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Since 1985, blood concentrations of polychlorinated quaterphenyls (PCQs), which are congeners that accumulate in the bodies of typical Yusho patients in the same way as PCBs, have been monitored by the Study Group for Yusho. We present here the tendencies and characteristics of blood PCQ concentrations in subjects examined for a possible diagnosis of Yusho from FY 2009 to 2019. The peak patterns of PCBs in the blood tended to be close to those of a typical Yusho patient as the blood PCQ concentration increased. The result of the secular change of PCQ concentration in a typical Yusho patient, suggested that lipophilic PCQ congeners were hardly excreted even in high-exposure cases. Almost all of the blood PCQ concentrations in subjects born after the rice oil poisoning incident were as with those of healthy individuals. Therefore we concluded that PCQ congeners had hardly transferred from Yusho patients to the next generation. The usefulness of blood PCQ concentratio n as a diagnostic criterion for Yusho is still unchanged, and a continuous follow-up survey will be important in the future., 本研究では，厚生労働省油症研究班が実施した2009年から2019年度の油症検診における受診者の血中ポリ塩化クアテルフェニル（PCQ）濃度の傾向及び特徴を把握することを目的とした．検査に用いたPCQ 分析法の精度は良好な結果であり，本分析法は再現性に優れた頑健な方法であることを確認した．2009 年から2019 年度の油症検診で採取したのべ1838 名の血液試料中のPCQ 濃度を解析した結果，血中PCQ 濃度レベルが高いほど，PCB パターンは油症患者のパターンに近いことが示された．また，1986 年から2019 年度にかけて，典型的な油症患者の血中PCQ濃度の経年傾向を観察した．測定開始から約14 年間見られた減少傾向は，2004 年度以降見られず，血中PCQ 濃度は3.9〜8.8ng/g の間で変動していた．事件発生から約50 年経過した現在でも，大量の暴露によって体内に吸収 されたPCQは血中に存在し，排泄されずに残留していることがわかった．ライスオイルによる食中毒事件発生後（1969 年以降）に出生した検診受診者のPCQ 濃度は，検出しないまたは健常者と変わらない濃度レベルであり，次世代へのPCQの移行はほとんどないと考えられた．血中PCQ濃度の油症診断基準としての有用性はいまだに不変であり，今後も継続的な追跡調査が重要である．

We have been measuring the concentrations of PCDDs (polychlorinated dibenzo-p-dioxins), PCDFs (polychlorinated dibenzofurans), and dioxin-like PCBs (polychlorinated biphenyls) in blood collected from Yusho patients in medical health examinations since 2002. The present study extends our previous studies by reporting changes in the concentrations of individual congeners of PCDDs, PCDFs, and dioxin-like PCBs in the blood of Yusho patients from 2004 to 2014. Out of 243 and 246 Yusho patients who received medical health examinations in 2004 and 2014, respectively, there were 118 patients in whom the blood concentrations of these dioxin like-compounds were measured in both years. The concentrations of individual congeners of PCDDs, PCDFs, and PCBs in the blood of these 118 Yusho patients measured in 2004 were compared with those measured in 2014. The total toxicity equivalence (TEQ) concentrations of PCDDs, PCDFs, non-ortho PCBs, and mono-ortho PCBs in the blood of 118 Yusho patients in 2004 and 2014 were 5.2−533 (mean : 80, median : 52) and 11−545 (mean : 78, median : 73) pg TEQ g-1 lipid, respectively. Among the individual congeners of PCDDs, PCDFs, and dioxin-like PCBs, most congeners did not significantly decrease from 2004 to 2014. Though the concentrations of 1,2,3,6,7,8-hexaCDD, 2,3,4,7,8-pentaCDF, 1,2,3,4,7,8-hexaCDF, and 1,2,3,6,7,8-hexaCDF―all considered characteristic congeners in the blood of Yusho patients― decreased significantly from 2004 to 2014, the decreasing ratios of these congeners tended to decrease slightly. These findings suggest that the half-lives of individual congener concentrations of PCDDs, PCDFs and dioxin-like PCBs in the blood are proving to be long to near infinity in the majority of Yusho patients., 平成16および平成26 年度，その両年度に油症検診を受診した118名の血液中ダイオキシン類濃 度の比較を行い，各異性体の濃度推移を調べた．今回調査した異性体の中で，最も濃度が減少して いたのは1,2,3,4,7,8-hexaCDF で，約30％の濃度低下が認められた．油症の主要原因物質である 2,3,4,7,8-pentaCDF は約10％濃度が減少していた．男女間での比較では，女性の方が高い値を示 したが，10 年間の濃度推移に関しては，男女間での相違は認められなかった．

In this study, we analyzed polychlorinated biphenyls (PCBs) in the blood of Yusho patients collected from medical check-ups, which were conducted in 2012. The results show that 65 PCB isomers, not including non-ortho PCBs, were detected in the blood samples, and the total concentration was 620 ng g^ lipid. This value was comparable to the concentration in blood samples collected in 2005, and indicated that PCB concentrations in Yusho patients remained unchanged from 2005 to 2012. Here, we focused onmajor and specific PCB isomers in the blood samples of Yusho patients and normal controls. Examples of the former include hexaCB-153, hexaCB-138, and heptaCB-180, which are detected in human blood, while the latter include hexaCB-156, hexaCB-157, and heptaCB-189, and are highly detected in the blood of Yusho patients. Additionally, we tried to determine why the specific isomers were highly accumulated in the blood of Yusho patients as compared to the normal controls. We therefore analyzed these isomers in the contaminated rice oil, and found that the concentrations of hexaCB-156, hexaCB-157, and heptaCB-189 were 1800, 450, and 190 ng g^, respectively. Notably, previous studies indicated that these isomers m ight not be easily metabolized in humans. Therefore, these findings demonstrated that these isomers were highly accumulated in the blood of Yusho patients., 2012 年に実施したカネミ油症検診において，油症患者から血液を採取して，PCB 分析を実施した．その結果，患者における総PCB 濃度の平均値は620 ng g^（脂肪重量換算）であり，2005年の濃度結果とほぼ同等であった．本研究では，ヒト血液中から高濃度で検出される主要異性体（hexaCB-153，hexaCB-138 及びheptaCB-180）と油症患者の血液から高濃度で検出される特定異性体（hexaCB-156，hexaCB-157 及びheptaCB-189）に注目し，なぜ油症患者に特定異性体が残留しているのか，その原因について調査した．その結果，油症の原因となったライスオイルから，hexaCB-156，hexaCB-157 及びheptaCB-189 が，それぞれ1800，450，190 ng g^で検出され，これらの異性体が極めて高い濃度で含まれていることが明らかになった．また，PCBs 代謝に関する過去の研究報告から，特定異性体は主要異性体とは異なり，代謝されにくい構造を持つ物質であることが示唆された．以上のことから，油症発症から40 年以上が経過した現在でも，特定異性体は油症患者の体内において高いレベルで残留していると考えられた．

BACKGROUND: In 1968, many people developed dioxin poisoning (Yusho) in Japan. Ingestion of 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF) was considered to be the cause of this poisoning. Although some patients had high concentrations of 2,3,4,7,8-PeCDF in their blood, individuals' half-lives of 2,3,4,7,8-PeCDF were long. OBJECTIVES: To evaluate the relationship between clinical and laboratory parameters and the individual half-life of 2,3,4,7,8-PeCDF in blood. METHODS: Clinical and laboratory data were collected during annual check-ups from 2001 to 2008. We enrolled 71 patients, who were measured more than 3 times, and who had 2,3,4,7,8-PeCDF concentrations in blood >50pgg(-1) lipid. The half-life of 2,3,4,7,8-PeCDF for each patient was estimated using linear regression. Moreover, relationships between clinical and laboratory parameters and individual half-life were investigated by linear regression. RESULTS: A shortened individual half-life for 2,3,4,7,8-PeCDF was significantly correlated with an increased red blood cell count, increased viscous secretions from the meibomian glands, existing black comedones, and severe cedar pollen allergy. CONCLUSIONS: Symptoms that accelerate excretion of lipids from the body, such as viscous secretions from the meibomian glands, may lead to a shorter half-life of 2,3,4,7,8-PeCDF. Red blood cells are related to the half-life of 2,3,4,7,8-PeCDF. However, further studies are required to investigate the excretory mechanism of 2,3,4,7,8-PeCDF., 博士（医学）・乙1325号・平成26年3月17日

To elucidate the exposure levels of polychlorinated biphenyls (PCBs) for Yusho patients, we conducted a congener-specific analysis of polychlorinated biphenyls (PCBs) in blood collected from 242, 237, 300, and 96 Yusho patients during medical check-ups performed from 2004 to 2007, respectively, and in samples from 74, 113, 125, and 148 Yusho-suspected persons during those same years, respectively, and compared the individual congener concentrations of PCBs among the groups of Yusho patients, Yusho-suspected persons, and normal controls with the concentrations previously reported. Among the 209 PCB congeners, 8 congeners of mono-ortho PCBs and 56 congeners of non-dioxin-like PCBs were identified in the blood of Yusho patients and Yusho-suspected persons. Among the PCB congeners measured in the present study, hexaCB-153, hexaCB-138, heptaCB-180, and heptaCB-182/heptaCB-187 showed high ratios to total concentrations of 64 PCB congeners detected in the blood of Yusho patients and Yusho-suspected persons from 2004 to 2007, and the profiles of the major congeners were the same as those obtained in normal controls. With respect to the minor congeners of PCBs, several differences were observed among the three groups. The sums of the concentrations of 64 PCB congeners in the blood of Yusho patients from 2004 to 2007 were 645, 760, 667, and 510 ng g-1 lipid for each year, respectively, and the concentrations were 1.5, 1.8, 1.5, and 1.2 times higher than those of normal controls for each year, respectively. Those of the Yusho-suspected persons were approximately 0.8, 1.1, 0.9, and 1.0 times higher than those of normal controls for each year, respectively. The ratios of heptachlorinated biphenyls (heptaCBs) to the total concentrations of 64 PCB congeners in the blood of Yusho patients and Yusho-suspected persons from 2004 to 2007 tended to be slightly higher than those in the normal controls. From the results comparing the concentrations of 64 PCB congeners in the blood between Yusho patients and normal controls, the concentrations of hexaCB-156, hexaCB-157, heptaCB-181, and heptaCB-189 for Yusho patients were 3.4, 3.8, 3.9, and 3.8 times, respectively, 3.9, 4.1, 3.9, and 4.4 times, respectively, 3.6, 3.9, 5.0, and 4.1 times, respectively, and 2.3, 2.5, 2.7, and 2.9 times higher than those of the normal controls for each year from 2004 to 2007, respectively. These results indicated that Yusho patients still have higher concentrations of hexaCB-156, hexaCB-157, heptaCB-181, and heptaCB-189 in their blood than do unaffected people, even though over 35 years have passed since the outbreak of Yusho. These four congeners can therefore be considered to be the most important congeners for evaluating the PCBs exposure of Yusho patients., 平成16年から平成19年度に, それぞれ242,237,300 および96名の油症患者およびそれぞれ74,113,125 および148名の未認定者から採取した血液中PCBの異性体濃度を測定し,一般健常人の結果と比較した．油症患者と未認定者の血液中において, PCB 64 異性体を分離・定量した. 油症患者の血液中, hexaCB-153, hexaCB-138, heptaCB-180 およびheptaCB-182/187 は他と比較して高い濃度を示したが, この結果は一般健常人と同じであった. 平成16 年から19年度に受診した油症患者血液中PCB の64異性体総濃度は, それぞれ645,760,667および510 ng g-1 lipid で, その濃度は一般健常人のそれぞれ1.5, 1.8, 1.5 および1.2倍であった．未認定者の場合, 総PCB濃度はほぼ健常人と同レベルであった. PCB総濃度に対する各異性体の割合を比較した結果, 油症患者と未認定者のheptaCBs 濃度は一般健常人より高かった. 油症患者の血液中64PCB 異性体濃度を健常人と比較した場合, hexaCB-156, hexaCB-157, heptaCB-181 およびheptaCB-189 の濃度は，一般健常人のそれぞれ2.3-3.9, 2.5-4.1, 2.7-5.0 および2.9-4.4倍高い値を示した. 以上の結果から. 油症発症から35 年以上が経過した現在も患者の血液中PCB 濃度, 特にhexaCB-156, hexaCB-157, heptaCB-181 およびheptaCB-189 濃度は以前高いレベルにあり, 油症患者のPCB暴露を評価する上で最も重要な異性体であると言える.

We measured the concentrations of polychlorinated dizenzo-p-dioxins (PCDDs),polychlorinated dibenzofurans (PCDFs),and non-ortho coplanar polychlorinated biphenyls (non-ortho PCBs) in blood collected from 242 Yusho patients and 74 Yushosuspected persons in 2004 and 237 Yusho patients and 114 Yusho-suspected persons in 2005. The sums of toxic equivalents (TEQ) concentrations of PCDDs, PCDFs, and non-ortho PCBs in the blood of Yusho patients in 2004 and 2005 were 126.1 and 124.2 pg TEQ/g lipid, respectively, and the concentrations were 3.4 and 3.3 times higher than those of normal controls that had been previously reported, respectively. Those of the Yusho-suspected persons were about 0.8 and 1.0 times higher than those of normal controls, respectively. Although the TEQ concentrations of PCDDs and non-ortho PCBs among Yusho patients, Yusho-suspected persons,and normal controls were nearly the same,the PCDFs levels of Yusho patients were about 9.8 and 9.5 times higher than those of normal controls in 2004 and 2005,respectively. The concentration of 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8- PeCDF),which was the highest among PCDFs congeners for Yusho patients,was about 10. 6 and 10.2 times higher than that of the normal controls in 2004 and 2005,respectively. In the case of Yusho-suspected persons, the concentrations were 0.9 and 1.4 times higher than those of normal controls, respectively. However, some of the Yusho-suspected persons showed a high concentration of 2,3,4,7,8-PeCDF that was approximately 15 times greater than concentrations in normal controls. Of 74 Yusho-suspected persons measured in 2004, 7 persons were officially registered as Yusho patients based on the “New Diagnostic Criteria”that officially became the diagnostic criteria for Yusho exposure on September 29,2004,which included a concentration of 2,3,4,7,8-PeCDF in the blood,and in 2005, 14 persons of 114 Yusho-suspected persons were officially registered as Yusho patients., 平成16年度に日本在住の242名の油症患者と74名の未認定者および平成17年度に日本在住の237名の油症患者と114名の未認定者から採取した血液中のPCDDs，PCDFs，およびnon-orthoPCBs濃度を測定し，平成15年度に測定した一般健常人の結果と比較した．平成16および17年度に受診した油症患者の血液中PCDDs，PCDFs，およびnon-ortho PCBsの総toxic equivalents(TEQ） 濃度は，それぞれ126.1および124.2 pg TEQ/g lipidで，その濃度は一般健常人のそれぞれ3.4倍および3.3倍であった．未認定者の場合，総TEQ濃度は，それぞれ一般健常人の0.8倍および1.0倍であった．油症患者の血液中PCDDsおよびnon-ortho PCBs濃度は，ほぼ健常人と同レベルなのに対し，PCDFs濃度は一般健常人のそれぞれ9.8倍（平成16年）および9.5倍（平成17年）高い値を示した．油症患者の血液中PCDFs異性体間で特に高濃度を示す2,3,4,7,8-pentachlorodibenzofuran（2,3,4,7,8-PeCDF）は，健常人のそれぞれ10.6倍（平成16年）および10.2倍(平成17年）高い値を示した．未認定者の2,3,4,7,8-PeCDF 濃度は，健常人のそれぞれ0.9 倍および1.4倍であった．しかしながら，未認定者の中には一般健常人と比較して異常に高い2,3,4,7,8-PenCD 濃度を示す人が数名認められた．これまでに行った追跡調査の結果を基に，2,3,4,7,8-PenCDF濃度を追補した新しい診断基準が平成16年９月29 日に策定され，平成16年度に受診した74名の未認定者のうち７名が，平成17年度も114名の未認定者のうち14名が新たに油症認定者と診定された．

水酸化ポリ塩化ビフェニル(OH-PCBs)は，人体内におけるPCB の主要代謝物である．OH-PCBs は体内でチトクロームP450酵素誘導によりPCBから生成され，油症認定患者の血清から390-1300pg/gの濃度で検出された報告がある．2010年度に183名の油症患者から採取した血液中のOH-PCBs濃度を測定し，これら化合物の濃度を比較した．主要なPCBの代謝物は，4-OH-CB187(ND-1300 pg/g-wet)，4-OH-CB146 + 3-OH-CB153(8.4-1200 pg/g-wet)，4-OH-CB109(ND-530 pg/g-wet)，4'-OH-CB172(ND-380 pg/g-wet)であり，その合計は36-3800 pg/g-wetであった．また，OH-PCBsとPCB濃度には正の関係が認められたが，OH-PCBsとPCDD/DFsの濃度には有意な関係は認められなかった．, Hydroxylated polychlorinated biphenyls (OH-PCBs) are formed as major metabolites of PCBs by cytochrome P450 enzyme-mediated oxidation. It has been reported that their total concentration in serum samples of Yusho patients ranged from 390 to 1300 pg/g. We measured the concentration of OH-PCBs in blood collected from 183 Yusho patients living in Japan in 2010. The major OH-PCB metabolites were 4-OH-CB187 (ND-1300 pg/g-wet), 4-OH-CB146 + 3-OH-CB153 (8. 4-1200 pg/g-wet), 4-OH-CB109 (ND-530 pg/g-wet) and 4'-OH-CB172 (ND-380 pg/g-wet). The total OH-PCBs ranged from 36 to 3800 pg/g-wet. A positive relationship between the concentrations of OH-PCBs and PCBs was observed, but no significant relationship between the concentrations of OH-PCBs and PCDD/DFs was observed.

Hydroxylated polychlorinated biphenyls (OH-PCBs) are formed as major metabolites of PCBs by cytochrome P450 enzyme-mediated oxidation. It has been reported that their total concentration in serum samples of Yusho patients ranged from 390 to 1300 pg/g. We developed a measurement method for OH-PCBs in blood samples by LC/MS/MS. This method is effective at determining the concentrations of PCDDs, PCDFs, Co-PCBs and OH-PCBs from the same sample without special treatment of the sample. The concentration of OH-PCBs in the blood of Yusho patients was examined using this method. The major OH-PCB metabolites were 4-OH-CB187 (54-906 pg/g-wet), 4-OH-CB146 + 3-OH-CB153 (32-527 pg/g-wet), 4-OH-CB109 (ND-229 pg/g-wet) and 4'-OH-CB172 (ND-143 pg/g-wet). The total OH-PCBs ranged from 95 to 1740 pg/g-wet., 水酸化ポリ塩化ビフェニル（OH-PCBs）は，人体内におけるPCB の主要代謝物である．OH-PCBs は体内でチトクロームP450 酵素誘導によりPCB から生成され，油症認定患者の血清から390-1300pg/g の濃度で検出された報告がある．OH-PCBs の測定法に関し，従来の分析法では複雑な前処理を必要としていたが，測定装置にLC/MS/MS を用いることで，前処理の簡略化を達成した．本法の利点は，従来から測定を行っているダイオキシン類分析用の血液試料から，OH-PCBs を分離することで，OH-PCBs の分析のために新たに血液試料を確保する必要が無いことである．油症認定患者の血液を用いて，本法に基づいて分析した結果，主要なPCB の代謝物は，4-OH-CB187（54-906 pg/g-wet），4-OH-CB146 + 3-OH-CB153（32-527 pg/g-wet），4-OH-CB109（ND-229 pg/g-wet），4'-OH-CB172（ND-143 pg/g-wet）であり，その合計は95-1740 pg/g-wet であった．