcr.u.iui paianiuoa sujoqM.m Sir R)R(I TABLE VI, Effect ofSmoking During Pregnancy on the Mtlfiwmalwm w lh Offspring; Epidtrabloglf EyMcnct* Inhumation snarking Retrospective O Rt-lmpettive 1 Retrospective l Sample hize 16.200 Births 16.000 Births 18.600 Births Malformations All Heart All Oral clefts No. cigarettes smoked >|/d >l/J >1/d Risk ratio smoker/non-snvsiet <1 1.5 12 2 Significance IP> No <0.001 No <0.05 Prospective.' Prospective I Retrospective J Retrospective Q Prospective 1 14.600 Births 50.300 Births 1.400 Cases lO.MAi Births 66 Cases Heart All All All Oral clefts >l/tl > l/d >20/d > I/d > I/d ~i <i u 1.6 - 1.5 1.7 No No No <0.05 <0.05 <0.01 Retrospective 1 Prospective I 66 Cases 69.000 Births 14.700 Births Retrospective 320 Cases 1 420 Cases 520 Cases ____________________________ *1. interview. Q. mailed questionnaire CNS All Ancnccphalia All All CNS Oral clclU Musculo* skeletal > I/d > I/d >20/d > I/d >20/d ? 1/d > I/d >l/d -1 -1 I.S -1 1.2 -1 1.3 1.3 NO <0.5 No <0.05 No No No Reference Underwood et!.. 1965 ||551 Fedrkketal. 1971 M3I] Andrews and MeGarrv. 1972 |I37| Yerushalmy (973 II 32| Hcinoncnet al. 1977 ]26| Ku'lscv et a!. 1978 II 33| Himmelhergcr et al. 1978 |I36| Erkstm ct al. 1979 |I38| Evans dal. 1979 M34| Christianson. 1980 II35J Hctwninki et al. 1983 |I39| > ooo o <o jo somi 3.*Ki3|RA3jd Mat'll Apnis joqiouR uj lunuaDE oiui o3r jeujajruj >jooj jsdsd s.uosjpug X]uo 'IZ.1't'9t'l) suone|3JJ03 oiqdejSosS qansjo DDuasqe psMoqsjjaAamoq `suoijr3ij3aui joqjo omj, uont'pjjoa oAiqsod e pouodoj pun uopcpuonu jdirm JO S|3A3l JO SDU09djbD ODJip OIUI popiAtp VUAVOl S!OU|||| ui DUIOJpUXs S.UMOQ JO S9)J 35U0|CA3id paiimmsa UodtufaH .i|qc|ioM* ojg saipms uopcpj-ioa `XluiRjq uoiiepponu jajBM sueurnq ui siaqpp quiq pue 9p;jo|ip jXuu 01 ajnsodxa jBUJdiod jo jbj `UauiuojiAuo uWMpq uoiicirxtt.'sB 041 jo souapiAd nonbipuu) apiAOJd saipms wjqi oqi imp DpnjDUoa om, '1^1 J uosaumiajo pun |tl 1 owrjuj puR jouo9g/^ Xq prpmojd ojc soipnjs 0|qiqiRAR Dip jo SMDiAOy '3u[punojuoo OAiinttou paanpoiiui OAsq pjnoa (qo[ ipiM pomjoosKR XpoiJis si qaiq-vi) imiinanpD pujDiRd Xq SmqoiRyij (^0*0 > d) sapjitacj DAd uiojj S3|iuj uiqiiM poAp sjoJiuca urqi sasno djojai uoiidaouoo ojojoq >)jom lanjjuoa e ipiM sjur|d 3/\d ui pa^JOM sjaqicj jojiuod |fr/ pus sjaqiBj ds-bd if/Q taiiin uopdaauoa 34) 9uijnp simpd oa<1 u! pa^jom sqojiuoa jo sjaqwj \ttZ puc sosRa jo ajaqjnj jo ino omj, -oorid aauopisaj pue s>UB[d SuumaRjnuniu 3Ad ut ijjom Jtaqi uo auoqdapi Xq jmdiajdiui ojdm sjuajRj sniBjs jeidos pue *dbj "quiq jo ipuoui d3 iBujriRiu `uonranpa iRUJawd Xq sasRa aqi 01 paqomtu pin? Xpnjs snouajd atp ui kb payijuap; satqcq [ojjuod jo dnoj5 e ipiM pDJBduioa aja*\ ! 3uijjnaDo suo|iriujoj[mu 5^43 jo sasca luoppui duo mq uv :(`STl *biui3jia lsA\) `Xiunoo Bi|A\nur>i ui [jfl j IR vpuoiupg Xq paianpuoa srm Xpnjs iojiuud.dsbd jaqiouy lURld S43JpASDU|Rd UIOJJ S3JHU Q1 Ultpi/A Sui^JOM sjoqioiu pcq sdsrd uuq) s|ojiuod djduj :viun|d ui pa^joA\ siunjcd [ojiuo.i jo omi pun siupjrrd dsrd $] aqi (o duom 'spjo.aaj inamip aqi uiojj paiaapna srm sjojiuod aqi joj uopRiuJOju; siruaqM `pomdiajojui djdm sdsrd oqi jo sjuaunj -(ssna oqi jaijrt Xpinipauiitii isji 1 aq) pun Djojaq X|D|Ripaiiiuii ujnq isjij aqi) votqrq |oj)uoa().|odnoj9 r qi|M ppjRduioD djdm (Rp|j[q uuids qiiM ru;u pui: X|i^|doouDur qi;M xis) u; jiijidsoq duiasduirj aqi ui suo;tmiuoj]RUi SN3 Ml!w ujcxj raiqRq qy '^IISasduirj ui ]ipi| ji! ia spuoiupg Xq paianpmu srm Xpms |ojiuod*dsi'd r `siscq siqi uq <SD|1I|IDR| JAd inoqiiM) DjljAafJpia quoN ui pun (so]ij]iat!j jaj qiiM) ajjusouiRj ui pDAjasqo sum ssddvo oqi 01 siDDjap SN3.1 uoimqijuina jofniu y siunid 3Ad inoqiiM saiiia jaqio omi ui os'|R punoj DJDM SD1RJ DDUDIRADjd JR^IUIIS 'JDADMOH `(l0`0 > JUIVRJIuSlS X|]RD1)SI]R)S srm ssdd\d aqj `sDijiunuiiuoD DDjqi oip u] '(s)ur|d 3Ad sap]umuuioa Dajqi aqi) D5(in UOAV u! '0Z Pur `DpASDuny m oi 'SI `Rinqciqsy ui `?l>nls !MO f'Jilua Dq) ui ypQi :smoj|oj sn djom (squiq da|I ooo'l -Od) siDDjap quiq jo sdirj ddud|Radj^ uoiiRJodo ui iuti|d uo;iRs;jDiuX|od apjju|qa |Xu;a duo )si:d| ir pnq qa;qM jo DDjqi `sdijiu -muuioa oiqo jo dmu3 r ui fi.-0t.6l u` sdicdijiuod quiq posXpiur [qvi 1 diucjuj apuomo |Au|a MlO/ S| DDUDpjAvl Dqj. safpnis oaouSdu aqjjo asmp 01 jou.xlns uaaq jou darij sajpms DAiiisixi aq) ,|o sutftsop aq.L '3u;pim<qiiua jo i.vijia ^i;da\ r amh|s Xihii suopiuiijoiiRiii uidisXs suoajdii [tuiuna pun (p/sdudjr3id or < > 3iii^i>uis Xardi{ UDDMioq s'Djpnjs irjdads ui udds imnm.Ntssu isapotu DLJ.J, 'pDJJD 3u<U|S JUDIMMIOD XllR MIHJS ol V|tRj tfuUtlsJJO Dq| III SIIOI|RUIJO|||HII |R!iud3uod no 3u}^oius irujdiriu jo si.idjjd oqi uo ajmiMopi Dip `jDqiofloi up^rj 'IfitTKI'Wl pDiuJijuio uaaq mu snq siqt uirSr inq MxcraTffll paAJDsqo uaaq sq vijd|d jrjo pun tfui'jouis |rujDiimi UDDMpq uoijridossi: ur saipnjs LLZ R|R(| <)p;u.Rln|u.ii|i 278 Hemminki and Vineb TABLE VII. Evaluation ofLevdi of Evidence on Teratogenicity in Humans {According to the Criteria Listed In the Teat) High level Limited Low level Inadequate Ethanol Mcihylmcrcury PCBs (Kancchlor) Laboratory work (solvents?) Anesthetic gases Carbon monoxide Codec HcxacMomphcoe LSD Nitrous oxide Tobacco Smelter work 2.4,5-T Fluoridation* Gasoline Hulothanc Lead Potato blight* Soft water- Spray adhesives Marihuana TCDD Vinyl chloride There is some evidence that potutn esmsumption. water fluoridation, and soft water arc not associated with human malformations. Down's syndrome were very similar in 30 towns before fluoridation, in the same towns after fluoridation, and in 321 other communities with levels of fluoride tower than 0.03 ppm. Confounders (ike maternal age and temporal trends of Down's syndrome were taken into account in the pre-/aner-fluoridation comparison. No short term effect of fluoride on risk of Down's syndrome was apparent (relative risk * 0.95: upper 95% confidence limit 1.2). A further .study dealt with congcnitul malformation patterns before and after fluoride introduction in Birmingham, U.K. 1149}. The minor changes in the preva lence of malformations were attributed to demographic changes or to modified ascertainment and classification. The authors' conclusion is that there was no evidence ` of an association. An American study shows prevalence rates of birth defects respectively in cities which hud and cities which did not have fluorinated water supplies, and it takes maternal age into account [150]. The result is negative. Since the design of negative studies is superior to that of the one positive study, there is some evidence that water fluoridation is not a determinant of malformations. The level of epidemiologic evidence, reviewed above, is summarised in Table VII. EVALUATION OF EPIDEMIOLOGICAL AND ANIMAL EVIDENCE Experimental findings regarding compounds with high or limited evidence of teratogenicity in humans (Table VII) have been analyzed and summarized in the Appendix. In the experimental studies, all expressions of cmbryotoxicity detected during pregnancy or at birth were taken into consideration. Below are compared the experimental and human findings in qualitative and quantitative terms. References to the articles summarized in the Appendix are indicated by A and the number of the reference (Al, A2. etc.). Oral or injected doses are compared directly between experimental animals and humans, For inhaled doses the calculations assume an inhalation volume of 15 nv'/24 AP00019921 J TABLE VIII. Animal Tacts m Chemicals With High and Limited Evidence on Ttnltgenkiijf in Man After a Quantitated Exposure (for details, sec text) Substance Carbon monoxide Ethanol Halolhanc* Methylmcrcury Daily dose (mg/kg) ? 2.000 60 ppm -- 0.6 mt/kg 1.0b Human data Risk CNS defects 3)16 (FAS) l.S times 25* microcephaly Ref. |4.3I.32| 137.40.4 j| 19-23.1561 165) Nitraia oxide* Polychlorinated biphenyls 3.000 ppm = 0.3 l/kg 0.5- 5.5 vs. 3.6% 1.5 risk 100% (symp> toms) 30% (small for dale) (13.156) (70.71.731 Species Mouse, rat. rabbit Mouse Mouse Mouse, rat Cat Rat Rat Monkey Animal data Daily dose (mgi'kg) Risk 30-250 ppm Resorptions 3.000-5.000 1.10 l/kg 5-10 0.25 300 t/kg 0.2 l/kg o.to - 30% (FAS-type) Threefold (skeletal! 50% Malformations 32% Malformations Malformations sixfold Fetal deaths 13% (Skin symp- touts) 50% (low birth weight) 40% (lethality) 'll is assumed that baMhane is die responsible agent in anesthetics; in fact the evidence is inadequate (see Table VII). kPor methylmercury Img/Vg is the total ingested dose; the daily doses were in the order of 80 *tg/kg. *It is assumed that ahnxis oxide ia the responsible agent in anesthetics: in fact the evidence is low Isee Table VII). ^Estimated intake of Kanechlor. Ref. from Appendix AI2. AI5. AI9 A28.A29 Al A40-A47 A48 AS.A10 A9 A59.A60 I > ooo 280 Hemminki and Vincis h by a person of SO kg by weight (=0,3 mVkg/d). The weights of mice are taken as 20 g and those of rats as 300 g. Oxygen consumption by weight is assumed to be two (rat) and three (mouse) times higher per time unit in rodents than in man. This equals daily inhalation volumes of 0.6 mVkg/d for the rat and 0.9 mVkg/d for the mouse. Complete absorption of the inhaled compound is assumed in the airways of experi mental animats and man. The quantitative comparisons between epidemiological and animal results are shown in Table VIII. Anaesthetic Cases, Halothane Cleft palates and skeletal malformations were induced in mice at a 3 h inhaled dose of 1 % halothane IA1 ]. In one study using a similar dose no effects were seen in rats and rabbits |A6]. Lower doses, about 0.2% halothane. were investigated only in rats exposed by inhalation for 8 or 12 h; fetal deaths and decreased fetal weights were noted |A3-A5|. When these results arc translated into an inhaled dose, halothane caused malformations in mice after inhalation of 110 L of I % halothanc/kg, ic 1.10 L of halothane/kg. Rats experienced fetoioxicity and depressed weight gain, when inhaling 300 L of 0.2% of halothane/kg. ie. 0.6 L of halothane/kg. The limited epidemiological evidence for teratogenicity of occupational expo sure in the operating rooms suggested an excess of malformations at different sites in different studies and was not consistently related to skeletal malformations. The halothane concentration in operating rooms ranges between 0.1 and 60 ppm [I56|: assuming a breathing volume of 5 nv' during an 8-h working day. these would correspond to intakes in the order of 0.0005-0.03 L of halothane, ic, 0,01-0.6 ml of halothane/kg. This is several orders of magnitude lower than the effective doses in mice and rats. However, the meaning of this comparison is doubtful, since the contribution of halothane to the teratogenicity of anaesthetic gases--if any--is not demonstrated. Anesthetic Gases, Nitrous Oxide Many types of malformations were induced in rats inhaling either 45-50% or 70-75% nitrous oxide for 24 h IA8.A10J. This translates to about 300 L of nitrous oxide/kg. Fetal deaths have been observed at a lower dose of 1.000 ppm inhaled lor 8 H IA9], This translates to 0.2 L of nitrous oxidc/kg. The concentrations of nitrous oxide in operating rooms have ranged between 30 and 3.000 ppm 11561. This would involve inhalation of 0.15-15 L of nitrous oxide in a working day, and a dose of 0.003-0.3 L of nitrous oxide/kg. It can be observed that the upper dose limit is in the range where fetal deaths have been observed in experimental animals. This may he related to the assumed role of nitrous oxide to account for the excess of spontaneous abortions in the female uncslhcsia staff I9.l3.18.22.156j. Cprbon Monoxide Several experimental studies are available indicating cmbryotoxic effects other than major structural malformations, In mice. 250 ppm of carbon monoxide induced .some resorptions anil lumbar ribs |AI2|. In rats, 150 ppm decreased the physical activity of the pups |A14|, 230 ppm decreased weights of the pups JA I5j. and 30 mul 90 ppm caused prcimplanlaiion losses JAl6j In rabbits exposed to 90 and 180 ppm, stillbirths were increased and bixly weights were decreased |A 19|; another study with -saojajui air jo jjnq "3uiuostod jo (eaidXi siaajjo SND a*Bl4 l PIN3 Joj Xiiitqiiqiud %os it pasnca Sq/Sui \ inoqn u ainsodxo pnuairui t icqi paieiuiisa 3Acq [g9l |n jo uos)fjR[3 `htTJ] tuojj nnp oqi uo posirg 'suo irjo sqi ueqi daiwjjo ojoui S9uh) ~z siums oinoj snooumnaqns oqj, Ximjdoixuaiui iou jnq saSurqa jenaqaioo Suipnpui `sdru! oqi jjcq inoqc ui sadXi snouBA ja suourujjojjcui pasneo St(/3uj 0 jo sosup |Rjo jo S^/gui oi-? jo ssi>p snoounnoqns Xp.Bp "03110 pue sjbj U] |Xt>v1 quiq )c m8i3 poonpsu ss ||0m sb soSurqa |Rnj3ojoKiq m^oqsjao poiepj-nsop paanpojd p/3ji/3ui 2 0-800 qi*<* wounrcui ps3uo|Oid `sica uj i6tVl 8/SW jj 3M>qc uo]hujudduoo joaij [cujoictu o) Suipuods auto siuaiuin^i 3uiau>i|oj punoj scan snO 3Ml jo sikojoou jqnipn `sjbj u| |*>vl s|tuiui>a u] m/o SA X.iucuflajd inoqSnojqi apijojip XjnaJOuqXqiaiu p/3>|/3iu [ uoaiS aaiui S9/8 ui pamiop ojom saSuHqn jnnoqwao 'uiRjq aqi ui saSuirqp |RP}3ojoisiq oi uoajS sr.v. uonuanr jutnaiurd `soipnis amos uj `Kjaqiuui aqi ui snwjja aixoi poanpiud qaiq/tt sasop m szfop pur auj/As oiniciuiw oqi ui po/aos-qo 3J3a\ suourui -jojieui on 'sjsisuiuq pur mcj ui nuoiirujjoj|ciu snoouofiojoiaq pun aaiui ui ainjed ipja pur sijap jcjo Xiiiinu) su(iruuoj|Riu irjnpnjis poanpui `sauiii ainijdixidde je uaAiS *3i|/3ui oj unqi sso| jo sasop a^uis `sjojsiucq pur "sicj 'aoim uj XjnojoiuiXqisn XpAisuaixa pajrSijs-aAui uaaq iou 3Afiq aauu pur sirj unqi jaqto sopady `xaprxJs siqi u] poAJ.isqo uaaq iou OAirq saijciuouc odXi-svj X|jn|naiurd pin: sutn)i!uiJO|[Rlu "(331111 ui sb j?pji> suiRs aqi jo sosop in) ij oqi ui 3ixoioXjquia uaoq srq (ounqia q3noqi upao irqi a/iseqdiua 01 panu c si aaoqi jdaoavoj-j 'ppiui ui sasop pAiipajp uiojj jnj ixn iou si siqi -p/S^/Sui 0055*l OAoqc "3i `jounqp 3 ooi AAoqn aq pjnoM suosjad q.ans Xq poumsuoa sosop Xpirp aqj, (uoiiaas ai3o|oiui3pido aas) %(jf moqr sj gvd ppqA r jnoq oi isi[oqo3|n .auuuqa r jo )^su oqi |qjVl pasroJPUj sbm uoji -njuriduii jo vso| `j3a3/v>oh :suoiiruiJoj|rui jo sauoi ui OAim^au srm sjiqqcj uo Xpms oqj_ l6tvl s8up ui s|ini a^uh pur "sXaupiij jo aouasqu `sysp pjo pur `[g^Vl sioi3wl ui suojiruijojjnu jo sadXi 3|dii|niu `litvl sSid rpumS ui Xiiimnuun utrjq oanpuj m pauodoj ospi sc,i loqioiv 'Uiu3 iqflpM poanpai pur suondaosaj pnsraj.iui st qans Xii.iuoi {triuaiiidopAap jo iiuoj niuos uodnj sutj ui ssipnis )ri3ADS `ssopquaAdfq joj poijooi X]|iT.*q]!3Pds iou u ji passim X]tsro nq um X|qdaaoJ3|ui sisai Xu.ijuoSoiRjni ui *purq aoqio aqi no 'pcuunauoa nm suonriujoj|BUi |i!jnpruis si! jj si! aaiii:3ou uooq a,\q sjnj uo saipnis `lotVl pavodaj X|3imbaprui srm qaiq/A "X|rqda."HU3}ui Sumoiiuom Xpms ouo jo uondwxa aqi qu^ 'p/3^/8 lnoqr .uom pasn sasop oq.|. lfttV'ScVl sajnssij irjqadpd pauouoqs pur `ritujrqiqd -OJ3UII "S]j3|a poo "Risn|dodXq Xjiq|ixnu su qans svd i Jrpiuis sajniraj *3uipn|9ui *aaiiu no snipms omi ut pannpui uaaq ?Arq s"ui:3jo lujajjip m suoiirtLijqiir^N joueqjg aiusmixa jo sjoa.ii rtufXjj.ipim aqi uo .i[qir[it!Ai; ojh irjirp |>tinos on 'X|an:umjojuji paAj.wqo uaaq 3Aq o^niunp mniq |Kit? spajafi jr.aiiSopunau "Mirnmq pasiHlxa pi asi:a aip u| \ZZV\ TiX.rpioiu siis.^qg (j/j ui uirjq jo suojb iw/uoj.wu pun siaajop |i!.ii3u|tun3u posmro uuM-jnau m mdd (XX)'t' <X)0`1 oi runsodxa q uruinq ui s3uipuij aqi oi Xjr||ojo3 mnuodiui uv ilCV"0ZVl ^id pun d33qs u; pJAJOsqo 9J3ai qu!q|||is pur sqiuop jnpj UlV| oaiibSou sum siiqqcj IKT BJRd vijaiuaHonuaj, 282 Hemminki and Vincis phalic. Thus, effective chronic doses in humans seem to be in the same order of magnitude and possibly somewhat lower than effective acute doses in rodents. Both in humans and rodents, histological damage to (he CNS has been noted at a 1-mg/kg dose. PCBs (Kanechtor 400) PCB compounds have reduced implantations in mice at very tow doses of 0.025 mg/kg in one study (A53j and at a dose of 0.5 mg/kg in another [A55|. Up to 50% malformations were seen in mice exposed to 8 and 16 mg/kg of 3.3', 4,4', 5.5'hexachlorobiphcnyl jA56J. Studies on rat and rabbits have not noted malformations {A57) but have observed a decrease in birth weight and an increase in stillbirth at 50100 mg/kg [A58). Feeding studies with monkeys at 5 ppm have shown weight reduction in the offspring and some fetal mortality. This corresponds to a dose in the order of 0.1 mg/kg. Thus, PCBs appear to be developmental toxins and cause byperpigmcntalion of the skin in monkeys similar to their effect in humans. In humans. Kancehlor 400 has caused 100% hyperpigmentation symptoms and 30% babies small fur date at estimated daily doses of 0.5 mg/kg PCB. the range being 0.06-0.8 mg/kg [70.71,73]. The contribution of dibenzofurans or other contam inants in the Yusho oil cannot be ruled out. Skin changes and low birth weight can be taken as a basis for comparison between effective human and monkey doses. Since 13% monkeys were affected by skin lesions at a dose of 0.1 mg/kg. linear extrapola tion would yield 100% response at a dose of 0.8 mg/kg. Thus, the ratio of human/ animal dose would be 0.65. This, however, is based on two monkeys. This is a dose range (0.025-0.5 mg/kg> where reduced implantations were observed in mice. Un fortunately, no reluted observations are available in humans. CONCLUSIONS Testing for teratogenicity is required by many national agencies responsible for the safety of food, drugs, and pesticides. Yet a quantitative evaluation of the predictive value of teratogenicity tests had been lacking, although arguments have been pre sented on qualitative grounds. In the present exercise, a quuliHlivecvaluulion was made of the level of evidence of the ability of several chemical exposures to induce _ malformations in humans. Kffcclivo doses and (he magnitude of effects were recorded as much as it was possible from the original studies. A number of exposures definitely or plausibly associated to human malformations were so identified. Qualitative and quantitative findings were then compared to observations resulting from animal experiments. Results are summarized in Table VIII. The accuracy (and therefore the validity) of these comparisons is impaired by several shortcomings: I) some substances induced different types of lesions in humans and experimental animals, eg. micro cephaly induced by mcthylmcrcury is only seen in humans; 2) exposure data in humans arc often crude: 3) dose-response data in humans (and often in experimental conditions) were largely unsatisfactory, so that comparisons were restricted (o tlx? order of magnitude of dose levels giving a similar magnitude of effects: 4) animal studies were by no means consistent, and observations under the most sensitive conditions were used for conijxirisons. In the ease of ethanol, McHg. and PCUs. the evidence for it causal association with human mall><nnations was high. Lliesc chemicals also induced malformattons AP00019925 I;0* ''`y inaunj (ij in | |oa sm)w3ou>w JHVI 'Rtnp |niuiu* pun ununq iki p*r*q xucuinq u; jaautta qiim paiBiaosst) so-swimd |rjj|snpui pue s|*iimni|i jn un;)m]RA tiy rdrvtrd Sut^jnM j&yi -f 'HIM 'JftK'UH'Nt* wy Ja.njej `js^urj uo q.ijTwnj joj Xsuatfe jpuiiiimijsiut 9i(i jo uiejrtojd i|drj3ouiHii aqi jo .iia3J v :sii?aiui3q.i jo Ainjurtfoutaiira mji jo uo!tfi|iAg :f ujnomiM "j J.-"(|i!M 'U ifaems *H nunsaun'W *r JJiH 'H ;> ap3y 'T snicumi z SOt` J `i'6| 'I'lOJd .muopMy ^"A '""N ..^joci quta waiuuojiAug,. :q( us|i/Vi 'I S30N33d3U paypsnf slums saiasds umunq aqi ui XipjuaSoinjai ju joiaipsjd 3[qissud b sb laajja aixoioXjquja imuauiuadxa Xue Suijapisuoa jo aapacjd aqi `suuai aiiRiuSEid ui `siseq sjifi uq uib3 iqfTn/n pasnsjaap pun 'qutq||tis `suopdjosaj paanpui ij jnq vuopeuuojieui |ejdj -anjis ou pasrma apjxououi uoqjiQ `suoisaj jouijoj aqi oi ucqi jsubj aqi oi saiiisuss ojoui ojam AipixoioXjquia jo wdX) jaqio pun suomcujjojicui qioq pasnca ipqi *go<f purr qounqia `opixo snojjiu *auBqio|nq su qans suunSti qjiM paiesji auauinp `ojouuoqi -jnj -sojaads aam aqi u; p32tu3ooaj uaaq 3ABq pjnoM suoijeuuojicuj puniaruis unqi jaqio ui saSunqa aixoioXjquis *punq jaqio oqi uo ,,'S0Ajin3au as|ej,, sn pajopisuoa aq iqdiiu Xaqi `suijai puis U| pniwiapun auoS 3ABq pjnom stjoiibuijojiriu oanpui 01 XiqtqR Jpqi '^iiqqiu pun shtj ui Xjuo poisai uaaq sgoj pun jouBqia pen -3uiiso) oujiniu innnuipAuoD jo sjsrq aqi uo pamaiop uaoq OArq pjnoAV suaiioiEjai uciunq aq 01 UMoqs XiflupujAuoa sjnauuaq.i aojqi asaqi joqpqM japuoM pjnoqs auo Xnnuij saiaods jo XScqoiq imuaiudopAsp ui sspuajpuip 01 pun ojnsodio jo sun ui sssuajsjjip 01 sppj suosrsj jsqio 'SuoiiRiaossB dn 3u;qa;d ui vnpms |R3i3o|oiui3p;da jo /Ciiaiiisuos .y\oj sqi 01 paquDsn aq uco 3DU3J3ijip snqi jo urd nnuK v `sin.iiiuaqa aojqi sqi jo q.'np uoaiS s|rui;ur XjojBJoqRi ui uoos uoaq 3ARq suiuunq ui paqu.vop asoqi iuojj luajojjip ssqs in s'uo;icuuoj]i:ui `uoiqppc uj 'vuoijipuoa |i!)uam;j3dx3 3qi ui pup untunq sqi ut lusjaj^qp 001 iou sum sastip SAipajjo ?qi jo opmiuflrtii jo japjo sqi pun pun *3h3W *|ouRqia <n -<|OAtpadsaj pairiaossc 3q oi UA\oqs suonruuoj]mu umunq aqi joj pa^ftuapi uaaq suq urdjniunon [nuaiuijodxa auo isr:nj in 'purq auo aqi uq MuaSe lunAOpj aqi m pasodxa uni ojr oq/* ojdiiod ui pjej Xjoa a.tn qniq/w suoiimiuojimu oi pajjajsj suoiiipuiP asaqi `uoiitppo u] 'sdiqsuoiiiipj lMjjo-osniP jo jaquinu ||cuis iOoa c jo mnquSo.vu aqi oi p3| scq satpms |RaiSot<quiapido aqi jo sis^jrur jo nuainp piSu Xj3a jo uonnai|dilR oqx '<|snounRD Xjoa pojapisuoa aq p|nnqv suosurdiuoa assqj^ sniapoj ui punoj aj3aa soils jaqio m suoimuuoju'iu |Bjn>anJiK ssajaqM '/Cjuo xXaquoui ut popopp sbm sasnpj ueuinq ui psanpu; saSunqa aq oi ucdjaiunoa |eiuauiu3dx3 up 's3Dd Jd 'mi^ds siql ui paunoao Xaqi peq `suBumq ui uonuone psdRasa /Cjpicq 3Aeq p|noM qaiqM sjeuiiUB /(joiBJoqsi ut uaas 3jsm suoi)buuoj|blu jaqio `purq joqjo aqj uo pasn ajaM ipoqiouj .iirudojddR uaq/v vim pun `mitj `aatui ui osjb paiaaiop ojom osoqi pur uttuq aqi ui saSunqa ic.ii^oinqdjom pa.mpojd Xjnajniui^qi.nu `surmnq uj 'luaindde uaaq aAiiq p|no,A Xuiixoi |niuoiudo|OAap jo muuoj jaqio 'ssiaads oam aq) ui `joadanoh *paa; jouun auoi OAcq p(no/A suiqiuuuojfmu aanpu; oi |oqo3]c jo Xiijiqr aqi 'sajaads omj asaqi oi paiiuit) uaaq saipnis aqi piqq [ouitqio oi pasodxa siiqqnj jo sirj ui pauodaj ajaM vadXi ^ur jo jo gvd l JBliuns Jaqip nuoiibiujojirui ufq ununq ui lusqoqoain jihi pniiiqia jaqpau qiiM pairtaossn oiiaipiq suoiiruuoj|i:iu jaqio se ||am sr gyj oj jiriiiuis ojniKaj paanptud |ourqia aaim u[ painSiivaAUi ajaA\ Xaqi qaiqM ui saiaads ju.-u.-tjlip aqi Uj Jiqiiuis aja, jou suirumq ui paAJasqo asoqi paanpojdoj Xpuaisis -cma jaiptau siaajja |i:iuaiiiuadxa aqi MaAa,wo|j siu>jpu<o iinuauiuadxa sums jajiun v"OT ,!ic<l -<ipiuaffoiuj.ii, i 264 Hemmlnki and Vinci*. 12. 19X0. 4. Harlow SM. Sullivan KM; "Reproductive Hazards or Industrial Chemicals." New York: Academic I1rust., 19X2 5. Wilson JQ: Environmental chemicals. In Wilson JO, Fraser FC: "Handhonk of leratology. Vol, I." New York: Plenum Press. 1977. pp 357 .1X5. ft. Shephard TH; "Catalog of Teratogenic Agents. 3rd Ed." Baltimore: John Hopkins University Press. 19X0. 7. Miettinun OS: Design options in epidemiologic research. Scant! J Work Environ tilth X (stippi. I >:7 14, 19X2. X. Ixck I: Correlations of malformations frequency wiih environmental and genetic attributes in mun. In Wilson JC5. Clark FC. "Handbook of ler.Uology. Vol. 1." New York: Plenum Press, 1977. pp 241-124. 9. Cohen EN. Bcllville JW. Brown BW: Anesthesia, pregnancy, and miscarriage: A study of operating room nurses and anesthetists. Anesthesiology 15:341-147. 1971. 10. Eriesi *n A. Kiillen B: Survey of infants horn in 1973 or 1975 u> Swedish women working in operating rooms during their pregnancies Anesih Arulg SX:3ft2-3(J5. 1979. I! Rosenberg P. Kirves A: Miscarriages among operating theatre staff. Acta Ancslhesiol Scant! 53:17-42. 1971. 12. Rosenberg PH. Vamtinen H: Occupational hazards to reproduction and health in anesthetists and pucdiairicians. Acta AnaCsthcsiul Scant) 22:202-207. 1978. 11. Cohen EN. Brown BW. Wu ML. Wliitcher Cli. Brodsky JB, Gift HC. Greenfield W, Jones fU', Driscoll EJ: Occupational disease in dentistry and chronic exposure to trace anesthetic gases. JAtJA 101:21-31. 1980. 14. lamwcrys R. Siddons M. Misson ('ll. Ilorlce I. Houckaen A. Lcchat MF, 1)e Temmerman P. Anesthetic health hazards among Belgian nurses and physicians. Int Arch (Xeup Environ Health 4X: 195 203. 19X1. 15. Knill-Jones RP. Mtiir 1)|). Rodrigues I.V. Spence AA. Anesthetic practise and pregnancy . Ijjikvi l.lt'h I.32X, 1972. Ift, Corbett TH. Cornell R(l. Fndres Jl.. 1 .ieding K: Birth defects among children of ntirse-anesihsitsis. Anesthesiology 41:341 .344. iy74. 17. Cohen EN. Brown BW, Bruce DL. Casoorhi HI-. Corhett TH. Jock's TW. Whiteher CL: <Kcti|H> tiona! disease among operating niton personnel: A national study, Anesthesioltigy 41:321 140. 1974. IX. Knill-Jones RP. Newman BJ. Spence AA; Anesthetic practiec and pregnancy, lamcet l!:X07 X09. 1975. 19. (jtilhe CJ. HoITman O: The consequences on pregnancy of smoking and occupational exposure tn anesthetic gases. Proceedings of the (V .Swedish-Yugoslav days of ttccupatsorul medicine. Skopje 1977. pp 11-27. 20. Pharoah POD. Albcrman E, Doyle I*. Chamberlain G: Outcome of pregnancy among women in anesthetic practice. Lancet 1:34 3ft. 1977. 21. Cohen EN. Brown BW. Bruce 1)1.. Casenrbi HF. Corbett TH. Junes TW. Whiteher CE: A survey nf anesthetic health hazards among dentists. JADA 90:1291-1296. 1975. ~22 Tomlin PJ: Health problems nf anesthetists and their families in the Wed Midlands. Br Med J Klin Res] 1:779-7X4. 1979. 23. Axclsson G. Rylandcr K: Exposure to anaesthetic gases and spontaneous abortions: Response bias in a postal questionnaire study. Int 1 Epidemiol 11.250-256. 19X2. 24. Morris MB. Weinstein l. Caffeine unj the fetus: |x trouble brewing? Am J Ohstet Osnevol 140:607-610. 1981. 25. Weathershec PS. Olsen LK. 1-ndgo JR: Caffeine and pregnancy: A retrospective survey. l*oslgr;ul Med 62:64- 69. 1977. 26. Heinonen OP, Slone 1>. Shapiro S Birth defects and drugs in pregnancy. Littleton. MA: I'ltl'lislunc Sciences Group Inc. 1977. 27. Borlce J., Iwchui M1J, Itmirkarn A. Misson C l.c cafe, fai'ivur tie risque jvndant la gros^-v*-1 1 jHivam Med 97 279 2X4. I97X 28. Ki.si-nlx.-rg l.. Mitchell AA. Sli.igiro S. Slone l> .Selected htrth delects in relaiHtu to catlcmc containing beverages JAMA 247 1429 1432. 19X2. 29. I.mn S. fichoenhuutti SC. Moiim.ii Rk, Kosnvr I). Suihhiefield 1*0, Ryan KJ No association between colTcc consumption and adverse outcomes of pregnancy. N ling! 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ARqaqojnaN i!sau?3oqitd woqt suoiittnwdt: put s>3*j auios iXqitdoXiquia luqoaiv :j iisMofeiq 'yy 56 * 1861 `ff^SA 31U3 .yrSnms ^ ytq.-MaSutMqas J5p ui sfausuoqo^iv *P uatfH'd U3P na unpnis aiBUUjsuawipjqaw `a!qiBdoiOqui>|oqo5||y ia,, uasntquiais`i-H jqods 'WA |1WN '8 `8161 '190! -90l :8AI PW f 1"3 N 'wmipuift |oq<it pnaj aqi 'A\<3 qinus 'MS *28 '9161 `8101 `9101-1 5uH uauuiM .tipKta*i|t j Sutuls^u ui aimuino ON sijnvnliimutu<v^ `jy qinSwails '^o qi`'S uif '18 6161 `512 ((iklnt) puts; Jitjpacd tpy X.iucuSajif 3uunp mtiqi ,ii|oqon|t ju pjiq.i aq> no nrpjjg :y X aau) *y aeuiia||X>| uinsjit^ uotAiUtqof *fl utpueS *W uus-ui)jy jaqrj `y pjfSsio 0861 *81 -SCI* '-ay <1*0 uIJ :<"S loqioiv -Ipniv aifluiuminpida uy :Xaucu3aMl Suunp avnqt toqo.iiv ;r> pcoy `is iatl'W 'H! 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Zt l&ttt'iiu.,*|.'fmiMpuXt iwjoainiBiaj aq.1, :>VV(] qjnus *t^j wuof oiAi 'in' vrv-Mi ns pwy an v nu.iwtdoqi<M>J.it .tSurq.no mi pgrsnPi (rnt: j.iqHMi iiirudouJ ,it|i ui .tpixoooui unqi^.j :f| oSuirj 'jj; ^ l |i/\ 'X3o|ii|w.i| jit 'V,q|iuRN.. .>.-! a.wj-J `l)f u<l!M U1 MAI `'"'A! mnu-iM 1'A *>`'N .nj.-iqJ^huiiy 0|VMqeii) n I |t!u'.| N X.iuiTLiTfajil Suunp uiijHlumsiuKi .MJi'M :*l *,?*rS `2861 'XW'I 90C rw ruin'i'y M Sj.iqiii|i>n '>{ cdijjn^ SRZ *iU XiiJiua^oicjax 286 Hcmnrinki and Vincis 5ft. McGInthlin WH. Sparkcs RS. ArnoU DO: Effect of LSD on human pregnancy. JAMA 212:148314X7. 197Q. AO. Kims BJ. Lmxgo LD: Mercury toxicity in the pregnant woman, fetua and newborn infant. Am J Obstet Gynecol 126:390-490. 1976. 6|. Chung LW. Wads PR, Pounds JG. Reuhl KR: Prenatal and neonatal toxindogy nd pathology of heavy mciulv Adv Pharmacol Chcinoiher 17:195-231. 1980, 62. Harudu M: Congenital minuiiuta disease: Intrauterine inelhylrocicury poisoning. Teratology 18:2*5 3HH. 1978. 63. 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Roan C, Morgan DP: "Alleged Effects on Human Health of the Live of Herbicides m the Area Around Globe, Arizona." Arizona community pesticide study project. Tucson: University uf Arizona, 1972. 288 Hemminkl and Vincis 115. Advisory Committee on 2.0-T: "Report in ihe administrator of the Environmental Protection Agency." Washington DC: U.S. Environmental Protection Agency. 1971. HA. Sare WH, Forbes PI. Possible dismorl'ogcnic c(Tes ts of nn agricultural chemical: 2.4,5-T. N7. Med J 75:37-38. 1972 117. New Zealand Agricultural Chemical Board: "Report of the Subcommittee on 2.4.5-T." Wellington. New Zealand: 1972. 118. Cutting RK. Phuoc TH. Ballo IM. Renenson MW. Evans CH: "Congenital Malformations. Hydatidiform Moles and Stillbirths in the Republic of Vietnam 1960-1969.** Washington I5C: Department of Defense. US Government Priming Office Nn. 903.233. (abstract). 1970. 119. McQueen EG. Veale AMO. Alcwamlcr WS. Bates MN: "2.4.5-T and Human Birth Defects.'' 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Clummcsen J: Mutagenicity and teratogenicity of vinyl chloride monomer fVCM). Epidemiologic evidence. Muiat Res 98.97-100. 1982. AP00CM9931 Teratogenicity Data 289 145. Rapapon I: Nuuvcllo rocherchos sue tc tnongohsme. A propos du role pathngcnkjue tlu floor. Bull Acad Nail Med {Paris! 143 .167-370. 1959. 146. Berry WTC: A study on (he incidence of mongolism in relation to the Jiuondc content of water. Am J Mem Defie 62.634-636. 1958. 147. Erickson JO, Oakley GP, Ftynt 1W. Huy S*. Water fluoridation and congenital nulfonmitiofts; No association. JA!)A 9.1:981-984. 1976. 148. Ncedlemun HL. Pucsehet SM. Rothman Kl: Hountijiion and die occurrence of I lover's syndrome. N Engl I Med 291:821- 823, 1974. 149. Kliux EG, Armstrong E, Lancashire R; Fiouridiitkm and the prevalence of congenital itulforma tions. Community Medicine 2:190 194. I9K0. 150. Erickson JD: Down syndrome, water lluondaMon. and maternal age. Teratology 21.177 180. 1980. 151. Askrog V, Hurvald B: Teratogen effect of inhidationsanaestctiku. Nord Med H3:49lt 500. 1970. 132. Tomlin PJ: Pollution by anesthetic gases. Lincet 11:142, 1970. 153. Spence AA. Cohen BN, Brown BW. KmllJnik> KP. Hiimitelhergcr DU: Occupational hazards ti*r operating rvxnit-hewd physicians. JAMA 238:955 959. 1977. 154. Tomlin PJ: Teratogenic effect* of waste anesthetic gases. Br Med J ItllW. 197X. 155. Underwood P, Hester LL. La fine T. Gregg KV- The rcLnionship of smoking to the outcome of pregnancy. Am J Obsict Gynecol 91:270-276. 1965 156. Vesscy MP. Nunn JF: Occupational hazard* of anesthesia. Br Med J |Clin Ris| 2X1:696-698. 1980. APPENDIX A Experimental studies regarding compounds with high and limited evidence of teratogenicity in humans (Table VIII in preceding section) are summarized below in Tables A-l--A-V. All expressions of embryoioxicity detected during pregnancy or shortly alter birth were considered. The results of these tests were used in the previous section, when human ami animal data were compared (Table VN1). (Appendix begins on page 290) AP00019932 i i TABLE A-l. TerHl(nkl Ttfllng of*Anesthetic Gmb* i Other Species. observations exposure. No. of Survivor*/ (TM = w*k effect* examination females Doses used________ implants MalformaootK/survivors in mothers) Rcferenee Halothane Mice; C-57 BL. -0 Lew lhan 4/410 (no CP) inhal. 3 h x I, 13 or 14 d, k?. tcdi. -- I and 1.5% - 24/99 CP + 23/95 limb defect* A+E Smith et al. 1971 |l| Rat: SpragueDawley. inlial. 12 h X 1.6-10 d. k 20 d. tech. A + E 81 0 {air + starvation) 77 0.8% 938/992 913/963 33.V937 with vcrlcbfii anomalies + 191/936 with lumbar ribs 371/911 with vertebral anomalies (M2/306 among those treated in days 9-10), 271/884 with lumbar ribs (145/306 among those treated in days 9-10) TM (anesthetic effect) Bastard and Fink. 1968 |2| Rat; Sprague-Dawley, 0.2% - inhal. 12 h x 7.6! 12 d. k 7, tech. A 50* feul death vs. about 10% in referents Doenicfce et al. 197513| Rat: Sprague-Dawley, 23 0 {pair-stressed 331/341 Pope el al. inhal. Sh x 21.0- t pair-red) 197814| 21 d. k 21 d. lech. B+E 1? 0.16-0.32% 238/246 No increase In malformations Decrease in fetal weight TM (stsbaneathetic Rat: Sprague-Dawley, 7 0.16% effects) -- No increase in malformations Decrease in fetal Lansdowct et inhal. 8h x 21.0- weight and crown- al. 1976 (51 20 d. k 22 d. lech. A+E ramp length length I APOOO19933 I LI r:6l |* p pjiwng |yl 9I.6I |B )? (pMJUS^ l9i 9i6l *|t XpMHI9)| 167 IWSCMMp qiSuat dturu UMOI3 'H|5(3m |BJ SUOOdlK3H |LU)U>K> Jll s' uoimidM pouwiop JUtifsl 11 fro) 601/91 UOtPM UXHIJOIS Jixa UK p*t| 81 -$| sXip IM paicui dnuid M|i tuojj nsopj 49 JJ JUQ -S3UIXJ IKIMJKl put |CHKUj pMJITOO XpiOfdUKJCKII pU MOlim lUMuapc pssnj pun |ch< po.woqs fl'OI sXcp uo paiKM) druui m| uiojj tasnmj 9fr ji> .-wo lie JD| JKjlUlK 3J9M vSuipcij >oqi JO 5303p*3UI MLL MjlJ pouavjljl put 'stjjj uejaiunuMdiK *<itkM]33<i UlMIJ.tH pMJtSMJUllU JO pDIJISMI 4pl3|dUHOU< p3pf>|^U| \3uipuij imapqs |Ktu3pi3U! :p?i.tap|> M3 SMHituuouqe |euj|ka smu3 ou inq 'UP.ufl H'M U3oS K'rJ (|eiuap|3ui>t sSutpuij 9ip )3jdj91U{ SJOIlinK) XUOII.-WS uinujaK paiji<iNOUUU jo ports'*' X|3W|dii>o.'Hi! jo oSeiua.ijad u; >c*3j.to! --w3ai3 mu j.'Ki.ipoui (tuioieuioq l||IM snpj I ) U3Al3 km SOU.'fH.MI U3.\[3 KIM USAIil WL9 mt<n tLii 99/Sf rk'SI/ttl ,411/Ctl SOt-/Vt juet|k>|ttt| *9 0 '^P!*0 SfcUflN 609 a+v vw *PSI I'll -0l '6 vrp uo t| f -ftumor SWJUMIJfl 16 :jnueH p<0 fniuijN t 3un|)0|e|| **`l fcfl ttfl (lit)0 01 L 6 t 3+Vqi 'P 6Z5! pgl-SI * PM-01-WP6-9 'it x N l l*Mu! outqiv zn Hwea 6M 6*1 t 1 <J*K> 0 01 6 01 0 3+Y ipai pocvpsi-u *0l-9**-l 'C x q 1 iw *a?mt APOOO19934 i TABLE A-l. Teratoliiekal Tetfln* of Anesthetic Ciases'' (Continued) Species, exposure. examination Nitrous Oxide Rat: Sprague-Dawley. 2. 4. 6 days starting da) a. k 2(1 0. lech. A+E No. of females Doses used 10 45-50* Survivors/ implants MaIfornwikwts/survivnrx 76/77, 105/147 (all treatment groups) U46 Control* had skeletal malformations vs, 57/57 of the irc-Jiod. mainly defects of vertebral ossification Rat, B or 24 h x 4-10 d between days 8 to 19 of pregnancy, k 20 d. tech. A Rat: Sprague-Dawley, inha!. 8 h x 21,021 d. k 21 d. lech. B+E 6-12/erouo 26 24 0 ppm. 100 ppm days 10-13. 1,000 ppm days 10-13. 1S.Q00 ppm days 8-13 0 (pair-stressed pair-fed] 1-50* -- 341/354 309/340 None reported No increase in malformations Other observations (TM = toxic effects in mothers! Reference Resorptions, fetal weight, crownrump length decreased depending on treatment time; sexratio changed Petal death rate increased in several treatment groups Fink ct al. 1967 [8| Corbett et al. 1973 |9| Pape ct al. 1978 HI Decrease in fetal weight at 10 and 50% nitrous oxide TM [subanestbetic effect*) AP00019935 R %*jue-Da>*leyl iohal. 24 h x 1,9 d, k 20 d. lech. B+E 31 OfaiO 30 70-759 328/343 286/340 Hamster: C.S.. inhal. 24 h X 1.7-lld.k IS d. tech. A + E+F 23 0 <0s + air) 283/286 52 70% or 10% in air 579/596 S2 90% or 95% in air 532/598 4/156 examined (1 CNS + eye); skeletal anomalies in I3'I70 exam (including fused ribs) 20/138 examined (18 CNS + eye). (In a concurrent group. 1/160 malformations following exposure in anesthetic doses of xenon occurred.) Skeletal anomalies nccurcd in 55/148 examined (including fused ribs). 0/283 TM [anesthetic effects) 16/579; in total IS CP. 22 limb defects. 28/532; 4 gut herniations Lane et al. 1980 110| Shah et al, 1979(111 *Thts proportion refers Ui a group of females killed at day [4. k. kilted: A. visual observation: B. magnified observation: C. dissection: D. razor blade sections on fixed Iissue: E. skeletal staining; F. histological examination: <J, histochemistry of central nervous system: H, electron microscopy. CL. cleft lip; CP. cleft palate; -- ih> data. APOOO19936 293 APOOO1 9 9 3 7 TABLE A-ll. Teraiologkal Truing of Carbon Monoxide utpmure. ctammaiinn Mice CF-I. inhal. 7 tr 24 h a. 6-15 d. V. 18 d. tech. A-B-C+E Rat. inhal $-8 rnm x |0. even other day Lif pngnincy. tech. A Rat: Lone-Evans. inhal throughout gestation, lech A Rat. inhal. from days 2-21. tech. A Rat: Long-Evans. inhal days 3-20. tech. A No. of females 28 20 17 18 -- 27 26 18 IS Doses used 0. 2S0 ppm (7 h/di. 0. 250 ppm (24 h/J) 0 5.900 ppm 15.000 ppm 0 150 ppm 0 230 ppm O 30 ppm 90 ppm Survivor*/ implants 336/364 231/273 204/238 198/234 -- -- -- - Malformation*/ survivors <3336 1/231 l/XM 2/198 - _ _ Other obsen mions <TM. unit cffixts in mothers] _____ Reference Restvrpiions increased in the 7-h exposure group. lumbar spurs in both ex posure groups, decrease in body eight in the 24h exposure group At 15.000 ppm most fe tuses rcwirbcd or aborted Schwctz el al. 1979 112| Wells. 1933 11-41 Nonsignificant reduction in body weight, low physi cal activity in pups Decrease in body weight at 24 h postaatally. minor skeletal variants Dose-dependent preimpianlatkm km. in the 90-ppm exposure only: 38% of pregnancies were suc cessful vs. 100% in the control Fechter and Antiau. 1977 113| Hoffman and Campbell. 1977115! Garvey and Longo. 19781161 86<S lOOOdV mlr >tz'f 3 sr 5 S:Ss8SP I*fips |n`. ft l I ip 3* i I L < if Z > 9 s-R>-?ri tfs'i I I| , *kjO Si>sJ*O *8 O I0 S 1 || | | 1 Ii K '5 $wj ^2 C**i Se II I! I I og pf go o3 II I I ' 1 1 I i I > s. 3 sr *! ^ ? *?5 -aIT a 3 I* "4s f* 111 * 8 If *r 3| S *& --j a -- tw XSTS3 "2 SE- -t $3 ffl kJ 3d 5 s* --<C aM x a --_ c9 f APOOO19939 TABLE A-IH. TcritoJoftical Testin* pt Ethanol .Species. exposure examination Ethanol Mice: B6D2F,/I. i.p. x i or x 2. 3-9 d or 10-M dor7-12 d. k 18 d. tech. A C No, of ferrates Doses used 43 0 (Solvent) (pair-fed) 13 0.03 ml/g of 23% ethanol 48 0.03 ml/g of 25% ethanol Mice; C57BL/6I. diet X 6. 5-10d, k I9d. tech. A + D 13 0 (Lab. chow + water) 16 0 (pair-fed isocal.) 16 * Mice: C8A. diet hefore conception and throughout preg nancy. k 18 d. tech. A+D+E 10 0 (lab. chow) 10 0 (isocal. sucrose) Survivors/ implants 393/413 67/122 321/456 83/90 99/105 103/122' 47/48 56/56 Malformations/survivon 13/393; 7 iris coloboma. 7 ethers 14/67: exencephaly in two fetuses: cctrodaciyly in the others 108/321; 74 iris coloboma; 16 ectrodactyly; 5 hypoplastic atria; 6 hydrone phrosis; 4 exencephaly; 19 others 3/83; I eye. 1 heart. 1 abdomen/urogenital 3/99; 1 skeletal, 2 eye 31/103 (40 defects); lOskclctal (syndactyly, adactyly. ectrodactyly. d1stonion of digits). 3 head, 4 eye. 11 heart, 12 abdomen/ urogenital Skeletal; 1/15 examined; soft tissues; 0/32 examined Skeletal: 0/18 examined: soft tissues; 0/38 examined Other observations (Tm. toxk effects in mothers TM (hypnotic dose) TH (hypnotic dose + weight loss) Reference Kronkk, 1976 123| Randall et a! 1977 [24J Chcrnoff. 1977 (25] 0t66(000dV 3 ml/100 17/40 S kcktfl: 6/6 cum ined (6 n ii it*m* ?s5 8s S '. R8 12 2. v ft n1 mmnnbliRirfiirt! isiI |t=i1+MsSi III " -'-I 5-M i > i. f ^ a 8 1 3 (continued) It6610006V ethanol I X JV rn - 8. :-3 1 >s sg ?V r :s S' RmT Dea * 3U u -sfe. n 0 S pg h ^i n ? H- jr & m_5 ill- Sf S B i!* 2. pi #3- II _ Vi a3 < 38 * > =. B- IlSlIPSli ifj 1 ? ST3 S"1r8"*-?U-'2f'*if2 *a * es s2 2. S' 83 s! MMli 11 < S' 2. .-- "+ 2. 5 2 * ^ = + 9- a I Cl _ J5?* "S 3 K. 3oD 8 r> (im tm c ti d 7): 30% maxillary hypopliuat y CL CP (treatment d 8): antphlhalmu; enlarge- resnrptir TM (6 b nnconK.*tmna Mice; C57 BL/6J.i.p. x2.7d.kl4d, tech. A+F f Nix given 0 [vehicle) Not given 0.015 ml/g (25% ethanol) Nm given 72.-? Rat; Sprague-Dawlcy, diet before concep tion and throughout pregnancy, end point; term tech. A 24 0 (isocal; 17/7 some pair- fed) 13 30 g/KX) ml 5/7 (water) Rat: Sprague-Dawley. >1 0 (water) 244/232 diet x JO. 6-15 d. k 21 d. lech. A * C +E 19 10 ml/kgd 223/224 (15% ethanol) Rat: Wioir. diet 49 0 (soya oil. 444/".* throughout preg isocal.) nancy. end point: term, tccfi. A F 43 7.3 m 11.3 g! 321/7 kg (total intake) 12% eye mulhvmalioru (mi crophthalmia. anophthal mia and others). Absolute numbers not given 30/72: eye malformation* (iris cokibonu. micro phthalmia, anophthalmia. shortened palpebral fis sures), 9 of the 30 had ab normal nasal and lip regions. Id addition. 1 cxcncephaly + 1 aneitccphaly Brain ni/c re duced + his tological changes of ncumcctoderm.. TM (lethargy) Sulik cl al. I9KI |29| Tze and Lee. 1975 m Unspecified number of fe tuses with microcephaly * cracked and dry skin 2/244: 1 fcuis with DCandia. clubfoot. ectopic ovaries, shortened trunk + 1 with one rib missing 0/223: delayed ossification of skull bones + unfused centre of the vertebrae 0/444 Low litter size + low binh weight 2/331: 1 gross malformation of hind pan of the htxly + 1 hydrocephaly Sehwct/ ct Bl. 197# |2ftf Oisund ct bI. 1974 l.'ll Uvwtfl<*(/) APOOO19942 299 i TABLE A-III. Teraiological TttHm of Ethanol (Continued) 1 Species. exposure examination Rat: Long Evans, gar age throughout pregnancy, end point: (erni. cedi. A Rac: Long Evans, gavapex IS, S-I9d. k 20 d.lech. A No. of females 74 25 21 11 IS Doses used Ofisncal.; some pairfed) 1 g/kg/d 2 g'kg/d 0 (Uocal. sucrose) 6 g/kg/d Survivors/ implants 770/? 250n 200/? Not given1' Not given1* Rac: Spragtte-Dawlcy. diet before concepnon and throughout pregnancy, k 20 d. tech. A + C 18 0 (isocal., 179/187 pair-fed) 18 0.02 mt/g/d 135/181 Rat: Sprague-Dawlcy, gavage twice a day x i. 11-13dor 1416 d. k 20 d. lech. A+C 12 + 15 12 + IS 0 (iMKal., pair-fed) log/kg/d 135/139+ 151/151 110/138+ 138/144 Malformacions/survivors No visiHc malformations Ocher observations (Tm, lock effects in mothers Reference Abel. 1978 |32] No visible malformations No visible mairormacions Not reported Nut reported. The siudy was nut designed to detect malformations Not reported Reduced fetal weight. TM4 Not reported Not reported Reduced organ weight (brain, hean. liver, kid ney) + weight toss Not reported Reduced organ weight (brain. heart, liver, kid ney). TM {severe mania) Abel and Greizersiein. 19791331 Henderson et al. 1979 1341 Henderson et al. 1979 IMI APOOO19943 Ran Sprgoe-D*wley. i.p. x 1.9d. cesarean sect. 22 d. tech. A R*l: Long Evans, diet before conception and throughout pregnancy, k 20 d. tech. A+CDE Rat: Long Evan*, diet throughout preg nancy. k 20 d. lech. A+C+D+E Guinea pig. diet 3 or 4 timet/week, end point: term, tech, A+G Rabbit: N.2.. diet x 13,6-18 d. k 29 d. tech. AC+E 6 8 7 10 9 9 9 Not given 8 14 0<NaC1j 0.02 ml/g/ animal 0.02 ml/g/ aninule Ofpdydipsial' 3% ethanol polydipsia 0 (tome pairfed) 5%echaaol (27% EDO) up to 3 ml/kg/ d 0 (water) 3 ml/kg/d 63/63 87/99 J7/58 97/106 79/89 136/142 43/51 Not given 64/72 84/126 Piglet: Sinclair S-I. diet before concep tion and throughout pregnancy, end point: term. tcch. A+C 12 O (pcit-fed) 72/80 12 > 3 g/kg/d 42/63 0.63 0/87 2/S7 (microphthalmia + hydrops fetalis) 0/97 0/79 0/136 TM (2 deaths) Reduced birth weight 0/43 Immaturity of brain at gross examination + cellular le sions, retardation of myclination 3/64 (! spina bifida: 1 anencephaly + sbtepharia: 1 fetus with missing spleen) 2/84 (1 CP + protruding tongue + encephalomalacia; 1 bent rail) + minor malformation* of carotid arteries 0/80 (malformations were looked for in stilHmrn also) TM (sterility. low birth weight, im maturity, stillbirth) 4/63 (1 case of each: pro lapsed rectum, undcscemJed testicle. hypoplastic testicular tis sue, micmphlhalrnwi Low birth weight: low renal weight 301 Lindcnschmkh and PCrsaod, 1980135| Samson. 1981 (36) Samson. 1981 (36| Papara-Ntcholsofl and Telford. 1957(371 Schweiz ct at. 1978 126] Dexter et al. 1980 |3*1 iranfkuiedl APOOO19945 TABLE A-III. Terntotogical Tcstliy* of Kthawd (Cnntlnucd) Species. exposure examination No. of females 6 Doses used >3 g/kgAJ Survivors/ implants 10/12 Doe: Bcaclc eavacc 10 0 lisocal. mi- 51/56 twice a day through crotc. pair- out pregnancy, end fed) point: term. tech. AsC 28 2.4. J O. 3,6. 61/86 4.2. 4.7. 5.7 g/kg/d Not given 4.2 g/kg/d x 17 d 49/? Mjlformuikxu/wirvivors 4/12(1 of each: anenccpMy. microcephaly, cra nial hone hypoplasia, micruphthaltnia. CP. hy poplasia of extremities, hvpodactylia. poiydnctylia. cryptorchidism, hypo plastic gonadal tissue, claacal atresia: 2 of each: micrognathia. syndactyly, hypoplasia of tail) 0/51 Other observation* (Tm. toxic effects in nxrhcrs Low birth weight; low renal weight J/22 examined (1 renal agencsi* + 2 kink tails) 15/49:3 absence of kidney; 4 CP: 7 kink (ail: 1 other Low birth weight + neonatal mortality. TM (weight loss) 'p < O.OOI in comparison with control*. Sri a further group of ten female* receiving 30% EDC f = ethanol-derived calorics! in diei no knplamx occurred. 'Ml animals failed to cany (heir pregnancies to day 20. 4UI' 15 animal* failed lo carry their pregnancies to day 20. 'Corresponding to 0.02 tnVg/dty. 'Pvxni supplements given lo match weight gain of treated animals. 'EDC = ethanol-derived calories. Reference Ellis and Pick. 1980 |39| i i TABLE A-IY. TeratofaRlcat Testing of McUiytmcrcwry (Mcti) Spefcie*. exposure. examination Mettg Mice: ICR. diet * 1, 10 d. end point: IS d, tech. ADE No. of female* 20 Doses used (m*/ke/d| 0 (water) Survivors/ implants 234/247 20 10 203/222 20 IS 214/2)1 20 20 215/232 Mairocmations/survvors Other observations (Ttn. oxic effects in mothers) 7/2)4 (0 CP; 6 clubfoot: Of 117* hydronephrosis: 0/ l(7*a absence of stemebrac; 41\ 17* incomplete fusions of stcmebraci' feiums examined 16/203 <4 CP: 6/102* hydronephrusis: I/101'decreascd occipital ossification: 2/101* ab sence of tierncbrae; 54/ 101* incomplete fusion) 1* fetuses examined 68/2)4 (60 CP; 3/108* hydnmephitKu: 0/106* de creased occipital ossification; 4/ (06* ab sence of stemebrae: 72/ 10b* incomplete fusion)* fetuses examined 137/215(126CP; 20/108* hydronephrosis: 6/107* decreased occipital ossifi cation: 11/107* absence of sterachiae: 82/107* incomplete fasion) * fetuses examined Low btnb weight Low birth weight Reference Fuyuia et al. 1970 |40J (mrtiiiutrth 303 APOOO19946 APOOO1 9 9 4 7 TABLE A-1V. Tcratokirkal Testing of Methyhnercqry (McIIr) (Continued) Species, exposure. examination Metis dicyanamide Mice 129/SvSJ, i.p. x 1.6-l3d.lt. IS <1. tedi. C *E Metig dievanumide Mice; Atl. i p. x l. 6-13 d. k IB d, tech. C+E M'Hg Mice: ddN. diet x I. 6-13 d. end potrti: I8d. lech. A+C MeHgO Mice. Swiss, diet x 12. 6 17 d. end txiim: term. tech. A No. of females 20 Doses used (mg/kg/d) 25 2) 0 (solvent) 2) 2 2) 4 t> F 4 0 (solvent) Survivors/ implants 199/226 92.696* 86.6%h 83.6*1' 83/294 83.3 * Malformations/suntvors 199/199(199 CP; 24/101* hydronephrosis; 22/98* decreased occipital ossifi cation; 20/98* absence of stemebrae; 89/98* incom plete fusion) 0 0.5* 0.7* 41/83 (including 25 CP; 8 excnccphaly: 7 enccphaloccle; 11 face or limb defects) 35/132 (3 CP) J2 tl 4 48 90 73* 30 83* 86* 72* 79/82 413/579 17 0 (vehicle) Not given 37 0.001 in 1 (4 Not given levels) 36/151 (2 CP) 72/201 (14 CP) 138/227 (91 CP+ It micrognathia) 0/79 338/413(231 vaulted cran ium; .305 CP; 144 microg nathia; 82 microglossia) 0'I73 0/619 Other observations iTm. otic effect* in mothers! Low birth weight TM (lft'90 died) TM (4/36 died) Developmental retardation Spyker and Smithberg. 1971 |41J Spyker and Smithberg. 1971 |4(| Inouyc et al. 1972 142} Khera and Tabacnv 1973 [4t| APOOO19948 MeHgO Mice: Swiss diet x 12. 6-17 d, frtincs k 2-21 d After birth kh.G 23 0(t vehicle) Not given Cerebellar changes: frill examined 8 0.1 13 1.0 Not given Not given Cerebellar changes: o/|6 examined Cerebellar changes: 8/65 examined (histochemistry of CNS) MtHgOH Mice: CS7BL/6J i.p. x tOl, k IBd. lech. C + E 6 0 (inlvent) 5109 84 56/73 78 2S'5H 0/51 3/56 [1 CP; 1 anophthalmia; 1 micrognathia) 9/25 1 TM 3 TM MeHgOH Mice: CD. s.c. ori.v. x I. lOd. k 13 d. tech, C+E 15 0 (Solvein) 168/194 10 2r 87/105 9 4' 80/95 15 8f 162/180 II V 106/124 1/168 (CP) 1/87 (CP) 1/80 (CP) 12/162 (I0CP +2 txencephaly) 6/106 (CP) MeftgOH Mice; 129/SvSl. s.c. x I. 10d, k 18d, tech. C + E MtHgOH Mice: 129/SvSI. s.c. X 6. 7->2d.k 18|9d. lech. C+E 5 0 (solvent) 33/36 48 28/32 9 12 47/? 27 0 (solvent) 172/196 6i 39/45 21 4 128/163 IS 5 83/110 0/33 0/28 11/47 (9 CP: t facial de formity; 1 skeletal) 0/172 5/39 (CP) 119/128 (CP) 81/83 tCP) 1 TM MeHgCt Rat: Wiatar. diet x |. 9-11 d.k 18-20 d. lech. G 2 20 16n 2 Prominent malformations of the cerebellum with de generation of nerve cells (incidence not give*) 22 20n Moderate malfonnaiiotis of the cerebellum (incidence not givenf 305 Khera and Tabacova. 1973 [431 Su andOkiu. 1976 |44| So andOkiu. 1976 [44| Su and Ofcita. 1976 |44[ Su and Ofcita. 1976 |44J Malsumoto et al. 1967 (451 (nmiinttetil 6fr66iq00dV & AP00019950 H'HgOH Rai: Charle* River. gavage x 14.6-19 d. k20d, lech. A+E I IteHgCt Rat; Wistar. diet throughout pregnancy. L at different limn. lech. A F 12 0 M 1.5 16 3.0 16 4.5 14k 6.0 35 0 (corn oil) 35 0.002 35 OOI 125/133 135/mi 154/170 I0X/I97 1/108 Ntx given N given Mil given 20/85 examined villi rib ah* normal'nics; 5/40 exam* inal with heart abnormalities 20/79 examined with rih ab normalities; 0/56 exam ined with interns! abnormalities 6/102 examined with rih ab normalities: 4/52 exam ined with twain .abnormalities; 7/52 exam ined with heart abnormali ties: 10/52 examined with testicular abnormalities 21/7.3 examined with rih ab normalities: 3/35 exam ined with txain abnormalities; 15/35 with heart abnormalities: 14/35 examined with testicular abnormalities (VI rib abnormalities. 1 /1 brain and l/t hcan abnormalities 2.1/167 with eyelid or eye lesions 25/17(1 with eyelid or eye lesions 35' 129 with eyelid or eye lesions Reduced binh weight Reduced birth weight. TM (6 mothers died) Reduced binh weight. TM <K mothers died) 4/167 Harderian gland lesion!* 12/170 HarrierMfl gland lesion" 10/129 HanJerian gland lesions 301 Scharpf et al. 1973 \4->] IChera and Tahacova 1973 J431 UOMlmmil I > oo *o in t TABLF. A-rV. Teramhuinl Testing of Methylrnereurr (Mellg) (Continued)___________ ___________ _ Specie*. exposure. examination No. of females 35 35 MeUxOH Rjt Spraguc-Dawky. s.c X 4. 1.5.9.13 d. k2l d. tech. A-rF 41 23 21 Doses used (mg/kg/d) 0.05 0.25 01 solvent) l Survivors/ implants Not given Not given 509/513 283/287 248/252 Malformations/survivors 28/139 with eyelid or eye lesions 51/184 with eyelid or eye lesions No grow, iiulfurmaiwn* No gross malformations No gross malformations 27 " 267/321 No gross malformations 20 * IIS/IS4 No gross malformations Other observations (Tin. otic effects in mothers) 4/139 Harderian gland lesions 16/184 Harderian gland lesions Cctkilar necrosis nfCNS + runring Cellular necrosis ofCNS + runring. TM (1 mother died) Cellular necrosis of CN5 + ruruing. TM <3 nxuIt ers died) Cellular necrosis of CNS + ruruing, TM <8 (noth' cn died) Reference Model. 1974149] 10 r 41/70 No gross noHornutiofls Cdlalar necro sis of CNS nutting + I hydropic fe tuses. TM (4 mothers 20 4 26/80 No gross milforniMMMts died) Cellular necro sis of CNS i -t- rurting * hydropic fe tuses. TM 111 females MeHgd died) Rat: Sprague-Dawtey, 4 0 isalinel if. K t.Sd.end point: term. tech. A+H 44 Not given Not given No malformations were ob served (incidence not given) No malformations were ob At electron mi Chang and Sprcchcr. 1976 150J served (incidence not given) croscopy: degenerative changes in the proximal butalCi of UtHtCi kidneys Hamster: Golden, i.p. x 1,5-10d. k IS 41 0 (solvent) 507/563 10 4 116/122 5/507 9/116 Harris dal. 1973 |5|| d. tech. A+D+E 72 8 384/689 65/384 for a total of 114 malformations including 38 clubfeet. 16 hydro cephalus. 12 microgna thia. 9 defi palate or lip. 39 other* tomiinutd) t 309 APOOOf9952 f TABLE A-IV. Teratologic*! Testing of Mcthylmercury (McHg) (Continued) Specie*. exposure. examination No. of females Doses used Survivor*/ tmg'kg/dl _____ implant* Malformations/survivnc* Other observations tTm. oxfc effects in tTkxhcrs) Reference Hamster: Golden, j.p, * 14. 1-14 d.k 15 d. lech. AD*F, MeHfCI Cal: Persian and Eu ropean. (fid x 49, 10-58 <J.k 59 d. tech. C+E-*-F 5 Otsadventl 54/63 10 69/112 7 0 (solvent) 20/24 5 0.03 35/40 6 0.083 22/2R 13 0 25 51/97 Not reported 25/69 for a tout of 30 mat- kvirwtions including It clubfeet. 5 hydrocephalus. H others 1/20 (skeletal) 2/15 < I skeletal + I spina bifida) 3/2212 skeletal I umbili cal hernial 1051* (9 skeletal + cscixcptui) + I umbilical hernial TM (2 mothers died I (VI7 cerebellar histological changes 0/7 cerebellar histologicsl changes; re duced birth weight |/M cerebellar histological changes: re duced birth weight 9/17 cerebellar histological changes: re duced birth weight Harris etal. 1973 I5H Khera. 1973 |48| A P 0 0 0 I9 9 5 3 HettgCt Miniature Swine, diet before pregnancy?, k 109 d, tech. A + E U'HgO Dog: beagle, dkt throughout preg nancy. k 60 d. tech. A+E 20 0 114'114 30 0.05 to 0.5 7|?/96 39 0 169,-178 51 0.1 lo 0.25 I38'I40 0/114 0/71 Earl ct al. 1973 |52| TM 2/16941 CL + shortened tail: 1 microphthalmiai 2/50 in the 0.1 rog/kg/d group (1 CP + enlarged umbilical openmg * en larged fortuneHe: 1 en larged umbilical opening) TM tstillbinh) Earl et al, 1973 |521 "The figure refers to the number of fetuses examined. "Absolute figures per group not given. The whole series included 214 litter* and 1.391 implants. `k 15 d. `Absolute figures not given per group. The whole series included 96 I-itcr> and 889 infants. 'Eight groups of females treated in different days. '*.c. *i.v. hNo contrnl group: lesions were much levs severe in animals eoneutremly given penicillamine. Three groups of females treated in different periods. In this experiment, each group of nts < including controls) was divided into three subgroups concurrently treated with 0. 0.1 and 20 mg/kg'd irisndium nhrilotrucetaie; however there was sigalkiant change due to the presence of NTA. kln a fimher group treated with S.O mg/kg/d 21 '21 females died. 'Dose unspecified: maternal liver concentration < ]5 pg/g Hg: range of (he total dose 2-16 ng/raf "id; maiemal liver concentration 15-2$ pg'g. "id: maternal liver concentration 25-50 pg/g. Td; masemal Hver concentration 50-75 >tg/g. rid; maternal liver concentration 75-99 ^g/g. *id: maternal liver conccntratimi > 99*g/g. It is anclear whether fetuses examined were 51 or 34. 311 APOOO19954 SS6610OOdV (fcBCTI 8H ' XN Ul xQ 5* >s 5 r--* R!* *v% > -^5 a. & 4. r> 2 a&* sg y- 5- '-i 7 * . wJ:n a S ^ 30 sr >-- IJf*3 ft 5* jr v 3 ^gsl ,al JJ 5 5 >|SS Nl W O S C! S* s If * _. * ilI [ 2 vi s.* = 1. 2. . * r 3 1 = * S' s- 81 } j| 2! 11S!: I* t[3 s'jf 8? I ||| Hi ~ 5: II 5l Ta AP00019956 JJUW+exaCB Mice: CD-I, gavagc x 10,6-15 d. k 18 d. di. A? 0 (vehicle) 2 4 8 16 Arochtor 1254 Rat: W'tstar. gavagc x 10,6-15 d. k22 d, lech. A + E 9 0 (sotveni) 93/96 (0 6.25 107/119 < . 10 12.5 113/117 Absolute numbers not given. Avenge percentlie malformed fetuses/ litter 0.9%* Absolute numbers not given. Avenge percent age malformed feme*/ Utter II.7%* Absolute numbers not given. Average percent age malformed fetuses/ liner 3.6%* Absolute numbers net given. Average percent age malformed fetuses/ litter 65.5 Absolute numbers not given. Average percent age malformed fetuses/ liner 60.6%* TM TM 17% with skeletal anomalies and 47% with visceral anomalies (absolute numbers not given) 10% with skeletal anomalies and 17% with visceral anomalies (absolute numbers not given) 8% with skeletal malforma tions and 24% with vis* ceral malformations (absolute number* we given) Staples etal. 1980b I56| ViHcneuvc ct al. 1971 [571 (conurmed) A P 0 0 0 I9 9 5 7 TABLE ,%-V. Teratologic*! Testing af PCH (Ciwlinind) Compound - species. CXpUMKC. examination No. of females 10 1 Draws used tmg/kg/ti) 25 Survivors/ iniplants 114/(31 9 50 103/107 7 100 *4/89 Ann hhir 1254 Rat. ilwrmun.*' gv- age x 9. 7-15 d. end point: weaning. lech. A Arochlor 1254 Rat: Sherman, ^gav- age > 9. 7-15 d. end point: weaning. tecti. A 19 0 (solvent! 230/? 9 10 109/? 10 50 IM? 9 100 9i n 12 0 (solvent) 148/? 12 100 150/7 Mulformat ituu/survivors 97 with skeletal malformatnxi' ;iikl 157 with visotral ntallormadons (absolute numbers not givenl 97 with skeletal malformalion* snd 287 with vis* cent! maltoravuvons (absolute numbers not given) 157 with skeletal malformatwns and 0% with vis ceral malformations (absolute numbers not given) Other observations (Tm, toxic effects in mothers) Reference U/230 0/109 WIH 091 227 weaned 106 weaned 12? weaned, ktw birth weight 8 stillbirths. 25 weaned, low birth weight Linder etal. 1974 |58J 0/14* 0/150 4 stillbirths. 138 weaned 10 stillbirths. 124 weaned Linder etal. 1974 158) i i AmMorl254 Rabbit, gavtgc X 28, 1-28 dJk29d. tech. A 16 0 (solvent) 126/127 3i 18/19 4 10 27/27 2 12.5 2/15 Arochior 1248 Monkey; Rhesus, diet before conception and throughout pregnancy, end point: term. tech. A ArocMor t24t Monkey: Rhesus, diet before pregnancy. end point: term 4- 4 postnatal months4. tech. A+F 8 25 3 50 4 2S' 35/72 0/21 235/37 12 0 12/12 14 2.5 or 5 6/14 ppm in diet 80 8/8 IS 2.5 or 5 7/15 ppm in diet 0/126 0.18 0/27 0/2 0/35 0/25 0/12 0/6 -- Vilkneuve ct at. 1971 |S7| Increased liver weight Cephalic subcuta neous hemor rhages and asymmetric shun in 2 of 5 dead fetuses, in creased liver weight Increased liver weight TM (2/3 died be fore term) Increased liver weight 7 abortions + | stillbirth, small sue of newborns Barton. ei a. 1976 1591 0/8 0/7 (hypcrpigmenuiion of skin; hyperplastic gastritis and kcratinization of face hair follicles occurred in 2 dead infanui 3 abortions ARcn et al. I<W |60| Predominant malfbrmMions we reported to be CP end hydronephrosis. *Thcse experiments were i put of a large aeries of undies on the effect* of PCBs on rat reproduction, including microscopic examination of the lfr in lev gciterations. Both Arodor 1234 and 1260 fed 5 ppm id the diet induced liver changes both in F( and Fj weanlings of either sex fl ppm for F. rules fed Attack* 1234). Liver changes included enlarged hcpatocytcs. cytoplasmic inclusions, foamy cytoplasm, pigment, fibrous unnli. adenofibrohii. j*J nodules. cx22<7-28 d). ^Therefore both transplncenul and breastfed exposure occurred. 315 - APOOOf 9958 316 Hemminki and Vineb APPENDIX A REFERENCES 1. Smith BE. Usubiagi LE, Lehrer SB: Cleft palate induced by halothane anesthesia in C-S7 black mice. Teratology 4:242, 1971. 2. Basford AB. Pink BR: The teratogenicity of halothane in the rat. Anesthesiology 29:1167-1173. 1968. 3. Doenicke A, Witlman R. Heinrich H. Pausch H: L'efTct abortifde I'halothane. Anesth Analg Rean 32:41-46. 1975. 4. Pope WDB, Halsey MJ, Lansdown ABG, Simmonds A, Bateman PE: Feuaoxiclty in rats following chronic exposure to halothane, nitrous oxide, or methoxyflurane. Anesthesiology 4:11-16. 1978. $. Lansdown ABO. 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