Search

Objectives: Toxins, such as PCBs, dramatically affect patients even decades after exposure. Although 40 years have passed since the accidental poisoning with polychlorinated biphenyl (PCB) in Western Japan in 1968, high concentrations of PCBs are still detected in the serum of the "Yusho" (oil disease) patients. In this study, an epidemiological examination was carried out to reveal the prevalence of the oral pigmentation and blood concentrations of PCBs and polychlorinated quaterphenyl (PCQ) in Yusho victims., Design: We performed a group examination of patients (Yusho victims) from 2004 to 2006, including 72 Yusho victims and 15 control subjects. The oral examination was performed by two oral and maxillofacial surgeons. The serum concentrations of PCB and PCQ were determined using gas chromatography; blood samples from Yusho victims were analyzed for PCB and PCQ by saponification in 1M NaOH ethanol solution, extraction with n-hexane column chromatography on silica gel, and then gas chromatography with electron capture detection., Results: The mean Yusho victim's serum PCB and PCQ concentrations were 3.3ppb and 0.9ppb, respectively. In controls, these were 0.7ppb and 0ppb, respectively. Oral pigmentation was observed in 24 out of 72 Yusho patients. In controls, oral pigmentation was observed in one out of 15 persons. Oral pigmentation was most frequently observed in the buccal mucosa, followed by gingival mucosa. The blood concentration of PCB in Yusho patients with oral pigmentations was significantly higher than that in Yusho patients without oral pigmentation., Conclusion: These results indicated that PCB-related compounds may be responsible for the higher prevalence of oral pigmentation in Yusho victims, even though a long time has passed since the Yusho poisoning accident., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

We performed PCB congener specific analysis using HRGC/HRMS and determined their concentrations and blood chromatogram classifications in 275 individual blood samples collected during annual Yusho examinations between 2007 and 2010. When both blood total PCB concentrations and blood chromatogram classifications were compared among eleven Yusho patients undergoing examinations between 2007 and 2010, the longitudinal concentrations and classifications in the respective individuals hardly changed over these years. In a subset of persons suspected of Yusho, it was found that the mean total blood concentrations of three index congeners, that is, 2, 3', 4, 4', 5-pentaCB (PCB118), 2, 2', 4, 4', 5, 5'-hexaCB (PCB153), 2, 3, 3', 4, 4', 5-hexaCB (PCB156) and mean blood total PCB concentrations gradually decreased between 2007 and 2010. Mean concentration of PCB118 in blood from persons suspected of Yusho was calculated as 0.035 ng/g in the 2010 examination, which was 36% lower than the mean value of 0.054 ng/g in the 2007 examination: the concentration of PCB118 showed the highest degree of decrease among the three index congeners. Among persons suspected of Yusho, occupational rates of persons with blood PCB concentrations below one ppb in the entire population increased from approx. 50% in 2007 to approx. 70% in 2010. The lowest concentration of PCB156 in blood of persons suspected of Yusho in 2010 was 0.43 pg/g, which was almost equivalent to the limit of the determination value on HRGC/HRMS, S/N = 10.

Forty years have passed since the accidental poisoning with polychlorinated biphenyls (PCB) in Japan in 1968, named Yusho. High concentrations of PCB are still detected in the serum of the Yusho victims. PCB produces superoxide (O(2) (-)) in the metabolic process and we reported high concentrations of serum nitrite, a stable metabolite reflecting nitric oxide (NO), in the Yusho victims. NO reacts with O(2) (-) and immediately produces peroxynitrite (ONOO(-)). ONOO(-) causes nitration of tyrosine residues and produces nitrotyrosine (NT). Therefore, we measured urinary concentrations of nitrite and NT in the victims and age-matched controls. The mean urinary concentrations of nitrite and NT were significantly higher than in the controls. There was a positive correlation between urinary nitrite and NT in the Yusho victims. Furthermore, there was a positive correlation between the ratio of urinary NT to nitrite and serum PCB concentrations in the Yusho victims. It was considered that the emergence of some ailments could be presumed to have been caused by high levels of urinary nitrite and NT in the Yusho victims.

Background: Kanemi Yusho was a food poisoning incident caused by rice bran oil that occurred in western Japan, particularly in northern Kyushu, in 1968. It is difficult to determine the symptoms in patients after many years since the occurrence. Techniques for measuring blood dioxins have advanced recently. More accurate data measurement has now become possible, and techniques for mass data analysis, such as data mining, have also advanced. It has also become possible to find unknown characteristics, even in an object group with elusive characteristics, by checking all the combinations in all the patients., Aim: There are already several reports on the incidence of symptoms in Yusho patients. These reports are limited to symptoms in a single period, and there has been no analysis taking into account the time that has elapsed. Here, we evaluated the relationship between recent and past symptoms and 2,3,4,7,8-penta-chlorodibenzofuran (PeCDF) levels in the same subject patient, in order to demonstrate the correlation between PeCDF levels and symptoms at a time point close to the incident., Methods: Subjects were examined for symptoms of Yusho and had blood PeCDF levels measured, both recently and in the past. Combinations were extracted using association analysis of data mining technique for comparison, which had strong correlations between the presence or absence of symptoms in the medical examination, tests including blood test, dermatological examination, dental examination and ophthalmologic examination in recent years (2001-2004) and the blood PeCDF levels and those between the presence or absence of past (1986-1989) symptoms and recent blood PeCDF levels., Results: Subjects with higher PeCDF levels were more likely to present with pigmentation, a symptom included in the diagnostic criteria for Yusho. Pigmentation was a commonly found symptom in the past. Past pigmentation was a common symptom in the present., Discussion: PeCDF levels were measured recently and therefore should not be compared directly with past symptoms. However, among the symptoms included in the diagnostic criteria, past symptoms tended to have a stronger relationship with PeCDF levels than did recent symptoms. We suggest that the present PeCDF level is strongly related to the past symptoms since the present PeCDF level is correlated with the past PeCDF level due to constant emission rate. More specifically, if the past PeCDF level is strongly related to the past symptoms, it can indirectly be concluded that the present PeCDF level is also strongly related to the past symptoms. Thus, the present PeCDF level cannot be related to the past symptoms directly but can indirectly., Conclusions: Combining recent and past symptoms further demonstrated that clinical symptoms are strongly related to PeCDF toxicity. This may have resulted from the increase in symptoms with aging, however, it was demonstrated that the symptoms of each patient were relieved and become obscure.

An epidemiologic examination was carried out to reveal the prevalence of the periodontal diseases and oral pigmentation in patients with Yusho in 2006. The results obtained were as follows. (1) 98 patients out of 106 patients with Yusho, who were measured periodontal pocket depth according to Ramfjord' methods, had at least one tooth with periodontal pocket deeper than 3 mm. Similarly, 343 teeth out of a total 494 examined teeth showed periodontal pocket with more than 3 mm depth. (2) Oral pigmentation was observed in 61 patients out of 116 patients with Yusho. In this study, gingival pigmentation was most predominant among oral pigmentation. The prevalence of oral pigmentation in male patients seemed to be somewhat higher than that in female patients. In addition, this examination revealed that the patients below the age of sixty had a high prevalence of oral pigmentation. These results indicated that PCB-related compounds may be responsible for the higher prevalence of both periodontal diseases and oral pigmentation.

We analyzed sixty-eight PCB isomers and determined their concentrations and characteristics in fifty-eight individual blood samples collected during the annual Yusho inspection in 2006. The method used in this study consists of a rapid GPC clean-up and sensitive PCB isomer-specific identification with HRGC/HRMS. As a result, the highest total PCB concentration in inspected subjects was 6.6 ppb on a blood weight basis, which was 8.1 times higher than that of a control blood sample. When blood PCB patterns were compared among twenty-seven persons in undergoing examinations both 2004 and 2006, the longitudinal classifications in the respective individuals hardly changed between these years. Mean concentrations of each PCB isomer in the blood of pattern A subjects (n=4) were compared with those in the blood collected from Fukuoka prefecture residents (n=127). Consequently, the respective blood concentrations of PCB #157, #156, #189, #137, #195, #170, #99 were obviously higher than those of Fukuoka residents, while those of PCB #118, # 05 was evidently lower than those of Fukuoka residents.

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 Yusho-suspected 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.

Background: Kanemi Yusho is the name given to a 1968 food poisoning incident resulting from the ingestion of PCB contaminated rice bran oil that had been used as a heating medium. At the time, victims presented with mainly cutaneous manifestations and various other symptoms such as of the eyes and teeth, general fatigue, headaches, and paresthesia of the extremities. The characteristic symptoms then resolved with time. Yusho patients have been followed from immediately after the incident. Blood levels of dioxins such as PeCDF have been measured for those who wishing to since 2001., Subjects and Methods: The presence or absence of relationships between blood PeCDF level and various examination items/symptoms was investigated in 359 subjects whose blood levels of PCB-related chemical compounds such as PeCDF were measured in the Yusho related examinations between 2001 and 2003. Characteristic symptoms were also compared with the results of examinations done 15 years previously., Results and Discussion: The average blood 2,3,4,7,8-PeCDF level in designated Yusho patients was 177.50 pg/g lipids; showing a markedly higher value than that of the normal control group (15.2 pg/g lipids). As well, the blood PeCDF level was related to PCB level, hexachlorobiphenyl level, urinary sugar, erythrocyte sedimetation rate (ESR) (2-hour), thymol and Na. There were also relationships with cutaneous findings (acneiform eruption and comedones), mucosal findings (oral pigmentation), constipation, numbness in the extremities, body weight loss, and abnormal abdominal ultrasonography. Symptoms seen in the skin and eyes in 2001 and 2003 had decreased compared with those in seen 1988. However, PCB and blood PeCDF levels remained high. Patients are continuing to present with mucosal and subjective symptoms as chronic conditions.

A nation-wide questionnaire survey on the past history of diseases and symptoms was conducted in 2005. The questionnaire was administered by mail to the 1258 registered Yusho patients, inguiring about the past incidence of 15 regions of malignant neoplasm, 42 diseases, and 5 symptoms. Out of the 717 patients responded to the questionnaire, 34 patients born after the Yusho outbreak were excluded, leaving 683 patients as the study subjects. Their mean age (SD) was 62.7 (14.0) years, ranging from 39 to 97 years old. Seven percent of the patients acknowledged the past history of malignant neoplasm in one or more regions. More than 40% admitted the past history of dental diseases, pain of joints, numbness of limbs, fatigue, headache, cough and sputum. Osteoporosis and myoma of the uterus, respectively, were reported by 22.8% and 15.6% of women. 14.2% of men reported prostatic hypertrophy. Logistic regression analysis was performed to estimate the association of the past history of diseases with the blood lipid level of 2,3,4,7,8-pentachlorodibenzofuran adjusting for sex and age. In the whole study subjects, 306 patients were measured the PeCDF level once or more in the years from 2001 to 2005. We found statistically significant elevation of the proportion of the patients with the past history of prostatic hypertrophy with increasing blood lipid level of 2,3,4,7,8-PeCDF (P = 0.03). The marginally significant positive association between the proportion of the patients with the past history of hypertension and 2,3,4,7,8-PeCDF was observed (P = 0.06).

In this study, we examined the dioxin levels and congener distributions in blood samples of Yusho patients and normal control subjects, especially in relation to the respective exposure routes. Remarkable differences were observed between the blood of Yusho patients and general population in terms of both congener distributions and concentration levels. Cumulative dioxin intake for Yusho patients was estimated using the mean Yusho oil consumption and congener-specific dioxin contamination data for Yusho oil; for control subjects, it was estimated from food consumption and dioxin congener contamination data. Estimated total intake of dioxins was 2.44 microg-TEQ for control subjects and 357 microg-TEQ for Yusho patients, respectively. The total intake of some congeners such as 2,3,4,7,8-PeCDF and 1,2,3,4,7,8-HxCDF for Yusho patients was more than 100 times higher than those of control subjects. The congener distribution of PCB and PCDD in the blood of control subjects was similar to those of the food. In the case of Yusho patients, however, the congener distribution did not resemble those of either the food or the causal Kanemi rice oil, nor did not match that of control subjects' blood. Selective metabolizing of congeners was suggested to have occurred in the Yusho patients. In a 2001 fiscal year survey, the concentration ratio of TEQ between Yusho and normal subjects was 4.5. However, the level of 2,3,4,7,8-PeCDF, thought to be the congener that had the closest relation to various symptoms of the Yusho patients, was ten times or more in Yusho patients than in controls. It is suggested that further examinations should be conducted in the future to follow up this survey monitoring the blood levels of toxic congeners in Yusho patients.

Polychlorinated biphenyls (PCB) causes the release of superoxide during the metabolic process. Therefore, Yusho victims are thought to be exposed to oxidative stress caused by PCB, because high concentrations of PCB are still detected in the serum of Yusho victims. Recently, total antioxidant power (TAP) has been proposed as one of excellent markers of defense capacity against oxidative stresses. In order to estimate the antioxidant capacity in Yusho victims, we measured serum TAP in certified Yusho victims and age-matched noncertified subjects. The mean values of serum TAP were 0.479 +/- 0.017 in certified Yusho victims and 0.397 +/- 0.013 microM in non-certified subjects, respectively. There was a significant difference in the serum values of TAP between certified Yusho victims and uncertified subjects. TAP was reported to increase in the case of severe oxidative stress and PCB can give rise to an oxidative stress in Yusho victims. Therefore, it was supposed that TAP could increase in the oxidative stress of Yusho probably by some negative feedback mechanisms. The exact mechanism is still unclear, and further examinations should be conducted in the future.

Polychlorinated biphenyls (PCBs) are known to cause the release of superoxide during the metabolic process. Therefore, it is suggested that the Yusho patients are exposed to oxidative stress caused by high concentrations of PCBs are still recorded in their serum. Recently, diacetylspermine (DiAcSpm) has been proposed as tumor markers or barometer of oxidative stresses. In order to estimate the ability of urinary DiAcSpm as a potential marker of dioxin or PCB exposure, we measured urinary DiAcSpm in Yusho patients and assessed the association of DiAcSpm with serum PCBs and dioxins levels. The statistical analysis did not indicat that urinary DiAcSpm is useful for detection of exposure to PCBs or dioxins, although a few Yusho patients showed high level of DiAcSpm.

We measured serum aldolase levels in Yusho sufferers annually between the years 2000 and 2005. We observed a decrease in serum aldolase levels in 47.7% of the patients studied. We researched the relations among serum aldolase, serum creatine kinase, blood polychlorinated biphenyls, blood polychlorinated quaterphenyls, blood polychlorinated dibenzofurans and toxic equivalent quantity statistically. We conclude that a high concentration of blood polychlorinated biphenyls might play a role in the decrease of serum aldolase levels in Yusho sufferers.

In the Yusho medical checkup, measurement of dioxin has been performed since 2001. Although the time trend of dioxin concentrations in blood from 2001 to 2005 has been reported for the whole measurement candidate, details in the trend are not known. Therefore, to verify the trend, we divided the Yusho patients into four quatertile groups based on the dioxin concentrations. About 39 years have passed since Yusho occurred, and it is said that a big change in the concentrations of 2,3,4,7,8-PeCDF in blood is now no longer seen. However, when the Yusho patients were divided into the four groups, a downward tendency was even now found in the higher dioxin groups, but not in the lower dioxin groups.

We evaluated the severity grades and the skin severity scores of the skin symptoms who visited the annual examinations of Fukuoka prefecture in 2003 and 2004. The severity of skin symptoms improved significantly in the first 20 years; nowadays, however, further improvement can hardly be observed. More than 36 years have passed since the Yusho incident, and about 60% of the patients currently present no skin symptoms. In contrast, in about 40% of the patients, characteristic skin symptoms of Yusho, such as pigmentation of skin, black comedones and acneform eruptions, could still be observed. Using Peason's correlation coefficient test and Spearman's correlation coefficient test, we analyzed correlation between "PCB pattern" and the blood PCB concentration, the skin severity grade and the skin severity scores. However, we could not find out any obvious correlation.

We measured the concentrations of polychlorinated dizenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and non-ortho-coplanar polychlorinated biphenyls (Co-PCBs) in blood collected from 279 Yusho patients and 92 Yusho-suspected persons living in Japan in 2002, 269 Yusho patients and 74 Yusho-suspected persons living in Japan in 2003 and 128 normal controls living in Fukuoka Prefecture, and compared with the concentrations of these compounds among the groups. The total TEQ concentrations of PCDDs, PCDFs, and Co-PCBs in the blood of Yusho patients were 3.6 times and 3.3 times higher than those in the normal controls in 2002 and 2003, respectively. In the case of Yusho-suspected persons, the concentrations were 1.1 times and 1.0 times higher in 2002 and 2003, respectively. Among the TEQ concentrations of PCDDs, PCDFs, and Co-PCBs, the concentrations of PCDFs in the blood of Yusho patients were 10.3 times and 9.4 times higher than those of the normal controls in 2002 and 2003, respectively, whereas the concentrations of PCDDs and Co-PCBs in blood were identical in Yusho patients, Yusho-suspected persons and normal controls. Yusho patients indicated the highest concentrations ratio of PCDFs to the total TEQ concentrations. Moreover, of the PCDFs congeners for Yusho patients, the concentrations of 2,3,4,7,8-PeCDF were about 11.0 times and 10.1 times higher in 2002 and 2003 than those in normal controls. These results indicated that Yusho patients have a much higher concentration of 2,3,4,7,8-PeCDF in their blood than do unaffected persons even though over 34 years have passed since the outbreak of Yusho.

The aim of the present paper is to summarize the history of the Yusho incidence that occurred in the western part of Japan in 1968. A strange disease was reported in October 1968. This strange disease was characterized by acne-like eruptions, pigmentation of the skin, and eye discharge, and it was named Yusho (oil disease). Through systematic epidemiological studies based on observation of initial case series, and extensive efforts to clarify causal agents by the Study Group for Yusho, it was concluded that Yusho was caused by ingestion of rice oil contaminated with PCBs and PCDFs. As of now, more than 1,800 patients, have been registered as having Yusho and around 300 are deceased. Clinical observation showed that typical symptoms of Yusho have decreased, even general fatigue, headache and numbness of extremities have still been complained by patients. No effective treatment has been found so far. Careful and systematic observation for Yusho patients and medical care services should be continued for a further understanding of Yusho.

An epidemiologic examination was carried out to reveal the prevalence of the periodontal diseases and oral pigmentation in patients with Yusho. The results obtained were as follows. 1) 95 patients out of 110 patients, who were examined periodontal pocket depth using Ramfjord' methods, had at least one tooth with periodontal pocket deeper than 3 mm. Similarly, 276 teeth out of a total 495 examined teeth showed periodontal pockets with more than 3 mm depth. However, the ratio of the teeth with periodontal pockets deeper than 4 mm to total examined teeth in each age fell to less than 25%. 2) Oral pigmentation was observed in 75 patients out of 121 patients with Yusho. In this examination, gingival pigmentation was most predominant among oral pigmentation. It is of particular interest that severe pigmentation tended to be observed at a much higher frequency in younger patients with Yusho. Taken these findings into consideration, it was suggested that PCBs and related compounds might play an important role in the development of both periodontal diseases and oral pigmentation.

We examined the association between blood PCB level and the serum concentrations of total cholesterol, high-density lipoprotein cholesterol and triglycerides. The data was retrieved from the dataset of the nationwide health examination for Yusho patients. We longitudinally analyze the laboratory data of the officially identified Yusho patients who underwent the health examination in Fukuoka and Nagasaki prefectures five times or more during the years from 1986 to 2000. For the longitudinal analysis, the generalized estimating equation model was used adjusting for the age as of 1986, the year of taking the health examination, smoking and drinking habits, body mass index and the site of the examination (Fukuoka or Nagasaki). Ten-fold increase in blood PCB level was associated with the elevation in serum concentration of total cholesterol by 18.4 mg/dL (95% CI, 7.8 to 29.0, P < 0.001) in men and 19.7 mg/dL (95% CI, 8.3 to 31.2, P < 0.001) in women, and the elevation of serum concentration of triglycerides by 43.4% (95% CI, 17.5 to 74.9, P < 0.001) in men and 42.8% (95% CI, 25.7 to 62.1, P < 0.001) in women. Association of blood PCB level with serum concentration of high-density lipoprotein cholesterol was not statistically significant in both men and women. Hypercholesterolemia is a well known risk factor of coronary heart disease. It might be suggested that the high blood PCB level in Yusho patients has some possible health effects on the incidence of coronary heart disease.

Follow-up survey of the blood concentration of polychlorinated dibezo-p-dioxin (PCDDs), polychlorinated dibenzofuran (PCDFs), Non-ortho-coplaner PCBs (Non-Co-PCB), and Mono-ortho-coplaner PCBs (Mo-Co-PCB) in Yusho patients is very important for their health control. We determined the blood concentration of these dioxin-like isomers in 78 blood samples collected in 2001 using by a high-resolution gas chromatograph/high-resolution mass spectrometer (HRGC/HRMS) equipped with a solvent-cut large volume injection system (SCLV). The accelerated solvent extraction (ASE) method was employed for the treatment of blood samples. The method employed here can allow a reduced amount of blood collecting from Yusho patients compared with the conventional method. In typical Yusho patients (Group A of PCB pattern), the mean TEQ concentrations of PCDDs, PCDFs, Non-Co-PCBs, and Mono-Co-PCBs in blood collected in 2001 were 36, 260, 9.3, and 64 pg-TEQ/g lipid, respectively. As well, the toxic contribution of PCDDs, PCDFs, Non-Co-PCBs, and Mono-Co-PCBs in typical Yusho patients (Group A of PCB pattern) were 10, 70, 3, and 17% of the total TEQ value, respectively. The toxic contribution rate of PCDFs TEQ was still at high levels in relation to total TEQ in typical Yusho patients as mention above. The Yusho patients showing B pattern also had the same A pattern contribution rate. In the patients of group C, however, the mean blood levels of dioxin TEQ in 2001 was two times those of the normal controls determined in 2000 in Fukuoka prefecture. As well, the contribution rates were similar to those of normal subjects, although some patients in this group showed a high toxic contribution rate of PCDFs TEQ in relation to total TEQ. Thirty-three years had passed since the Yusho accident, and the total blood concentrations of PCDFs in the blood of Yusho patients were still higher than those of normal subjects. Among the different groups of PCB patterns, the concentration of 2,3,4,7,8-PeCDF, 1,2,3,4,7,8-HxCDF and 1,2,3,6,7,8-HxCDF showed significant differences. These findings indicate that these isomers are not metabolized in the human body since traces of them continued to be detected in these patients since they had been contaminated by the rice oil in the original incident.

Thirty-five years have been passing since the outbreak of Kanemi rice oil poisoning, namely, Yusho in the western Japan. However, even now the patients with Yusho have been still suffering from several objective and subjective symptoms. In order to improve or, if possible, to cure the such symptoms, the most important therapeutic treatment is considered to actively excrete the most toxic causative PCDFs/DDs congeners, that is, 2,3,4,7,8-pentachlorodibenzofuran (PenCDF) and 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HxCDD) from the bodies of the patients and to reduce their body burdens. In rats, dietary fiber and chlorophyll have been shown to promote the fecal excretion of dioxins and to reduce their levels in rat liver. In this study, we examined whether such kinds of effect were also observed by FBRA, which was the health food and relatively rich with dietary fiber and chlorophyll in nine married Japanese couples. As a result, concentrations of PenCDF and HxCDD on the lipid weight basis in the blood of the FBRA-intake group in which they took 7.0 to 10.5 g of FBRA after each meal and three times a day for one year were more lowered than those in the blood of the non-intake group; Blood levels of PenCDF and HxCDD in the FBRA-intake group were decreased by 30.5 and 33.9%, respectively, and those decreases were 22.0 and 24.5% in the non-intake group. Their total body burdens just before and one year after the study were calculated on the assumptions that the body fat was also contaminated with these congeners at their blood levels on the lipid weight basis and the content of body fat was 20% of the body weight. Then, we computed the average amounts in excretion of PenCDF and HxCDD from the body in both the FBRA-intake and non-intake groups. Consequently, the amounts of excretion of PenCDF and HxCDD in the FBRA-intake group were 2.1 and 1.9 times, respectively, greater than those in the non-intake group. Therefore, FBRA seemed to promote the fecal excretion of PenCDF and HxCDD, the main causative PCDFs/DDs congeners of Yusho, from the human body. We also expect FBRA to reduce their body burdens of patients with Yusho and to improve some objective and subjective symptoms of Yusho patients.

Concentrations of polychlorinated biphenyl (PCB) congeners, hexachlorobenzene (HCB) and dichloro dichlorophenyl ethylen (DDE) in the blood of Yusho patients (n = 28) were statistically compared with those in the blood of Fukuoka residents (n = 151). The PCB concentrations in the blood of Yusho patients were higher than those of Fukuoka controls and concentration ratios of Yusho/Control were various depending on PCB congeners, being 1.6 on 2,3',4,4',5-pentaCB (# 118), 17.5 on 2,3,3',4,4',5-hexaCB (# 156) and 5.4 on total PCBs. Correlation coefficients between age and concentrations of 7 PCB congeners, HCB and DDE in the blood of Fukuoka residents were significantly positive each other (p < 0.001), while in Yusho patients, the correlation coefficients were positive but various depending on the congeners. However, correlation coefficient between PCB # 118 and PCB # 156 in the Yusho patients was remarkably low, indicating their peculiar accumulative properties in Yusho patients. The concentration of PCB # 118 had been markedly decreased after the ingestion of PCBs and would be metabolized to hydroxylated PCB, which might cause estrogen disturbance in the Yusho patients.

We evaluated the severity grades and the skin severity scores of the skin symptoms of Yusho patients who visited the annual examinations in 2001 and 2002. The patients who participated in the examinations had been decreased gradually. However, because of enhancement of social interest, the number of the patients who visited the examination increased. The pattern of the severity grades and the severity scores was different from that of the past. A careful follow-up and analysis is required.

As of January 31, 1996, 292 deaths among registered patients of Yusho were identified by three follow-up studies conducted in 1986, 1990, and 1996. In this study, we attempted to identify underlying causes of death by linkage of the registered data to the National Vital Statistics Data provided by the Management and Coordination Agency of Japan, which included 15 million deaths between 1978 and 1996. The two datasets were linked by matching for six variables; birth year/month/day, death year/month, and sex, along with a variable of death day or death place, or both. The matched cases were 203 among 235 deaths between 1978 and 1996 (matching rate was 86%). Among the 203 deaths, 58 underlying causes of death were newly identified, 146 causes of death were already grasped by the follow-up studies, and 31 deaths did not have matching pair in the National Vital Statistics data. Among the 146 deaths, 110 causes of death were concordant with each other, however, 35 causes of death were completely discord. The reason of the discordance and the unmatched deaths might be due to difference in information of the matching variables in the two datasets. In order to conduct an efficient follow-up study of Yusho patients, identification of underlying causes of death by linkage to the National Vital Statistics Date is evitable. For that, we need to substitute basic information in the Yusho database to those compatible to the National civil registration system.

An epidemiologic examination was carried out to reveal the prevalence of the periodontal diseases and oral pigmentation in patients with Yusho in 2000. The results obtained were as follows. 1) 63 patients out of 69 patients with Yusho, who were measured periodontal pocket depth according to Ramfjord' methods, had at least one tooth with periodontal pocket deeper than 3 mm. Similarly, 188 teeth out of a total 285 examined teeth showed periodontal pocket with more than 3 mm depth. 2) In this examination, intraoral sinus tracts stoma were observed in 9 patients out of 70 patients. Radiographic examination and probing examination of pocket depth indicated that periapical lesions were involved in these intraoral sinus tract formation. 3) Oral pigmentation was observed in 46 out of 76 patients with Yusho. In this study, gingival pigmentation was most predominant among oral pigmentation. These results indicated that PCBs had yet affected the mechanism of oral pigmentation and metabolism of alveolar bone.

To examine the association between blood PCB level and manifestations of symptoms and signs by Yusho patients, a cross-sectional study was conducted using the results of nationwide health examination for Yusho. The subjects were the officially identified Yusho patients who admitted the health examination from 1986 to 1997. The number of examinees with known blood PCB level was 334 in 1986, and decreased to 214 in 1997. The numbers of male and female patients were similar. The geometric mean (95% confidence interval) of blood PCBs concentration was 4.05 ppb (3.75 to 4.37) in 1986 and 2.85 ppb (2.63 to 3.08) in 1997. Multiple logistic regression analysis was carried out for the data of each year with log-transformed blood PCB level as an explanatory variable and a manifestation of a sign or symptom as a response variable. Sex and age adjusted odds ratio and significance level (P) were computed. Positive association of blood PCB level with manifestations of comedones on the trunk and acneiform eruptions on the genital and gluteal regions was statistically significant for five, eight and six times, respectively. No other symptoms or signs showed such strong associations. Associations between manifestations of these signs and blood PCB level, however, did not seem to diminish in the twelve years of observation. It is suggested that the positive association of these signs with blood PCB level will still be maintained.

A cross-sectional study on the association between the results of blood test and the blood concentration of PCB was conducted on the chronic Yusho patients. The subjects were 265 Yusho patients (134 men and 131 women) who received the annual nationwide health examination for Yusho in 1993. The results of the blood test and questionnaire survey at the annual health examination were used for the analyses using ANCOVA. Serum levels of triglycerides, total cholesterol, GOT, GPT, gamma-GTP, total bilirubin, and conjugated bilirubin were associated with the blood concentration of PCB adjusting for sex, age, drinking habit, smoking habit and body mass index (BMI). Because the distribution of the serum levels was strongly skewed to the right except that of serum concentration of total cholesterol, they were log transformed to approximate to the Normal distribution. The association between age and the blood concentration of PCB was significant (P < 0.001), although the associations of sex, drinking habit, smoking habit and BMI to the blood concentration of PCB were not significant. With the adjustment for sex, age, drinking habit, smoking habit and BMI, the serum concentrations of triglycerides and total cholesterol were significantly associated with the blood PCB level expressed by loge (blood concentration of PCB in ppb-1) (P = 0.02 and P < 0.001, respectively). The associations of serum levels of GOT, GPT, gamma-GTP, total bilirubin and conjugated bilirubin to the PCB level were not significant. The results of this study suggests the need of careful observation on the serum lipids of Yusho patients, especially those with high concentration of blood PCB, because the serum concentrations of total cholesterol and triglycerides are prominent risk factors of heart diseases.

We analyzed the severity grades of the skin symptoms of Yusho patients who visited the annual examinations in 1997 and 1998. The severity grades of the skin symptoms clearly improved. The patients graded as 0 I-II increased and those graded as II III-III decreased as compared to the data in 1993 and 1994. The skin severity scores did not change much, although the patients who showed 0 or 1 reached more than 60% in both 1997 and 1998. The blood PCB concentration of Yusho patients also clearly decreased, especially in the patients who showed "A" pattern.

All PCB congeners were analyzed by high separation gas chromatography/low resolution mass spectrometer, using 209 PCB congeners as standards. They were separated into 169 peaks, including 28 peaks containing 2 PCBs and 8 peaks containing 3 PCBs. The rice oil samples of Fukuoka and Taiwan Poisonings were analyzed for PCB congeners. They showed 115 separated peaks of PCB congeners. Total PCB concentrations were 879 and 769 ppm in 2 samples of Fukuoka rice oil and 57 and 83 ppm in 2 samples of Taiwan rice oil.

An epidemiologic examination was carried out to reveal the prevalence of the periodontal diseases and oral pigmentation in patients with Yusho 30 years after PCBs exposure. The results obtained were as follows. 1) 69 patients out of 71 patients with Yusho, who were measured periodontal pocket depth using Ramfjord' methods, had at least one tooth with periodontal pocket deeper than 3 mm. Similarly, 241 teeth out of a total 348 examined teeth showed periodontal pocket with more than 3 mm depth. 2) Oral pigmentation was observed in 46 out of 79 patients with Yusho. In this study, gingival pigmentation was most predominant among oral pigmentation. In addition, it is of particular interest that oral pigmentation tended to be observed at a much higher frequency in younger patients with Yusho.

Literature review on clinical picture was made on two food poisoning episodes of Yusho and Yucheng in comparison with occupational PCB exposures. It was found that the dose-response relationship is quite different between Yusho/Yucheng patients and workers occupationally exposed to PCBs, when PCB levels in blood were taken as a common indicator of exposure intensity; the clinical manifestations were much severer in the former than in the latter, even when blood PCB levels were comparable. This conclusion is in support of the suggestions that chemicals such as polychlorinated dibenzofurans should have played an important role in the etiology of Yusho and Yucheng.

We reported the grades of severity of skin symptoms and the blood PCB patterns and concentrations in Yusho patients who were examined in the annual examinations in 1993 and 1994. The skin severity grades and skin severity scores showed the same tendency as recorded in the last 15 years. Approximately 20% of the patients, however, claimed the tendency of recurrence of skin infections and/or infected epidermal cysts, and still approximately 30% of the patients exhibited acneiform eruptions. Ten patients recorded with more than 6 points of skin severity scoring in these examinations were further investigated their initial skin severity grades and blood PCB patterns and concentrations. It was found that most of their blood PCB patterns showed the A pattern, and the level of the blood PCB in one patient was 55.5 ppb in the initial stage. Five patients out of 10 patients still have more than 10 ppb of blood PCB concentration. Thus, it is concluded that small populations of Yusho patients still have active skin symptoms with considerable blood PCB levels even at present.

An epidemiologic examination was carried out to reveal the prevalence of the periodontal diseases and oral pigmentation in Yusho patients 26 years after PCB exposure. The results obtained were as follows. 1) 158 teeth of the total 284 examined teeth had the periodontal pockets deeper than 3 mm and the lower left first molar showed the highest prevalence of the periodontal pocket among the examined six index teeth. There was no definitive difference not only between sexes but also between age groups. However, 42 teeth had the periodontal pockets deeper than 4 mm. 2) Oral pigmentation was observed in 25 Yusho patients (33.8%). Chronological examination revealed that the prevalence of oral pigmentation seemed to be higher in the patients below the age of 49 than in those beyond the age of 50, but there was no definitive difference between sexes. It was of particular interest that the incidence of oral pigmentation appeared to decrease with decrease of the teeth present in number.

The occurrence and progress of Yusho (PCB mass poisoning) is briefly described. Various investigative studies on Yusho are also briefly reviewed. Yusho occurred in the northern district of Kyushu Island in 1968. A specific product of rice oil used for food was accidentally contaminated with PCB during its manufacturing process and consequently, the customers who ate it showed severe intoxication symptoms. Major clinical symptoms of Yusho were acneiform eruptions and circumscribed pigmentation. These skin and mucous membrane eruptions, because of their appearance, caused severe mental suffering for the patients. The government-authorized patients amounted to 1,860. These symptoms have gradually declined with the passing of years and presently the principal clinical problems are only various subjective complaints. At first, it was naturally thought that the causative agent of Yusho was PCB (Kanechlor 400) itself. However, it was found later that the causative rice oil contained PCDF (polychlorodibenzofuran) and PCQ (polychloroquaterphenyl) which were proved to be formed during the heating process used in the deodorization of the oil. PCDFs show, in animal studies, a high toxicity and therefore its role for the pathogenesis of Yusho is seriously evaluated in spite of its rather small contaminating amount. On the other hand, PCQs are recognized as the specific marker of Yusho, since almost no PCQ is a general environmental pollution substance.

We reported the skin symptoms of the patients with Yusho in the 1989 and 1990 annual examinations. We also studied the alteration of the skin symptoms in 33 patients followed up for 14 years (1977-1990). Most of these patients showed obvious improvement in their skin symptoms during 12 years (1977-1988). However, a remarkable improvement was not observed in recent 3 years and approximately 40% of the patients still had comedones and/or acneiform eruptions.

The relationship between polychlorinated biphenyl (PCB) and polychlorinated quaterphenyl (PCQ) concentrations in the blood and hair was investigated. The materials in this study consisted of 49 blood samples and hair obtained from 27 patients with PCB poisoning (Yusho) and 22 normal controls. The alkaline decomposition method described in the official standard analytical methods for the isolation of PCB and PCQ fractions was used. In the blood of the control group, the mean concentration of PCBs was 2.25 ppb, while the concentration of PCQs was too low to be detected by our analytical method. On the other hand, the mean concentration of PCBs in the Yusho group was about 2.8 times higher than that in the control group. The mean concentration of PCQs in the blood was 0.61 ppb in the Yusho group, but PCQs were not detectable in the control group. In the hair, the mean concentration of PCBs was 25.85 ppb and 9.41 ppb in the Yusho group and control group respectively. The mean concentration of PCQs in the hair of Yusho patients was 0.44 ppb, but PCQs were not detected in the control group. The PCB level in the hair was higher than that in the blood, but the PCQ level in the hair was lower than that in the blood. These results suggest a difference of excretory system among polyhalogenated compounds such as PCBs or PCQs. We consider that PCBs display a greater affinity than PCQs for the pilosebaceous system of the human skin.(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate relationships between blood PCB (polychlorinated biphenyls) level and symptoms of Yusho patients, twenty years after outbreak, a comparative study was designed in accordance with the results of medical examination conducted in 1988. For this examination, standardized forms were introduced in 1986, and a whole system for data-processing has been completed through two-years' efforts. Study subjects were 259 Yusho patients (male: 136, female: 123) for whom PCB concentration in blood was reported, among a total of 285 patients examined (91%). And 31 examination items which correspond or relate to the diagnostic criteria for Yusho (1976) were selected from the examination form for analysis. Mean blood PCB concentration in the subjects was 4.78 ppb ranging 0.6-32.0 ppb. The subjects were stratified for four blood PCB levels, less than or equal to 2.6 ppb; less than or equal to 4.0 ppb; less than or equal to 6.0 ppb; greater than 6.0 ppb, by dichotomized categories (normal/abnormal) for the results of each examination. This two-by-four table was transformed to two-by-two table with a cut-off point where the largest chi 2-value was obtained. Then the odds ratio (OR) adjusted for gender and age was calculated for the examination item which showed a statistically significant decrease or increase in crude odds ratio, to assess the association between blood PCB level and symptoms of Yusho patients. (ABSTRACT TRUNCATED AT 250 WORDS)

Ocular manifestations were studied in 91 Yusho patients who took the contaminated rice oil 22 years ago. Tear film dysfunction was examined using the rose bengal test. Eighty-seven percent of the patients complained eye discharge, although edema of the eyelid and pigmentation of the conjunctiva were rarely seen. Cystic swelling of the tarsal glands was seen in 16 patients (18%) and white cheese-like contents in the tarsal glands were detected in 7 patients (8%). Twenty-five patients showed positive staining with the rose bengal test, although the intensity of the staining was slight. From this study it appears that there may not be tear film dysfunction in Yusho patients.

Information processing system for newly established, unified medical examinations of yusho patients which started in September 1985 was presented. Some comparative analysis was also shown on the "important findings" in yusho patients residing in Fukuoka or Nagasaki prefecture. In the 1986 survey, Fukuoka male patients showed higher percentages of pigmentation in toe nail, gingiva and palpebral conjunctiva than Nagasaki (p less than 0.01), whereas Nagasaki male patients showed higher percentages of pigmentation in buccal and lip mucosa. Average concentration of PCB in blood was higher in Nagasaki male patients (6.79 ppb) than in Fukuoka patients (4.39 ppb), the difference being significant at 1% level.

Thyroid function was investigated in 123 yusho patients who were exposed to toxic levels of polychlorinated biphenyls (PCBs) 16 years ago. In yusho patients, compared with the patients without evidence of yusho or normal controls, the serum triiodothyronine (T3) and thyroxine (T4) levels were significantly higher, while thyroid stimulating hormone (TSH) levels measured by sensitive assay were normal. There was no difference in serum levels of albumin, alkaline phosphatase, total cholesterol, and thyroxine binding globulin (TBG) between the two groups and the prevalence of positive antithyroid autoantibodies was almost the same, suggesting that hyperthyroxinemia in yusho patients was not due to increased TBG binding or abnormal autoimmune mechanism. Serum free T4 levels, however, were not elevated, although T4/TBG ratio was significantly higher. The thyroid hormone levels were higher than normal value in 4 of 123 yusho patients but only 1 case had clinical symptoms such as excessive perspiration. Despite higher serum PCBs in yusho patients, there was no correlation between PCB levels and levels of T3, T4, or TSH. The present results suggest hyperthyroxinemia without obvious clinical symptoms in yusho patients long after exposure to PCBs.

The relationship between PCB and PCQ concentrations in the blood, subcutaneous fat tissue and hair was investigated in this study. PCB and PCQ concentrations in twenty four patients with PCB poisoning (yusho) and 59 normal controls were analyzed. The alkaline decomposition method described in the official standard analytical methods for the isolation of PCB and PCQ fractions was used. The mean value of PCB concentrations was 2.43 ppb, CB% ratio was 0.69 and the PCQ concentration in the blood of the control group was too low to be detected by our analysis. On the other hand, the PCB concentration and CB% ratio in the yusho group were two times higher than those in the control group. The mean value of PCQ concentration was 1.34 ppb in the yusho group although it was below the level of detection in the control group. The mean PCB concentration in the hair of patients with yusho was 28.92 ppb, and 8.06 ppb in the control group. CB% ratio in the hair of patients with yusho was two times higher than that in the control group. The mean value of PCQ concentration in the hair of patients with yusho was 0.55 ppb although it was not detected in the control group. The PCB and PCQ concentrations in the hair were not greatly elevated when compared with those in the subcutaneous fat tissue. However, the hair is an excellent sample for the detection of these chemicals because it can be collected simply without operation.