Document mB6wwxbkMVMe9gE3wqVYjd49Q

f_f{\ (McwcL ino ,6^ \- SOME OF THE RECENT FINDINGS CONCERNING YUSHO Masanori Kuratsurse, M.D Yoshito Masudo,** and Junya Nogayama* AbstrJit Analysis of Yusho disease, which was first detected in f 963, has been limited and analyses have produced varying results Yusho oil has been determined to conlain a high level of polychlorinated d'bemoftirans fPCQFsl N,gayenta et a! found that PCDF levels in the oil were especially high when the oil was contaminated with PCff I used as a heat transfer medium, Their studies also showed that the concentration of PCDf s is much closer to that of PCB's iti liver than in adipose tissues in patients with Yusho. Jbe current clinical state of patients with Yusho is dicussed at length Subicctire symptoms, dermatological findings, serum triglyceride levels, liver conditions, mortality rales, and the effects on children bom fo inuilicrs with Yusho arc all reported, INTRODUCTION Moic than 7 years have passed jince the outbreak of an epidemic of Yusho in 1968 According to the latest tabulatim, Prof Omac, current chief of the Study Group for the Therapy uf Yusho, reported that a total number of 1,291 patients have Ivon regisn red as Yusho tn 22 prefectures of Western Japan by April 30, 1975 (ref II Wi would like to describe some of the recent find ings concerning Yusho which we think to be particular ly releva.it for understanding of toxicity of PCB's. For morr detailed mini niat'c-n, readers arc advised to refer to onipn.il papers appearing mainly In the fuuith and !if(fs repom of the study on Yusho and PCD [ref 3) Mo;t of til- patients described in these reports arc those Itv. iq in I ukuok.i prifeeturc. Published information of patients living in other areas arc unfortunately very few, so svnh a few exceptions no rclcrcrice will be made to thrni PCQ'j IN THE BODIES OF PATIENTS WITH YUSHO 1 Tissues First of alt, the concentration of PCB'l rota-ned li the tissues and fluids o< patients wuh Yusho should in referred to before then current clinical state will bo dis cussed Although nn accurate estirn,mon is Icasible becaus of the very limited number of analyses so far made, th concentration of PCD's in adipose tissues of patient seems to have txren fairly high soon after the occurrcnq of poisoning-(hat is, in November 19GS, at least month after the discontinued use of the toxic tire oil b patients, as shown in table 1. The corresponding concer trations were considerably lower in 3 patients who dm in the next year, 1969 However, no such mstked ih fercnce coutd be seen bc1wi.cn (hose whn (tied m UK and the subsequent decedents, although cases 7 and H who died in 1970 or 1975. showed qtutc low levels PCB's in adipose tissues As comparetfwith the liqur available fiom a nationwide survey on*rs*iu.li| PCB's autopsied tissues, the levels noted1 rn_the recent dec dents are considered to be fairly close to die usual lev of ordinary autopsied materials. Similar facts were a! noted for PC8 concentration in the skin and liver 2. `Blood Since the analysis of PCB's m blood started oi after 1972. no figures are available in icgard to the bto levels of PCB's in patients in the earlier stage of pois ing, As shown in table 2. however, it is clear that t blood levels of patients had approached the level ordinary poisons already in 19/2 although they va still significantly higher than that level This tact as w< as the previous fact o1 towered tissue levels of PCB's recent decedents seem to he rather surprising if wc cp sider also that the ma|ority of patients are still shown various clmicat symptoms, as will be discussed later. 'MuiftiWi Kttnuuti!' .tml Jof*Yi woh |!ie Opoihm nl Pul>1 c Fsicully o* Mrjtcino* Kyushu Ui*vpt m*v 0* An <l\ hi pi Ofia'nintFy Collrgo of rilAi at Si* Th Flf^la^Vj J.hiiim Ph iimu i Mr nil i l Mti Llimh* Cu<iii|tr nf 1 *s| t**i \ * < I u^uo^i). 3a G9SCft?QM1tnor9pf)lC Pjt\i fns of ^CP J m rhe &(JL of Parents Mosuda (fst rtolrtl 4 p'Xuli.V comnmn g,n rl inoioor^hic ot PCO Irjcho/is iujloi*d horn * ous tusurs, Wood. breast n1k o* patients * Yusho amt ralhil ihe i1lrntiui* n? Hi** Snidy Gimp* the T[ir*nny of Yusho 10 (I pjiIv )*)!'? f igui shows * h pir.14 example of surf* a imIIlmm m comp,if ^>T/V, A/ft 2- DSTtfoW 60-?^ HONS 209937 Table 1. PCS's concentration m tissues of patients with Yusho and other diseases Case '1 Time of death, operati on Case 1 High school f boy * Case 2, 3 Adult male. female Nov. 1968 Nov. 1968 Ski n Whole Fat basis basis Case 4 Boy, 13 yr Case 5 t^ale, 25 yr Case 6 Hale, 73 yr Case 7 Female, 48 yr Case 8 Kale, 46 yr Case 9 Female, 33 yr Case 10 Hale, 72 vr National survey Males and females 25 - 49 yr 'w July 1969 July 1969 Nov. 1969 Dec. 1970 Kay 1972 Sept. 1972 April 1975 1973 1.2 B.7 1.0 4.4 0,6 0.8 1.8 3.2 0,04 - 1,7 (n = 54) PCS's (pom) Adipose t issue Whole Fat basis basis Liver Whole Fat basis basis Reference 76 (face) 13 (abdomen) 32, 46 (cheese-like substance from acneform eruptions) 1,3 (mesentery) 2.8 (mesentery) 3.8 (mesentery) 0,7 (mesentery) 4.3 3.7 15.1 8,4 0.9 6,5 0.14 0.2 0.07 0.07 0.08 | 10 9.5 10.4 3.1 1.3 8,4 11, 12 1,9 (subcutaneous) 2.9 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) 13 ' ii * ' 1 ' -f u. 1 MONS 209938 Table 2 PCB's in blood patients with Vuslio, workers and ordinary persons Material No. of subjects Time of examination PCB's (ppb) Whole basis Refer- mean + S.D. Ran je 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 1-12 2.8 + 1,5 1- 6 8 Whole blood Workers3 23 1972 364 + 262 60-920 9 aWorkers engaoed in the production of Kanechlor 200-600 in the air^ontaimng 0.05 to 0.2 mg/nr of PCB's [Kanechlor-300 + Kaneclilor-4*00- " (1:1)). Two of them showed dermal signs. with lli'1 ci.minon nnc seen in ordinary persons, which is very much close to thal of a mixture of Kanechlor 600 * 600 (1 1). h is easily notable that the peak I. which appears .rniiu-diaicly alter p.ji'-DDE in the gas chrcimato grain m (inure 1, is vciy low ip patients wilh Yusho es compar'd with ordinary persons, while the peak D is much more pronunrnt m Yusho than in ordinary per sons Mi.sudd anti his associates obscrvcil this peculiar p.utcin (desuj rated as type "A") in blood of about 60 iwiccnt of tiatients with Yusho, and a somewhat similar pjttem (desolated a< tyjw "D") m dlrout 37 percent fiefs. 4,7,1 1,W2L_ Takamatsu ct a! also nbscived the same peculiarity in the Mood of patients with Yusho (rcl 8). It was lutlhcr ilrmonstiated that those patients who show the peculiar ms ct'iomatorpaphic itntu-m ns designated as [Mttern A by M.isuda et ah hate a higher average concmi- tration of PCB's in their hlood than do other patients (refs. 4,7) Ahe et al (ref. 23) examined in 1974 the PCD residues in the plasma of 30 childien born to IB mothers who had consumed Yusho oil at Onto Islands. Nagasaki prefecture. The specific gas chromatographic pattern of typ" A was seen among 34 percent of the children and 44 prreent of their mothers, but the pecu lianty seemed somrwhar less marked as compared with the one seen among patients in Fukuoka ptcfcctutc. The chemical and toxicological natuic of the com pound or compnuntls yielding the atiuve mentioned peak 5 must lie claidied but have not yet fully been ex amined Mnsuda, however, consnlcis the peak 5 to be 3,4,2 ,3 t4`,b' hcxactilorobiphcnyl, judging from its retention time on the Apieron L column developed b Jensen and Suodsbon (ref 22}. 16 HONS 209939 f A : Fatty tissue of Yusho patient " E : Fatty tissue of ordinary person C : Kanecmlor 5D0 * &00 (i 1) Figure 1. Gaschromatogrums (ECD) of PCB's on SE-30. POLYCULOniNAirD DIUENZOFURANS IN KANCCHLORS, "YUSHO OIL," AND TISSUES OF PATIENTS1 1 Polychlorinated DrOenrofttrans ttt Kancchlors and "Yusho oil" (U'cuiuly N.ujayoma ct al. analyzed Kancchlort and ItifiN samples ol toxic ''Yusho oil" mud by three inde pendent families With Yusho for polychlorinated diIviwolw ans (PCDf 'si and polychlorinated tfibenzo pilijmii (PCDU's) (ref. VGK They did a column chromatoguphic fractionation of PCDF's and PCDD's from a hulls of 1'CIVs by using acwalt^t alumina as adsotbent, jud n hexane, n hexane containing 70 percent carbon nlijcMsimiIp, 01 n hexane eontamintj 20 percent methylcnrtihiiiite as eluent TRc fiactions thus ubljined were tiihi<[.ti(f 10 ij.is ehioni.noyf .iptiic and mass iihcuonis'tric it x.iiiiuijiioii Quantitative csnni.uron of PCDF's nil t'COD's w,u made by two methods, namely by measuring the cm chromatoiji.iphic peak heights and by iiwjiuiiiiij the y.ts clirorrutogratihic peak aica of per * -mi.in d 11*' 1 ivative s of these compounds. Although no PCDD's were found in any of these w iph't. PCTOf i weic found in all ol them. As shown in table 3, l\C `100 contained the highest Concentration of PCDF's, about IGppmof PCDF's consisting of dichloroop to pentachloro- dibenzofurans. A peak with the same retention time as that of 2,3,7,8 letrachlorodibcnzo furans, 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, the major constituents of which were tclra and pentachlorodibenzofurans, Merc again, the peak with the same retention time as 2,3,7,8-lcuachlotodibenzofuian was noted. Kashunoto also found 1.0 ppm of PCDF's in another batch of "Yusho oil," as shown in table 5 (icf 18). Table 4 summarized the concentrations of PCDT's in Kanechlor-400, reported by several authors As clpady noted, there is a fairly large discrepancy m their findings Whether or not it was due to their analytical procedures or to batch difference cannot be decided at the present tune. Another important fact was disclosed by Nagayama et St They determined the concentration of .PCB's in "Yusho oil" n$ approximately 1,000 Ppm or slightly less than 1,000 ppm. as shown in table 3. Since "Yusho oil" is known to have been containmatud with Kjnt-chlor 400. the ratio of the concentration of PC8's to that of PCDF's m "Yusho oil" is expected 10 Ixt about 1.000 0 010 The observed ratio, approximately 1,000 5, 17 HONS 2099*0 Table 3. PCDF's and PCB's in Kancchlors and Yusho oil PCOF's (ppm) PCB's (ppm) Sample Peak height method Perchlori nation method Peak height method Pcrchlori nation method 300 1 1 .5 Kanechlor 400 soo 18 4 16.6 2.5 600 5 2.7 -_ ---- Yusho oil A B C 5 4,4 830 870 4 5.1 900 920 5 5.2 1030 980 Table 4. Reported concentrations of PCDF's in Kanechlor-400 Authors Year Concentration (PPM) Roach ct al.a Nagayattsa et al.b Kasliimoto et al.c 1974 1975 1975 , 1 18 33 aRef. 17. bRef. 16. CRcf. 18. was rtius about 250 limn higher than expected liable 5), The reasons tor this great discrepancy are not clear yei. It should be noted, however, lhat the sample of Kanechlor "100 analyzed was an 1 unused" one, white the H.ini>rhl(ir -100 present m "Yusho oil" was "used" ns heat bander mulium Hus laci suqgesls a practically important ixmiljdily ihat Kanechlor 400 and probably other commercial PCB's, too, will increase iheti PCDF concentrations when used as heat transfer medium. 2, i'CO( 'j m 7issues fif Patients wrr.'t Yus/in Nagay.irna el al. (rel. 24) further examined the tissues ril patients with Yusho for their possible content of PCbF's Table 6 summarized their findings. Adipo tissues and liver Ironi two ordinary persons who died . accidents contained no detectable amount (< 0 1 pp of PCDF's, but those from three patients with Yus' who died in I960 or 1972 were alt'shown to conn PCDF's, Figures 2 and 3 show their g.is cliromatoqrar and mass spectra The concqnlialion on a whole bj was 0.009 ppm on average for aditwse tissues and 0 0 ppm tor liver, This seems lo be a rather surprising la because in lh case of PCB's Iho concentration on whole basis is usually much lower in liver than rn adipo tissues, When compared on lat basis, another intcresti' fad was noted that PCDr concentiation was much hig er in liver than in adipose tissue, Although the minib 18 HONS 209941 ri L Tabl? 5 Concentrations of PCB's and PCOF's and their ratios m various materials -- Malerials PCB's (ppm) PCOF's PCB's (ppm) PCOf^T Ref erence Kanechlor-400 Yusho oil A Bb 1 ,000,000 ca. 1,000 134 ca. 20 5 1.6 50,000 200 84 (6 18 Patient Adipose with tissue Vusll Liver 1.3 0,05 0.009 0.013 144 24 4 ^Samples of the rice oil produced on February 5 or 6, 1968. bA sample of the rice oil produced on February 10, 1960. Table 6. PCB's and PCOF's in tissues of patients with Yuslio and ordinary persons T ime PCB's PCOF's (ppm) Ratio Case of Whole Fat Whole Fat PCB's/RCOF's Subjects Tissue No. death basis basis basis basis Whole Fat 1 2 Adi (rose 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 2.1 0.007 0.01 171 210 Yusho Avg. 1.3 4.7 0.009 0.003 144 157 patients - 1969 0.05 4.7 0.025 2.3 ' 2 2 z__ 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 0,00 0.02 l.if 0.7 1.3 1.0 NO NO NO NO NO NO NO NO HONS 209942 19 Upper : PCDF FRACTION FROM Liver of Yusho Patient Lower : PCDF FRACTION FROM Yusho Oil, 30 M[N. Fiyure 2 Gaschtcunatograms of PCDF fractions from liver of patient with Yusl'o and from "Yusho oil." o( analyses made is mute limited and nothing can be said wnh eertanUy, this (act seems lo deserve attention. As shown ii> tabic G. tlirst' diflcicm behaviors in tissue d>s tnbution ol the coiiii'ounds caused a remarkable differ* i nee in r,mu o' PCU's to PCDF's between adipose tissues and Piece It w.is thus demonstrated that the concentra tion of PCOT's is msi'-h closer to that of PCO's in liver th.iii in adipose tissues in patients with Yusho The PC LIP* idem diet! m liver were mainly ponta- and hexa- rhlnioihlx'ii/oluram, containing only a Pace of tetra- cliloi oisonieu _ f CUIlfttNT CL1MCAI. STATE OF PA44ENTS WITH YUSHO In 1174, f'iol Urabj tre( 7). lormei chief of the S'.u-ty Group, minuted that Ihe dermal ansi mucosal signs that were mp't marked at the incipient stage of the poisoning had gradually been improved, while symptoms such as gcneial fatigue, poor appetite, in constant ab doniinal pam, heavy headcdticss and headache, feeling ol numbness and pain at the limbs, and rough and expccto ration of sputum, all of which are considered lo be due to some internal distuibancrs, have become more promi nent year by year In view of these tendencies together with the discovery of a characteristic gas chromato graphic p3ltrrn of PCO's remaining in the blood and tissues of patients, the diagnostic criteria for Yusho was revised in 1972 (ref, 7), as shown in table 7. As com pared with the former one, the revised criteria describe briefly the derma! and mucosal lesions but newly retci to other noncutaneou* ohieclive signs anti findings (tom several la1>oratory tost* It should be noted, however, that the new cirtena do not refer to any specific liver function tests 20 HONS 209943 IOOi c12h3oci, M 338 I 1 r0/M-COCI-CI2T 205 ! j J____ 04 t iM-COCfl* 275 '* `T ` i J___________i---------------------- : Lx Re l a t iv e in t e n s it ^ U ) Figure 3. GC-MS of PCDF's fraction from liver of patient with Yusho (upper) and of synthesized PCDF's (lower). MONS 209944 i I- Table 7. The diagnostic criteria for Yusho {revised in October, 1972). Yusho is considered as an acute or subacute poisoning with PCO. 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, acneform eruption and pigmentation as cutaneomucosal lesions and ocular symptoms are seen. 1. Conditions of attack Tact of ingestion of Konemi 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-1ike symptom -- 2) sensory neuropathy - 3) bursitis __ 4) inhibition in growth and abnormal teeth in children 5) Small-For-Dates baby and pigmentation of the entire- skin of newborns . c. Results from clinical examination 1) abnormal properties and concentration of PCB in blood 2) increase of neutral lipids in blood 3) anemia, lymphocytosis, hypoalbtimincmia 4) reduced velocity of the sensory nerve conduction and adrenocortical hypofunction 3. Cutaneomucosal 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 mode by Kuiatsuno) 2 MONS 209945 'v....' 1, Suit/cchvc Symptoms TjLili; B shows that o considerable purtion of the pjlit-nn oic mil sulluring trdih various sub|ecbvc symptoms in recent years KcnJj and Mjsuda examined it.fii possible association with PCB concentrations in L.1 d cm I, finding no poulwc association ai all (ref. 4), Llmi [Ja also reported on vaiious symptoms due to distuibancss of higher nervous activities (eg , forgetfulness) compl.nru'd ol by rnosl patients, but no del nine associa tion imiwi eu such symptoms ami the blood levels of PCB's was obsei ved (ref 6) 2, Ocuiuuilogicol Fintlint/s Kodj anti Masuda examined 7? patterns wild Yusho Ini dermitultiitical signs and PCD levels in the blood liom A|rl 1973 to Mjrdi 1974 (erf. 4). As shown in table 9, the niajonly of patients were still suffering from skin lesions such as pigmentation, deformation ol nail, and hypersecretion of Mrrltomian gland oven 5 years alter the poisoning They also demonstrated another im portant fact that group A, consisting o! patients whoso blood shows Use gus chromatographic pattern A, had ' ulicaiitly higher piev.dcnccs of dermatologic signs li as pigmentation, note I or ns e.up'ioia, and deformed nu's tlun did group R, whirls consisted of pJhcnts show mg no tiit.li typical gas chrumatograplnc pattern Smco group A had a higher averago concentration of PCB's than group 0, the dermal lesions seen among cur reni patients, contrary to the subicctive symptoms, seem to be Causally associated with the current level or pat tern of PCD's remaining in their blood However, no ronclusion could be readily made in this regard Firsl ol all, tho current excess of PCB's in the blood ol patients is not remarkable in degree and is almost negligible as compared with the enormous elevation seen among the occupationally exposed workers, who nevertheless showed a rallter low prevalence of derma! symptoms (table 21. It seems rather hard, therefore, to explain ihe persisting dcmial lesions by elevated PCB levels in blood alone The chemical peculiarity ol such PCD's and the presence of PCDF's in the bodies of current patients S'-em to be particularly impodant 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 nun might also be possible. The skin lesions currently f seen may merely be the persisting original skin lesions, the seventy of which ntust have been detei mined prtnsanly 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 t. " &- Tabid 8 Frct|ticncy of subjective symptoms complained by patients with Yusho from 1973 to 1974 Symptoms Proportion3 % fatigue Headache -fhymata in articular region fever Couqli and sputum Digestive disorder Numbness of extremities Menstrual disturbance 51.4 41.7 8.3 2.8 56.9 40.3 33.3 26.9 (7/26) llCnl ciliated by Kiiratsune from original finures published by KOda and Masuda (,vf- 4).- 23 MQNS 209946 Table 9 Prevalence of cfcrmatoloqrcal and other signs among patients with Yusho from April 1973 to tO Marrh 1974 in rnnnnrtiriri with rnnrontrpt'On atrd gaschromatographic pattern of PCB's in blood -- Prevalence (3)c Signs Group A Group B Group C Total (43 cases) (26 cases) (33 cases) (72 cases) Shin Pigmentation Nail Acneform en.ption Comedo Infection of skin Doforma lion of nail Alopecia Disorder in teeth Dypersecreiion of Meibomian gland PCB's in ConC- (ppb) bl00d Pattern 572K. 2lbb 9754'.34bb 34.9b 34.9 32.6 65.la 0 18.6 93.0 7.2 + 4.9 Ad 1D9.2bb 57.7^ 34.6b 0b 23.1 11.5 38.5a 3.8 7.7 80.8 4.3 + 3.1 Bd 0 0 66.6 0 0 0 0 0 0 0 100.0 1.7+02 cd 30.6 50.0 80.6 56.9 20.8 29.2 23.6 52.8 1.4 13.9 68.9. _- 5.9 + 4r8- Significant (P < 0.05) difference. ^Significant (P * 0.01) difference. LCalculat--J by Kuratsune from figures published by Koda and Mdsudr (ref. 4). d"A" means the characteristic g-is chromatographic pattern of PCB's i 'gaining in the body of most patients witii Yusho. "8(` i-reat*gus chromatoqraphic patterns somewhat similar to "A". "C" means patterns indistinguishable from those of normal persons. olii'nvod jiiuMh'I' <'l t tc dermal lesions with current tiliKul l>vi-K I'l ecu's n t iji.'iili'n'il ns .1 phenomenal one bm not .is i r.nisiil me I t iiiili'r to evaluate these clil hnrnl poss'lnldirs (t Serin' essential In rximme chemitally ,ip1 toxirolot|<> iilty (h I'C'G's arxl PCbT-ls still ic m.jiiiin'i in |Mlir ih' ln'i4('s ) 3 Severn Triglyceride One ol tlic most dominant ohicclivc signs seen , the incipient sl.itie of Yusho was a markedly mcmasi conconuation of seium [rii|lyceiufe Okuniura and h associates reported recently the results ol then cxtensiv followup study nn <10 patients who were examined fo 34 HONS 209947 /"'N urn triglyceride at least once a year successively (or 6 .ars (rom 1069 to 1974 (ret, 19) As shown in table 10, a group ol 14 male patients has shown no significant ciungi in scrum tiiglyccndc levels since 1069, still mam taming levels as high as ICO * 118 mg/100 ml even in 1974 For ?G female patients, however, a significant de crease was seen in 1973 and 1974 when compared with the levels m the previous years However, 42 percent of them still showed higher levels than 110 nig/100 ml m 1974 Okumura ct al (ref 20) examined the possible asso Ciation between serum triglyceride levels and PCD con cenlrauons m blood in patients As shown in table 11, they observed a srgmficantty higher mean level ol scrum triglyceride in a group of pata'isli who showed the characteristic gas chromatographic pattern A, as com pared with other patients who did not show such a typr c<s! pattern They also observed a significantly positive Correlation hetween serum triglyceride levels and PCB conccntialiens in blood It - 0 4Q5| Table 10 Resuhs of followup study on serum triglyceride levels m patients with Yusho^ Subjects Patients W! til Yusho Cent rols Controls PCB ' s no. Age pattern cases me a r 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 2.8 + 1.6 Triglyceride mg/100 ini Reference 134 + 60.0a 91 + 39,8kb 20 74 + 29 19.21 < 0 05. b|> < 0.005. -- *I -- - * Table 11. PCB's concentrations in blood jnd scrum triglyceride levels in patients with Yuslto in 1973 Patients Triglyceride (mg/100 ml) Mean + S.D. y Sex Age No. ' 1969 1970 1971 1972 1973 1974 Male 11 - 73 14 159 + 57 166 4 55 169 + 60 174 + 69 164 4 68 160 + 118 r entitle 7 - 59 26 155 + 75 161 +70 155+80 153 + 63 129 + 50b 111 + 56b dCiU'<J fi'otn a report by Okumura et al. (ref. 19). L 1 'Significantly lower than in 1969, 1970, 1971, and 1972 (P < 0.05). HONS 209948 25 ;.4 i< i -A Hcic ay.mi, ii '.iiniiif question can I)' ihiiciI m regard In 'iiicli qIimtvi'iI loruljiion. a. a!n ally chsgusu-d m con unction wuh the di tma! lesions Am ihe current elevated levels ol 1'CB's m blood and ihor peculiarities tn gas thronutoyrophic naU'-ms causally cu...... .. with the abnormally high seium lriglycertdc levels found in patients? _Smicc. as mentionttl, the female pahents started :o d|jcujii'i M1 si urm tnijtyct ndr rLincrntratiOn m recent years, n Ipllowcp examination of PCB's in llieir blood might gwr a good cfuc to answer the above ques lion A. Lirrr of PatirnU with Yusfio Both I'Cft's and RCDr'sare wed known toxic agents 10 tlu- liver PCDT's si-em to oe poibcularly toxic bc- cause a single oral administiation of PCDF's os small as about 1 mijAg could k'll rabbits try severe liver necrosis (u-fs 23,29) Ihcielorc, it is reasonable in expect that pitients with Yusho would have a severe Irvcr damage. Okiimura ct at (ref 30) performed detailed medical examinations on 2*1 pa'>cnts soon alter the onset but, unexpectedly, olitaincd no objective hnclmgs to indicate dMimlc liver disorder* No patients presented jaundico and only tfiree of them had palpable livers Howcvpr.an ctrctron mirgoscotni' examination of Irver tnopsy speci mens conducted on a paticnl irr Fehmary 1969 revealed a niniked liypeiimp n; rd smooth endoplasmic reticu lum, indicating siimul.-led eriiyin" induction in the liver fief 31| Okumura cxriminerl 33 patients with various Sub|"C live symptoms foi serum rirymes. mclirding isorymes fiom ! 971 lu 19 7 2 (i cl 3*') An .-lc-easi; m a fraction of laclat" (l-'fi vs If ns*' II ''H S) and high liters in thymol turbidity tests woir* nhsr>' ed in s-vn*' id the severe cases but no definite evidence *o' liver disorders was ohtaiund. fli'Lr-ulv M-ovinia et ,u (ml 33) r x,um-ied 121 aduli pdicim wit' Ytisl'u and 297 healthy .iduli controls fur smiini liilitubt'i rjeiurupti l(ii'r| a siijnilicaut lower ever ,>jr eiviir mi.I'nui in llu pal"'iit group than in the con li'U 'hey i!*o showed si pn'ieantly negative conelalions be'wf-ri sfinm bilii'd.m and h'cud PCB's in toncentra t,on (r ' 0,3411 p'CO P,b' mail smni n ly b-*iween serum bilirubin anti si'ilm liglv ,* ul (t 0 210, p<0 00r fhey ions.tiered thgl a h-wued eoiiccnuonon of serum Uihrubiit >n frTTienr- sernu-rt m.ieily due tn an aecchn oleil bihrobin dtii*Tsrrf bom |'ie blnml -+ln;iy.im.i ''t al uiv stm null 1 20 (utients foi AusUa lia antigen ,md mt-hody liy the immunoeb'cti o osmop'iuiesi* m 1071 (mf 3r1) Hn* antigen was positive in thrre, while il'e antn-mly was negative in attuf them, imlic.lt 111') m> id l)i i eni i ,i I ill m Ills1 in . vail* urns I n't win n the nalii-ms mil healthy i nni'nls This f nikng si ems h. lx- nnpiiil ml in roiini'ri' a- wi|h ihi hiruie e.k of i.ei-i ivliuh '.ue-uts *i|l11 i |i"nrii<r In view ol all these findings, hver function tests Cur rently available do not maddy delect serious over les'On m the patients but it is highly desirable that adcqual caution will continuously be paid to this well knosvi target oryan of chtonnated hydrocarbons CHILDREN BORN TO MOTHERS WITH YUSHO The birth of unusual babies from mothers who too "Yusho od" during pregnancy is already well know/ (rets 25.2G1 Then clinical feature; were d.nk brow prgmenialion of the mucous meinb-ario and (be enlu skrn, gingival hypcrplasis with pigmentation, a tcndcnc to be small for die date, emotion of teeth at butl liypcrsrcreiation of th' Mc'bomi.m gland, and ed"ma c the orbital area Pigmentation of the skm disappea-er) > 2 to 5 months, followed by gruwtli similar to that o normal babies It seems noteworthy, however, that balnt-s wiin th dark brown pigmented skin continued to Im horn for few years after Hu- intake of "Yuslso^oil" was discotinued by mothers Yoslurnura reported on nine lube with such skin who were born r0 mrrthcrs wuh Yuslio r Nagasaki prefecture from 1 9G9 to 1'97^tr(d 27) Tltrc of suefi babies find been deliverer! Jiy. a pjtient fror 1969 to 1 17 1 Abe et el. bef 23) tf-C7-"dv reported o PCB levels in the plasma of 30 children {.yprf 0- TTbcv to 10 mothers with Yusho m Nagaoki prefecture Him examination was made in 1971. As shown in tabfr 1/ the rco levr |s of Pn-'i- i hiidrcn were s onibcantl/ fuglm than 'those of o'Omaiy children hut lowr |lwi tin* li-vcl of then mothers The-i gas chromatographic patterns o PCFI's in plasma wi rv jlreullv referred to oiil-ci m Hu papi-r Ch-ldu-ri fr-1 vi !'irjst mill hem rnpihen witl Yusho leiidcd In iliow a higher plasma <'OP'-i,nt'atmn o PCB's than ihnse who were not fed on *urh nniv Yoslnniura dho ii-)>niti-il an inten'siinii c.iv-, wlieie baby was thought h> fiac- suffcinf Irom Yusho due ex chi lively to intake ul PCB's through hieast mbit from n woman wp.fi Yusfio bhf 27) Very few data are availjli1-' in rcgaid to the cone Ml'atiC'n yf PCB's i i l"i ast nnlk u' mothers with Yuxhc- Masuna at al fuund 0 03 - 0 OP lijuii id PCB's in b '3iiipln of l>("ast mdk collected hem a woman with Ynshn within 6 rlavs-idtei delivery n 19 73 (n-f 1?) Masudd also luunrl about 0 03 ppm o' PCB's in another sambti- td hieast milk coh"Cted a I*", day s af tn a woman with Y usho dr In err'd a I a by with nt (lerin.tf signs (ref Id) The PCB h-vets m breast mils hom p iti*'*irs with 3 u*ho were ihrrefi *c |ust willsim th* mnmill i mgr lh'Wi-\"r, the gas t hn-nialugi .-I'bn n-i jn-'S or tlirse s.iniph s vvrie qin'i inuitvi . the Sjnm a tti.il ih, i.-( l-.i i n,i VtuVi HONS 209949 Table 12. Concentration of PCG's tn pfasmd of children born to mothers with Yusfio Subjects PCB1 s in plasma (pbb) Subjects Range Mean + S.O, Mothers with Yusho Children born to above mothers Ordinary chi 1 dren 18 3-33 11.2 + 7.32 30 1-20 6.7 + 4.20 14 1-8 3.7 + 1.97 Ref erence 23 Table 13. Deaths seen among patients with Yuslio^ Cause of death Maliqnant neoplasms Stomach cancer Stomach cancer + liver cancer liver cancer + liver cirrhosis Lung cancer Lung Tumor breast cancer Ma 1 i gna nt 1 ymphonia Cerebrovascular lesion Amyloidosis Osteodystrophia fibrosa Myocardial degeneration + pericardi ft s Status thymicolymphaticus Liver cirrhosis Suicide-- Senility Traffic accidents TOTAL _ Number 9 2 V r i i i 2 3h ]b ]b ]b r i i i 3 22 aCitod from a report by Uragc 1974 (ref, 2). bAutop$ied cases. 27 MOWS 209950 MORT/UJTY or PAT1E NTS WITH YUSHO Omoc repotted in 197b that 29 deaths occurred amonq 1,291 patients with Yusho up to April 30, 1975 (ref 1J^Ileuses of lb* S" d( alhs were not given, however, Urahe also (Opened on 22 deaths seen among 1.200 patients until September 13, 1973, and rrfetred to their causes (ref 2} As shown in tablp 13, 9 of 22 deaths we'e canted by malignant neoplasms, suggesting a (xissildc exiess of u< edis from cancer Since some essen tial intonn.suon needed for epidemiological analysis <s not available to us, no lurihrr reference can t>e made with certainty to such a possibility at the present time, CONCLUSION / As mentioned earlier, we demonslmlcd the presence of PC'Or s in "Yirsfui oil" ar a much higher concentra tion than expreted Wc also showed that PCDF's are relatively more criiicrntiat"d in liver. Although neither the rbi'micai naiurc nor the loxiritv of PCDF's con tained in "Yusho oil" and in the bodies of patients arc known yet, out findings clearly indicate the necessity to pay gieatvr attention to PCDF's for clarification of the nature of Yusho I" ur theneorc, out studies suggested the possible formation of PCDF's from PCB's when used as heat trnnsScr medium Beside ibis, another possibility llini PCDF's might be formed by heating PCB's with peroxides, which ore svell known to be formed during fie,itiin| cooking oils should also be investigated. rri f ptnccs 1 T, Omae. `Tmcword the Tifth depot t of the Study for Yushn an'1 PCB,' Fukuoka Acta Med, Vol. GG, No 10 (October 19751. pp, 517-153 (in Japanese). 2 ! I, Chain*, ''Foreword, the Fourth Rcooit of the Study on Yosho amt PCU," Fukuoka Acta Med, Vt>l 65, No. 1 (January 1974), pit 1-4 (m Japanese) 3, "f ninth Report," Fukvoka r1< ta Mc\t, Vol 65, No. 1 (January 1974), pi. 105 'Tilth Report," Ibid, Vol GG, No, 10 (October 1976), pp 547 64 U 4. II. Kiotla and Y Masuria, "(tclntion Bel ween PCD - bevel ut Hie (Ih*ml and Cluneal Symptoms of Yusho Patients'' Fukuoka 4rf,i Mod. Vol 66, No 10 (October IdHO.iyi 624 6711 (n> Japanese) 5 G Unnl.i, "f linu si Av|>ccts of PCfT Piusoniitq," /lorfo no klr.aiku Vol 70 (1973), pp 3G 42 (m lipanese). G II Knlidi S A'.slu, and S 1 oshitjni, ''Di'immIoIoiii cal Tim'iiiys uf 'In- f'atri'iit' With Yusho (I'CB Poisoning) in General Examm, Fukuoka Acta Med, Vol G5, No \ (January 197 pp, 81 83 (in Japanese). 7 Y M.ssuda, 8 Kagawa, K Shimamurj M Taka and M Knratsune, "Polychlorinated Biplicnyls the BloorJ of Yusbo Padenis and Ordinary Pei son Fukuoka Acta Med , Vol G5. No 1 (January 19 7 pp 25-27 (in Japanese), 8 M Takamatsu, Y, Inpue, and S Ahe, "Dive'O' Mcjning ol the Blood PCD '' Fukunl a Act! A*r Vol fib. No 1 (January 1971), pp 2U31 Japanrse) 9 H Masertnwa. M, Sato, and H Ts.rru'a. "PC8 C centratron in the Blood of Worhtrs Handling PCI Bodo Fisn, Vof 13, No 10 (1977), pp 00 55 Japanese) 10. M Goto and K. Ihguchi, "The Symptomatology Yusho (Chlorohrphenyls Poisoning) in Dermato . gv." Fukuoka Acta Med, Vol GO, No G Us. 1969), pp 409 43* lin Japanese), 11. Y. Masuda, R Kagawa, and M. Knratsune, "Co pansors of Polychlorinated Biphenyls >n Yus Patients and Otdinary PeisonSjC Bull Enviri Con (am, Toxicol, Vol, 11 (1974), pp, 213 21G 12 Y, Masuda. R Kagawa, M KuratJSnet "f'olychlor alecf Diphenyls in Yusho Patienl^antt Ordinary P sons," Fukuoka Acta Med , VobCS, No 1 (Jomi 19741, pp 1 7-24 (in Japanese), -_ 13 Committee for Investigation and Study of PCB t Others, "Study on the Distribution of Concent Hons of Inttacciporally Accumulated PCB' (19/ r (in Jaitancse), 14. Y. Masuda, Unpublislted dalj 10 M Asahi H, Koda, and S Toslntam, "Alteration Skin Srverily Grading of Yusho n pie General f .ummtion in 1373 and 1074, and Piesentation o New S'andard for the Skin Seventy of Yusho < Point Count 5vstrm,'` Tukunka Artj Aferf , Vof 6 No, 10 (Octoliyt 1975), pp 679 G34 bn Japanese 16. J Nmiayam-t, Y Masuda, anil M. Knratsune, ' Cb` ruinied Dib'mrnfiirans in Kaiu'chluts and Rice 0> Ltsi'il by Patients With Yusho,'' Fukuoka Acta Mr* Vol. G6, No. 10 (OclobcgT975), i>p 59J 599. 17 J A O (loach and I, H Pomei.vH/, The Fmth of Chloi mated Dibenrofurans m a Japanese P( Sjnipl," Bull Eovuon Contain Toxicol, Vol (19741 pp 330 3 12 18 T. Kashmioln, personal rummii" > Hum (1975) 19. M, Ol'umuia, M Yamanaka. S. Nakamuta, and Urawj, "Consecutive Six Yc.ii rulluvv up Study i Seium Ttglvccrnle Levels in Patient; V71111 I'l Pnisoumg, ' rukuuka Ado Af,-i/, V.il 6fj. Ho (Oclober 1975), pp G70 07.) f.n f.ui.iu- se) 28 MONS 209951 , . ,, 20 M Okumura. Y Mesuda, and S Njkamula, "Cor Between Dlood PCB and Scrum Triglyceride Lcvi'ls in Patients wrlh PCD I'ouoning," Fukuoka Acta Mat, Vol CD, No 1 (January 1974). nil 04 07 (m JapanrSr)_ _ 21 H U;>iwj, A Notnmi, S Njkamtrta, and Y fkeura, "Conscrulive Thru: Year follow (Jn Study at Scrum Tnrjtyrcrulc Concentrations of 82 Subjects Willi PCD Poisoning," Fukuoka Acta Med.. Vol 63, No 10 (October 197?) nn rim <10-1 (m Japanne) 72 S Jensen and G. Sunrisuon, "Sit or tines and Levels of Must Cliloiobiphcnyli in Two Technical PCD Products and in Human Adrpose Tissues,'' AMDIO, Vol 3, No 2 (1974), pp. 70 76. 23 S Abe, Y Intiur, and M Takamatsu, "Polychlorin ated Biphenyl Residues in Plasma q( Yusho Children Dorn to Molhcrs Who Had Consumed Oil Contam inated by PCD," Fukuoka Acta Mat, Vo(, GO, No 10 (October 19761, pp COG GOO (m Japanese). 24 J Naciayama, Y Masuria, and M Kuraljunt*, "PoJyclilonnated Drtirwofmarts in Tissues ol Patients with Yusho," paper 330 piesenied at the 34th Annual Meeting of Japanese Society o( Public Health. Yokohama. October 29 31, 1975, preprint, 21 5 pp.. Oclobci 1975 (m Japanese) 25 I Funatsu, F. Yamasltda, Y Ito. S Tsugawa, T Fiinatsu, T. Yushikane, M. Hayoihi, T. Kaio, M. Yaknshi|t, G Okamoto, S. Yamasaki, T. Anma. T. Kiuio, H. Ide, and ( Ihe. "PCD Induced Fetopathy, 1 Cluneal Ohsei vatinn," Kuruute Med, J., Vol 19 (1977), pp 4 J G1 26 I. laki, S Mis.inaga, and Y Amayase, "Report on Yusho fChloiobrpitcnyf! Poisoning) Pregnant Wom en and 1 Itcrr Fetuses," Fukuoka Acta Med Vol 60, No G (June lilbflj.pp 471 4 74 lm Japanese) 27. T, Yoslnmtira. "Epidemiological Study on Yusho Dairies Dom to Mothers Who Hod Consumed Oil Cnnuimnated by PCD," Fukuoka Actj Med., Vol. 65, No. 1 (Jamury 19/4), pp. 74 80 (in Japanese), 70 H Oaiier, K H Scliub, and U. Spicgcllrery, "Dmillichc Verijiltungon bci der Herstcifung von Chlniiihenol-Vi'ibindunqen," Arch. Gewetbemads. Gt'wcrMiyg , Vol.196!|, tgi, 538 5G5. 79 H 1 It. Hofmann'; "Nruetc Erfdhrungen mit Hochunuscften Chkn kolilemvaiser jloflen," Arch Fi./t Pathol Phatmakol Vol 232 (1958), pp 228 230 30, M Okunuua and S Kalsuki, "Clinical Observation -- on Yusho (Dllnrobiplienyls Putsonlng)," Fukuoka Arr.r Med , Vol 60, Nu. C (June I960), pp,-140 446 (m Japanese) 3L C Hirayjrn,!, T. hrsa, and T Yamamoto, "Fine Stiucim.i! Ch.miji's o( the Lwor tn a Patient With Chlotobiphenyts Intoxication," Fukuoka Acta Med, Vol GO, No 6 (June 1969), pp. 455 4G1 (in Japanese), 3? M Okomura, "Course ot Scrum Enzyme Change m PCD Poisoning," Fukuoka Acta Med, Vol 63, No 10 (Oclobcr 19721, tip 396 400 (m Japanese) 33 C Hrrayama, M, Okumura, J Nagar, an<l Y Masuda, "Hypobiluubinemia in Patients With Polychtonn and Brphenyls Poisoning," Chntca Chun Acta. Vol 55 (1974), pp 97-100. 34 C. Hnayama, M Nakamura, and M Yoshmarr, "Australia Antigen in Patients With PCD Poisoning," Fukuoka Acta Med, Vol G3, No, 10 (October 1972). pp 405 407 (m Japanese) DISCUSSION MR. ALLEN GREY (IIT Research Institute, Chicago, Illinois) Oo you have any lee; whether dibetuo {mans concentrating in the body are more rapJ in mclabolism than the result of polychforin.yed'Hji' phenyls! ' DR KURATSUNE, Unfortunately ) have no defiptle- idea. It is a more potent compound than PCB. 1 guess ) really cannot say. -' DR, ORVILLE PAYNTER (EPA, Washington. D.C): Arc there any reproductive problems or ir regularities continuing for many years after the ingestion o( these materials? DR. KURATSUNE There is some disturbance of men situation There have been some disturbances and them have been some related problems. MS. OtBQRAH A. BARSOTTI (University of Wiscon sin, Madrson, Wisconsin): Were there are dotngs that suspected any ivtdespicad gastre ulcerations or an erosion tn the patients-gastric ulcers? DR. KURATSUNE. No, I do not think so. Some of the patients had very persistent disorders of the intes tines, disorders of tire digestive system, but l do not know if they were suffering as a lesisll ol this or not. VOICE: Any n-sidujl changes m the sebaceous gland during the autopsy? DR, KURATSUNE. No, ( do not know very'much about il VOICE: I would (ike to ask one more question. Have you been able to specifically identrly any ol the ditx-nrofurjns other than those in ihe hotly? DR. KURATSUNE. You are asking if we could identity any of ibe dibiwofurans? No 29 MQNS 209952