benzofurans and Porphyrias

The controversy about dioxin effects on human health received a great deal of attention recently when the State of Missouri was declared to have a dioxin crisis. However, dioxin and several related chemicals are widespread throughout the world. Cutaneous signs play an important part in evaluating toxicity of dioxin and similar chemicals. Chloracne is the most sensitive indicator of significant dioxin exposure. Porphyria cutanea tarda and hyperpigmentation are other known cutaneous effects, and malignant fibrous histiocytomas of the skin may possibly be associated, although data are inconclusive on this point. The AMC Council on Scientific Affairs recommended that all physicians become familiar with chloracne and other toxic effects of dioxin. Dermatologists, especially, should be aware of the problem and may discover early cases of previously unsuspected exposure to this group of chemicals.

Topics: Abnormalities, Drug-Induced; Animals; Benzofurans; Dibenzofurans, Polychlorinated; Dioxins; Dose-Response Relationship, Drug; Environmental Exposure; Environmental Pollutants; Histiocytoma, Benign Fibrous; Humans; Hydrocarbons, Chlorinated; Lethal Dose 50; Naphthalenes; Pigmentation Disorders; Polybrominated Biphenyls; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Polychloroterphenyl Compounds; Porphyrias; Skin Absorption; Skin Diseases; Skin Neoplasms

Yusho was a mass food poisoning event due to the ingestion of rice oil contaminated with polychlorinated biphenyls (PCBs) and various dioxins and dioxin-like compounds. At its outbreak in 1968, Yusho patients suffered severe skin symptoms. Although the blood concentrations of PCBs and dioxins, especially highly toxic 2,3,4,7,8-pentachlorinated dibenzofuran (2,3,4,7,8-PeCDF) remain high in these patients, extensive analysis has not been performed on their current skin symptoms. We categorized and evaluated the specific skin symptoms in Yusho in 2012 by grading their severity using an arbitrary scoring system, and analyzed their correlations with the blood concentrations of 2,3,4,7,8-PeCDF and PCBs. A total of 352 Yusho patients underwent annual dermatological check-ups, in which five skin symptoms: black comedones, acneiform eruptions, scar formation, pigmentation and nail deformity, were evaluated for their distribution and severity. Approximately one-third of Yusho patients still presented with black comedones, acneiform eruptions and scar formation; the distributions of these symptoms were similar to those at the time of the Yusho outbreak. The mean blood concentrations of 2,3,4,7,8-PeCDF and total PCBs in Yusho patients were still higher than those in controls. The prevalence and severity of black comedones were correlated with age. Severity scores of black comedones and scar formation were positively correlated with 2,3,4,7,8-PeCDF blood level, and those of black comedones, scar formation, and pigmentation were positively correlated with total PCBs blood level. This study suggests that 2,3,4,7,8-PeCDF and PCBs remaining in Yusho patients still play crucial roles in the development of skin symptoms in Yusho.

Topics: Benzofurans; Dibenzofurans, Polychlorinated; Environmental Exposure; Female; Food Contamination; Humans; Male; Middle Aged; Oryza; Polychlorinated Biphenyls; Porphyrias; Skin Diseases

Half-lives of blood levels of 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) are varied in Yusho patients. The objective was to evaluate a relationship between half-lives of PeCDF levels and types of SNP rs10249788 of aryl hydrocarbon receptor (AHR) gene in 93 Yusho patients. Based on physical symptoms, age, sex, body mass index and other factors, we set up suitable calculation formulas to fit the actual PeCDF levels thorough rates of change in PeCDF. We found that patients with C/T SNP had longer half lives than patients with C/C and T/T SNPs. Patients with T/T SNP are known to express higher amount of AHR mRNAs. However, detailed analysis could not be carried out in T/T group due to a limited number of patients (n = 11). Further research is warranted to determine the cause of the longer half-lives in C/T patients.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Female; Half-Life; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Porphyrias; Receptors, Aryl Hydrocarbon

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.. To evaluate the relationship between clinical and laboratory parameters and the individual half-life of 2,3,4,7,8-PeCDF in blood.. 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.. 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.. 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.

Topics: Acne Vulgaris; Adult; Aged; Aged, 80 and over; Benzofurans; Erythrocyte Count; Fatigue; Female; Half-Life; Humans; Japan; Male; Middle Aged; Porphyrias; Rhinitis, Allergic, Seasonal

Yusho disease, a polychlorinated biphenyl (PCB) and polychlorinated dibenzofuran (PCDF) mixed poisoning caused by contaminated rice oil, occurred in Japan in 1968. The evidence on reproductive outcome is limited. We therefore evaluated the regional impact of the exposure to the PCB and PCDF mixture on stillbirth rate and secondary sex ratio among the residents in two severely affected areas. We selected the regionally-affected towns of Tamanoura (n=4390 in 1970) and Naru (n=6569) in Nagasaki Prefecture, Japan, for study. We obtained data on stillbirths (spontaneous/artificial) and live-born births (total/male/female) from 1958 to 1994. For a decade and a half after the exposure, an increase in the rate of spontaneous stillbirths coincided with a decrease in the male sex ratio. Compared with the years 1958-1967, the ratios for spontaneous stillbirth rates were 2.16 (95% confidence interval: 1.58 to 2.97) for 1968-1977 and 1.80 (95% confidence interval: 1.25 to 2.60) for 1978-1987. The sex ratio (male proportion) was 0.483 (95% confidence interval: 0.457 to 0.508) in the first 10years after exposure. Exposure to a mixture of PCBs and PCDFs affected stillbirth and sex ratio for a decade and a half after the exposure.

Topics: Benzofurans; Dibenzofurans, Polychlorinated; Female; Food Contamination; Humans; Japan; Male; Oryza; Plant Oils; Polychlorinated Biphenyls; Porphyrias; Sex Ratio; Stillbirth

We developed a more effective method to measure the concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and non-ortho-coplanar polychlorinated biphenyls (non-ortho PCBs) in the blood of Yusho patients using high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS) equipped with a newly large-volume injection system. The new injection system linked a LaviStoma system with a unique stomach-shaped inlet liner (SSIL) and a solvent-cut large-volume (SCLV) injection system. This approach made it possible to introduce volumes up to 200 microl into the HRGC/HRMS in comparison with the 20microl volume of the previously reported conventional SCLV method. Based on experiments conducted using the same blood sample, the concentrations of PCDDs, PCDFs, and non-ortho PCBs obtained by the developed method showed a close correlation to that by the conventional SCLV method. By improving the injection method, the operation time and labor for the purification procedure from blood could be reduced. Furthermore, the developed method was more effective than the conventional SCLV method for recovery of PCDDs, PCDFs, and non-ortho PCBs.

Topics: Benzofurans; Dibenzofurans, Polychlorinated; Dioxins; Gas Chromatography-Mass Spectrometry; Humans; Injections; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Porphyrias

We measured the concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) in blood collected from Yusho patients during medical health examinations performed from 2004 to 2010. Out of the 242 and 200 Yusho patients who received medical health examinations in 2004 and 2010, respectively, the concentrations of PCDDs, PCDFs, and PCBs in the blood of 136 patients were measured in both of those years. The concentrations of individual congeners of PCDDs, PCDFs, and PCBs in the blood of these 136 Yusho patients measured in 2004 were compared with those measured in 2010. Among individual congeners of PCDDs, PCDFs, and PCBs, most congeners of these compounds did not significantly decrease from 2004 to 2010. However, the concentrations of 1, 2, 3, 4, 6, 7, 8-heptaCDD, octaCDD, 1, 2, 3, 4, 7, 8-hexaCDF, tetraCB 52/69, pentaCB 101, octaCB 198/201, and octaCB 196/203 in the blood of Yusho patients were significantly decreased from 2004 to 2010. In addition, the concentrations of 1, 2, 3, 6, 7, 8-hexaCDD, 2, 3, 4, 7, 8-pentaCDF, and 1, 2, 3, 6, 7, 8-hexaCDF tended to decrease slightly from 2004 to 2010. These findings suggest that the PCDDs, PCDFs, and PCBs have remained in the blood of Yusho patients for a very long time, with over 40 years having passed since the outbreak of Yusho.

Topics: Benzofurans; Dibenzofurans, Polychlorinated; Dioxins; Humans; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Porphyrias; Time Factors

Maternal exposure to polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) may result in adverse health effects in their children. In Japan in 1968, an accidental human exposure to rice oil contaminated with PCDDs, PCDFs, and PCBs, led to the development of Yusho disease. Yusho mothers delivered descendants with low birth weights and hyperpigmented skin and mucosa, which are characteristic of fetal Yusho disease (FYD). The Yusho cohort was used to evaluate the effect of maternal exposure to PCDDs, PCDFs, and PCBs on the development of FYD. Blood samples, obtained from 64 Yusho mothers (117 descendants: 10 with FYD and 107 without FYD), were analyzed for congeners of seven PCDDs, 10 PCDFs, and four coplanar PCBs. We investigated the association between the maternal estimated blood levels of dioxins at delivery and the risk of fetal Yusho disease. We also studied the differences in dioxin blood levels in 24 mother-descendant pairs (5 with FYD and 19 without FYD). The estimated levels of total PCDD TEQ, total PCDF TEQ, total coplanar PCB TEQ, and total TEQ in the maternal blood at delivery were associated with significantly increased risk of FYD. The odds ratios, which present the risk of FYD for a 10-fold increase in blood dioxin, were largest for 1,2,3,6,7,8-HexaCDD (odds ratio=28.6, 95% confidence interval=1.67-489.9, p=0.02). The levels of 1,2,3,6,7,8-HexaCDD in both the Yusho mothers and their descendants with FYD were higher than the levels in those without FYD. These findings suggest that 1,2,3,6,7,8-HexaCDD is the most important causative congener for the development of FYD.

Topics: Adolescent; Adult; Aged; Benzofurans; Child; Child, Preschool; Dibenzofurans, Polychlorinated; Environmental Pollutants; Female; Humans; Infant; Infant, Newborn; Japan; Male; Maternal Exposure; Middle Aged; Mothers; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Porphyrias; Young Adult

Studies on the association of maternal exposure to polychlorinated dibenzo-p-dioxin (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) with decreased birth weight in humans have produced conflicting results. In Japan in 1968, an accidental human exposure to rice oil contaminated with PCDDs, PCDFs, and PCBs, led to the development of Yusho disease.. The Yusho cohort was used to evaluate the effect of maternal exposure to PCDDs, PCDFs, and PCBs on birth weight.. Blood samples, obtained from 101 Yusho women (190 births) who gave birth after exposure, were analyzed for congeners of seven PCDDs, ten PCDFs, and four non-ortho PCBs.. Total PCDD TEQ (adjusted beta=-161.9g; 95% CI, -265.3 to -58.6), total PCDF TEQ (adjusted beta=-105.9g; 95% CI, -179.5 to -32.2), and total non-ortho PCBs (adjusted beta=-178.4g; 95% CI, -318.3 to -38.5) levels were inversely associated with birth weight. Significant inverse associations with birth weight were also found for total PCDD TEQ, total PCDF TEQ, and total non-ortho PCB TEQ levels among male, but not female, infants. Significant inverse associations with birth weight were also found for nine congeners among all infants; the adjusted beta coefficients were largest for 1,2,3,6,7,8-HxCDD and smallest for 2,3,4,7,8-PeCDF.. In the setting of exposure to high levels of dioxins, maternal blood levels of PCDDs, PCDFs and PCBs are associated with lower birth weight in Yusho patients. The association exhibited gender-specific differences, as male infants are more susceptible than females to growth restriction induced by in utero dioxin exposures.

Topics: Adult; Benzofurans; Birth Weight; Cohort Studies; Dibenzofurans, Polychlorinated; Dioxins; Female; Food Contamination; Humans; Infant; Japan; Male; Maternal Exposure; Oryza; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Porphyrias; Young Adult

In Japan in 1968, rice-oil contaminated by polychlorinated biphenyls and polychlorinated dibenzofurans caused severe food poisoning, termed "Yusho" (oil disease). Several previous studies attempted to evaluate the effects targeting officially-certified Yusho patients. However, these studies have several limitations such as the left-truncated nature of the registry or residual confounding arising from the referent population selection. We thus conducted an area-based standardized mortality ratios (SMRs) study using vital statistics. A severely affected area (Tamanoura area) was adopted as the exposure group, with a reference population from Nagasaki prefecture in Kyushu, which included the Tamanoura. A large number of residents in Tamanoura were exposed to the rice-oil (28% of all the certified cases as of 2009). We estimated SMRs of non-cancer and cancer diseases for the years 1968-2002. Shortly after the exposure, SMRs of all causes, diabetes mellitus, cardiovascular disease, pneumonia/bronchitis, and bronchus/lung cancer were elevated. In particular, SMRs of heart disease were 1.97 [95% confidence intervals (CI): 1.09-3.56] in 1968, 2.05 (95% CI: 1.16-3.60) in 1969, and 1.89 (95% CI: 1.05-3.41) in 1975. However, we did not observe clear increase in SMRs more than 10 years after the exposure. This study provides further evidence in Yusho, especially on acute effects on non-cancer mortality.

Topics: Adolescent; Adult; Benzofurans; Cause of Death; Child; Child, Preschool; Dibenzofurans, Polychlorinated; Dietary Fats, Unsaturated; Environmental Exposure; Female; Food Contamination; Humans; Infant; Infant, Newborn; Japan; Male; Middle Aged; Polychlorinated Biphenyls; Porphyrias; Young Adult

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (233 nmol/kg) causes a significant increase of hepatic uroporphyrin, heptacarboxyporphyrin, and total porphyrins in female C57BL/6 mice, ovariectomized C57BL/6 mice, male C57BL/10 mice, and male C57BL/6 mice 3 weeks after treatment. In contrast, 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) was inactive at a dose of 750 mumol/kg. Cotreatment of the mice with TCDD (233 mol/kg) plus MCDF (750 mumol/kg) resulted in partial antagonism of TCDD-induced hepatic porphyrin accumulation only in the female mice. Parallel studies in female C57BL/6 mice showed that the TCDD-induced porphyria was accompanied by the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) activities and the depression of uroporphyrinogen decarboxylase (UROD). MCDF (750 mumol/kg) did not significantly affect these enzymes. In the cotreatment studies (MCDF plus TCDD), MCDF partially antagonized TCDD-induced hepatic porphyrin accumulation but did not affect the levels of hepatic AHH, EROD, or UROD. These results indicate that other factors, in addition to the induction of cytochrome P450-dependent monooxygenases and depressed UROD activity, are important in TCDD-induced porphyria in C57BL/6 female mice.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Benzofurans; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System; Dioxins; Drug Antagonism; Female; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Ovariectomy; Oxidoreductases; Polychlorinated Dibenzodioxins; Porphyrias; Porphyrins; Uroporphyrinogen Decarboxylase

Topics: Animals; Benzofurans; Body Weight; Chlorobenzenes; Dioxins; Drug Contamination; Female; Hexachlorobenzene; Liver; Lung; Mixed Function Oxygenases; Polychlorinated Biphenyls; Porphyrias; Rats

Topics: 5-Aminolevulinate Synthetase; Animals; Benzofurans; Liver; Male; Polychlorinated Biphenyls; Porphobilinogen Synthase; Porphyrias; Rats

Topics: Animals; Benzofurans; Body Weight; Chlorophenols; Diet; Dioxins; Drug Contamination; Female; Liver; Pentachlorophenol; Pharmaceutical Preparations; Porphyrias; Porphyrins; Rats