Document 5DERmv4E8q3GXB5ByBEed3ga0

Congenital Poisoning by Polychlorinated Biphenyls and Their Contaminants in Taiwan Walter J. Rogan, Beth C Gladen, Kun-Long Hung, Shin-Lan Koong, Ljng-Yu Shih, James S. Taylor, Ying-Chin Wu, Dorothy Yang, N. Beth Ragan, Chen-Chin Hsu In 1979, a man poisoning occurred in Taiwan from cooking o3 contaminated by thermally degraded polychlorinated biphenyls. Because these chemkal* persist in human tissue, children born to female patients after the outbreak were exposed in etero. In 198S, 117 children born to affected women and 108 tmexpoaed eone-ots were examined and evaluated. The exposed dtildren were shorter ami lighter than controls; they had aboormaiitics of gingiva, skin, nails, teeth, and kings more frequently than did controls. The exposed children showed delay of developmental milestones, deficits on formal developmental testing, and abnormalities on behavioral assessment. These findings are most consistent with a generalized disorder ofectoder* mal tissue. This syndrome is one ofvery few documented to result from transplacental exposure to pollutant chemicals. OOKING OIL CONTAMINATED BY riod during which oil was consumed but Cpolychlorinated biphenyls (TCRs) mothers were asymptomatic was about 6 and dibenzofurans led to an out months. Chinese-speaking nurses inter break of illness (called yuduv# or "oilvdieiswed the mothers in their homes and ease") in Taiwan. The illness consisted of scheduled the examtnariora. The women chtoracne, hyperpigmentation, and meibo reported 159 pregnancies in this time; 3 mian gland dilatation among other findings were ongoing. 5 miscarried, 8 were aborted, (1, 2). The epidemic was noted in May 6 were stillborn, and 5 bom Ihe later died, 1979, and the oil was removed from the leaving 132 living children. Wc obtained market in October; cases were identified usable information on 128. One more child retrospectively from as far hack as December died between interview and examination. 1978. There is a registry* of about 2000 Twenty-nine families had 1 eligible child, 34 persons who were exposed to the oil. A had 2,9 had 3, and 2 had 4. Controls came similar outbreak ("yudw") had occurred in from 96 families who lived in the same Japan in 1968. neighborhoods. These 96 mothers reported Because these chemicals persist in human 205 pregnancies in this period; 3 were tissue (similar dioxins have half-lives in hu ongoing, 8 miscarried, 4 were aborted, and mans of about 7 years (J)], offspring of 190 produced the births; we obtained data ferrule patients continue to be bom affected, on 115. The exposed children averaged 32 even though maternal exposure has ceased. months dd, range from 1 to 82 months; the By 1983, 8 of 39 hyperpigmented children controls averaged 31 months, range 3 to 98 bom to exposed mothers had died (1). In April 1985 we performed a field survey ofall living children who were known to haw been in uteto during nr after the period of oil contamination. These children would have had transplacental exposure and possi bly exposure through breast milk, but would not themselves have consumed the contam inated oil. Seventy-four women in the health depart ment's registry had living children hum between June iv7H and March 1985.1'sc of tltcsc dates should identify any child with transplacental exposure, since rite Lucra pe W. |. KifM, I. C. GUtm. X. I. mpn, Xatnoul Itwrituw nf Envinmnmul Ifeatih Sckncrv tU\rifO> Triaiwtr Part. XC 27709. K-l. I tuna. Dcnarimcnt uf Pedum,*. Gathar Incttl HnapitaL Taipei, Taiwan, ROC ` S-L Knmut, tXnannum of tlrahh, lamnm Yuan. Tauxi, Tam-an, ROC l-l SNA. OniioB of Human Gmtia, Umvmkv of Madkine end Dentistry nf New )cncy. Nrwwfc,' N1 07103. f|a. nSd. GTciynfckwF, rSaeactdtioantiuonf, Industrial Dcmuttihicr, Ocvriand. OH 44106' Gcnr- Y-C Wu, Department of Derma*tingy. Natitmal Taiwan llnivmity I (<Ef)il, Tupri. Taiwan, ROC. IV Yang. IVrwmrum nt Pcdutri,*, SUNT BnariK-n. ItnmUvn. NT 11201. ' t'A'. Iliu, Otjumwia <(' Pwvhutrv. Natural Tmai Unrirruty lltnfMal. Taipn, Taiwan^ ROC SCIENCE, VOL. 241 WATER PCB-SD0000010284 month*. The families lived near each other and knew ofeach other's medical difficulties, ami Mime mother* still had obvious chloracne, so that was not pmsiblc to use a blind study design. Exposed mother* reported lower birth weight (mean SE: 2749 g 46 g. n 128; 3228 g 40 g. rr 115), hyper pigmentation, conjunctivitis, nail changes, and natal teeth in the children at birth (Table 1). The largest difference in the medi cal histories was the higher rate of bronchitis Table t. Physical signs present at birth and srkvtcd medical history items as reported by mother*. Frequencies are those reporting "yes" over those reporting "yes" or "no." "Don't know" and missing values are not included. Physical sign Exposed At birth White eve discharge F.velhl swelling Teeth present (muted or swollen gumt HyperpipmentJtion 32/108 25/106 11/127 11/ 99 54/127 lX-fnrmcd nr small oath Auk 30/122 16/125 Suhir^H*ttf hi.Ui*ry Hninchtm or pneumonia 30/124 in first 6 months . Rnmchitis had enough firr 2 dav* m bed Seizure with (ever Seizure without lever (hipped or broken teeth 21/126 15/127 1/127 38-107 Hair kiss Acne scars 14/115 11/115 Loss of muscle strength 5/ 89 Joint pain . Generalized itching Skin abscesses or boils S/ 91 32/115 26/116 Wart* 8/114 Control 5/113 0/111 0/113 0/114 2/114 1/113 0/114 5/115 3/111 5/115 1/113 25/106 2/105 0/106 01 85 01 84 12/102 11/103 1/106 Tatsla 2. Sekcml findings on physical examina tion. Ratios represent number recorded positive over number examined. in the exposed children. There was consist ent reported developmental delay in the exposed children; of the 33 milestones that we asked about, the exposed children were behiiul in 32 (the nts-cffcct value would he 16.5). The physical examinations were carried out during 11 days in April 1985 at lour local clinics; 117 exposed children and 108 control children attended. There were neu rologic, dysmorphologic, dermatologic, dental, and general examinations. The ex posed children were smaller than controls, averaging 93% (95% confidence interval (Cl), 90-96J of control weight and 97% (95% Cl, 96-99) of control height, adjust ed for age and sex. The gum hypertrophy or swelling noted by the mothers at birth was still apparent on examination (Tabic 2). Neither acne nor conjunctival cysts were much more common in the exposed, but the differences in hyperpigmenrarion and nail deformities and pigmentation arc large. Most of the pulmonary auscultation abnor malities were consistent with bronchitis, and this diagnosis was made clinically* in several of the children. The marked differences in eyebrow flare, hypertelorism and dinodactyh* were not expected. There were no abnor mal reflexes or any localizing findings in the neurologic exam; however, the exposed chil dren were delayed compared to conrrols in the age at which they performed tasks such as saying phrases and sentences, turning pages, carrying out requests, pointing to body parts, holding pencils, imitating drawn drdes. or catching a ball. The neurologists had an overall clinical impression of devel opmental or psychomotor delay in 12 (10%) of the exposed compared with 3 (3%) ofthe conrrol children, and ofa speech problem in 8 (7%) versus 3 (3%). We did age-appropriate testing of cogni tive development and behavioral assessment in the home after the survev, using nos* controls matched for neighborhood, sex, age, sib order, and family socioeconomic status. Except for verbal IQ on the Wcchxler Intelligence Scale for Children (WlSCj, the exposed children always scored lower than the controls on the three developmental and cognitive tests (Table 3). On the Rutter scales, the exposed children showed higher (that is, worse) scores on all three scales. There are no Taiwanese norms for the Rut ter scales; both exposed and control children scored higher than would be expected based on the norms developed by Rutter rt J. (4). Thermally degraded PCBs were identifed as human teratogens in the Japanese epi demic in 1968. Children bom to jw/m* mothers had low* birth weight, hyperpig mentation of gums and nails, conjunctivitis, dysplasric nails, wide fontanels, metastatic scalp calcification, diffuse dark skin pigmen tation, and natal teeth; 2 in 13 were stillborn (5). Four of these children were reported as normal at ages 8 to 19 months (6, 7), but Harada (8) reported that the 13 children he examined up to 7 years after the exposure were apathetic and dull with IQs in the 70s. In Taiwan, Wong and Hwang (9) noted skin desquamation, deformed, pigmented nails, hypersecretion of the meibomian glands, hyperpigmentation of the nose, and acne in six offspring of ytuhaig mothers. Four of these children weighed 2500 g or less at birch. Lan rt a/. (10) added another case with diffuse skin hyperpigmentation and low birth weight who died at 22 months. Law rt *J. (II) reported twins seen at 3 months of age for respiratory distress and pneumonia. They weighed 1800 and 2820 g at birth, and had wide fontanels, hyperpigmcniation, and persistent conjunc tival swelling. The effects in the children vve saw are most apparent in nails, hair, teeth, gums. Physical sign Exposed Control Gum hvpertmphv Tooth chipping Imrsoral hvpeTpigmematton Caries Acne or acne scars Hyperpigmentation rcrincal'gcntfal Head or face Pigmcmcd or cidormcd nails. FmgcT\ Toes Conjunctivitis or cysts l.ymphadcnoparhv F.ycbmw dare Lungs n clear to auscultation Hirsutism Hypertelorism Oinodactyly 7/116 11/101 43/116 68/101 20/117 50/117 13/117 19/117 74/117 12/117 28/117 25/117 19/116 18/117 24/117 47/117 0/107 0/100 33/107 54/100 10/106 29/106 4/106 1/106 22/106 9/106 11/106 4/106 6/106 5/106 10/106 25/106 Table 3. Results of formal developmental testing and behavioral assessment. Entries are mean SE; number in parentheses are sample sues. The BayIcy Scales of Infant Development were used until 30 months. The Stanford-Binet yields an intelligence quotient (IQ) and was used from 30 to 72 months. The Wcchsler Intelligence Scales for Children (WISC) were used after 72 months. On the Rutter scale higher scores represent more behavior disorders. Test' Exposed Control Bavk-v Mental scakMinor scak Stanford-Rinct (IQ) wise: Verbal IQ Performance IQ Full IQ Rutter Health problems Habits Behavior too 2.5 (45) 101 2.7 <4S) 85 2.7 (52) 82 3.1 (21) 90 2.7 (21) 84 2.9 (21) 2.64 s 0.21 (118) 1.50 0.13 (117) 11.08 0.45 (117) 106 2.4 (45t 108 2.1 (45) 89 2.7 i52i 82 2.3 (21) 97 2.9 (21) 88 2.4 (21) 1.43 0.15(120) 0.98 0.11 (120) 9.24 0.41 (119) i{ WLY 1988 RiroRTS ttt WATER PCB-SD0000010285 dan hypapigmatorion, sod growrfj md devdapmaat, abd are thus gawaBy eeossrh wii an acquawd (oHo)eaodermfil dys plasia, The acne pteiest st birth and persist ed is same duldren is a specific effect ofthe dan of polycydic, potyhalogauccd hydroorbosu, but msy &bo be a pan of the apparent dfcm on ectodermal structures. The increased frequency of bronchitis may be due to a specific pulmonary lesion, which has been seen in adults (12) and children (//) spwcd to this class ofagents, or due to a more generalized immune disorder (1J, 14). The developmental effects are consist ent with those seen in rhesus monkeys ex posed transpbeentaUy (15), and the behav ioral problems may be secondary to the developmental dday or a form of direct tQBdty (16). , These children have been exposed only by transplacental passage ofthe chemicals or by breast milk exposure. It is impossible to separate ckanly effects that persist because ofstructural changes during the final period from those that persist because ofcontinued internal exposure. Transplacental passage of the chemicals has been documented in au topsy studies (10), and it is reasonable to suspect that the chemicals will persist in die children. There were metabolic changes in the placentae ofsome of these children (17) and a fine have mild hepatic porphyria (IS). The kinds of toxicitks seen are consistent with PCBs, but the exposures are relatively low. The children of workers exposed to PCBs uncomaminated by polychlorinated dibenaoforans (PCDFs) do not show nearly so much toxicity, hut the mothers achieve blood PCB levels that are comparable to those seen in the outbreaks (19). The most likely reason is the presence of the very toxic PCDFs (2) in the cooking oil. Qualitatively, the PCBs and PCDFs are similar in toxkaty, but the PCDFs ate active at much lower doses. The oil in Taiwan had about 100 ppm PCBs, and about O.i ppm PCDFs (20). Although there has not been a human expo sure to PCDFs in the absence of PCBs, it is reasonable to assume that much ofthe toxic ity seen in both outbreaks is due at lean in part to PCDF contamination. 2S (auppL), I <1TO). 18. B. C Gk*a, W. |. fUgm. R 8. Ragan, F. W. 9. K-CWtgtMM-YHei%a.AM.fr#i)7. fipkrea, Ai. Bmbm. Nad* 4S, 64 (1988). a (Wty 10. 19. L Ham, Bmtma. UmM E9,8S (1983). 30. P.H-$Om0,MLIsa,CKWong,C-JO<m,A. 2,64 (19(7). / kd. t&d. S, 128 (1984). 11. K-L Uv, B-T Hwang, gu, Om AM. (Tm- 21. We <h* M L Hvmg. L Haag, md J. S&A, f*) 7.(8(1981). Raknorc; CC TdS, Haatl Taiwan Unhrenity 12. N. Shtfrmma el, Bomm. fej 16, 92 (1971). Hoswod; S-T Km, NsfamJ kawtae ef IWmire 13. K-| Chang. KH Hu*. T-P Ut, T-C Tung. ** 28.329 (19(21. Melons, Taipa; M. Malta. Apptiod Epdassote*v Treating mgiwa. Taipri; C-C tin, Prco-ncu! M. K-| Chang. K H Hai*. S-T Tang. T-C Tur*. J Heafeh Oaatn>,Tani !-C Su. National So rM. Bmmm. Hmt& 9, 217 (1982). ents Council, Took <*t few) J. D. Kiawandn and IS 1. E. Bowman, M. P. Hcwmumta, J R. AStn, R. W. Mbs ef NJH. Suppomd by N1EHS ran- Phwind Utktr, 9,49 (1978) emu and by pm JOC74-OJOI H002-29 few tte 16. R. C. ISnamtsa and M. P. Hcimnimua. .Vnn***1 2 3 4 5 6N7ational Soas Coanl. Twav ROC. Tmid. TmM. 8, IS (1981). 17 T-K W*at.. Un i, 731 (IVKSt. 9 Fthnuuv 1988. Kvxpcd 24 May 1988 REFERENCES AND NOTES t. S-THwi(.,laiiwiw. HfMiPmfnt. f9,S(198S). 2. T. Maauda, H. Kuroki. T. Vamama, K. Hangudu, M. Kwatxanc, S-T Hau, Cbmmph,w 11. 199 (1982). 3. P. C Kahn at d.,J. Am AM Aum 2S9. 1661 (1988). ' 4. M. Runtr, J. Taaid, K. Whitmore, in Bdmmm, H*M, md Bdummr mj .\Mud Smfy / CkiUkmJ Dndmmml (WOty. New Vwt, 1970). PP 4)2-2) 5. W. |. Rngan, 26.2S9 < I982l. 6. 1. Funatiu n at. Xmw AM J 19. 43llV72(. 7. I. Funanul,K*lM Atu AM 62, IJV(!V7I|. R M. Hamda, &4. tma. Out. AM. (Mr WATER PCB-SD0000010286 Table 1. Physical signs present at birth and selected medical history items as reported bv mothers. Frequencies arc those reporting "yes" over those reporting "ves" or "no." "Don't know" and missing values are not included. Physical sign Exposed Control At birth White eve discharge 32/108 F.vclid swelling 25/106 Teeth present 11/127 Irritated or swollen gums 11/ 99 Hyperpigmentation 54/127 Deformed or small nails 30/122 Acne 16/125 5/113 0/111 0/113 0/114 2/114 1/113 0/114 Suh.<Ci]iH i}t hii.</or)* Bronchitis or pneumonia 30/124 in first 6 months . Bronchitis bad enough 21/126 for 2 davs in bed Seizure with fever 15/127 Seizure without fever 1/127 Chipped or broken teeth 38-107 Hair loss 14/115 Acne sears 11/115 D>ss of muscle strength 5/ 89 Joint pain , 5/ 91 Generalized itching 32/115 Skin abscesses or boils 26/116 Wans 8/114 5/115 3/111 5/115 1/113 25/106 2/105 0/106 0/ 85 0/ 84 12/102 11/103 1/106 =gg=,...-`v WATER PCB-SD0000010287 Table 2. Selected findings on physical examina tion. Ratios represent number recorded positive over number examined. Physical sign Exposed Control Gum hypertrophy Tooth chipping Intraoral hyperpigmentation Caries Acne or acne scars Hyperpigmentation Perineal-genital Head or face Pigmented or deformed nails Fingers Toes Conjunctivitis or evsts Lympludenopathv Eyebrow flare Lungs not clear to auscultation Hirsutism Hypertelorism Clinodactyly 7/116 11/101 43/116 63/101 20/117 50/117 13/117 19/117 74/117 12/117 28/117 25/117 19/116 18/117 24/117 47/117 0/107 0/100 33/107 54/100 10/106 29/106 4/106 1/106 22/106 9/106 11/106 4/1C6 6/1C6 5/1C6 10/106 25/106 WATER PCB-SD0000010288 Toblo 3. Results of formal developmental testing and behavioral assessment. Entries are mean SE; number in parendieses arc sample sizes. The Bayley Scales of Infant Development were used until 30 months. The Stanford-Binct yields an intelligence quotient (IQ) and was used from 30 to 72 months. The Wechslcr Intelligence Seales for Children (W1SC) were used after 72 months. On the Rutter scale higher scores represent more behavior disorders. Test Ravlev Mental scale i Motor scale Stanford*Binet (IQ) wise Verbal IQ Performance IQ Full IQ Rutter Health problems Habits Behavior Exposed 100 2.5 (45) 101 2.7 (45) as - 2.7 (52) 82 3.1 (21) 90 2.7 (21) 84 2.9 (21) 2.64 0.21(118) 1.50 0.13 (117) 11.00 0.45 (117) Control , 106 2.4 (45) 108 2.1 (45) 89 2.7 (52) 82 2.3 (21) 97 2.9 (21) 88 2.4 (21) 1.43 0.15 (120) 0.98 0.11 (120) 9.24 * 0.41 (119) WATER PCB-SD0000010289