Aryl Hydrocarbon Receptor and Dioxin-Related Health Hazards-Lessons from Yusho.

Poisoning by high concentrations of dioxin and its related compounds manifests variable toxic symptoms such as general malaise, chloracne, hyperpigmentation, sputum and cough, paresthesia or numbness of the extremities, hypertriglyceridemia, perinatal abnormalities, and elevated risks of cancer-related mortality. Such health hazards are observed in patients with Yusho (oil disease in Japanese) who had consumed rice bran oil highly contaminated with 2,3,4,7,8-pentachlorodibenzofuran, polychlorinated biphenyls, and polychlorinated quaterphenyls in 1968. The blood concentrations of these congeners in patients with Yusho remain extremely elevated 50 years after onset. Dioxins exert their toxicity via aryl hydrocarbon receptor (AHR) through the generation of reactive oxygen species (ROS). In this review article, we discuss the pathogenic implication of AHR in dioxin-induced health hazards. We also mention the potential therapeutic use of herbal drugs targeting AHR and ROS in patients with Yusho.

[Wood manufacture and dioxins: a case prospective study on maintenance of boilers powered by wood chips and shavings]. / Industria del legno e diossine: studio prospettico su un caso di manutentori di caldaie a scarti di legno e trucioli.

OBJECTIVES: to verify if a carpenter using wood scraps, treated or not, to operate the heating system may involve an exposure to dioxins in a given target of workers. DESIGN: the research was structured on literature sources analysis, study on field of the most relevant exposure, occurs through sampling. The results were recorded and plotted, and compared with the data available in literature. SETTING AND PARTICIPANTS: the study has involved maintenance workers of the heating system by means of wood refuse incineration. These workers were informed of the methods and aims of the sample. MAIN OUTCOME MEASURES: the results confirm a potential exposure to ash containing dioxins, presumably also in other similar situations, in this case not even evaluated by the employer. RESULTS: the average exposure to the light ash during the maintenance operations of the plant dust abatement in emissive phase is about 5 mg/m(3), with a consequent exposure to dioxins inferred, at about 20 pg. CONCLUSION: operators are exposed to dioxins: this implies that in some operations it is crucial to review the risk assessment and consequently the measures on prevention and health protection to activate.

[Associations of exposure to dioxins and polychlorinated biphenyls with diabetes: based on epidemiological findings].

Persistent organic pollutants (POPs) are a group of chemical substances that have the common properties of resistance to biodegradation, wide-range transportation, high lipophilicity, bioaccumulation in fat, and biomagnification in the food chain. POPs are persistent in the environment worldwide and have potential adverse impacts on human health and the environment. Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) are well known chemicals that are considered as POPs. The association between high-level exposure to dioxins and type 2 diabetes among U.S. Air Force veterans who had been exposed to Agent Orange contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during the Vietnam War was reported in the late 1990s. This association has been supported by similar epidemiologic studies, whose subjects were exposed to high doses of dioxins in their places of work involving phenoxyacid herbicide production and spraying, and in the industrial accident in Seveso, Italy. Recently, low-level exposure to dioxins and PCBs has been reported to be linked to type 2 diabetes. Cross-sectional studies in the U.S. general population and Japanese general population showed that body burden levels of some dioxins and PCBs were strongly associated with the prevalence of type 2 diabetes. Very recently, following these cross-sectional studies, several prospective studies have suggested that low-level exposure to some PCBs predicted the future risk of type 2 diabetes in the general population. Environmental exposure to some dioxins and PCBs, which mainly accumulate in adipose tissue, may play a role in the development of type 2 diabetes.

[Time serial changes in the concentrations of the related agents to fetal Yusho--dioxin-like PCBs and PCBs].

We determined dioxin-like polychlorinated biphenyls (PCBs) and PCBs in 6 preserved umbilical cords of fetal Yusho patients and in 11 preserved umbilical cords of Yusho suspected persons who were born to mothers with Yusho from 1970 to 2002, which were Yusho group. As a control, we also analyzed dioxin-like PCBs and PCBs in 15 preserved umbilical cords of babies who were born to healthy mothers, which was healthy group, in the same period of time. As a result, concentrations of three dioxin-like PCBs, that is, #156, #157 and #189 which were 6 to 20 times higher in fetal Yusho patients than in healthy babies were still 4 to 6 times greater in Yusho group than in healthy group about 20 years after the outbreak of Yusho, but could not recognize this characteristic anymore about 30 years after the outbreak. Decreasing rate in concentrations of dioxin-like PCBs and PCBs seemed to higher in Yusho group than in healthy group during this period of time. Therefore, we considered due to heavy exposure to PCDFs some drug metabolizing enzymes such as aryl hydrocarbon hydroxylase were induced and excretion of the related agents to fetal Yusho were enhanced from the bodies of Yusho group. In order to clarify this hypothesis, further more detail studies are needed.

Nutritional Intervention with Dried Bonito Broth for the Amelioration of Aggressive Behaviors in Children with Prenatal Exposure to Dioxins in Vietnam: A Pilot Study.

Dioxins have been suggested to induce inflammation in the intestine and brain and to induce neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), partly due to deficits in parvalbumin-positive neurons in the brain that are sensitive to inflammatory stress. Previously, we reported ADHD traits with increased aggressiveness in children with prenatal exposure to dioxins in Vietnam, whereas dried bonito broth (DBB) has been reported to suppress inflammation and inhibit aggressive behavior in animal and human studies. In the present study, we investigated the association between dioxin exposure and the prevalence of children with highly aggressive behaviors (Study 1), as well as the effects of DBB on the prevalence of children with highly aggressive behaviors (Study 2). METHODS: In Study 1, we investigated the effects of dioxin exposure on the prevalence of children with high aggression scores, which were assessed using the Children's Scale of Hostility and Aggression: Reactive/Proactive (C-SHARP) in dioxin-contaminated areas. The data were analyzed using a logistic regression model after adjusting for confounding factors. In Study 2, we performed nutritional intervention by administering DBB for 60 days to ameliorate the aggressiveness of children with high scores on the C-SHARP aggression scale. The effects of DBB were assessed by comparing the prevalence of children with high C-SHARP scores between the pre- and post-intervention examinations. RESULTS: In Study 1, only the prevalence of children with high covert aggression was significantly increased with an increase in dioxin exposure. In Study 2, in the full ingestion (>80% of goal ingestion volume) group, the prevalence of children with high covert aggression associated with dioxin exposure was significantly lower in the post-ingestion examination compared with in the pre-ingestion examination. However, in other ingestion (<20% and 20-79%) groups and a reference (no intervention) group, no difference in the prevalence of children with high covert aggression was found between the examinations before and after the same experimental period. CONCLUSIONS: The findings suggest that DBB ingestion may ameliorate children's aggressive behavior, which is associated with perinatal dioxin exposure.

Tetrachlorodibenzodioxin: an accidental poisoning episode in horse arenas.

Tetrachlorodibenzodioxin was identified as the apparent cause of an outbreak of poisoning in humans, horses, and other animals. Exposure was related to the spraying of contaminated waste oil on riding arenas for dust control. The contamination resulted from improper disposal of a toxic industrial waste. The pathologic effects and chemical identification of tetrachlorodibenzodioxin are described.

Thyroid lesions in the great cormorant (Phalacrocorax carbo) of Niigata, central Japan: a possible association with dioxin accumulation.

Necropsy and histopathologic examination of three Great Cormorants (Phalacrocorax carbo) shot in Niigata, central Japan, revealed goitrous changes in the thyroids. Thyroids had a hypertrophic follicular epithelium, loss or deficiency of luminal colloid, occasional small follicles suggesting hyperplasia, and occasional collapsed follicles. Irregularly shaped follicles were frequent, and hyperemia, deposition of dark pigment, and sporadic lymphoid aggregates were also seen. Chemical analysis simultaneously conducted showed higher than normal levels of dioxins in the liver, muscle, and fat, i.e., polychlorinated dibenzo-dioxins, polychlorinated dibenzo-furans, and coplanar polychlorinated biphenyls. The present results, together with those of relevant previous studies, strongly suggest an association between these pollutants and thyroid lesions in the Great Cormorant.

[Estimation of anti-SS-A Ab and anti-SS-B Ab in the serum of Yusho victims].

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. Furthermore, oxidative stress contributes to the generation of autoantibodies because of oxidative modification. In order to estimate the autoantibody in Yusho victims, we mesured serum levels of anti-SS-A antibody (Ab) and anti-SS-B Ab both in certified Yusho victims and age-matched controls. The mean values of anti-SS-A Ab were 4.0 +/- 17.1 (Index) in certified Yusho victims and 0.7 +/- 0.5 (Index) in controls. And the mean values of anti-SS-B Ab were 7.4 +/- 4.6 (Index) in certified Yusho victims and 5.6 +/- 1.7 (Index) in controls. Although the occurrence rates of anti-SS-A Ab and anti-SS-B Ab were high in Yusho victims, there were no significant difference between Yusho victims and controls.

[Lymphocyte subpopulations in patients with Yusho].

To investigate chronic immune effects of polychlorinated biphenyl (PCB) and polychlorinated dibenzofuran (PCDF), lymphocyte subpopulations in peripheral blood were studied in 156 patients with Yusho in 2008. Significant relationships between the concentrations of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) in the blood and the absolute densities of the total lymphocyte population, or of the T-cell subpopulation reactive with CD4 were observed, while there was no correlation between the blood PCB levels and the densities of total lymphocyte population, or CD4, CD8 or CD20 positive cells in peripheral blood. Mean absolute densities of total lymphocyte population and T-cell subpopulation expressing CD4 were significantly increased in the Yusho patients with high 2,3,4,7, 8-PeCDF levels compared with those in the patients with low 2,3,4,7,8-PeCDF levels. We conclude that the increase of CD4 positive cells in patients with Yusho may be associated with blood 2,3,4,7,8-PeCDF levels.

Concentrations of polychlorinated biphenyls in blood collected from Yusho patients during medical check-ups performed from 2004 to 2007.

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.

[Differential correlation of medical/laboratory examinations with blood levels of polychlorinated biphenyls, polychlorinated quarterphenyls and 2,3,4,7,8-pentachlorodibenzofuran in Yusho patients from 2001 to 2004].

BACKGROUND: Since 1968, when the Yusho poisoning incident occurred, annual physical, dermatological, dental, and ophthalmological and laboratory examinations, collectively called Yusho health checks, have been conducted for Yusho patients. The Yusho incident was a health hazard caused by intake of rice-bran oil contaminated with PCB and PeCDF; therefore, since 2001 the levels of dioxins such as PeCDF in the blood have been measured in applicants. Here, we investigated correlations among findings from various medical examinations and those between those findings and PeCDF, PCB, and PCQ. PATIENTS AND METHODS: Subjects were Yusho patients who underwent Yusho annual health checks and had their levels of PeCDF measured between 2001 and 2004. The results of 4 years of health checks of those who underwent the health checks for 2 years or longer were aggregated to extract representative inspection items by principal component analysis. We also investigated the presence or absence of correlations among these items and PeCDF, PCB, and PCQ levels in blood. RESULTS: Using 49 variables extracted by principal component analysis as objective variables, we determined that there were correlations between the following combinations: arthralgia, A/G ratio and PeCDF level, ophthalmological symptoms such as excessive eye discharge and PCB level, and total cholesterol, inferior gingival pigmentation and PCQ level.

[Dioxin concentration in the preserved umbilical cord from Yusho patients].

Dioxins are known as endocrine disrupters and widespread environmental contaminants. They are bioaccumulated in the human body. In this study, we determined concentrations of dioxins (PCDD, PCDF, Non-ortho PCB and Mono-ortho PCB) in eighteen umbilical cords provided by twelve mothers of Yusho patients and twelve umbilical cords provided by ten mothers of normal controls. The average concentrations of PCDD, PCDF, Non-ortho PCB, Mono-ortho PCB and total dioxins (PCDD/ F + Dioxin-like PCB) in the umbilical cords of Yusho patients and normal controls were 0.55, 4.55, 0.08, 0.08 and 5.26 pg-TEQ/g, respectively, and 0.50, 0.11, 0.03, 0.02 and 0.66 pg-TEQ/g, respectively. Total dioxins and PCDF concentrations in the umbilical cords of Yusho patient were about 8 and 40 times higher than those in the umbilical cords of normal controls, respectively. The average concentration of 2,3,4,7,8-PeCDF in the umbilical cords of Yusho patients was 10 pg/g. We couldn't detect 2,3,4,7, 8-PeCDF in the umbilical cords of normal controls. We suspected the 2,3,4,7,8-PeCDF concentrations in the mothers' blood were related to the 2,3,4,7,8-PeCDF concentrations in umbilical cords.

[Investigation of PCB pollution evaluation for Yusho victims using their preserved umblical cord].

PCB and dioxin-like PCB (DL-PCB) in 28 umbilical cords preserved from the time when 3 Yusho victims and 11 healthy subjects gave birth were examined in order to investigate the pollution evaluation with both the compounds in Yusho victims on the basis of the analytical value. As a result, in a period of 1968 to the 70s immediately after Yusho incident, the total concentration of the 12 DL-PCB isomers in both the Yusho victims s and healthy subjects was very high. After that, the total DL-PCB concentration decreased temporally. However, there was not observed a significant difference in the concentration and composition of both contaminants between the two groups.

[Estimated half-life of penta-chlorodibenzofuran (PeCDF) and simulation of PeCDF excretion].

The half-life of 2,3,4,7,8-penta-chlorodibenzofuran (PeCDF) in the Yusho patients has been reported to be approximately seven years. In the present study, we estimated the half-life of PeCDF using data from the medical check-ups of more than 300 Yusho patients. We performed linear regression analysis with a binary logarithm of PeCDF blood level in Yusho patients as the dependent variable, and the measurement year as the independent variable. Our results showed that there were many patients who had shown no reduction of their blood PeCDF level for several years. This result contradicts the previously reported half-life period. Therefore, we believe that a more complicated excretion model needs to be established to explain the discrepancy we found. We hypothesized that there might be two mechanisms of PeCDF assimilation in human digestive tract. In the present study, we also used our hypothesis to simulate PeCDF excretion in Yusho patients.

[Evaluation of dermatological symptom of Yusho patients in the annual examination in 2005-2007].

Yusho is recognized as a poisoning by a mixture of polychlorinated biphenyls (PCBs), dioxins and related compounds. We have continued a follow-up of skin symptoms in patients not only for supporting patients' health but also for understanding the possible prolonged effects of exposure to PCBs and dioxins in humans. We evaluated the severity grades and the skin severity scores of the symptoms who visited the annual examinations of Fukuoka prefecture from 2005 to 2007. Forty years have passed since the Yusho incident, and about 70% of the patients currently present no skin symptoms. In contrast, in about 30% of the patients, characteristic skin symptoms of Yusho, such as pigmentation of skin, black comedones and acneform eruptions, could still be observed. We analyzed statistical correlations between blood levels of PCBs or dioxin and skin severity grades.

[Prevalence of atopic dermatitis and serum IgE of Yusho patients].

Dioxins may have impact on the human immunological system, which would increase the risk to develop allergic diseases, such as atopic dermatitis. In order to determine the lifetime prevalence of atopic dermatitis in Yusho patients, a questionnaire-based survey was conducted in 2007. Six hundred and thirty-eight out of 731 certified yusho patients answered the questionnaires, and the prevalence of atopic dermatitis in Yusho patients was 8.8%. We also measured serum IgE in 83 certified and 98 non-certified Yusho patients who attended an annual medical check-up in 2007. Mean serum levels of IgE in certified Yusho patients were 386.2 +/- 1128.0 IU/ml, whereas those in non-certified Yusho patients were 272.1 +/- 603.6 IU/ml. There was no significant difference in serum levels of IgE between certified and non-certified Yusho patients. In addition, no significant correlation was observed between serum levels of IgE and blood levels of dioxins in certified Yusho patients.

[Bone mineral density, PCB, PCQ and PCDF in Yusho].

We measured bone mineral density of the distal end of radius with dual energy X-ray absorptiometry, serum cross-linked N-telopeptides of type I collagen, serum bone-specific alkaline phosphatase, serum Ca, serum P, blood PCB level, blood PCQ level and blood PCDF level in Yusho. As a result, the osteoporosis group (< 70% of the young adult mean [YAM] bone mineral density [BMD]) was observed in 7.1% of the studied male subjects. And, the moderate group (> or = 70% and < 80% of YAM BMD), 16.1%, the normal (> or = 80% of YAM BMD) group was 76.8%. Also, 42.3% of all female tested subjects observed in osteoporosis group. The moderate group, 19.2%, the normal group was 38.5%. There was no difference in PCB blood level, PCQ, PCDF for men and women in osteoporosis group, moderate group, and in the normal group. Serum cross-linked N-telopeptides of type I collagen increased in the male osteoporosis group, but serum bone-specific alkaline phosphatase did not change. This study was inconclusive since the results did not determine the influence that PCB, PCQ, PCDF gave to bone density and bone metabolism.

[An epidemiologic examination on the prevalence of the periodontal diseases and oral pigmentation in Yusho patients in 2008].

An epidemiologic examination was carried out to reveal the prevalence of the periodontal diseases and oral pigmentation in patients with Yusho in 2008. The results obtained were as follows. 1) Yusho patients complained of tooth pain and periodontal diseases such as gingival swelling, gingival bleeding, but not of oral pigmentation. 2) 116 patients out of 148 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, 399 teeth out of a total 710 examined teeth showed a periodontal pocket with more than 3 mm in depth. However, it was determined that 74 teeth had a periodontal pocket deeper than 4 mm. 3) Oral pigmentation was observed in 91 patients out of 155 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, the prevalence of oral pigmentation tended to be higher in younger patients than in elder patients. Pigmentation of the buccal mucosa, lip or palate, however, was observed only in patients beyond the age of fifty. These results indicated that PCB-related compounds may be responsible for the higher prevalence of both periodontal diseases and oral pigmentation.