Association of maternal serum concentration of hydroxylated polychlorinated biphenyls with maternal and neonatal thyroid hormones: The Hokkaido birth cohort study.

BACKGROUND: Evidence on the toxicity of hydroxylated metabolites of polychlorinated biphenyls (OH-PCBs) for thyroid hormones (TH) is limited, and the underlying mechanism remains unknown. OBJECTIVES: We aimed to investigate the effects of environmental prenatal exposure to OH-PCBs and maternal and neonatal TH levels, taking the maternal-fetal TH transfer into account. METHODS: In this prospective birth cohort (the "Hokkaido study") we included 222 mother-neonate pairs. We measured five OH-PCB isomers in maternal serum samples either during pregnancy or within 5 days of delivery. Thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from maternal blood samples at an early gestational stage (median; 11.1 weeks) and from heel prick samples of neonates between 4 and 7 days after birth. Multiple linear regression analysis and structural equation modeling (SEM) were performed to investigate the associations between maternal OH-PCB and maternal and neonatal TH levels. RESULTS: Median concentration of ∑OH-PCBs was 25.37 pg/g wet weight. The predominant isomer was 4-OH-CB187, followed by 4-OH-CB146+3-OH-CB153. In the fully adjusted linear regression analysis, maternal ∑OH-PCBs was positively associated with maternal FT4, and 4-OH-CB187 was positively associated with both maternal and neonatal FT4 levels. Maternal OH-PCBs showed no significant association with TSH among mothers and neonates. Path analysis indicated the indirect pathway from 4-OH-CB187 exposure to increased neonatal FT4, via maternal THs and neonatal TSH. CONCLUSIONS: These findings suggest that maternal exposure to OH-PCBs during pregnancy may increase both maternal and neonatal FT4 levels. Neonatal FT4 is presumed to be increased by prenatal 4-OH-CB187 indirectly, and this process may be mediated by maternal THs and neonatal TSH.

Current state of yusho and prospects for therapeutic strategies.

The mass food poisoning incident yusho occurred in Japan in 1968. It was caused by the ingestion of rice bran oil contaminated with polychlorinated biphenyls and various dioxins and dioxin-like compounds including polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDFs). Notably, PCDFs were found to contribute to approximately 65% of the total toxicity equivalent in the blood of yusho patients. Lipophilic dioxins are retained in the body for a longer period than previously estimated. Victims suffered from characteristic skin manifestations associated with non-specific systemic symptoms, neurological symptoms, and respiratory symptoms. The severe symptoms seen in the initial phase subsequently faded, but recently, improvements have scarcely been observed. The Yusho Group has been researching treatments for this condition. Several clinical trials with chelating agents or dietary fibers aimed at accelerating the excretion of compounds. While some treatments increased dioxin excretion, none provided satisfactory symptom relief. Concurrently, various phytochemicals and herbal extracts have been found to possess biological activities that suppress dioxin-induced toxicity via aryl hydrocarbon receptor or activate the antioxidant nuclear factor-erythroid 2-related factor-2 (NRF2) signal pathway, making them promising therapeutic candidates. Here, we summarize the current status of yusho and findings of clinical trials for yusho patients and discuss the treatment prospects.

Gender-specific association of exposure to non-dioxin-like polychlorinated biphenyls during pregnancy with methylation levels of H19 and long interspersed nuclear element-1 in cord blood in the Hokkaido study.

BACKGROUND: Associations between prenatal exposure to polychlorinated biphenyls (PCBs) and reduced birth-size, and between DNA methylation of insulin-like growth factor-2 (IGF-2), H19 locus, and long interspersed nuclear element-1 (LINE-1) and reduced birth-size are well established. To date, however, studies on the associations between prenatal exposure to PCBs and alterations in methylation of IGF-2, H19, and LINE-1 are lacking. Thus, in this study, we examined these associations with infant-gender stratification. METHODS: We performed a prospective birth cohort study using the Sapporo cohort from the previously described Hokkaido Birth Cohort Study on Environment and Children's Health conducted between 2002 and 2005 in Japan. In the final 169 study participants included in this study, we measured the concentrations of various non-dioxin-like PCBs in maternal blood during pregnancy using high-resolution gas chromatography/high-resolution mass spectrometry. IGF-2, H19 and LINE-1 methylation levels in cord blood were measured using the bisulfite pyrosequencing methods Finally, we assessed the associations between prenatal exposure to various PCBs and the gene methylation levels using multiple regression models stratified by infant gender. RESULTS: We observed a 0.017 (95% confidence interval [CI]: 0.003-0.031) increase in the log10-transformed H19 methylation levels (%) in cord blood for each ten-fold increase in the levels of decachlorinated biphenyls (decaCBs) in maternal blood among all infants. Similarly, a 0.005 (95% CI: 0.000-0.010) increase in the log10-transformed LINE-1 methylation levels (%) in cord blood was associated with each ten-fold increase in heptachlorinated biphenyls (heptaCBs) in maternal blood among all infants. In particular, we observed a dose-dependent association of the decaCB levels in maternal blood with the H19 methylation levels among female infants (P value for trend=0.040); likewise a dose-dependent association of heptaCB levels was observed with LINE-1 methylation levels among female infants (P value for trend=0.015). Moreover, these associations were only observed among infants of primiparous women. CONCLUSION: Our results suggest that the dose-dependent association between prenatal exposure to specific non-dioxin-like PCBs and increases in the H19 and LINE-1 methylation levels in cord blood might be more predominant in females than in males.

Dioxin-metabolizing genes in relation to effects of prenatal dioxin levels and reduced birth size: The Hokkaido study.

OBJECTIVES: We investigated the effects of maternal polymorphisms in 3 genes encoding dioxin-metabolizing enzymes in relation to prenatal dioxin levels on infant birth size in Japan. METHODS: We examined the relationship between dioxin exposure and birth size in relation to the polymorphisms in the genes encoding aromatic hydrocarbon receptor (AHR [G>A, Arg554Lys]), cytochrome P450 (CYP) 1A1 (T6235C), and glutathione S-transferase mu 1 (GSTM1; Non-null/null) in 421 participants using multiple linear regression models. RESULTS: In mothers carrying the GSTM1 null genotype, a ten-fold increase in total dioxin toxic equivalency was correlated with a decrease in birth weight of -345g (95% confidence interval: -584, -105). CONCLUSIONS: We observed adverse effects of maternal GSTM1 null genotype on birth weight in the presence of dioxins exposure during pregnancy.

Effect of colestimide on the concentrations of polychlorinated dibenzo-p-dioxins, polychlorinated dizenzofurans, and polychlorinated biphenyls in blood of Yusho patients.

BACKGROUND: Oral colestimide was reported to lower the concentration of PCDDs, PCDFs, and PCB in the blood of humans. A pilot study showed that the arithmetic mean total TEQ concentrations of PCDDs, PCDFs, and PCBs in the blood of subjects after the trial decreased approximately 20 % compared to pre-trial levels, suggesting that colestimide could decrease human dioxin levels. We designed the current clinical trial study based on this information. In this study, we examined whether colestimide could reduce the individual congener concentrations of PCDDs, PCDFs, and PCBs in the blood of Yusho patients. METHODS: Out of the 36 Yusho patients who participated in the clinical trial, 26 patients self-administered colestimide 3 g/day orally for 6 months. The concentrations of PCDDs, PCDFs and PCBs in the blood of 26 Yusho patients before the trial were compared with those after the trial. RESULTS: The arithmetic mean total TEQ concentrations of PCDDs, PCDFs, non-ortho PCBs, and mono-ortho PCBs in the blood of the 26 Yusho patients before and after the clinical trial were 42-303 (mean: 130, median: 120) and 43-283 (mean: 132, median: 118) pg TEQ/g lipid, respectively. The sums of the concentrations of 58 PCB congeners measured in the blood of Yusho patients before and after the trial were 321-2643 (mean: 957, median: 872) and 286-2007 (mean: 975, median: 806) ng/g lipid, respectively, indicating that the concentrations of PCDDs, PCDFs, and PCBs after the trial were almost the same as those before the trial. Among congeners of PCDDs, PCDFs, dioxin-like PCBs, and non-dioxin-like PCBs, most congeners of these compounds did not show a statistically significant decrease after the trial. CONCLUSION: Colestimide may not be beneficial in reducing the high blood levels of dioxin-like compounds in Yusho patients.

[The Distribution of Dioxin Concentrations in the Blood of Yusho Patients].

In 1968, the contamination of cooking oil by heat-degraded polychlorinated biphenyls (PCBs) caused a case of mass poisoning, the so-called Yusho incident. The cause of Yusho disease is thought to be ingested toxic substances, including not only PCBs but also polychlorinated dibenzofuran (PCDFs) in Kanemi rice oil. We previously measured dioxins concentrations in the blood of 854 Yusho patients by annual medical examination from 2001 to 2013. We determined the concentrations of 2,3,4,7,8-PeCDF, 1,2,3,4,7,8-HxCDF, 1,2,3,6,7,8-HxCDF and 3,3',4,4',5,5'-HxCB (#169) in the blood of Yusho patients were more than double those of normal controls. In 2012, a new Yusho criteria was established. Family members living with a Yusho patient were also certified as Yusho patients and called Yusho family cohabitant patients. In this study, we compared the distribution of 2,3,4,7,8-PeCDF concentration in the blood of Yusho patients and Yusho family cohabitant patients. It was suspected that the distribution of 2,3,4,7,8-PeCDF concentration in Yusho family cohabitant patients would be lower than that of Yusho patients.

A Study on Polychlorinated Biphenyls Specifically--Accumulated in Blood of Yusho Patients Collected from Medical Check-Ups in 2012.

In this study, we analyzed polychlorinated biphenyls (PCBs) in the blood of Yusho patients collected from medical check-ups, which were conducted in 2012. The results show that 65 PCB isomers, not including non-ortho PCBs, were detected in the blood samples, and the total concentration was 620 ng g(-1) lipid. This value was comparable to the concentration in blood samples collected in 2005, and indicated that PCB concentrations in Yusho patients remained unchanged from 2005 to 2012. Here, we focused on major and specific PCB isomers in the blood samples of Yusho patients and normal controls. Examples of the former include hexaCB-153, hexaCB-138, and heptaCB-180, which are detected in human blood, while the latter include hexaCB-156, hexaCB-157, and heptaCB-189, and are highly detected in the blood of Yusho patients. Additionally, we tried to determine why the specific isomers were highly accumulated in the blood of Yusho patients as compared to the normal controls. We therefore analyzed these isomers in the contaminated rice oil, and found that the concentrations of hexaCB-156, hexaCB-157, and heptaCB-189 were 1800, 450, and 190 ng g(-1), respectively. Notably, previous studies indicated that these isomers might not be easily metabolized in humans. Therefore, these findings demonstrated that these isomers were highly accumulated in the blood of Yusho patients.

Effects of in utero exposure to polychlorinated biphenyls, methylmercury, and polyunsaturated fatty acids on birth size.

The adverse effects of in utero exposure to polychlorinated biphenyls (PCBs) or methylmercury (MeHg), and the beneficial effects of nutrients from maternal fish intake might have opposing influences on fetal growth. In this study, we assessed the effects of in utero exposure to PCBs and MeHg on birth size in the Japanese population, which is known to have a high frequency of fish consumption. The concentrations of PCBs and polyunsaturated fatty acids in maternal blood, and the total mercury in hair (as a biomarker of MeHg exposure) were measured during pregnancy and at delivery. Maternal intakes of fish (subtypes: fatty and lean) and shellfishes were calculated from a food frequency questionnaire administered at delivery. Newborn anthropometric measurement data were obtained from birth records. The associations between chemical exposures and birth size were analyzed by using multiple regression analysis with adjustment for confounding factors among 367 mother-newborn pairs. The birth weight was 3073±37 g (mean±SD). The incidence of babies small for gestational age (SGA) by weight was 4.9%. The median concentrations of total PCBs and hair mercury were 108 ng/g lipid and 1.41 µg/g, respectively. There was no overall association between mercury concentrations and birth weight, birth length, chest circumference, and head circumference. We observed that the risk of SGA by weight decreased with increasing mercury concentration in regression analyses with adjustment for polyunsaturated fatty acids. Our results suggest that the beneficial effect of essential nutrition may mask the adverse effects of MeHg on birth size. The concentrations of PCBs had no association with birth size.

Demographic, behavioral, dietary, and socioeconomic characteristics related to persistent organic pollutants and mercury levels in pregnant women in Japan.

Persistent organic pollutants and mercury are known environmental chemicals that have been found to be ubiquitous in not only the environment but also in humans, including women of reproductive age. The purpose of this study was to evaluate the association between personal lifestyle characteristics and environmental chemical levels during the perinatal period in the general Japanese population. This study targeted 322 pregnant women enrolled in the Hokkaido Study on Environment and Children's Health. Each participant completed a self-administered questionnaire and a food-frequency questionnaire to obtain relevant information on parental demographic, behavioral, dietary, and socioeconomic characteristics. In total, 58 non-dioxin-like polychlorinated biphenyls, 17 dibenzo-p-dioxins and -dibenzofuran, and 12 dioxin-like polychlorinated biphenyls congeners, perfluorooctane sulfonate, perfluorooctanoic acid, and mercury were measured in maternal samples taken during the perinatal period. Linear regression models were constructed against potential related factors for each chemical concentration. Most concentrations of environmental chemicals were correlated with the presence of other environmental chemicals, especially in the case of non-dioxin-like polychlorinated biphenyls and, polychlorinated dibenzo-p-dioxins and -dibezofurans and dioxin-like polychlorinated biphenyls which had similar exposure sources and persistence in the body. Maternal smoking and alcohol habits, fish and beef intake and household income were significantly associated with concentrations of environmental chemicals. These results suggest that different lifestyle patterns relate to varying exposure to environmental chemicals.

[Inter-laboratory crosscheck study of dioxins and PCBs in human blood samples].

We developed an analytical method for accurately determining the concentrations of dioxin and polychlorinated biphenyls(PCBs) in a blood volume of 5 g. Inter-laboratory crosscheck is available for maintaining the quality of dioxin and PCB analysis. We carried out the crosschecks of dioxin and PCB analysis in the blood with domestic analysis organizations. Two crosschecks each of dioxin and PCB analysis were carried out from 2007 through 2011. As a result, the findings of our analysis accorded well with the analyses of the other organizations. We believe that our analytical method is sufficiently reliable.

Development of a newly large-volume injection system for dioxin determinations in blood of Yusho patients.

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.

The changes in dioxin concentrations in the blood of Yusho patients from 2004 to 2010.

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.

Improvement of measurement method for hydroxylated polychlorinated biphenyls (OH-PCBs) in blood samples using LC/MS/MS.

Hydroxylated polychlorinated biphenyls (OH-PCBs) are well known as metabolites of PCBs in the human body. We improved a measurement method for OH-PCBs in blood samples using LC/MS/MS. A new 2 microm particle column was used, and the analytical conditions for the LC/MS/MS measurements were optimized. The improved method is more sensitive than the conventional method for 5g blood samples. And, this method is effective at determining the concentrations of OH-PCBs, PCBs and dioxins from the same sample without special treatment of the sample such as derivatization.

Concentration of hydroxylated polychlorinated biphenyls (OH-PCBs) in the blood of Yusho patients in 2010.

Hydroxylated polychlorinated biphenyls (OH-PCBs) are formed as major metabolites of PCBs by cytochrome P450 enzyme-mediated oxidation. It has been reported that their total concentration in serum samples of Yusho patients ranged from 390 to 1300 pg/g. We measured the concentration of OH-PCBs in blood collected from 183 Yusho patients living in Japan in 2010. The major OH-PCB metabolites were 4-OH-CB187 (ND-1300 pg/g-wet), 4-OH-CB146 + 3-OH-CB153 (8.4-1200 pg/g-wet), 4-OH-CB109 (ND-530 pg/g-wet) and 4'-OH-CB172 (ND-380 pg/g-wet). The total OH-PCBs ranged from 36 to 3800 pg/g-wet. A positive relationship between the concentrations of OH-PCBs and PCBs was observed, but no significant relationship between the concentrations of OH-PCBs and PCDD/DFs was observed.

Individuals' half-lives for 2,3,4,7,8-penta-chlorodibenzofuran (PeCDF) in blood: correlation with clinical manifestations and laboratory results in subjects with Yusho.

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

Genetic association of aromatic hydrocarbon receptor (AHR) and cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) polymorphisms with dioxin blood concentrations among pregnant Japanese women.

Dioxins are metabolized by cytochrome P450, family 1 (CYP1) via the aromatic hydrocarbon receptor (AHR). We determined whether different blood dioxin concentrations are associated with polymorphisms in AHR (dbSNP ID: rs2066853), AHR repressor (AHRR; rs2292596), CYP1 subfamily A polypeptide 1 (CYP1A1; rs4646903 and rs1048963), CYP1 subfamily A polypeptide 2 (CYP1A2; rs762551), and CYP1 subfamily B polypeptide 1 (CYP1B1; rs1056836) in pregnant Japanese women. These six polymorphisms were detected in 421 healthy pregnant Japanese women. Differences in dioxin exposure concentrations in maternal blood among the genotypes were investigated. Comparisons among the GG, GA, and AA genotypes of AHR showed a significant difference (genotype model: P=0.016 for the mono-ortho polychlorinated biphenyl concentrations and toxicity equivalence quantities [TEQs]). Second, we found a significant association with the dominant genotype model ([TT+TC] vs. CC: P=0.048 for the polychlorinated dibenzo-p-dioxin TEQs; P=0.035 for polychlorinated dibenzofuran TEQs) of CYP1A1 (rs4646903). No significant differences were found among blood dioxin concentrations and polymorphisms in AHRR, CYP1A1 (rs1048963), CYP1A2, and CYP1B1. Thus, polymorphisms in AHR and CYP1A1 (rs4646903) were associated with maternal dioxin concentrations. However, differences in blood dioxin concentrations were relatively low.

Maternal exposure to high levels of dioxins in relation to birth weight in women affected by Yusho disease.

BACKGROUND: 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. OBJECTIVE: The Yusho cohort was used to evaluate the effect of maternal exposure to PCDDs, PCDFs, and PCBs on birth weight. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Concentrations of polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and polychlorinated biphenyls in blood and breast milk collected from pregnant women in Sapporo City, Japan.

We measured the concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), dioxin-like polychlorinated biphenyls (PCBs), and non-dioxin-like PCBs in paired samples of blood and breast milk collected from 67 secundiparas in Sapporo City, Japan, and combined this data with those of the 30 secundiparas previously measured. The arithmetic mean total toxic equivalents (TEQ-WHO) concentrations of PCDDs, PCDFs, non-ortho PCBs, and mono-ortho PCBs in blood and breast milk of the 97 secundiparous subjects were 3.0-23 (mean: 13, median: 14) and 2.7-20 (mean: 8.6, median: 8.5) pg TEQ g(-1) lipid, respectively. The sums of the concentrations of 56 non-dioxin-like PCB congeners that were measured in the subjects' blood and breast milk were 16-326 (mean: 107, median: 100) and 12-252 (mean: 73, median: 67) ng g(-1) lipid, respectively. The partitioning ratios of individual congeners of PCDDs, PCDFs, dioxin-like PCBs, and non-dioxin-like PCBs from blood to breast milk in secundiparas were almost the same as those of primiparas that have been recently reported, suggesting that the partitioning ratios of these compounds from maternal blood to breast milk in women is little affected by delivery. Furthermore, the partition of PCB congeners with chlorine at the 2-, 3-, 4'-, and 5-positions or the 2-, 4-, 4'-, and 5-positions of the biphenyl ring from the blood to the breast milk tended to occur at a higher level than that of other congeners. In particular, the levels of tetraCB-74 and hexaCB-146 in the breast milk for both primiparous and secundiparous mothers were slightly higher than those in the blood.

Comparison of the concentrations of polychlorinated biphenyls and dioxins in mothers affected by the Yusho incident and their children.

Accumulated maternal dioxins are passed onto the fetus and neonate via the placenta and maternal milk. In Japan in 1968, an accidental human exposure to rice oil contaminated with polychlorinated biphenyls (PCBs) and other dioxin-related compounds, such as polychlorinated dibenzofurans (PCDFs), led to development of Yusho oil disease. We investigated differences in blood dioxin concentrations in mother-children pairs affected by the Yusho incident. From 2002 to 2008, blood samples were collected from 26 pairs of Yusho mothers and their children (19 mothers, 26 children). Specific congeners of seven polychlorinated dibenzo-p-dioxins (PCDDs), ten PCDFs, and four non-ortho PCBs were analyzed. The children had significantly lower TEQ concentrations of PCDDs, PCDFs, and coplanar PCBs compared to their mothers. The mother-child difference in blood concentrations varied with the congeners; the largest for 2,3,4,7,8-pentaCDF and the smallest for 1,2,3,4,6,7,8-heptaCDD. The level for 2,3,4,7,8-pentaCDF, which characterizes Yusho oil disease, was approximately 17-30 times higher in the mothers than in the general population, whereas there were no significant differences between children in the formula-fed group and the general population. In contrast, the mean level for 2,3,4,7,8-pentaCDF in the breast-fed group was approximately 1.5 times, (range 0.5-6.5 times) higher than that in the general population. Over 30 years after the Yusho incident, the mean blood dioxin levels in the offspring were only a fraction of the levels in their mothers. This is more consistent with exposure via breast milk than via transplacental transfer in the Yusho incident.

Measurement method for hydroxylated polychlorinated biphenyls in the blood of Yusho patients by liquid chromatography-electrospray tandem mass spectrometry.

Hydroxylated polychlorinated biphenyls (OH-PCBs) are formed as major metabolites of PCBs by cytochrome P450 enzyme-mediated oxidation. It has been reported that their total concentration in serum samples of Yusho patients ranged from 390 to 1300 pg/g. We developed a measurement method for OH-PCBs in blood samples by LC/MS/MS. This method is effective at determining the concentrations of PCDDs, PCDFs, Co-PCBs and OH-PCBs from the same sample without special treatment of the sample. The concentration of OH-PCBs in the blood of Yusho patients was examined using this method. The major OH-PCB metabolites were 4-OH-CB187 (54-906 pg/g-wet), 4-OH-CB146 + 3-OH-CB153 (32-527 pg/g-wet), 4-OH-CB109 (ND-229 pg/g-wet) and 4'-OH-CB172 (ND-143 pg/g-wet). The total OH-PCBs ranged from 95 to 1740 pg/g-wet.