Hironori Hirakawa

Effects of Prenatal Exposure to Polychlorinated Biphenyls and Dioxins on Mental and Motor Development in Japanese Children at 6 Months of Age

Several studies have shown that prenatal and/or postnatal background-level exposure to environmental chemicals, such as polychlorinated biphenyls (PCBs) and dioxins, induces adverse effects on the neurodevelopment of children. However, other studies have not detected any harmful influences on neurodevelopment. Furthermore, except in western countries, no developmental tests have been carried out in relation to detailed assessment of exposure to PCBs and dioxins. In this study (the Hokkaido Study on Environment and Children’s Health), the effect of prenatal exposure to background levels of PCBs and dioxins on infant neurodevelopment in Japan/Sapporo was elucidated. The associations between the total or individual isomer level of PCBs and dioxins in 134 Japanese pregnant women’s peripheral blood and the mental or motor development of their 6-month-old infants were evaluated using the second edition of the Bayley Scales of Infant Development. The mean level of total toxicity equivalency quantity (TEQ) was 18.8 (4.0–51.2) pg/g lipid in blood of 134 mothers. After adjustment for potential confounding variables, the total TEQ value was shown not to be significantly associated with mental developmental index (MDI) or psychomotor developmental index (PDI). However, the levels of one polychlorinated dibenzo-p-dioxin (PCDD) isomer, total PCDDs, and total PCDDs/polychlorinated dibenzofurans (PCDFs) were significantly negatively associated with MDI, and the levels of two PCDD isomers and three PCDF isomers were significantly negatively associated with the PDI. In conclusion, the background-level exposure of several isomers of dioxins during the prenatal period probably affects the motor development of 6-month-old infants more than it does their mental development.

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.

Postnatal exposure to chlorinated dioxins and related chemicals on lymphocyte subsets in Japanese breast-fed infants

Effects of postnatal exposure to polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and coplanar polychlorinated biphenyls (Co-PCBs) on lymphocyte subpopulations were investigated in the peripheral blood of 36 breast-fed Japanese babies. As a result, estimated total intakes of these chemicals in toxic equivalent quantity (TEQ) converted into 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) equivalents from the breast milk positively and negatively correlated with the respective percentages of CD4+ and CD8+ lymphocytes in the blood of breast-fed babies. Consequently, the ratios of CD4+ to CD8+ T cells showed significant increasing tendency with the estimated total TEQ intakes. Therefore, our study suggests that exposure to background levels of the highly toxic organochlorine compounds through the breast milk influences the human neonatal immune system.

Polychlorinated dibenzo-p-dioxins and related compounds: Correlations of levels in human tissues and in blood

We investigated PCDDs and related compounds levels in human tissue and blood obtained from the general population, and the correlation factor was calculated from the findings. None of the congeners in brain, muscle and lung were correlated except for 2,3,7,8-tetrachlorodibenzo-p-dioxin and octachlorodibenzo-p-dioxin in the brain (p < 0.05). In other tissues, all congeners had relatively good correlations to those in blood (r > 0.707). These congeners detected in blood were at high concentrations in the environment and human body. Therefore, we concluded that these congener levels in the blood might be useful for estimating these congener levels in human tissue.

Effects of contamination level of dioxins and related chemicals on thyroid hormone and immune response systems in patients with "Yusho".

Effects of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and coplanar polychlorinated biphenyls (Co-PCBs) on thyroid hormone and immune response systems were examined in 16 Yusho patients at about 30 years after the outbreak of the Yusho accident. Their toxic equivalent (TEQ) levels in the blood were 27.8-1048.5 pg/g fat with the median level of 222.4 pg/g fat, which was about seven times higher than that of healthy Japanese people. Even at such high blood TEQ concentrations, they seemed not to affect the serum levels of thyroid hormones, thyroid stimulating hormone (TSH), immunoglobulins (A, G and M), autoantibodies (antinuclear antibody, rheumatoid and lupus erythematosus (LE) factors), and lymphocyte subsets in the blood. However, positive rates of rheumatoid factor were considered to increase in higher blood TEQ groups. This investigation was done using rather small number of Yusho patients, so further large-scale investigations are needed to get more conclusive findings concerning their effects on thyroid hormone and immune response systems.

Congener-specific analysis of non-dioxin-like polychlorinated biphenyls in blood collected from 195 pregnant women in Sapporo City, Japan.

We conducted a congener-specific analysis of non-dioxin-like polychlorinated biphenyls (non-dioxin-like PCBs) in blood collected between July 2002 and July 2004 from 195 pregnant women living in Sapporo City of Hokkaido Prefecture, Japan. The present study is one of the few studies in which full congener concentrations of non-dioxin-like PCBs have been measured in the blood of pregnant women. Of the 195 pregnant women, 101 were primipara (mean: 28.8 years, median: 28.0 years) and 94 were multipara (mean: 32.3 years, median: 33.0 years). Among the 197 non-dioxin-like PCB congeners, 58 congeners were identified in the blood of pregnant women. The arithmetic mean total concentrations of 58 non-dioxin-like PCB congeners in the blood of primiparous and multiparous mothers in Sapporo City were 42.2-329.3 (mean: 114.5, median: 98.6) and 31.5-258.0 (mean: 100.3, median: 91.4)ngg(-1)lipid, respectively. The results show that the contamination of non-dioxin-like PCBs in the blood of women has decreased compared to past levels in other domestic areas, in which the subject age was similar to that in this study. The results of the present study indicate that current levels of non-dioxin-like PCBs in the blood of Japanese women and can be used as baseline data for future temporal trends. The sums of the ratios of the concentrations of hexaCBs and heptaCBs to the total concentrations of 58 non-dioxin-like PCB congeners in the blood of primiparous and multiparous mothers were 78.5% and 77.7%, respectively. The hexaCBs ratios in the blood of primiparous and multiparous mothers were 45.4% and 44.7%, respectively. HexaCB-153 among hexaCBs congeners, the most abundant congener in the blood of primiparous and multiparous mothers, contributed approximately 22.0% and 21.8% to the total concentrations of 58 non-dioxin-like PCBs congeners that were measured in the blood, respectively. Among the non-dioxin-like PCB congeners measured in the present study, hexaCB-138, heptaCB-170, heptaCB-180, and heptaCB-182/heptaCB-187 also showed high ratios to total concentrations of 58 non-dioxin-like PCB congeners detected in the blood of primiparous and multiparous mothers. With regard to the relationship between the total concentrations of 58 non-dioxin-like PCB congeners in maternal blood and the number of deliveries or the age of primiparous and multifarious mothers, the total levels of these PCB congeners tended to decreases with increases in the number of deliveries and significantly increased with increasing maternal age in both groups. Furthermore, significant correlations were observed between the total concentrations of these PCB congeners in blood and the age of primiparae and multiparae. The concentrations of hexaCB-153 in the blood of primiparous and multiparous mothers showed a close correlation to the total concentrations of these PCBs, suggesting that hexaCB-153 could be an indicator of total concentrations of non-dioxin-like PCB congeners in the blood of pregnant women.

Polychlorinated dibenzo-p-dioxins and related compounds: the blood levels of young Japanese women.

We investigated PCDDs and related compounds in the blood of young Japanese women, approximately 20 years of age, who had not yet had children, and discussed how the TEQ level of PCDDs and related compounds in their blood may affect the next generation. Means of total TEQ levels were 0.063 pg/g for whole blood basis and 21 pg/g for lipid basis. TEQ of PCDDs, PCDFs and coplanar PCBs accounted for about 43, 34 and 23% of the total TEQ in the whole blood basis, respectively. In the lipid basis, their values were about 44, 34 and 22%, respectively. Previously, we investigated PCDDs and related compounds levels in mothers breast milk, lymphocyte subpopulation and thyroid function of their children, and found negative correlations between the TEQ level of PCDDs and related compounds and CD4+/CD8+, and/or the TEQ level of PCDDs and related compounds and the T4 level in 36 mothers and children. Of these cases, the average age was approximately 28 years. PCDDs and related compounds may be related to immunopathy, such as atopic dermatitis. The effects of PCDDs and related compounds on babies of young Japanese women are important and must be further evaluated.

Concentrations of polychlorinated biphenyls in blood of Yusho patients over 35 years after the incident

We conducted a congener-specific analysis of polychlorinated biphenyls (PCBs) in blood collected from 242 Yusho patients (mean: 65.5 years, median: 67.0 years) and 74 Yusho-suspected persons (mean: 54.7 years, median: 55.0 years) in 2004, and compared each congener concentrations of PCBs among the groups of Yusho patients, Yusho-suspected persons, and normal controls (mean: 68.1 years, median: 67.0 years) 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, and the congener profiles were the same as those obtained in normal controls. The sums of the concentrations of 64 PCB congeners in the blood of Yusho patients and Yusho-suspected persons were 40-3032 (mean: 645, median: 536) and 20-1418 (mean: 355, median: 317) ng g(-1) lipid, respectively, and the concentrations were 50% higher and 20% lower than those of normal controls, respectively. The relative contribution ratios of the concentrations of the triCBs, tetraCBs, and pentaCBs to the total concentrations of 64 PCB congeners in the blood of Yusho patients were slightly lower than those of Yusho-suspected persons and normal controls, and the ratios of nonaCBs and decaCB-209 concentrations were nearly the same among the Yusho patients, Yusho-suspected persons, and normal controls. However, the ratios of the concentrations of hexaCBs, heptaCBs, and octaCBs to the total concentrations of 64 PCB congeners in the blood of Yusho patients tended to be slightly higher compared to those of the Yusho-suspected persons and 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 of the Yusho patients were 3.4, 3.8, 3.9, and 3.8 times higher than those of the normal controls, respectively, indicating that even now, 35 years after exposure, Yusho patients still have a higher concentration of hexaCB-156, hexaCB-157, heptaCB-181, and heptaCB-189 in their blood than do unaffected people. These four congeners may be considered the most important congeners for evaluating the PCBs toxicity of Yusho patients.

Toxic evaluation of PCDDs, PCDFs and coplanar PCBs in breast-fed babies of Yusho and healthy mothers

Abstract Levels of PCDDs, PCDFs and coplanar PCBs were measured in human breast milk obtained from two Yusho patients and nine healthy subjects. The concentrations of PCDDs, PCDFs and coplanar PCBs in breast milk of respective Yusho patients were 18.8 and 29.6, 168.2 and 417.3, and 23.8 and 55.1 pg Toxic Equivalents (TEQs)/g fat, respectively, and their mean concentrations in normal controls were 8.1, 4.8 and 21.8 pg TEQs/g fat, respectively. The results also indicated that there was a significant difference between Yusho patients and normal subjects in breast milk concentrations of certain isomers of PCDDs, PCDFs and coplanar PCBs. Daily intakes of TEQ values were estimated to be 519 and 2216 pg TEQs/kg/day for breast-feeding babies of Yusho patients, and to be from 93 to 197 pg TEQs/kg/day for healthy subjects. These TEQs values were much more greater than the ADI of 1 pg/kg/day. therefor, we should give due attention to the possible health effects due to PCDDs, PCDFs and coplanar PCBs in the breast milk of healthy mothers, as well as Yusho mothers.

Effects of highly toxic organochlorine compounds retained in human body on induction of sister chromatid exchanges in cultured human lymphocytes

In this study, we investigated the effect of mixture of the organochlorine compounds, which very resembled their contamination of healthy Japanese people in its composition, on the induction of sister chromatid exchanges (SCEs) in human whole-blood cultures in order to clarify their genotoxicity as a whole. The following results were obtained. Regardless of the presence or absence of 7,8-benzoflavone (ANF) in the blood culture system, we could observe a fairly good dose-response relationship between the concentration of the mixture of organochlorine compounds and the induction of SCEs/cell. In particular, we found that 50% effective concentration of the mixture of the organochlorine compounds was considered to be only about 3 times greater level over the average concentration in the healthy people, namely 70ppt as 2,3,7,8-TCDD, in the absence of ANF and about 8 times more than that in the presence of ANF.