Document 4ax4wZ7kEaz5QkgBYab6EqqJx

KXIKonMI \ HIVI XH< II 16. v: l(KK 1^781 * Respiratory Involvement in Polychlorinated Biphenyls Poisoning1 mi Noiuaki Simckma isi>, Surzo Ism mart. Riiko Sai io. Toi.o Ikih v. Ki.mc hi Maisi'Ha, Koi aro Si'oiyama. ami Yosiiiiii M vsi nx Thf Mt uiinh Instituti1 fut <*/ the ( ftvsi ( 'iincrun I <<< if/(\ i>f Mctluiuv. amt Analyinat Chrmhtrx hihinaiory. Dtaithi ( .>//i av of I'luamai t aia <it A< <<<>. takuoka. N2 Japan Received June 6. 1V77 Clininil. iHhoralory. mul pathological findings on respiratory involvement tn polyihlon nated biphenyl (K'B) poisoning were studied in 401 patients nd thvtt pathological itumgcv weir produced in nils given PCBs orally. Respiratory symptoms included expectoration m AIK} of the 2H** nonsmoking patients with PCB poisoning and mild wheezing in 2'f The incidence and severity of Ihe respiratory symptoms correlated well with the eoncentration f PCBs in thr blood and sputa, (`best roentgenographk findings, pulmonary function (esis and pathological findings revealed bronchiolitis in many, and pneumonia or aiekMasis in about one-tenth of ihe patients with rcticulo-lineai shadows Peribronchiolar changes mux be primarily due to cilhvi PCB poisoning or associated infection Respiratory distress was often exacerbated by vital or bacterial infection persisting for more than a half year in about half of tbc patients examined The IgA and IgM levels in the serum deueased considerably within 2 years aflct the onset of Ihe disease and definite decreases in IgA levels may correlate well with the badctial infection PC'lls found in sputa may have been prevent in association with lipid in type II cells ol the lung with cxtielion trom hmiKhtal veils) .iml may have been phugocytoscd iu alveolar macrophages aud may change the it phttgocytu function. INTRODUCTION In Ihe summer of 1968 patients with polychlorinated biphenyl (PCB) poisoning began to appear throughout the western pan of Japan. The cause was traced to the contamination of edible rice bran oil by PCBs used as a coolant < Kanechlor (KC) 400. the trade name for a mixture of PCBs) in Ihe manufacturing process 127i. Since then the disease has been called '`Yusho," which means "the oil disease." Respiratory distress occurring in these patients improved gradually hut persisted in most cases (26), especially in those with high blood concentrations of PCBs and with signs of chronically infected airways. The accumulation of PCBs has recently been reported in mouse bronchial mu cosa with dose dependence (3) and with structural requirements (5) of PCBs. but it has been staled that the biological significance of these observations is unknown The purpose of this report is to present details of clinical, laboratory, and pathological findings of respiratory involvement in 'Yusho" which have not been reported so far. MATERIALS AND METHODS Clinical ami palholtffjit al examinations. Pour hundred one patients with PCM poisoning form the basis of the present study. They were subjected to the follow 1 this study wav suppoitcd by giants Irom (lie Japanese Mimstiy of Wclfaic Mill VUI/7K/II.1t IHfCIIMNI.lt I iifviifhi n ivw h, ittildiw ISrvv. Iih All mhiv i.l icpitHltitiitm in .tn\ Itxm irrivn HONS 00X310 HI SI'lUA I OKY |KVm.V|-MI'\ I 1 ** II I'OISON'INO 93 ing examinations: an assessment of subject symptoms, chest roentgenograms, pulmonary fund ions, microbial siudy of the sputum, and determination of im munoglobulin levels and PCH concentration in scrum and sputum. A pathological study was done on the lungs from seven autopsy cases and from rats given PCHs. as described below Hlood sampling and immttnohmiral and chemieal analyxes. Immunoglobulin levels were examined by radial single immunodiffusion (24) using Parligcn (Behringwcrkc. West Germany) Immunoglobulin levels in 149 samples of scrum out of 72 patients (59 adults and 15 children! from March 1970 through March 1972 and IgA in sputum from 9 adults were determined. Rough estimates of the PCB concentrations in sputum samples, averaging Ml g, collected from the patients hefoio 1972 were obtained by comparing total peak heights on gas chromatograms (18) Sputa collected after 1975 from 20 patients and avciaging 40 g were semkpianlitatively analyzed using the Japanese standard analytical method for PCI! (20). Since 1975. about 10 ml of blood taken from each patient and each of 57 healthy volunteers has been analyzed by the latter method Idi PCI). Aninud experiments. Male rats of the SO strain, weighing about 200 g. were given, by gastric intubation. 25mg of KC 400 in 0.5 ml of edible oil once (Group 1 PCDs) and only 0.5 ml of oil (Group I control) and the same dose four limes per week (Group II PCBs and control). Groups of five animals were killed by cervical.-- dislocation at 2. 7, 14. and 28 days after the last ingestion. Tissues were prepared lot light atul electron microscopy. RESULTS Ne\pirat<ry symptoms and their relaiitm to f*CIt < om ( titration in htood. The ages of the 401 patients with Vusho were distributed between newborn and 80 years and (he sex distribution was approximately equal. Respiratory symptoms were cough, expectoration, and wheezing, the former two appearing with skin eruptions and I he latter ensuing several months later. Expectoration was nonvis eitl in those without airway infection, comprising 40'/ of the 289 nonsmoking patients and mild wheezing was noted in 2'/. In one case with bilateral cicaliical thickening of pleura due to tuberculosis which healed in 1945. tespiialon insufficiency and CO... narcosis have developed three limes since 1970 because of airflow obstruction exacerbated by bacterial infection. His PCD concentration in (he blood and sputum w'as high. 27 and 8 ppb, respectively, in 1975. The incidence of respiratory symptoms correlated well with the coiiceniration of PCHs in the blood (this trend was significant, p 0.05) (I), hut not with the pattern of PCHs (the hitter being noted in fable I). Chest X rav and laboratory findings. On chest roentgenograms 5V of the patients revealed rctictilo-lincar shadows, upon which admit, patchy (bronchopneumonic), or atelectatic shadows were superimposed in about 10'/. These . roentgenographic findings did not correlate well with the severity of the dermal eruption (25). The results of pulmonary function tests in 12 nonsmoking patients ate presented in l ahle 2. Vital capacity {VC) and the ratio IT- V,/FVC were almost normal but arterial oxygen tension (/>().,> decreased in 8 and maximal expiratory flow at 50 and 25' / of vital capacity (V'mMV and l'WHX ..r>) showed mild decreases 001.3V1*Ot*S 94 SI 11 < I M .\ ISt' M AI I A III .1 I Ki sm. WHO S>MIrIMMS WM Pm \ ....... II.......MIS IS Mill. M. PCII P( 11 cntueiilraUnn Kospnitoiv s\mplnms potter n tpphi IVuvntniiv 1 Ol.ll A It It ( C total 14 a lit 19 2ti \\ 14 A9 10 |9 1J A9 14 A9 21 t2r 21 t2i 7 141 2 A t 11 t 12l 1 A (At A 1 ll X? t141 7 t;i 17.X XA K (7j 19 i121 7 4 } (2l 2 2 11) |r on l Alt' { l A | A (XI 119 1710 27 f. 47 A AO.O Mi 7 V* A 40 0 ItHI ll 4I< 4 V A tf. A 41 " 40 1 2V <9t 4(1 ( IJ> 14 ('1 h X |A| A l2l : 11> 2K l I4i Xil> 1 V" i4*i 12 IOi 2X9 ili.'i ' I Ik* ihiimIvp'n m paienlliescs icpii'scnt patients with smnknie h.ihit ivilinliil *' lorn out ol the (hnlecn patients li.ul .1 past Insloiv ol asllima ' Ivso out ol ihi' 111IV p.itii'MK hail .1 past histon ol'asthni.i in about half of 11tc patients: in the latter both inspiratory and expiratory rhonchi were audible al all times Serial bacteriological examination of sputa in 12 nonsmoking patients with re spiralory distress for over 2 years revealed the presence of Siuf>h\loi *< < n\ tut- I \hi.i: : Pi 1 MM S VMS 1 l V. "MS 1*1 s 1 is 12 Nmssmmkisi. I'mhvis1 hi Ml Rill! i M IIM in Smiihiiis \HMI 1 I A 1 \K \l * i ii Os si i mi Rt si'ih \ imnn Dim mi SS VSII M 1 Mcasuicmenl 1970 1971 |974 V( pu .lu lvil vc r; t 1 1 V, 1 VCtM 100 90 NO XII 'A A > 1A 1 t0 t 1 ilnets seel t ,M1X titters seel /',,<>. limit Opt 4 0 1, 2 II *' 1 A A I0 A II 7 -XA \ 4 7(1 2 * Ml l 1 " Apes wi-ii- tlistiilmiot between '0 ainl 49 vcais, ami hall ol them itolucil lost in 1970 that then tespiraloiy ilistn-ss nnphl lv ulaletl to the poisoning HONS 001312 HI SI'IM A I < *H\ ISAUIVUIIVI l\ H II I'UlMiMM, 93 tens, list hrnt hut tali. f*.scutlouu>na.\, or llemaphilns The bjKterin wore foil ml persisting for more th;in 1 year in three eases ami less than ) year in two cases. In these five cases the PCB concentrations were over 10 ppb in the blood and .1 ppb in the sputa, while the enses with PC ft concentrations under 10 ppb were affected without persistence. Therefore, chronically infected airways seemed to he present in about half of the patients with respiratory distress, and further, it was often cxaccrtnited by viral infection w ith the appearance of inflammatory symptoms in the upper airways. Ctise pre.wntaiitm. Asa typical case of Yusho involved in respiratory disorders, the 4tycar-old wife of a patient with respiratory insufficiency described above hHd complained of expectoration since April 1968 and mild wheeling since July 1968. complicated by dermal ehloracnelikc eruptions and black pigmentation, hepatomegaly, and the like (23) since April 1968. Chest roentgenograms showed bilateral reticulo lincar ami micronodulor shadow's. In a pulmonary function test petlormcd in 1973. the following results were found: VC. 2470 ml (92*/<): FliV,/ FVC. 7KJ: VI1)IK 2,6 liters/scc: Vmil^0.7 lilcrs/xcc; />();.. 72 mm Hg: /C02, 37 mm Hg. Abnormality in the flow'-volume curve and blood oxygen tension suggests that she had been involved in small airway disease. In microbial examina tion of sputum hndcriu w ere delected, i.e.. Staphfoeotms aureus in each culture in 1970 nnC^lit'iiutphiltis in 1975. Rhonchi wxre improved after appropriate chemotherapy. The blood PCB content of this patient was 12 ppb and pattern A in both 1972 and 1973 and the PCB content in the sputum was 3.3 ppb and pattern B. finnnm<n>lobalin levels. The IgA and IgM levels in the serum decreased and the |g(> level increased in 1970 but ail were restored to normal in 1972. except in three cases (one adult and two children) where the IgA level remained low (24). Though no statistically significant relationship between IgA levels and clinical symptoms was detected. IgA levels of less than l(X) mg/100 ml were found in 5 of 29 eases with respiratory symptoms but none in 24 cases without. The IgM levels were significant!) lower in patients with severe dermatological symptoms (grade IV. (9). while the IgA levels in sputum w-erc not low (24). /*( lls in hlthul. sputum, anil fat tissue. (as chromatograms of PCHs in blood weio icpoitcd in a separate paper (20). In the gas chromatograms, the peak ap peared immediately after 2.2 his<4 chlorophonyl)-1, l-dichloroclhylcnc <1)1)1-1 was low and the fifth major peak with DDF was high in the majority of the patients (pattern A): the reverse was present in the peaks of normal persons (pattern C). I'ullern B resembled pattern A but was not as pronounced. The sputa collected from December 1909 to July 1970 were analyzed for PCBs by gas ehromatoglaphy. The definite PCB peaks with late retention limes were always delected in the sputa collected before Max 1970 and apparently were lower in those after June 1970. In sputa collected after 1973. about the same level of PCB concentration was found as in those after June 1970 und was about onc-third to one-tenth of the blood concentration, flu- PCB peaks of the same pattern demonstrable in the fat tissue of autopsy patients in 1969 were over 100-fold gtcater than those in sputa collected at about the same lime (26). Puihaloniral sttuly. Pathological stud)' of lung specimens front seven autopsy patients disclosed lymphocyte infiltration in bronchial and bronchiolar walls and HONS % Sim.I MA I St' I.T Al macrophage infillralion in alveoli, particularly around bronchioles associated with alveolar collapse in four al the age of 13 to 48 (Fig. I). Focal hemorrhage and/or pulmonury edema and pleural and pericardial effusion or adhesion were aho de tected in three patients who died within 4 to 12 months after the onset of the poisoning (14. 15) (Fig. 2). Marked hyperemia, atelectasis, and alveolar hemor rhage were noted in a stillhorn.case (13). ___ In rat lungs peribronchial and peribronchiolar cell infiltrations, especially the latter, were observed (Fig. 3). Electron microscopic studies in Group II PCBs revealed large lipid vacuoles and altered lamellar bodies or lysosomes in a type II alveolar cell and alveolar macrophage (Fig. 4). These pathological changes were most marked at a week after the last ingestion of PCBs and more intense in the Group II PCHs than in Group 1 PCBs. DISCUSSION The muse ami tlinittil syni/Hotn.\ oj TCH /Mw'.wwi/tg ( Yusho). In February l%8. leakage of PCBs used as a coolant in the manufacturing process caused the con tamination of edible l ice bran oil which was distributed mainly in Ihc western part of Japan (IV). Shortly thereafter unusual skin lesions were encountered (V). A certain hut definite dosc-cffcct relationship was noted between the amount of oil consumed and the clinical grade of dermal eruption (31). The average amount of oil consumed was 800 ml per person (31). The oil contained, as later found by chemical and activation analyses, 1000 ppm of PCBs (22) and caused a heavy poisoning affecting over 2000 persons. ha. I I .imp tissue lioni an autopsy case will) IH'II poisouiup Death was caused by acute catdiac insufficiency 4 years after I hi- onset of the disease at the ape of 46 Chronic inflammatory cell iflflltra lion ami productive chimpes are displayed in and around (he bronchioles, and edemu and mac mphapes ate seen in the alveoli. * 42 MQNS 00131S !.. 2. I.un|t tissue fu*m another tunnpsv ease with PCM poisoning. Death was uiused by acute t'iiuliMi- insullidcik'y I yciu wftet the onset of the disease at the age of IV Lymphocyte and macrophiige mriltraiion are seen in bromhiolar walls, amt hemorrhage and macrophages are present in the alveoli. V2 The other symptoms in Yusho. whi :h varied a great deal, arc given in the tables tltt, 19). Respiratory symptoms have been omilicd because of unawareness of their relationship to PCB poisoning at (hat time. Although PCBs arc lipid soluble and vigorous lipid metabolism is known to be present in the lung (II, 12). no respiratory involvement in PCD poisoning has been reported until now. apart from plcuritis occurring in chlorparaffin poisoning (12) and in chloracnc eases (2). _ ( mu entrufion and distribution of PCHs in tissue, blood, and sputum. The determination of PCBs in tissues from autopsy patients showed that Ihe total amount present in the lung was about 1/15th to I/40th of that present in the skin or in fat tissue (18). The distribution of PCBs in animals has been studied extensively <4 f). In nils the distribution of KC-400 administered orally was highest in the skin, adipose tissue, and liver, followed by plasma. It was somewhat lower in the lung (.10). Tctrachlorobiphcnyl. the major constituent of KC-400, is almost com pletely eliminated from the body in 3 to 4 weeks, but penta- and hexa-unalogs. although they are minor components, are still retained after 9 to 10 weeks, persist ing most tenaciously in the skin (29). As mentioned above. PCR concentrations in the fat tissue of patients (20) is much higher than that in blood or sputa. These different PCI) concentrations imply that PCBs deposited in the fat tissue are being removed slowly and then appear in blood and sputum. Recent studies in mice showed that a number of discrete PCBs were not taken up by the bronchi but were distributed very evenly throughout the lung paren chyma (4). However, the author also showed specific dose dependence (1) and structural requirements (1) of PCBs Tot accumulation in the mouse bronchial `)K Slllf I MAIM' n M I' li. y. I mi): 1 issue ftom ml mlminisimU PCHs once h week fur 4 w eek' IVrihronchiolar tvmpho i yU' iiml muemphnKe infiltmlion arc seen I'onspmiously anil niiitroptuif-es arc found 1i> a lessci e\lenl in the alveoli, focal hemoi rhayes are also seen in the alveoli * V.V 1" I'1 f*atht>i>hyxiofttf!ic(il t hrttixrs. Pathological findings in the respiratory system in seven autopsy cases with Yusho consist primarily of macrophage infiltration and . foeal atelectasis in alveolar spaces. Alveolar collapse around bronchioles may ( c result from disturbances of lipid metabolism in the lung, as is observed from | \\ measurements of the surface activity of lung extracts (25). Peribronchiolar p changes may be primarily due either to PCB poisoning or to associated infection. , I' Kocntgcnographic findings and altered pulmonary function correlate well with << these pathological findings. b Focal hemorrhage and/or edema and pleural and pericardial effusion were mainly observed in the patients who died within I year after the onset of the disease. In February IW>8, a large number of chickens died when fed with fodder mixed with oil from the same company. The feeding of Kanechlor 4(H) al a 0.04Cf level resulted in labored respiration and distended abdominal cavity, similar to chick edema (7. 10). Alterations in the defense mechanisms of the respiratory tract. Respiratory distress is often exacerbated by viral or bacterial infection. In ihc latter. Gram negative bacilli were often detected and found to persist in about half of Ihc cases examined. Factors involved in altering the defensive mechanisms of the respiratory tract include the clearance of PCBs, which is nol known in detail. Follicle atrophy in the spleen (7. Ml or spleen atrophy (17) has been noted and in guinea pigs only the humoral immune response was depressed (28). In (ho patients with PCB poisoning IgA and IgM levels in serum apparently decreased for 2 years after the onset of the disease, but they were restored to normal in most cases in spite of the persistence , of respiratory symptoms. __ _____ _ MONS 001316 I HI SI'IH \ M'K\ l\ V< >| \ | Ml \ | |\ |M || hlNIMM, t i&fVVi I'It.. 4. I imp tissue limn iai pupated lot big. 4 fixed hy IVimeis method if). Note the attenuated lamellar bodies <ind det teased osmiopluha m n type II veil, iind iminetoiis dark bodies (lysosomesl uml phagotyloscd lipids m a macrophage As. alscolar space: lb, inclusion body; I. lipid: l.y. lysosomc. Vju. vacuole. 4000. r'urthermorc. ihc incidence of respiratory symploms correlates welt with the concentration of 1VB. In sputum. PCBs may have been present in association with excretion from bronchial cells and/or with lipid in type II cells of the lung, phugocytoscd in alveolar macrophages, and expectorated. PCB is a lahilizerof the lysosomal membranes in vino (8) and it resulted in low acid phosphatase activity in alveolar macrophages (25). These findings may imply ils decreased phagocytic function. REFERENCES I Aimilngc I*. tiv") 'tests lot lincat ttends in pioporlions and Ircipicmics Hintmiii, II. 17'. ' llt'iaitl I i I'Hi'l I'lctucsic pm mloviudton an chlotc \fi j ( Itn Hint. IV, K7 t lb limit I (|V7'i. Disrnhuhon of ?.r\.|.4,',V hc\acMoiobiphctnl in mice and Chinese hamslcis Dose dependent accumulation in die imittsc bronchial mucosa. An h /.mu./ 34. Ml 4 14* until. I tJV7't Ihc disirtbiiiion ol 2.2* .*.4.4*.6' and 2.3.4.4.'.A iHsachli'iohiphcni I in mice studied In autoiadtogiaphs /.w. ./,.* 4.27.'. V Itiiindl. I . Hctgimm. A., ami Wmhitmi'ici. A. (!9?M. Disituhlion of polychlorinated biphenyls: StiiH'iiiKil ici|micntents lor accumnlaiion in the mouse bronchial mucosa l.\f< nctin<i 32. 4V7. <> I Vinter, (i II t l%'i| Ihc It salu>o pulmonary snrfnctunt lor election mis niscopy I. I he alvs'olai surface lining laser .1 Ulimuiin i N< \ 21, KH. 7 l ilt k I) I O IX II H <; . and Childs. V Ak. tm.'i. Studies of tin' thick edema disease: V .Stiinliirils sif symploms pi mim ed b\ feeding chlorinated biphenyl t`<mln \ \<. 44. 14M4. X I tigila. S . I siiji. II.. Kato. K . Nacki. S . and I sukantolo. It t IV7| I lilted of biphenyl chlorides on tat live* nuernsomos fiikunkii l< in Vnl. 62. .3(1. V (iolo. O , and Higuehi. K (IV6VI ) tu- svmpt>mulology of Vushti irhlombiphcnyU poisoning) in derntiilologs t tikttoko Ai In Ml,I 60. 4I)V. 10. (iolo. M.. Sakagiit bi, K.. and Ogavt a h Hydroperiuodiuni assay of rice oil u hieh caused Vusho and Kaneehlt'i 44NI m t hickens / nkimkn t. in M> ,l 60. 'U < |V6V HONS 00131-7 [f 100 SHK.tMAIM 1.1 At Hemcmunn. H. ().. and Fishman. A. I' 1IW1. Nonrespiratory functions of mammalian lung Plniol. K' i 49. I. Hcr/.berg. i. J. (I94H). Chloraknc nnch Cemiss von chloiicncm Paraffin />c H hi 7. 42' Kikuchi, M.. Hashimolo. M.. Hozumi. M.. Kogu. K.. Oyoshi. S . and Nagakawa. M (I9f9i An autopsy cum* of stillborn of chlorohiphenyls poisoning I nknnkn Ai in Mitt 60. 4H9 Kikuchi. M.. Mikagi. V.. Hashimolo. M.. and Kojima. I. < 1**711 1 wo autopsy cases ol chionic c hloiohiphenyls poisoning, inkuokn At in Mt tl 62, 4X9 . Kikuchi, M. (19721. An autopsy cme of PCB poisoning with livci cirrhosis and liu-i cell cars mo mx. luktionk Atitt Mitt. 63, ?K7. . Kimbrough, R. I). (1974). The tonicity of polychlorinated polycyclic compounds and idated chemicals, ( ftC Oil. Hr%\ Tnxivot. 2. 44?. . Kimtira, N . and Baba. T. I1973). Neoplastic changes in the rat liver induced by polychlorinated biphenyl. (<'(> 64, 10?. . Kojima. T. 119711. Chlorohiphcnyls in the sputa and tissues /nknnkn At in .?/*</ 62. 2? . Kuratsunc, M (1969). Group of epidemiologic study on Yusho: An epidemiologic study m "Yusho" or chlorohiphenyls poisoning. Ittktinkn Attn Mrtl 60. ?IV . Masuda. Y.. Kugnwa. R.. and Kuratsunc. M. <19741. Comparison of polychlorinated biphenyls in Yusho patients and ordinary persons. Hull, l.nvirtui. (Kninm. 11. 213. . Morgan. T. F.. Finley. T. N.. and F'lalkow, H. 11%?I. Comparison of the composition and siiifacc activity of "alveolar" and whole lung lipids in the dog. Hint him At in 106. 4(1? . Naguyuma. ) . Masuda. Y.. and Kuratsunc. M. 1197?) Chloiinaird dihcnrnfuians in Kanechlois and rice oils lived by pulients with Yusho. l ukintkn .4. in Mrtl 66. '93. . Okumuru. M . and Kalsttki. S. < 1969). Clinical ohservaton on Yusho (chlotobiphcnyls poisoning' fiikitnkti A In Afed. 60, 440. . Snilo. R.. Shigcmalsii. N.. and Ishimaru. S. < 19721. Immunoglobulin levels in scrum and sputum ot patients with PCH poisoning. Iiikitoitt At in Mf<l. 63. 347. . Shigemalsu. N., Ishimaru. S.. Hirose. T.. Ikeda. T.. Fmoii. K.. and Miyazaki. N (|9M Clinical and espc i imental studies on nptpitalory involvement tn poisoitmg t H l / nknnkn 3 in W< </ 65. 8H i. Shigemalsu. N.. Ishimuru. S.. Ikeda. T.. and Masuda. Y. (1977). F'urthci studies on tespiratory disorders in polychlorinated biphenyls tK'Bl poisoning. 6H. I?3. . Tstikamoto. If. C 1969). Group of chemical studies on Yusho Ihc chemical studies on detection on toxic compounds in the rive bran oils used by the patients of Yusho. I uknnkti At in \lttl 60. 497 i. Vos. J. t>., and Roi.i. T. I) (1972). Immunosuppressive activity of a polychlorinated biphenyl preparation on the humoral immune respond' in guinea pigs, /.on nl. Appl Winniun nl 21. ?49 i. Yoshimura. H.. and Oshimu. M. 11971). Studies on the tissue distribution ami elimination ol several components of K( -4(K) (chlorohiphenyls) in mice, hiknnko Ai in Mat 62. V I. Yoshimura. H. (1971). Croup of studies on the tissue distribution of PCH; Studies on the tissue distribution and the urinary and lecal excretion of 'H-Kanechioi (chlorohiphenyls) m rats lukunkn A tin Mttl 62, 12. i. Yoshimura. 1. (1971), F.pidcmiologica! analysis of" Yusho" patients with special reference to sex. age. clinical grades and oil consumption, liiknnku At tn Mrtl 62, 104. MQNS 001318