Death following consumption of MDAI and 5-EAPB.

5-(2-ethylaminopropyl)benzofuran (5-EAPB) and 5,6-methylenedioxy-2-aminoindane (MDAI) are two new psychoactive substances (NPS) exhibiting MDMA-like properties. In this paper, we report the case of a 28-years old man, known as drug addict, found dead at home, with two unidentified powders next to him. External examination by the forensic pathologist was unremarkable but no autopsy was performed. Powders, blood and urine (which were the only samples available) were submitted to general unknown screening by high pressure liquid chromatography with a diode array detector (HPLC-DAD) and ultra high pressure liquid chromatography with a time-of-flight detector (UPLC-TOF-MS), after liquid-liquid extraction for biological samples, or simple dilution for powders. Analysis revealed 68% of MDAI in one powder and 87% of 5-EAPB in the other one. Significant levels of the same substances were found in blood (MDAI: 2.09 mg/L and 5-EAPB: 6.45 mg/L). The cause of death was therefore attributed to the consumption of these NPS since screening for other drugs of abuse and for alcohol was negative (oxazepam was found in urine only). 5-methylaminopropylbenzofuran (5-MAPB) and 5-aminopropylbenzofuran (5-APB) were also found in blood (0.089 and 0.546 mg/L, respectively) and urine (1.00 and 4.88 mg/L, respectively). In addition to the inherent complexity of NPS identification by itself, another analytical difficulty in this case was the identification of the EAPB positional isomer. Our routine screening methods were not able to distinguish the positional isomer, but an additional classical gas chromatography technique was able to make the distinction. Anyway, in our case, this issue was simplified thanks to the availability of a relatively pure powder that was analyzed by nuclear magnetic resonance (NMR).

A fatal blood concentration of 5-APB.

For the new psychoactive drug 5-(2-aminopropyl) benzofuran (5-APB), very limited knowledge is available regarding lethal concentrations. We present a case and report the post mortem blood concentration of a fatal outcome for a 25 year old man related to the consumption of 5-APB. After intake, he became unconscious and stopped breathing. Cardiopulmonary resuscitation was started without success. After 30min he was declared dead at the scene. During autopsy, whole blood from the femoral vein was collected and screened for a wide range of medicinal drugs and drugs of abuse. 5-APB was initially identified by ultra high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) and subsequently confirmed by using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The only toxicological findings were ethanol 0.6g/L, tetrahydrocannabinol (THC) 0.0024mg/L and 5-APB 0.86mg/L. The cause of death was attributed to intake of 5-APB. Only one previous report of a fatal 5-APB concentration as the main toxicological agent exist in the literature, and the present concentration indicated that 5-APB could be lethal in lower concentrations than previously reported.

Current skin symptoms of Yusho patients exposed to high levels of 2,3,4,7,8-pentachlorinated dibenzofuran and polychlorinated biphenyls in 1968.

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.

Mortality after exposure to polychlorinated biphenyls and polychlorinated dibenzofurans: a meta-analysis of two highly exposed cohorts.

Both Yucheng and Yusho were events of accidental exposure to highly doses of polychlorinated biphenyls and dibenzofurans in Asian people. Mortality experiences caused by various diseases were reported in both cohorts with similar and dissimilar findings. We thus conducted a meta-analysis of two cohorts to reevaluate the effects of PCBs and PCDFs on major causes of mortalities. Two recently updated Yucheng and Yusho mortality studies were included. For selected diseases, standardized mortality ratios (SMR) and 95% confidence intervals (95% CI) were extracted. Meta-analyses were conducted using a random-effects model only when heterogeneity (I(2) > 50% and/or p value <0.10 by the Q test) was not found. A total of 1,803 Yucheng subjects (male, N = 830; female, N = 973) with 48,751 person-years of follow-up and 1,664 Yusho subjects (male, N = 860; female, N = 804) with 50,773 person-years are included. An increase in all-cause mortality (pooled SMR=1.2, 95% CI: 1.1-1.3, I(2) = 0.0%), all cancers (pooled SMR=1.3, 95% CI: 1.1-1.6, I(2) = 0.0%), lung cancer (pooled SMR=1.7, 95% CI: 1.2-2.3, I(2) =0.0%), heart disease (pooled SMR=1.3, 95% CI: 1.0-1.7, I(2) = 43.4%) and hepatic disease (pooled SMR=1.9, 95% CI: 1.3-2.8, I(2) = 0.0%) were found in pooled males. Significant elevation from liver cancer was found in pooled females (pooled SMR=2.0, 95% CI: 1.1-3.6, I(2) = 0.0%). This meta-analysis of Yucheng and Yusho cohorts showed similar elevation from all cancer, lung cancer, heart disease and hepatic disease mortalities in exposed men. Furthermore, a new finding of elevated liver cancer mortality in exposed women was identified.

Cancer and non-cancer excess mortality resulting from mixed exposure to polychlorinated biphenyls and polychlorinated dibenzofurans from contaminated rice oil: "Yusho".

PURPOSE: In 1968, rice oil contaminated with polychlorinated biphenyls and polychlorinated dibenzofurans caused a severe outbreak of food poisoning in Japan and was termed locally as "Yusho" (oil disease). In our previous study, we found that area-based standardized mortality ratios (SMRs) of some diseases were elevated shortly after the incident. This previous study, however, was unable to determine whether these elevated SMRs were a result of other area-specific factors. To overcome this limitation, we obtained mortality data from the 5 years before the incident and conducted an area-based study using vital statistics records dating from 1963 to 2002. METHODS: The population of Nagasaki Prefecture was set as the reference population for calculating SMRs. We also included data on cause-specific mortality attributable to cancer and expanded the population to encompass two severely exposed areas where contaminated rice oil was distributed (namely Tamanoura and Naru). We also calculated SMRs in the remainder of the Shimo-Goto region, excluding the exposed area, which was used as a comparison area. RESULTS: Even after considering the time trends in mortality before the incident, mortality due to diabetes mellitus and heart disease, as well as all-cause mortality, was found to be elevated shortly afterward. Additionally, mortalities due to uterine cancer in Tamanoura and leukemia were also elevated at 30-34 and 10-59 years after the event in both exposed areas, respectively. SMRs for leukemia in Tamanoura were as high as 3.0 (95% confidence interval 1.4-6.2) and 2.4 (1.2-4.8) 10-19 years later. In this period, SMRs for leukemia in the comparison area were not elevated. CONCLUSIONS: Further epidemiological studies are needed regarding this rice-oil, "Yusho" outbreak, especially with regard to cancer and non-cancer mortality.

Acute 5-(2-aminopropyl)benzofuran (5-APB) intoxication and fatality: a case report with postmortem concentrations.

A 20-year-old man, a college student, became unresponsive in front of his girlfriend. He was known to consume alcohol and take an unknown drug at some point while in attendance at a local music festival earlier in the day/evening. Upon arrival of emergency personnel, he was noted to be asystolic and apneic. Despite aggressive medical intervention by emergency personnel and at a local hospital emergency room, he was pronounced deceased within 1.25 h of initial medical attention. Postmortem blood initially screened positive for methamphetamine by ELISA. An alkaline drug screen detected 5-(2-aminopropyl)benzofuran (5-APB) which was subsequently confirmed and quantified by a specific GC-MS SIM analysis following solid-phase extraction. Concentrations were determined in the peripheral blood (2.5 mg/L), central blood (2.9 mg/L), liver (16 mg/kg), vitreous (1.3 mg/L), urine (23 mg/L) and gastric contents (6 mg). No other common amphetamine-like compound was detected, although 5-(2-aminopropyl)-2,3-dihydrobenzofuran (5-APDB) was presumptively identified in both peripheral blood and urine. Alcohol, the only other drug identified, was confirmed at a concentration of 0.02% (w/v).

A Critical Review about Human Exposure to Polychlorinated Dibenzo-p-Dioxins (PCDDs), Polychlorinated Dibenzofurans (PCDFs) and Polychlorinated Biphenyls (PCBs) through Foods.

Dioxins include polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and part of polychlorinated biphenyls (PCBs). Only the compounds that are chlorinated at the 2,3,7, and 8 positions have characteristic dioxin toxicity. PCDDs, PCDFs and PCBs accumulate in the food chain due to their high lipophilicity, high stability, and low vapor pressure. They are not metabolized easily; however their hydroxylated metabolites are detected in feces. They cause a wide range of endocrine disrupting effects in experimental animals, wildlife, and humans. Endocrine related effects of PCDDs, PCDFs and PCBs on thyroid hormones, neurodevelopment and reproductive development were referenced. In addition, some studies of contamination of foods, bioaccumulation, dietary exposure assessment, as well as challenges of scientific research in these compounds were reviewed.

Fatal intoxication with 3-methyl-N-methylcathinone (3-MMC) and 5-(2-aminopropyl)benzofuran (5-APB).

The emergence of a large number of new psychoactive substances (NPSs) in recent years poses a serious problem to clinical and forensic toxicologists. Here we report a patient who administrated ca. 500mg of 3-MMC (3-methyl-N-methylcathinone) and 400mg of 5-APB (5-(2-aminopropyl)benzofuran) in combination with 80g of ethyl alcohol. The clinical manifestations included agitation, seizures, hypertension, tachycardia, hyperthermia and bradycardia. The patient did not recover and died around 4h after the use of drugs. The cause of death was acute cardiovascular collapse that occurred following mixed intoxication with NPSs and alcohol. Toxicological analysis of post-mortem blood revealed 3-MMC and 5-APB in concentrations of 1.6µg/mL and 5.6µg/mL, respectively. Moreover, the serum alcohol concentration was 1.4g/L in ante-mortem sample collected 1h after admission to the hospital. This is the first report on blood concentration of 3-MMC and 5-APB in fatal intoxication.

Patterns of presentation and clinical features of toxicity after reported use of ([2-aminopropyl]-2,3-dihydrobenzofurans), the 'benzofuran' compounds. A report from the United Kingdom National Poisons Information Service.

OBJECTIVE: To characterise the patterns of presentation and clinical features of toxicity following reported recreational use of benzofuran compounds ((2-aminopropyl)-2,3-dihydrobenzofurans) in the UK, as reported to the National Poisons Information Service (NPIS), and to compare clinical features of toxicity with those after reported mephedrone use. METHODS: NPIS patient-specific telephone enquiries and user sessions for TOXBASE(®), the NPIS online information database, related to (2-aminopropyl)-2,3-dihydrobenzofurans and associated synonyms were reviewed from March 2009 to August 2013. These data were compared with those of mephedrone, the recreational substance most frequently reported to NPIS, collected over the same period. RESULTS: There were 63 telephone enquiries concerning 66 patients and 806 TOXBASE(®) user sessions regarding benzofuran compounds during the period of study. The first telephone enquiry was made in July 2010 and the highest numbers of enquiries were received in August 2010 (33 calls, 112 TOXBASE(®) sessions). Patients were predominantly male (82%) with a median age of 29 years; 9 reported co-ingestion of other substances. Comparing the 57 patients who reported ingesting benzofuran compounds alone with 315 patients ingesting mephedrone alone, benzofurans were more often associated with stimulant features, including tachycardia, hypertension, mydriasis, palpitation, fever, increased sweating, and tremor, (72% vs. 38%, odds ratio [OR] 4.2, 95% confidence interval [CI] 2.27-7.85, P < 0.0001) and mental health disturbances (58% vs. 38%, OR 2.3, 95% CI 1.29-4.07, P = 0.006). Other features reported after benzofuran compound ingestion included gastrointestinal symptoms (16%), reduced level of consciousness (9%), chest pain (7%), and creatinine kinase elevation (5%). CONCLUSIONS: Reported ingestion of benzofuran compounds is associated with similar toxic effects to those of amphetamines and cathinones. Mental health disturbances and stimulant features were reported more frequently following reported ingestion of benzofuran compounds than after ingestion of mephedrone.

Species-specific relative AHR1 binding affinities of 2,3,4,7,8-pentachlorodibenzofuran explain avian species differences in its relative potency.

Results of recent studies showed that 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are equipotent in domestic chicken (Gallus gallus domesticus) while PeCDF is more potent than TCDD in ring-necked pheasant (Phasianus colchicus) and Japanese quail (Coturnix japonica). To elucidate the mechanism(s) underlying these differences in relative potency of PeCDF among avian species, we tested the hypothesis that this is due to species-specific differential binding affinity of PeCDF to the aryl hydrocarbon receptor 1 (AHR1). Here, we modified a cell-based binding assay that allowed us to measure the binding affinity of dioxin-like compounds (DLCs) to avian AHR1 expressed in COS-7 (fibroblast-like cells). The results of the binding assay show that PeCDF and TCDD bind with equal affinity to chicken AHR1, but PeCDF binds with greater affinity than TCDD to pheasant (3-fold) and Japanese quail (5-fold) AHR1. The current report introduces a COS-7 whole-cell binding assay and provides a mechanistic explanation for differential relative potencies of PeCDF among species of birds.

Regional impact of exposure to a polychlorinated biphenyl and polychlorinated dibenzofuran mixture from contaminated rice oil on stillbirth rate and secondary sex ratio.

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.

Mortality after exposure to polychlorinated biphenyls and dibenzofurans: 30 years after the "Yucheng accident".

BACKGROUND: In 1979, approximately 2,000 people in central Taiwan were accidentally exposed to polychlorinated biphenyls and dibenzofurans due to ingestion of contaminated cooking oil. This event was called Yucheng, "oil-syndrome" in Chinese. We followed the exposed persons and compared their cause-specific mortality with that of neighborhood referents 30 years after the accident. METHODS: We obtained age- and gender-matched referents from the 1979 neighborhoods of the exposed people. Cause-specific mortality was compared between exposed subjects (N=1803) and their neighborhood referents (N=5170) using standardized mortality ratios (SMR). Total person-years for the Yucheng subjects and neighborhood referents were 48,751 and 141,774, respectively. RESULTS: The SMR for all causes (SMR=1.2, 95% CI: 1.1-1.3), diseases of the circulatory system (SMR=1.3, 95% CI: 1.0-1.6), and diseases of the musculoskeletal system and connective tissue (SMR=6.4, 95% CI: 2.8-12.7) were elevated in Yucheng subjects. Among Yucheng males, the SMRs for diseases of the digestive system (SMR=1.9, 95% CI: 1.2-2.8), malignant neoplasm of stomach (SMR=3.5, 95% CI: 1.5-7.0), and malignant neoplasm of lymphatic and hematopoietic tissue (SMR=3.0, 95% CI: 1.1-6.6) were increased. The SMR for total neoplasms was increased (SMR=1.3, 95% CI: 0.9-1.7). CONCLUSION: We conclude that exposure to PCBs/PCDFs at levels that produced symptoms in many affects mortality patterns 3 decades after exposure.

[Promotive excretion of causative agents of Yusho by fermented brown rice with Aspergillus oryze in Yusho patients].

Forty two years have passed since the outbreak of Kanemi rice oil poisoning, namely, Yusho in the western Japan. However, even now the Yusho patients have been still suffering from several objective and subjective symptoms. In order to improve or, if possible, to cure such symptoms, the most important therapeutic treatment is considered to actively excrete the causative agents, that is, polychlorinated dibenzofurans (PCDFs) from the bodies of the patients and to reduce their body burdens. In rats, chlorophyll and dietary fiber have been shown to promote the fecal excretion of PCDFs and polychlorinated dibenzo-p-dioxins (PCDDs) and to reduce their levels in rats. In this study, we have examined whether such kinds of effect are also observed by fermented brown rice with Aspergillus oryzae (FBRA) containing 5% spirulina, which is so-called spirulina HI * GENKI, the health food and relatively rich with chlorophyll and dietary fiber, in eighteen Yusho patients. They were divided into two groups, namely group A, ten patients (3 males and 7 females) with the mean age of 67.7 years old and group B, eight patients (4 males and 4 females) with the mean age of 64.1 years old. Among the patients of group A, three patients were especially highly contaminated with PCDFs and we classified them into group A (High). Respective mean concentrations of PCDFs in the blood just before initiating this study were as follows; group A : 145 pg/g lipid, group A (High) : 371 pg/g lipid and group B : 52.1 pg/g lipid. Contamination levels of PCDFs, PCDDs and dioxin-like polychlorinated biphenyls (PCBs) in group A (High) were 1.7 to 2.6 times higher than those in group A and 2.4 to 7.1 times higher than those in group B. Accordingly, concentrations of dioxins (PCDFs + PCDDs + dioxin-like PCBs) in the blood of groups A, A (High) and B were, respectively, 194, 458 and 85 pg-TEQ/g lipid. Concentrations of PCBs were also the highest in group A (High) : 1399 ng/g lipid, in group A : 748 ng/g lipid and the lowest in group B : 456 ng/g lipid. Groups A and A (High) took around 7.0 g of spirulina HI * GENKI after each meal and three times a day for the first one year and for the second one year, they did not take spirulina HI * GENKI anymore. Group B took spirulina HI * GENKI with the same manner as the group A only for the second one year. The concentrations of PCDFs, PCDDs, dioxin-like PCBs and PCBs in the blood were also measured at the end of the first and second year, respectively. Assuming the body fat is also contaminated with these compounds at their concentrations on lipid weight basis in the blood and the content of body fat is 20% of 60 kg body weight, we computed the average amounts in their net excretion from the body of the patients due to spirulina HI * GENKI in the three groups. As a result, in group A (High), 341 ng-TEQ/patient of dioxins was excreted from the body, which was 3.4 times greater than that in group A and 12 times higher than that in group B. Therefore, promotive excretions of causative agents of Yusho were the most effective in group A (High) and we consider spirulina HI * GENKI is more effective from the therapeutic point of view in more highly contaminated Yusho patients.

Menstrual effects among women exposed to polychlorinated biphenyls and dibenzofurans.

BACKGROUND: Polychlorinated biphenyls (PCBs), dibenzofurans (PCDFs), and dibenzo-dioxins (PCDDs) may affect the female reproductive system in humans. A mass poisoning occurred in Taiwan due to PCBs/PCDFs-contaminated cooking oil, and was called the Yucheng (oil-disease in Chinese). We aimed to determine whether Yucheng women were affected in their menstruation. METHODS: After the event, we followed the exposed individuals and an age-matched neighborhood reference group. Menstrual cycle characteristics and age at menarche were obtained by a telephone interview. We used multiple linear and logistic regression to examine the association between PCBs/PCDFs and menstrual cycle characteristics, after adjusting for confounding factors. RESULTS: Totally 445 women responded satisfactorily and were included in the analyses of menstrual characteristics. Menstrual cycle irregularity and dysmenorrheal did not differ between Yucheng and referents. Yucheng women's menstrual cycles were 0.5 (95% CI: 0.0-0.5; p=0.03) days shorter than those of the referents. The Yucheng women with skin lesions caused by PCBs/PCDFs were more prominently affected, with the cycles 1.2 days shorter than the referents. Yucheng women exposed to PCBs/PCDFs at the premenacheal period had reduced cycle length (-0.7 day, 95% CI: -1.4 to 0.0; p=0.04) and longer days of menstrual flow (0.5 day, 95% CI: 0.0-1.0; p=0.04). Among those women who were exposed at an age of 5-9 years, menarche started slightly earlier with borderline significance. CONCLUSIONS: Shorter menstrual cycle length and a longer duration of bleeding in each cycle were found among women previously exposed to PCBs/PCDFs. These effects were more obviously observed among those exposed at premenarcheal ages.

Polychlorinated dibenzo-p-dioxins and dibenzofurans in different tissues of the cormorants (Phalacrocorax carbo) from Dongting Lake, China.

Tissue distribution provides important information regarding the pharmacokinetic behavior of pollutants and is invaluable when analyzing the risk posed to avian species by the exposure to such kind of pollutants. In this study, concentrations of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) were determined in muscle, liver, spleen, kidney, stomach, gall bladder, skin, heart, pancreas, intestine and lung tissue extracts of cormorants collected from Dongting Lake, China. Tissue distribution results showed preferential accumulation of PCDD/Fs in both liver and skin. The total concentration of PCDD/Fs ranged from 421 to 5696 pg/g lipid weight. Octachlorinated dibenzo-p-dioxin (OCDD) was the predominant congener in all tissues and contributed between 31% and 82% to all 17 PCDD/Fs in different tissues. The liver/muscle ratios progressively increased with the degree of chlorination of PCDDs, except for OCDD. The relative toxic potential of PCDDs and PCDFs in tissues were calculated using the World Health Organization (WHO) Toxic Equivalency Factors (TEFs) for birds. The concentrations of WHO-toxic equivalent in different tissues ranged between 14.8 and 2021 pg/g lipid weight. These results indicated PCDD/Fs may have been bio-accumulated in cormorant via food-web. Furthermore, when compared with studies reported in the literatures, the PCDD/Fs levels in the cormorant collected from Dongting Lake were still relatively high.

Tremetone and structurally related compounds in white snakeroot ( Ageratina altissima ): a plant associated with trembles and milk sickness.

Ingestion of white snakeroot ( Ageratina altissima ) can cause trembles in livestock and milk sickness in humans. The toxicity has been associated with tremetol, a relatively crude, multicomponent lipophilic extract of the plant. In this study, 11 different compounds were isolated from white snakeroot-derived lipophilic extracts from 18 collections. Six of the isolated compounds have not been previously reported to be found in white snakeroot. High-performance liquid chromatography (HPLC) analysis indicated that there are three different chemotypes of white snakeroot from the plant samples analyzed. Elucidation of these chemotypes may explain the sporadic and unpredictable toxicity of white snakeroot to livestock and humans.

Prenatal exposure to PCDDs/PCDFs and dioxin-like PCBs in relation to birth weight.

Several human studies have shown that low-level exposure to environmental contaminants, such as polychlorinated biphenyls (PCBs) and organochlorine pesticides, negatively influences birth outcomes. However, the effects of low-level exposure to polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like PCBs (DL-PCBs) on birth outcomes have not been clarified in human studies. A prospective cohort study was established to investigate the possible adverse effects of PCDDs/PCDFs and DL-PCBs on fetal growth and neurodevelopment. We recruited 514 pregnant women between July 2002 and October 2005 in Sapporo, Japan. We measured 29 congener levels of PCDDs/PCDFs and DL-PCBs in maternal blood. Using multiple liner regression analysis of the association between birth weight and the levels of PCDDs/PCDFs and DL-PCBs with full adjustments for potential confounders, a significant adverse effect was observed regarding total PCDDs toxic equivalents (TEQ) levels (adjusted beta=-231.5g, 95% CI: -417.4 to -45.6) and total PCDFs TEQ levels (adjusted beta=-258.8g, 95% CI: -445.7 to -71.8). Among male infants, significant adverse associations with birth weight were found for total PCDDs TEQ level, total PCDDs/PCDFs TEQ level, and total TEQ level. However, among female infants, these significant adverse associations were not found. With regard to individual congeners of PCDDs/PCDFs and DL-PCBs, we found significantly negative association with the levels of 2,3,4,7,8-PeCDF (adjusted beta=-24.5g, 95% CI: -387.4 to -61.5). Our findings suggest that prenatal low-level exposure to PCDDs and PCDFs, especially 2,3,4,7,8-PeCDF, may accumulate in the placenta and retard important placental functions, which result in lower birth weight.

[Relationship between blood dioxin levels and present/past clinical symptoms in Kanemi Yusho patients].

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.

[Serum levels of estradiol, progesterone and prolactin in patients with Yusho].

To evaluate chronic effect of polychlorinated biphenyls (PCB) and polychlorinated dibenzofurans (PCDF) on sex hormones and prolactin, serum levels of estradiol, progesterone and prolactin were studied in 71 female patients with Yusho and 23 controls in 2006. A negative correlation was found between blood PCB concentrations and estradiol levels. There were no significant correlations between blood PCDF concentrations and estradiol levels, progesterone levels or prolactin levels. However, the mean serum estradiol level was significantly lower in 29 patients with high PCDF concentration (higher than 200 pg/g lipid in blood) than in 30 patients with low PCDF concentration (lower than 200 pg/g lipid in blood). We conclude that abnormality of estradiol levels may be associated with blood PCB concentration and blood PCDF concentration in patients with Yusho.