Satoko Shibata

Recently, methods for measurement of dioxins in the blood have improved. Also, techniques for analyzing large quantities of data have been developed, such as data mining. Even in subjects with elusive characteristics, it is becoming possible to find previously unknown characteristics by checking all combinations of symptoms.

Yusho an intoxication caused by oral dioxins and polychlorinated biphenyls occurred in 1968. Patients suffered from various systemic symptoms, including general fatigue, nausea, muscular and articular pain, acneform eruptions, black comedones, cutaneous and oral pigmentation, and increased eye discharge. The major causative factor was the contamination of rice oil with 2,3,4,7,8-penta-chlorodibenzofuran (PeCDF). Recent technical advances have allowed us to measure blood levels of PeCDF. However, there is little information on which symptoms and laboratory data are directly associated with PeCDF levels.

The Yusho poisoning incident, which was caused by rice bran oil contaminated with polychlorinated biphenyls (PCBs), polychlorinated quarterphenyls (PCQs) and polychlorinated dibenzofurans (PCDFs) generated by heat denaturation of PCB, occurred in 1968 in western Japan. Annual physical, dermatological, dental, ophthalmological and laboratory examinations were conducted for Yusho patients after the incident. From 2001, blood levels of individual PCDF congeners were also measured. The blood levels of 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF), PCBs and PCQs in Yusho patients were found to be significantly higher than those of the general population. We investigated the relationships between blood concentrations of 2,3,4,7,8-PeCDF, PCBs and PCQs in Yusho patients and the items measured in the annual medical examination.

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. 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. 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.

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.

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. 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. 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. 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. 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. 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.

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).

Atopic dermatitis (AD) is a multifactorial disease that usually decreases the quality of life of affected patients. We monitored the incidence of AD and serum total IgE levels annually among nursery school children in Ishigaki Island, Okinawa, Japan, from 2001 to 2004. A total of 1731 children were enrolled. The prevalence of AD ranged from 3.7 to 11% in each year, with no significant difference between boys and girls. 869 children were examined at least twice. 71.6% (53/74) of AD patients regressed spontaneously, whereas 5.5% (44/795) of non-AD individuals developed AD during the 3-year follow-up. Increases in total IgE levels were greater and more rapid in children with long-term AD than in those who had spontaneously regressed, had newly-developed AD or did not have AD. The regression rate of AD was > 70% while new-onset AD occurred at a rate of 3.67%/person year in nursery school children of Ishigaki Island.