Document OEae1Q41xDJnLKz8y53mRdLJ1

I/McucIa \<n& SOME OF THE RECENT FINDINGS CONCERNING YUSHO Masanori Kuratsune, M.D..' Yoshito Masuda,** and Junya Nagayama* Abstract Analysis of Yusho dispose, which was first detected in 19G8, h.ts been limited and analyses have produced varying results. Yusho oil has been determined to con tain a high level of polychlorinated dibemofurons (PCDP'sJ. N.ignyama ct at. found that PCDF levels in the oil were especially high when the oil was contaminated with PCfl s used as a heat transfer medium. Their studies also showed that the concentration of PCDT-'s is much closer to that of PCB's in liver than in adipose tissues in patients with Yusho. The current clinical state of patients with Yusho is dicusscd at length. Suh/ective symptoms, dermatological findings, serum triglyceride levels, liver conditions, mortality rates, and the effects on children bom fo mudicrs with Yusho are all reported. INTRODUCTION Mote titan 7 year* have passed since the outbreak of an epidemic of Yusho in 1968. According to the latest tabulation, Prof. Omac. current chief of the Study Group lor the Therapy of Yusho, reported that a total number of 1,291 patients hove been registered as Yusho in 22 prclectures of Western Japan by April 30, 1975 (ref. !>. We would like to describe some of the recent find ings concerning Yusho which we think to he particular ly relevant for undemanding of toxicity of PCB's. For more detailed inlnimabon, readers arc advised to refer to original papers appearing mainly in the fuuith and fifth trpo'ts of the study on Yusho and PCD (ref. 3). Most o' th patients described in these reports arc those livinq u> f'ukuokii prefecture. Published information of pahc-nij living in other areas are unfortunately very few, so with a few exceptions no reference will be made to them. PCB's IN THE BODIES OF PATIENTS WITH YUSHO 1. Tissues First of all, the concentration of PCB's retained in the tissues and fluids of patients with Yusho should ha referred to before their current clinical state will bo dis cussed. Although nn accurate estimation is feasible because of the very limited number of analyses so far made, the concentration of PCB's In adipose tissues of patients seems to have been fairly high soon after the occurrence of poijoning-that is, in November 19G8. at least I month after the discontinued use ol the toxic rice oil by patients, as shown in (able I. The corresponding concen trations were considerably lower in 3 patients who deni in the next year, 1969. However, no such marked dif ference could be seen between those who tiled in t9**'C and the subsequent decedents, although cases 7 and 10. who died in 1970 or 1975, showed quite low levels o PCB's in adipose tissues. As compared with the figureavailable from a nationwide survey on residual PCB's i autopsied tissues, the levels noted in the recent dece dents are considered to be fairly dose to the usual leve of ordinary autopsied materials. Similar facts were alsc noted for PC8 concentration in the skin and liver. 2. Blood Since the analysis of PCB's in blood started onl- after 1977, no figures are available in regard to the bloc levels of PCB's in patients in the earlier stage of poisor ing. As shown in table 2, however, it is clear that ih blood levels of patients had approached tire fcvel c ordinary persons already in 197?, although they wet still significantly higher than that level. Tins fact as w< as the previous fact o* lowered tissue levels of PCB's l recent tieerdtrnts seem to l>e rather suspiring if we coi sidcr also that the majority of patients are still showin various clinical symptoms, as will be discussed later. i Kiimihiw am/ Junvs Ne>}<->yar'j are woh tln Oi'l>aitiMi-ni v.r Pulilc Faculty 0* Medicine. Kyushu Uitivf-in<y, ui An.*l\ ii. nl Onmisirv. I'a-icN Collri/D of i'hjiimo'uiH at Sr iew i\ f lAuok a, J.nwm. * ' Yor*!r<i Mt'dil,. it with LV>(<.h> Collf'/t nl Ph.irm.ii. uii .1 ........ l uUiak.i, Jm<M\ 3. Gaschroniatngraphic Patterns of PCB's in the Dude of Patients Masuda lust noted a peculiar common g.ischr rnatofirnphic p.itic-'o of PCU fractions isolated fiom vj ou$ tissues, blood, and breast milk of patients w. Yusho and railed Ihe attention o! the Study Gioup f the Thri.ipy <d Yusho to <t in earlv 107V* figur-shows a lyrical example of such a pattern m compare. MQNS 086443 Id <ST/V. a/ 0- OSTftoU 60-?^ Tab*e 1. PCB's concentration in tissues of patients with Yusho and other diseases Case Ti~e of death. operation Ski n Whole Fat basis basis PC3`s (pJtn) Adipose t issue Whol e Fat basis basis liv er Whole Fat basis basis Reference Case 1 High school boy Case 2, 3 Adult male. female Nov. 1968 Nov. 1968 76 (face) 13 (abdomen) 32, 46 (cheese-like substance from acnefortn erup tions) 10 Case 4 July 1.3 3.7 0.14 9.5 Boy, 13 yr 1969 (mesentery) Case 5 July 1.2 8.7 2.8 15.1 0.2 10.4 5 Kale, 25 yr 1969 (mesentery) Case 6 Nov. 1.0 4.4 3.8 8.4 0.07 3.1 Male* 73 yr 1969 ' (mesentery) 11, 12 Case 7 Female, 48 yr Dec. 0.6 0.8 0.7 0.9 0.07 1.3 1970____________________________(mesentery)__________________________ _ Case 8 Male, 46 yr Case 9 Female, 33 yr May 1972 Sept. 1972 1.8 3.2 4.3 6.5 1.9 (subcutaneous) 2.9 0.08 8.4 Case 10 Male, 72 yr National survey Males and females 25 - 49 yr Apri 1 1975 1973 0.04 - 1.7 (n = 54) 0.19 (mesentery) 0.4 0.04 3.0 14 0.2 - 4 (n = 47) 0.3 - 6.4 0.01 - 0.6 0.02 - 3.1 (n = 48) (n = 51) (n = 30) Tabic 2. PCB's in blood patients with Yusho, workers and ordinary persons Material No. of subjects Time of examination PCB's (pph) Whole basis Refer riean + S.D. Range ence Whole blood Yusho patients 41 March - August 7 2-26 1973 7 Ordinary persons 37 1972 3 1-7 Plasma Yusho patients Normal persons Whole blood Yusho patients Normal persons 15 82 Jan. 1972 25 11 6.3 + 4.0 2-15 3.0 + 1.3 1- 7 4.8 + 2.9 M2 2.8 + 1.5 1- 6 8 Whole blood Workers8 23 1972 364 + 262 60-920 9 aWork'ers engaged in the production of Kanechlor 200-600 in the air con taining 0.05 to 0.2 mg/nr of PCB's [Kanechlor-300 + Kanechlor-400 (1:1)). Two of them showed dermal signs. with thr ciiminon cno wen in ordinary persons, which is very much close to that of a mixture of Kanechlor 800 + COO (1 : 1). It is easily notable that the peak 1, which appears immediately alter p.p'-DDE in the 93s chromato gram in (inure 1. is vciy low in patients with Yusho as compart'd with orrJinary persons, while the peak D is mud) more prominent in Yusho than in ordinary per sons. M.-sudd and h<s associates observed this peculiar pattern (designated as type "A") in blood of about GO l>ciccn( of patients with Yusho, and a somewhat similar pjtliun (designated o type "[}") m about 37 percent (ids. 4.7,11.171. Takamatsu el a(. also observed the same peculiarity in the blood of patients with Yusho (ref. 81. It was further demonstrated that those patients who show the peculiar jas chromatographic pattern as designated as pattern A by Matilda et al. hast a highlit average concen tration of PCB's in their blood than do other patients (refs. 4,7). Abe et al. Ircf. 23) examined in 1974 lire PCD residues in the plasma of 30 children bom to 18 mothers who had consumed Yusho oil at Gto Islands, Nagasaki prefecture. The specific gas-chromatographic partem of type A was seen among 24 percent of the children amt 44 percent of their mothers, but the pecu liarity seemed somewhat less marked as compared with the one seen among patients in Fijkuoka prefecture. The chemical and toxicological nature of the com pound or compounds yielding the above mentioned peak 5 must be clarified but have not yet fully been ex amined. Masada. however, considers th peak & to be 3,4,2 .3'.4',5*-hcxachlorobiphcnyf, judging from its retention time on the Apic/on L culunm developed tv Jensen end Sundslron (ref. 22). 16 MQNS 086445 A : fATTY TISSUE OF YuSHO PATIENT ' B s Fatty Tissue of ordinary person C : Katie CHLOR 500 GOO (1:1) POLYCHLORINATED DIUENZOFURANS IN KANECHLORS, "YUSHO OIL," AND TISSUES OF PATIENTS 1. Polychlorinated Dihen/o/urans in Kanoch/ors and "Yusho oil" Flcrvntly Nagayarna et l. analyzed Kancchlors and ihiL-t vompliu of toxic "Yusho oil" used by three inde pendent families with Yusho for polychlorinated diIviwoluMm (PCDF's) and polychlorinated diben/opd'Oxiin (PCDU's) {ref. 16). They did a column chroma tographic fractionation of PCDF's and PCDO's from a bulk pi PCH's by using activated alumina as adsorbent, ud nhi-ruHH'. n-hexanc containing 70 percent carbon Uluchl.iiuic, or n hexane containing 20 percent methyl(nchlondo as eluent The fractions thus obtained were liihieeii'd to yatchiomatogiaphic and mats specoottxMric examination. Quantitative estimation of PCDF's amf PCDD's was made by two methods, namely by measuring the gas chromatographic peak heights and by mcasuiing the gas chromatographic peak area of per- '**n.ired ili'Mvaiives ol these compounds, Although iso PCDD's were found in any of these W'.Hiiet, PCDF's were found in ail of them. As shown in table 3, KC 400 contained the highest concentration of PCDF's, about 18 ppm of PCDF's consisting of dichforoup to pcntachloro- dibenzofurans. A peak with the tame retention time as that of 2,3,7,8 tetrachlorodibonzofurans, which was kindly provided by Dr. J. G. Vos, was noted in its gas chromatogram. All of the three samples of "Yusho oil" also contained about 5 ppm of PCDF's, tho major constituents of which were tetra and pentachiorodibcnzofurans. Here again, the peak with the same retention time as 2,3,7,8-ictrachlorodibenzofuran was noted. Kashimoto also found 1.6 ppm of PCDF's in another batch of "Yusho oil," as shown in table 5 (ref. 18). Table 4 summarized the concentrations of PCDF's in Kanechlor-400. reported by several authors. As clgarly noted, there is a fairly large discrepancy in their findings. Whether or not it was due to their analytical procedures or to batch difference cannot be decided at the present time. Another important fact was disclosed by Nagayama et al. They determined the concentration of.PC0's in "Yusho oil" as approximately 1,000 ppm or slightly less than 1,000 ppm, as shown in table 3. Since "Yusho oil" is known to have been contaminated with Kanechlor400. the ratio of the concentration of PCB's to that of PCDF's in "Yusho oil" is expected to tro about 1,000 0.018. The observed ratio, approximately 1.000 6, 17 MQNS 0S6446 Table 3. PCDF's and PCB's in Kanechlors and Yusho oil PCDF's (ppm) PCB's (ppm) Sample Peak height method Perchlorination method Peak height method Perchlo- rination method 300 1 1.5 Kanechlor COO 500 18 4 16.6 2.5 600 5 2.7 _ - Yusho oil A B C 5' 4 5 4.4 5.1 5.2 830 900 1030 870 920 980 Table 4. Reported concentrations of PCDF's in Kancchlor-400 Authors Year Concentration (PPM) Roach ct al.a Nagayama et al.b Kashimoto et al ,c 1974 1975 1975 . 1 18 33 aRef. 17. bRef. 16. cRcf. 18. was thus about 250 times higher than expected (table 5). The renums (or this great discrepancy are not clear yet. It should be noted, however, that the sample of Kancchlor-400 analyzed was an "unused" one, while tho Kanethlor-400 present in "Yusho oil" was "used" as heat transfer medium. This (act suggests a practically important possibility dial K.mcchlor 400 and probably other commercial PCO't. too, will increase their PCDF concentrations when used as treat transfer medium. 2. /`COf 's in liisursof Patients *vu!> Yusho N.njayarn.i et al. (ref. 24| further examined the tissues nf patients with Yusho for thmr possible content of PCbF's. Tabic 6 summarized their findings. Adipo:> tissues and liver from two ort/inary persons who died o accidents contained no detectable amount {< 0.1 pph of PCOF's. but those from three patients with Yushr who died in 19C9 or 197? were all'shown to contai* PCDF's. Figures 2 and 3 show their gas chromatoqran. and mass spectra. The concentration on a whole bas< was.0.009 ppm on averago for adi|x>se tissues and 0.01 ppm for liver. This teems to be a rather surprising fac because in the case of PCD'* tho concentration on whole basis is usually much lower in liver than in adipos tissues. When compared on lat basis, another interests fact was noted that PCOP concentration was much high cr in liver than in adipose tissue. Although the numbv HONS 06644 7 r\ ^ Tablo 5. Concentrations of PCB's and PCDF's and their ratios in various materials Materials PCB's (ppm) PCDF's PCB's (ppm) Pcdf'T Reference Kanechlor-400 Yusho oil Ad Bb 1,000,000 ca. 1,000 134 ca. 20 5 1.6 50,000 200 84 f6 18 Patient Adipose with tissue Yu5h0 Liver 1.3 0.05 0.009 0.013 144 24 4 8$amples of the rice oil produced on February 5 or 6, 1968. bA sample of the rice oil produced on February 10, 1968. Table 6. PCB's and PCDF's in tissues of patients with Yusho and ordinary persons Time PCB'S im). PCDF's (ppm) Ratio Case of Whole Fat Whole Fat 3CB's/RCDF's Subjects Tissue No. death basis basis basis basis Whole Fat 1 2 Adipose 3 1969 1969 1972 1.4 1.3 1.2 3.4 0.013 0.03 108 113 8.5 0.006 0.04 217 213 2.) 0.007 0.01 171 210 Yusho Avg. 1.3 4.7 0.009 0.003 144 157 patients 1 1969 0.05 4.7 0.025 2.3 ' 2 2 2 1969 0.06 5.6 0.010 1.1 65 Liver 3 197? 0.03 3.5 0.003 0.3 10 12 Avg. 0.05 4.6 0.013 1.2 44 Ordinary persons Adipose Liver 1 2 1 2 1975 1975 1975 1975 1.0 0.4 0.08 0.02 1.4 0.7 1.3 1.0 NO NO NO ND ND . ND ND ND > HONS 086448 19 Upper : PCDF FRACTION FROM Liver of Yusho Patient, Lower : PCDF FRACTION FROM Yusho Oil. Figure 2. Gaschromatograms of PCDF fractions from liver of patient with Yusho and from "Yusho oil." o( analytes made is quite limited and nothing can be said wdh certainty, this tact yrorm to deserve attention. As shown it> t.ilUc G. these different behaviors in tissue dis tribution cd the compounds caused a remarkable differ- t ncc in ratio o* PCB's to PCOF's between adipose tissues and livci It was ihm demonstrated that the concentra tion of PCOT's is much closer to that of PCB's in liver than in adipose tissues in patients with Yusho. The PCDF's ideniiliod in hvrr were mainly penta- and hexa- chlotndib.;n>olurans. containing only a boce of tetra- chlnioisomeis. t CUMMCNT CLINICAL STATE OF PATIENTS WITH YUSHO In 1974, prof, Ural}-' Irrf. 2), former chief of the Study Group, repourd ift.it the dermal and mucosal signs th.il were imni marked at the incipient stage of the poisoning had gradually been improved, while symptoms such as general fatigue, poor appetite, in constant ab dominal pain, heavy headedness and headache, feeling of numbness and pain at the limbs, and cough and expecto ration of sputum, all of which are considered to be due to some internal disturbances, have become mote promi nent year by year. In view of these tendencies together with die discovery of a characteristic y.rs chromato graphic pattern of PCH's remaining in the blood and tissues of patients, the diagnostic criteria for Yusho was revised in 1972 (ref. 2), as shown in tahle 7. As com pared with the former one. the revised criteria describe briefly the dermal and mucosal lesions but newly rclor to other noncuuncous objective signs and findings from several laboratory tests. It should be noted, however, that the new criteria do not refer to any specific fiver function tests. 20 HONS 006449 MOWS 086451 Figure 3. GC-MS of PCDF's fraction from liver of patient with Yusho (upper) and of synthesized PCDF's (lower). Table 7. The diagnostic criteria for Yusho (revised in October, 1972). Yusho is considered as an acute or subacute poisoning with PCB. The general symptoms currently seen are retarded growth, neuroendocrine disturbances, phenomenon of enzyme induction, disturbances in the respiratory system, and abnormal lipid metab olism. As the local symptoms, acncform eruption and pigmentation as cutancomucosal lesions and ocular symptoms are seen. 1. Conditions of attack Fact of ingestion of Kanemi rice oil contaminated with PCB and familial occurrence seen in most cases. 2. General symptoms a. Subjective symptoms 1) general fatigue 2) heavy headedness and headache 3) inconstant abdominal pain 4) feeling of numbness and pain at the limbs 5) swelling and pain at the joints 6) cough and sputum 7) changes in menstruation b. Objective symptom 1) bronchitis-like symptom 2) sensory neuropathy 3) bursitis 4) inhibition in growth and abnormalteeth inchildren 5) Smal1-For-Dates baby and pigmentationof the entire skin of newborns c. Results from clinical examination 1) abnormal properties and concentration of PCR in blood 2) increase of neutral lipids in blood 3) anemia, lymphocytosis, hypoalbumincmia 4) reduced velocity of the sensory nerve conduction and adrenocortical hypofunction 3. Cutancomucosal siqns a. Acneform eruption Black comedones and acneform eruptions which are seen at the face, buttocks, and other intertriginous sites and their suppurative tendency. b. Pigmentation Pigmentation of the face, palpebral conjunctiva, gingiva, and nails of the fingers and toes. ' c. Ocular signs Swelling and hypersecretion of the Meibomian gland and palpebral edema. (Translation was made by Kuratsune) 22 HONS 086^5x V,-'' Subjective Symf)toms Tito)*! B Shows ttiot o considerable portion of the p|l(L,,m a, Mill suffering born various subjective lympioms in recent years. KoJa and Masuda examined ttifir possible association with PCB concentrations in Wood. Imdmg no positive association at all (ref. 4). Uroeda also reported on venous symptoms due to dis turbances of higher nervous activities (e g., forgetfulness) complained of by most patients, but no definite associa tion between such symptoms and dm blood levels of PCU's was obseived (ref. >). 2. Ovinuiolcgical Findings Koda ami Masuda examined 77 patients with Yusho for dorm,itologicai signs and PCB levels in the blood from Ajtril 1973 to March 1974 (ref. 4). As shown in table 9, the majority of patients were still suffering from ikm lesions such as pigmentation, deformation of nail, and hypersecretion of Mrsilwmian gland even 5 years after the poisoning. They also demonstrated another im portant fjet tlsal group A, consisting of patients whose blood shows the gas chromatographic pattern A, had ' tilicantly higher prevalences of dcrmjtoloyic signs ) as pigmentation, acnelorm eruption, and deformed ruilt dun did group B, width consisted of patients show ing no such typical gas chromol ograpli re pal tern. Since group A had a higher average concentration of PCB's than group B. the dermal lesions seen among cur rent patients, contrary to the subjective symptoms, seem to be causally associated with the current level or pat tern of PCB's remaining in their blood. However, no conclusion could be readily made in this regard. First ot all, the current excess ot PCB's in the blood of patients is not remarkable in degree and is almost negligible as compared with the enormous elevation seen among the occupationally exposed workers, who nevertheless showod a rather low prevalence of dermal symptoms (table 2). It seems rather hard, therefore, to explain the persisting dermal lesions by elevated PCB levels in blood alone. The chemical peculiarity of such PCB's and the presence of PCDF's in tire bodies of current patients vrem to be particularly imjjortant in this connection. However, our present knowledge does not allow us to continue discussion of the matter along this line without speculation. Furthermore, an entirely different explana tion might also be possible. The skin lesions currently seen may merely be the persisting original skin lesions, the severity of which must have been determined pri mal ity by the amount of intake of PCB's; such intake must in turn be reflected by the current PCB levels in blood of patients. According to this explanation, the Table 8. Frequency ol subjective symptoms comphrinecJ by patterns with Yusho from 1973 lo 1974 Symp Loins Proportion3 % Tatigue Headache Phymata in articular region Fever Cough and sputum niyeslive disorder Numbness of extremities Menstrual disturbance 51.4 41.7 8.3 2.8 56.9 40.3 33.3 26.9 (7/26) `^Calculated by Kurotsune from original figures published by KOda and Masuda (Of. 4). 73 HOHS 086451 Table 9. Prevalence of dermatological and other signs among patients with Yusho from April 1973 to to March 1974, in conrsArtinn with rnnrntration and gaschromatographic pattern of PCO's in blood Prevalence (7,)c Signs Group A Group 8 Group C Total (43 cases) (26 cases) (33 cases) (72 cases) Skin KS? Nail Acneform eruption Comedo Infection of skin Deformation of nail Aloperia Disorder in teeth Dypersecrefion of Meibomian gland 51. 72.1? 95.3? 7344-.49bb 34.9 32.6 65. la 0 18.6 93.0 109.2?h 57.7? 34.6 0b 23.1 11.5. 38.5a 3.8 7.7 80.8 0 0 66.6 0 0 0 0 0 0 0 100.0 30.6 50.0 80.6 56.9 20.8 29.2 23.6 52.8 1.4 13.9 83.9 7.2 + 4.9 4.3 + 3.1 1.7 + 0.2 5.9 + 4.5 Ad B~d l* a$ftinincanl (P < 0.05) difference. ^Significant (P < 0.01) difference. ^Calculated by Kuratsuno from figures published by Koda and Masuria (ref. 4). d"A" means the characteristic gaschromatcnraphic pattern of PCB's remaining in the body of most patients with fusho. "il" means gas chromatographic patterns somewhat similar to "A". "C" means patterns indistinguishable from those of normal persons. ohstnved .issrx..jtitM of toe dermal lesions with ament hlund levels ol 1'CU`s >v uinvideiot! as o phenomenal one hoi not as ' causal roe li older to evaluate these cldfeo'itt poss'hiliiH's, ii si'i'in'. essential to examine chcmi^.il'y ami Utxico(o<|n:ally tf>" t'CQ's and PCDT's still ienuHioni| in pahiMl>' hodfi ) 3. Scrum Triglyceride One ot the most tlominatsl objective signs seen a tho incipient static of Yushu was .1 markedly increase concentration of serum triglyceride. Okumura and hr associates leporonl recently the icsults ot their extemiv followup study on 40 patients who were examined for 24 MONS 086453 vm triylyceridc at least once a year successively for 6 V. ,as from 19G9 to 1974 (ref. 19). As shown n table 10, i group of M male patients has shown no significant change in setmn triglyceride levels since 10C9. still main taining levels as high as 100 f 118 mg/100 ml even in 1974. For ?G female patients, however, a significant de crease was seen m 1973 ami 197*1 when compared with the levels in the previous years. However, 42 peiccnt of thrm anil showed higher levels than 110 mg/100 ml in 1974. Okumura ct al. (ref. 20) examined the possible asso ciation between serum triglyceride levels and PCO con centrations in blood in patients. As shown in table 11, they observed a significantly higher mean level ol scrum triglycoride m a group of patients who showed ttie characteristic gas chromatographic pattern A. as com pared with other patients who did not show such a typi cal pattern. They also observed a significantly positive correlation between serum triglyceride levels and PCB concentrations in blood (r * 0.405). Table 10. Results ol followup study on serum triglyceride levels in patients with Yusho^ Subjects Patients wi th Yusho Controls Controls PCB's No. Age pattern cases mean A 20 31.9 B 14 C 2 .21.4 C 37 34.5 PCB's in blood (ppb) 8.6 + 5.2b 3.8 + ?.2 2.8 + 1.6 Triglyceride mg/100 ml Reference 134 + 60.0a h 91 + 39.8 20 74 + 29 19.21 flP < 0.05. bP < 0.005. Table 11. PCB's concentrations in blood and scrum trirjtyccride levels in patients with Yuslro in 1973 Patients Sex Age No. Male 11-73 14 female 7 - 59 26 Triglyceride (mg/100 ml) Mean + S.0. y 1969 1970 1971 1972 1973 1974 159 + 57 166 l 55 169 + 60 174 + 69 164 * 68 160 + 11(1 155 + 75 161 + 70 155 + 80 153 t 63 129 + 50lj 111 j 56b ''Cited from a report, by Okumura et al. (ref. 19). ^'Significantly lower Ilian in 1969, 1970, 1971, and 1972 (P < 0.05). 25 *ONS 086454 Here again. ,i simitar question can raised in regard to Mich oUvoitil correlation. a-, alf ady dise.uvsed in connvction witt* the dermal lesions. Arc the Current elevated levels ol I'CO's m Uood anti theif peculiarities in gaschromatographic noU;in> cau'iotty conm-clcd with the abncmally high scrum triglyceride levels found in patents? Since, 3s mentioned, site lemate patients started to decrease it) triuin triglyceride concentration in recent years, a followup examination of PCB's in their blood might give a good clue to answer die above ques tion. if. Livvr of Palion(% with Yusho Doth PCR's and PCDP's ate well-known toxic agents to the liver PCDP's seem to be particularly toxic be cause a single oral administration of PCDP's as small as about 1 my/kg could loll rabbits by severe liver necrosis (icfs. 28.79). Therefore, it is reasonable to expect that patients with Yusho would (rave a severe liver damage. Okumura ct al. {ref. 30) performed detailed medical examinations on 24 parents soon alter the onset but, tinrxiM'dedly, obtained no objective findings to indicate definite liver disorders No patients presented jaundice and only three of them had palpable livers. However, an electron miti.oscopic examination of liver biopsy speci mens conducted on a patient in February 1969 revealed a maikrd hypeitrnpiy ol smooth endoplasmic reticu lum. indicating stimulated ctwyrne induction in the liver {tel. 31). Okumura examined 32 natients with various subjec tive symptoms lot smtm eniymev including tsotymtts bom 1971 ly 1972 {icf. 32). An increase m a fraction of lactate dehydrogenev (I :'H r>) jrulhigh liters in thymol Uiibidn/ tests wore observed in some of the severe cases but no definite evidence (oi liver disorders was obtained. Receodv Mhayama et ai Irel. 33) examined 12) adult patients wir- Yusho anil 257 healthy adult connols lor semti' hihrubm. d'M**r.*r)5t*:dirij a significant lower averjp coonDii.i'iixi in Ihr- patint group than in the conh\'. 'fury -iio showed significantly negative correlations lit:w(-Ti serum hthinl.in ami h'ootl PCB's in concentialion {i '' 0.340. p<0.9?5) .mil similnly between serum bilirubin ind se*um lr advy,dc (r - 0 215. p<0.05/. fhi-y considered t>\n a Imv-rcd concentration of serum hihu-hm n iMUonir- seemed m.n-tly due to an accelerated bihrulMP disposal Iron) thr- blond. I hrayama -t al. mvsini ned I 25 patients for Austra lia antigen .md antibody by the immunoclecti o ounophoicsi* in 1971 (irf. 34). The antigen wjs positive in three, while the antibody was negative in all >( them, indicatm'i no d.lirienri: at .ill mi the tn.-vMrnres between the paper's mil healthy control' Tins boiling st-ems tr. he tmj'oM.m) in ronu.-m .r with tin tinun* : i*.k ol r.i"C<-' whuti '.itM-nts -v.*nhl -p-iieni In view of all these findings, bver function tests cur rently available do not readily detect serious liver lesions m the patients, but it is highly desirable that adequate caution will continuously be paid to (hit well-known target organ of Chlorinated hydrocarbons. CHILDREN DORN TO MOTHERS WITH YUSHO The birth ol unusual bahres from mothers who took "Yusho oil" during pregnancy rs already web known {refs. 25,2G). Their clinical features wore dark brown pigmentation of the mucous membrane and the entire skin, gingival hypcrplam with pigmentation, a tendency to be small for the date, eruption ol teeth at birth, hypcrsecrctatton of the Meibomian gland, and edema of the orbital area. Pigmentation of the skm disappeared in 2 to 5 months, followed by growth similar to that of normal babies. It seems noteworthy, however, that babies with the dark brown pigmented skin continued to !* born for a few years after the intake of "Yusho oil" was discon tinued by mothers. Yoshunuia leported on nine babies with such skin who were bom to mothers with Yusho in Nagasaki prefecture from 1909 to 197? (ref. 27). Three of such babies had been delivered by a patient horn 1969 to 197), Abe et cl. {ref. 23) recently repot led on PCB levels in the plasma of 30 children (ag-d 0--7) born to 18 mothers with Yusho in Nagi-ki prefecture. Their examination was m-tdc in 1974. A\ shown in table 12, tbc PCD levels of these i.hihlrcn were sgnihcantly higher than those of O'dinaiy children but lower than tt>e levels of thcii mothers. The*' gjs-chromainyraph'c patterns of Pen's in plasma Were jlic.idv referred toe.vlvt in this paper Children fed in hipj't mill; bom mothers wnl) Yusho tended to show a higher plasma r-oncentiatmn of PCD's than those who were not fed on such nuiw. YoshimuM also reported an interesting cas", wheie a baby was thpnghi p have suffered from Yusho due ex clusively to intake ol PCU's through breast mdk from a woman with Yusho bef. 27). Very few data are available in regard to the ronf-nb,ihon \)( PCH'v in hir-ast rnilk o' mothers with Yusho. Masnba el al. found 0 03 - OOP* ppm of PCR's in 5 '.jmp!"$ uf hmast milk collected from a woman with Ymhn vvillun 5 davs-ahei delivery m 1973 (ref. 12) Masada also found about 0 03 ppm of PCR's in another sample of bieast milk collected a few days after a woman with Yusho delivered baby with no dermal signs (ref. 14). The PCI) levels m breast milk fmm patients with Yusho were themfr-rc just within the normal i inqe, However, the rtas r hr'-m.t'i"T*ephie p,.| ton's nr ihese sample* wem qui'e unique, the sjni" ,iv that ihet/i i-ii-.i'r be Yudin. . 26 MONS 086455 Tabic 12. Concentration of PCD's in plasma of children born to mothers with Yusho . Subjects PCB's in plasma (pnb) Subjects Range Mean + S.D. Mothers with Yusho Children born to above mothers Ordinary chil dren 18 3-33 11.2 + 7.32 30 1-20 6.7 + 4.28 14 1-8 3.7 + 1.97 Ref erence 23 Table 13. Deaths seen among patients with YushpA Cause of death Malignant neoplasms Stomach cancer Stomach cancer liver cancer Liver cancer + liver cirrhosis Lung cancer Lung Tumor Breast cancer Malignant lymphoma Cerebrovascular lesion Amyloidosis Osteodystrophia fibrosa Myocardial degeneration + pericarditis Status thymicolymphaticus Liver cirrhosis Suicide Seni1ity Traffic accidents TOTAL Number 9 2 llbb 1 1 1 2 3b ]b ]b 10 1 1 1 3 22 aCited from a report by Urage 1974 (ref. 2). bAutopsied cases. 27 MQNS 086456 mortality op patients WITH YUSHO Omae reported in 197b that 29 deaths occurred among 1.791 patients with Yusho up to April 30, 1975 (ref. 1). Causes of these deaths were not given, however. Uratte also repotted on 72 deaths seen among 1,200 patients until September 13. 1973, and refetred to thoir causes (ref. 7). As shown in table 13, 9 of 22 deaths were caused by malignant neoplasms, suggesting a possible excess o> deaths bom c;mccr. Since some essen tial information needed for epidemiological analysis is not available to us, no further reference can be made with certainty to such a possibility at the present time. CONCLUSION xT, As mentioned earlier, we demonstrated the presence of PCDF's in "Yusho oil" at a much higher concentra tion than expected. We also showed that PCDF's are relatively more concentrated in liver. Although neither the chemical naituc nor the toxicity of PCDF's con tained in "Yusho oil" and in the bodies of patients are known yet. our findings dearly indicate the necessity to pay greater attention to PCDF's (or clarification of tha nature of Yusho. Furthermore, our studies suggested the possible formation of PCDF's from PCB's when used as heat transfer medium. Betide this, another possibility that PCDF's might be formed by heating PCB's with peroxides, which arc well known to be formed during heating cooking oils, should also be investigated. PCI CP.FNCES 1. T. Omae. "Foreword, the Fifth ileooit of the Study fur Yusho am1 PCB," Fukuoka Acta Med., VoL GG, No 10 (October 19751. pp. 517-153 {in Japanese). ?. H. Utah*', "Fomwoid. the Fourth Ropoit of tire Study on Yusho and PCB," Fukuoka Acta Med., Vol. fib, No. 1 (January 1974), pp. 1-4 (in Japatutw). 3. "t north Ri?iort." Fukuoka Acta AW., Vol. G5. No. 1 (January 1074). pu. 1-90; "Filth Report," Ibid., Vol. GG. No. TO (October 1075), pp. 547-64U. 4. H. Kodn and Y Matuda, "((elation Between PCB Level in the Blood and Clinical Symptoms of Yusho Patients." Fukuoka Acta Mod.. VoL F>6, No. 10 (Octolier 1975). pp. fi?4 620 (in Japanese). 5. <5. Unn-ilii, "Clinu:.d Asi*ccls o( PCI) Poisoning." Undo no Kaaaku. Vol. 20 09731. pp. 36-42 (in Japanese). G. II. Kolvh, S. Asahi, and S Toshitam, "Drrmatologtcal Findings <d die Patient* With Yusho (PCD Poisoning) in General Examn ' Fukuoka Acta Mad., Vol. G5. No. '> tJanuary 197*s pp. 61-83 (in Japanese). 7. Y. Masoda, ft. Kagawa, K. Shimamurj. M. Takar and M. Kuratsune, "Polychlorinated Biphenyls the D'ood of Yusho Patients and Ordinary Persons Fukuoka Acta Med., Vol. 65. No. 1 (January 197-' pp. 2S-27 (in Japanese). 8. M. Takamatsu, Y. tnoue. and S. Ahe, "Diagnos1 Meaning of the Blood PCB." Fukuoka Acta AV Vol. 6b, No. 1 (January (97-1). pp. 26 31 i Japanese), 9. M. Hasegawa, M. Sato, and H, Tr.uro'a. "PCB Co centration in (he Blood of Workers Handling PCD Rodo Eisci, Vol. 13, No. 10 0977). nn. 50 55 ( Japanese). . 10. M. Goto and K. Higuchi, "The Symptomatology Yusho (Chlorobiphenyls Poisoning) in Dermatol 9V." Fukuoka Acta Med.. Vol. GO. No G (Ju. 1969), pp. 109 43' (m Japanese]. 11. Y. Masuda, R. Kagawa, and M. Kuratsune. "Cor paiison of Polychlorinated Byshcnylj in Yusf Patients ond Ordinary Poisons," Bull. Enviro Contam. Toxicol., Vol. 11 0974), pp. 213 216. 12. Y. Masuda. R. Kagawa, M. Kuratsune. "Polychlnr. atod Biphenyls in Yusho Patients and Ordinary P< sons." Fukuoka Acta Med., Vol 65, No. 1 (Janua> 1974), pp. 17-24 (in Japanese), 13. Committoo for Investigation and Study of PCB ,t> Others, "Study on the Distribution of Concunp tions of Intraccrporally Accumulated PCB*' (19/ _ (in Japanese). 14. Y. Masuda, Unpublished data. 15. M. Asdhi. H. Koda. and S. Tosliitani. "Alter,ipon Skin Severity Grading of Yusho in the General F iimin.ition in 1973 and 1974, and Presentation of New S'andard for the Skin Severity of Yusho i. Point Count System," Fukuoka Acta Med., Vol 6' No. 10 (Oclolvr 1975). pp. 029 634 (m Japanew 16. J Nagayanvi. Y. Masuda, anil M. Kuratsune, "Ch! ritau>d Di(wn/sfran$ in Kanechtois ano Rice Oi Used by Patients With Yusho." Fukuoka Acta MrJ Vol. 66. No. 10 (Octobeg1975), pp. 593 599. 17. J. A G. Hooch and I. H. Pomrtjmi/. "The Futile of Chloiinaicd Dibtm/ofuram in a Japanese Pf. Sample." Bull. Environ. Contam. Toxicol.. Vol. I 0974). pp. 339 312. 18. T. Kashmsoin, personal common --0100 (1975). 19. `M. Ol'iiinum, M. Yamanaka, S. Njkainuta, and I Utawa, "Consecutive Six Yc.t Follow up Study Serum Tiiylvccnde Levels in Patients With Ptj Poisoning,'' Fukuoka Acta Med, Vol fifi. No 1 I0c1cl**t 1975), pp. G20 623 f.n Janun-vd. 28 MQNS 086457 20. M. Okumura, Y. Masuda. and S. Nakamuta, "Coru-lation Between Blood PCD and Scrum Triglyceride levels in Patients with PCB Poisoning," Fukuoka Acta Med.. Vol. GO, No. t (January 1974). pp. 04 07 (in Japanese). 2t. H. U/awa, A. Notomi. S. Nakamuta, and Y. tkcura. "Consecutive Three Year follow Up Study of Serum Triglyceride Concentrations of 82 Subjects With PCU Poisoning," Fukuoka Acta Med.. Vol. 63, Nrt. 10 (October 1972). pp. 401-404 (in Japanese). 77. S. Jensen and G. Sondstron. "Strucuncs and Levels of Most Chlorobiphcnyls in Two Technical PCB Products and in Human Adipose Tissues," AMUIO, Vol. 3. No. 2 (1974), pp. 70 76. 73. S. Abe, Y. Inoun. and M. Takamatsu, "Polychlorin ated Uiphcnyl Residues in Plasma of Yusho Children Bom to Mothers Who Had Consumed Oil Contam inated by Pen," rukuoka Acta Med.. Vol, 00, No. 10 (October 1976), pp. 605G09 (in Japanese). 24. J. Nagayama, Y. Masuda. and M. Kuratsune, "Poly chlorinated Gibcnzofuiuns in Tissues of Patients with Yusho," paper 330 presented at the 34th Annual Meeting of Japanese Society of Public Health, Yokohama, October 29-31, 1975, preprint. 215 pp., October 1975 (in Japanese). 25. I. Funatsu, F. Yamashita, Y. Ito, S. Tsugawa, T. Funatsu, T. Yoshikanc, M. Hjyavhi, T. Kato, M. Yakushiji, G. Okamoto, S. Yamasaki, T. Arima, T. Kuno, H. Ide, and I. the, "PCD Induced Fetopathy. 1. Clinical Observation," Kumme Mod. J., Vol. 19 (1972), pp 43 01. ?G. (. laki, S. Hisannga, and Y. Amayase, "Report on Yusho (Chlorobiphcnyls Poisoning) Pregnant Wom en and Their Fetuses," Fukuoka Acta Med Vol. 60, No. fi (June 10(19). pp. 471-474 (in Japanese). 27. T. Yoshimura, "Epidemiological Study on Yusho Rabies Rom to Mothers Who Had Consumed Oil Contaminated by PCft," Fukuoka Acta Med.. Vol. 05, No. 1 (January 1974), pp. 74-80 (in Japanese). 70. H. Oauer, K. M. Schulz, and U. Spicgeltscrg, "Bmifliehc Vrujiltunqcn bci der Herstelkmg von Chlotphenol-Vi'ihindonQcn," Arch. Gewerbvoath. Gfwvthtihyg., Vol. 18 (1961), pp. 538-555. 29. II. Tli. Hofmann, "Ncuurv Erfyhrungcn mil llochtoxischon ChlorkuMvnwavtorttoHen," Arch. f*p. Pathol. Pharniakol Vol. 232 (1958), pp. 220 230. 30. M. Okumura and S. Kattuki, "Clinical Observation on Yusho (Cltlurobiphenyls Poisoning)," Fukuoka Acta Med.. Vol. GO, No. G (June I960), pp. 440-446 (m Japanese). 31. C, Hirayam.1, T. Irisa, arid T. Yamamoto. "Fine Structural Changes ol the Liver in a Patient With Chlorobipbenyls Intoxication." Fukuoka Acta Med.. V.ol. GO, No. 6 (June 1969). pp. 455 461 (in Japanese). 32. M. Okumura, "Course of Scrum Enryme Change in PC8 Poisoning." Fukuoka Acta Med., Vol. 63, No. 10 (October 1972), pp. 396-400 (in Japanese). 33. C. Hiravama. M, Okumura, J. Nagai, and Y. Masuda, "Hypobiliiubincmia in Patients With Polychlorin ated Diphenyls Poisoning," C/intca Chim. Acta, Vol. 55 (1974), pp. 97-100. 34. C. Hirayama, M. Nakamura, and M. Yoshinari, "Australia Antigen in Patients With PCB Poisoning," Fukuoka Acta Mod.. Vol. 63, No. 10 (October 1972), pp. 405-407 (in Japanese). DISCUSSION MR. ALLEN GREY (I IT Research Institute, Chicago, Illinois): Do you have any feci whether diben/ofurans concentrating in the body are more rapid in metabolism than the result of polychlorinated bi phenyls? DR. KURATSUNE; Unfortunately I have no definite idea. It is a more potent compound than PCB, I guess, f really cannot say. DR. ORVILLE PAYNTER (EPA, Washington, D.C): Arc thore any reproductive problems or ir regularities continuing for many years after the ingestion of these materials? DR. KURATSUNE: There is some disturbance of men struation. There have been some disturbances and there have been some rotated problems. MS. DEBORAH A. BARSOTTI (University of Wiscon sin, Madison, Wisconsin); Were there are doings that suspected any widespicad gastic ulcerations or an erosion in the pjticnts-gastric ulcers? DR. KURATSUNE: No, I do not think so. Some ol the patients had very persistent disorders of the intes tines, disorders of the digestive system, but I do not know if they were suffering as a result ol this or not. VOICE: Any iesidu.il changes in the sebaceous gland during the autopsy? DR. KURATSUNE: No, I do not know very'much about it. VOICE: I would like to ask one more question. Have you been able to specilically identity any of the dihenzofurans other than those in the body? DR. KURATSUNE: You are asking if we could identify any of the dibenzofurans? No. 29 HONS 086<*5