Association of prenatal exposure to dioxin-like compounds, polychlorinated biphenyl, and methylmercury with event-related brain potentials in school-aged children: The Hokkaido study.

Previous studies have indicated that prenatal exposure to dioxin-like compounds (DLC) or polychlorinated biphenyl (PCB) has a negative association with neurodevelopment in school-aged children. Event-related brain potentials (ERP) can reveal subtle and specific differences in the modulation of cognitive processes that are assumed when they are associated with lower levels of prenatal exposure to DLC or PCBs. This prospective birth cohort study was conducted to examine the association between prenatal exposure to relatively low levels of DLC, PCB or methylmercury (MeHg), and ERP. A total of 55 children who were 13 years old participated in a 3-stimulus oddball task to detect P3a and P3b waves. The task required participants to respond to a target among random stimuli at two difficulty levels. The P3a amplitude reflects an automated attention capture process, and P3b reflects a voluntary attention allocation process. We analyzed DLC congeners in blood samples from four groups, including 7 polychlorinated dibenzo-p-dioxins (PCDD), 10 polychlorinated dibenzofuranes (PCDF), 4 non-ortho PCBs, and 8 mono-ortho PCBs. PCB-153 was chosen as an indicator because of its high correlation with the sum of 58 NDL (non-dioxin-like)-PCBs. MeHg exposure level was assessed by the mercury concentration in hair samples (HHg) taken during the perinatal period. The reaction time to the target stimulus during the oddball task shortened with the increasing MeHg exposure level. Furthermore, P3b latency, which reflect response decision and correlates with reaction time, was also shortened with increasing MeHg level in the difficult condition. These results are counterintuitive because shorter reaction times or rapid decision making reflected by P3 latency are generally favorable. This might be due to nutritional factors such as fatty acids, which have beneficial effects on brain development. The P3a amplitude decreased with non- and mono-ortho PCB and HHg levels, regardless of the difficulty level, and with PCDD, PCDF, and total DLC levels, especially in the difficult condition. P3b latency shortened with HHg, and P3b amplitude decreased with mono-ortho PCBs and PCB-153 in both conditions and with PCDD, PCDF, non-ortho PCBs, and total DLC in the difficult condition. In conclusion, we found an association between prenatal exposure to DLC and a decrease in both P3a and P3b amplitude, even when DLC levels were lower than in most previous studies. Additionally, our results suggest that the automated attention capture process reflected by P3a is associated with maternal MeHg exposure and that the voluntary attention allocation process reflected by P3b is associated with PCB-153. However, these results should be interpreted with caution because of the limitations on sample size, population bias, and statistical analyses.

Differences in the responses of three plasma selenium-containing proteins in relation to methylmercury-exposure through consumption of fish/whales.

Putative protective effects of selenium (Se) against methylmercury (MeHg) toxicity have been examined but no conclusion has been reached. We recently reported the lack of serious neurological symptoms in a Japanese fish-eating population with high intakes of MeHg and suggested a potential protective role for Se. Here, relationships between levels of Hg and Se in the blood and plasma samples, with a quantitative evaluation of Se-containing proteins, obtained from this population were examined. While levels of the whole-blood Hg (WB-Hg) and plasma Se (P-Se) showed a positive correlation, stratified analysis revealed that they correlated only in samples with higher (greater than the median) levels of MeHg. A food frequency questionnaire showed that consumption of fish/whales correlated with WB-Hg, but not with P-Se, suggesting that the positive correlation between WB-Hg and P-Se might not be the result of co-intake of these elements from seafood. Speciation of plasma Se revealed the differences in the responses of two plasma selenoproteins, glutathione peroxidase (GPx) and selenoprotein P (SePP), in relation to Hg exposure. In the high-Hg group, SePP showed a positive correlation with WB-Hg, but GPx did not. In the low-Hg group, neither SePP nor GPx showed any correlation with WB-Hg. These observations suggest that the increase in P-Se in the high-Hg group might be associated with an increase in SePP, which may, in turn, suggest an increased demand for one or more selenoproteins in various organs, for which SePP supplies the element.

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.

Methylmercury exposure and neurological outcomes in Taiji residents accustomed to consuming whale meat.

Methylmercury (MeHg) is a major environmental neurotoxicant that causes damage to the central nervous system. In Japan, industrial emission of MeHg has resulted in MeHg intoxication in Minamata and Niigata, the so-called Minamata disease. Humans are exposed to MeHg derived from natural sources, primarily fish and fish predators. Therefore, MeHg continues to be an environmental risk to human health, particularly in susceptible populations that frequently consume substantial amounts of fish or fish predators such as whale. This study aimed to investigate the health effects of MeHg exposure in adults. The subjects were 194 residents (117 males, 77 females; age 20-85 years) who resided in the coastal town of Taiji, the birthplace of traditional whaling in Japan. We analyzed hair for mercury content and performed detailed neurological examinations and dietary surveys. Audiometry, magnetic resonance imaging, and electromyography were performed to diagnose neurological defects. Whole blood mercury and selenium (Se) levels were measured in 23 subjects. The geometric mean of the hair mercury levels was 14.9 µg/g. Twelve subjects revealed hair mercury levels >50 µg/g (NOAEL) set by WHO. Hair mercury levels significantly correlated with daily whale meat intake. These results suggested that residents in Taiji were highly exposed to MeHg by ingesting MeHg-contaminated whale meat. Multivariate regression analysis demonstrated no significant correlations between hair mercury levels and neurological outcomes, whereas some of the findings significantly correlated with age. A significantly positive correlation between whole blood mercury and Se levels was observed and the whole blood mercury/Se molar ratios of all subjects were <1. These findings suggested that sufficient Se intake might be one of causes of the absence of adverse effects of MeHg exposure in this study.

Methylmercury monitoring study in Karakuwacho peninsula area in Japan.

Methylmercury (MeHg) is a worldwide concern owing to its adverse health effects. To explore MeHg exposure burdens and the potential contributing factors in different subpopulations in a peninsula area (Karakuwacho) in Japan, a cross-sectional survey was performed. This study included 189 individuals from 102 families. The geometric means of total hair mercury (THg) were 5.74, 3.78 and 2.37 µg/g for adult males, females and children, respectively, of which 56.5 %, 30.9 % and 12.9 % had hair THg exceeding 5 µg/g, respectively. Tuna and mackerel were the common fish species that were positively correlated with hair THg levels in different subpopulations (standardized coefficient ranged from 0.20 to 0.58, p < 0.05). Frequent consumption of these fish species and a large amount of fish intake are likely major contributors of MeHg exposure in this area. Local-scale risk evaluation and risk communication should be highlighted in future studies.

Effect of methylmercury administration on choroid plexus function in rats.

Methylmercury (MeHg) is a well-known environmental neurotoxin. The choroid plexus (CP), the main component of the blood-cerebrospinal fluid (CSF) barrier (BCSFB), protects the brain from xenobiotics, similar to the blood-brain barrier. Because CP is considered a critical target site of MeHg-induced neurotoxic damage, functional alterations in CP may be caused in relation to the extent of MeHg-induced brain injury. To test this hypothesis, we examined time-dependent pathological alterations in rats administered subtoxic (asymptomatic group) or toxic (symptomatic group) MeHg doses for 3 weeks after the cessation of MeHg administration. We primarily assessed (1) mercury concentrations in the brain, CSF, and plasma; (2) histopathological changes in the brain; (3) albumin CSF/plasma concentration quotient (Q(alb)), an index of BCSFB dysfunction; and (4) concentration of CSF transthyretin (TTR), which is primarily produced in CP. Mercury concentrations in the brain, CSF, and plasma decreased, and Q(alb) and CSF TTR concentrations did not change significantly in the asymptomatic group. In the symptomatic group, brain and CSF mercury concentrations did not decrease for 2 weeks after the cessation of MeHg administration, but no pathological alteration occurred in the brain during this period. Pathological changes in the cerebellum became evident 3 weeks after the cessation of MeHg administration. Furthermore, Q(alb) continued to increase after the cessation of MeHg administration, whereas no decrease in CSF TTR concentration was observed, indicating selective impairment of CP function. These findings suggest that MeHg at toxic doses causes selective functional alteration of CP before leading to pathological alterations in the brain.

Paradoxical increases in serum levels of highly chlorinated PCBs in aged women in clear contrast to robust decreases in dietary intakes from 1980 to 2003 in Japan.

OBJECTIVE: Exposure to polychlorinated biphenyls (PCBs) is considered to have culminated between 1950 and 1970 in Japan, and exposure through diet, the major exposure route, has decreased significantly over the last 10 years. The primary goal of the present study was to investigate the long-term trends and congener profiles of serum and dietary levels of PCBs using historical samples. METHODS: Using banked samples collected in 1980, 1995, and 2003 surveys, we determined the daily intakes and serum concentrations of 13 PCB congeners (#74, #99, #118, #138, #146, #153, #156, #163, #164, #170, #180, #182, and #187) in women. RESULTS: The total daily PCB intake [ng/day, geometric mean (geometric standard deviation)] decreased significantly from 523 (2.5) in 1980 to 63 (3.2) in 2003. The serum total PCB level (ng/g lipid) in women <40 years of age decreased significantly from 185 (1.8) in 1980 to 68 (1.8) in 2003. In contrast, the level in women >50 years of age increased significantly from 125 (1.7) in 1980 to 242 (1.7) in 2003. Specifically, the serum concentrations of hexa (#138, #146, #153, #156, #163, and #164) and hepta (#170, #180, #182, and #187) congeners increased significantly. A comparison of the serum PCB levels of women born from 1940 to 1953 revealed that their serum total PCB level was significantly higher in the 2003 survey [242 (1.7), n = 9] than in the 1995 [128 (2.0), n = 17] surveys. This increase in the total PCB level was attributable to increases in the hepta congener groups. CONCLUSION: Present results suggest a decreased rate of elimination of hepta congeners with aging in females, rather than a birth-generation phenomenon.

Historical and geographical aspects of the increasing perfluorooctanoate and perfluorooctane sulfonate contamination in human serum in Japan.

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) have recently received attention due to their widespread contamination in the environment, as well as in wildlife and humans. We measured the PFOS and PFOA concentrations in historically recorded human serum samples at an age range between 20 and 59 years collected in Kyoto, 20 persons per each time point (n=100), and also the PFOS and PFOA concentrations in human serum samples at an age range between 20 and 59 years from 10 locations throughout Japan (n=200). The historical samples collected from 1983 to 1999 demonstrated that the PFOA concentrations in males and females from Kyoto have increased 4.4-fold and 4.3-fold at a rate of increase of 0.49 ng/ml/year and 0.42 ng/ml/year, respectively. In contrast, serum concentrations of PFOS reached a plateau in the late 1980s. There are also regional differences in both the PFOS and PFOA serum concentrations. The concentrations in serum [geometric mean (geometric standard deviation)] (ng/ml) in 2003-2004 ranged from 7.6(1.6) in the town of Matsuoka in Fukui prefecture to 27.8(1.6) in Kyoto city, and ranged from 2.3(1.5) in Matsuoka to 14.5(1.3) in Osaka city for PFOS and PFOA, respectively.

Accumulation of inorganic mercury in hair of rats exposed to methylmercury or mercuric chloride.

The concentration of methylmercury (MeHg) in human hair is an excellent marker for its exposure, since a portion of MeHg is taken up from the blood circulation to the hair protein in a dose-dependent manner. However, a small portion of the mercury in human hair is found in the inorganic form, though the mechanism of its occurrence is not well established. Here, we examined the hair uptake of inorganic mercury in the rat. Male Wistar rats were exposed to MeHg (1 microg Hg/ml) or HgCl(2) (20 microg Hg/ml) for 84 days through drinking water. The hair, grown from 49 to 84 days, was collected from the MeHg-exposed rats, and the hair samples showed 54.5 microg/g hair of the total mercury concentration, 6.1% of which was in the inorganic form. The inorganic mercury in the plasma (0.022 microg/ml), which would probably be formed from MeHg in rat tissues, accounted for as high as 29% of the total mercury (0.076 microg/ml). The hair uptake rate of inorganic mercury estimated from the hair/plasma ratio was about 1/6 lower than that of MeHg. On the other hand, the total hair mercury level in the HgCl(2)-exposed group at the same time point was 2.86 microg/g, with the inorganic portion being as high as 62%. These findings suggest that the inorganic mercury is also taken up by rat hair from the blood circulation, as is the MeHg, irrespective of the consequences of the biotransformation of MeHg or exposure to inorganic mercury itself. Accordingly, a selective quantification of inorganic mercury in human hair may be useful in detecting inorganic mercury exposure.

Large-scale evaluation of the current level of polybrominated diphenyl ethers (PBDEs) in breast milk from 13 regions of Japan.

Polybrominated diphenyl ethers (PBDEs) were measured in 2004 in 105 breast milk samples collected from 13 regions of Japan (Hokkaido, Akita, Miyagi, Tokyo, Gifu, Fukui, Kyoto, Hyogo, Wakayama, Shimane, Yamaguchi, Kochi and Okinawa). Six congeners (BDE-28, BDE-47, BDE-99, BDE-100, BDE-153 and BDE-154) were determined by gas chromatography /mass spectrometry (GC/MS). Total PBDE levels ranged from 0.01 to 23.0 ng/g lipid (geometric mean (GM), 1.34 ng/g lipid). BDE-47 (GM, 0.66 ng/g lipid, 59% of sigmaPBDE) was the most abundant congener present in breast milk and was detected in 99% of the samples. Total PBDE levels were higher in northern Japan than in other regions. We analyzed the effects of occupation, age, smoking status, alcohol consumption and number of deliveries on total PBDE levels. None of these factors were significantly associated with the level of PBDEs. The present study revealed that the current level of exposure to PBDEs in Japan is lower than that in the USA or Sweden. GMs (ng/g lipid) (GSD, geometric standard deviation) and medians (ng/g lipid) of PBDE levels in each district are as follows: Hokkaido 2.70 (1.70), 2.74; Akita 4.49 (2.19), 5.44; Miyagi 1.77 (4.37), 1.11; Tokyo 1.39 (2.09), 1.63, Gifu 2.83 (4.79), 2.23; Fukui 1.05 (2.34), 1.18; Kyoto 1.31 (2.95), 1.33; Hyogo 1.02 (2.69), 0.88; Wakayama 1.33 (3.80), 1.70; Shimane 0.83 (2.51), 0.66; Yamaguchi 1.74 (2.82), 1.76; Kochi 0.50 (2.69), 0.74 and Okinawa 1.91 (2.75), 1.22. This is the first large-scale study of current PBDE levels in breast milk in Japan.

Assessment of human exposure to polychlorinated biphenyls and polybrominated diphenyl ethers in Japan using archived samples from the early 1980s and mid-1990s.

Persistent organic pollutants have been linked to various adverse effects on human health. We conducted a retrospective exposure assessment for 11polychlorinated biphenyl (PCB) congeners and 4 polybrominated diphenyl ether (PBDE) congeners. We analyzed paired samples of blood and food duplicate portions collected in the 1980s (1980 survey, N=40) and the mid-1990s (1995 survey, N=40) from females (five participants from each of eight sites per survey) living throughout Japan, from Hokkaido to Okinawa. The study populations in the 1980 and 1995 surveys were different but had lived in the same community. We measured PCBs and PBDEs in serum and PCBs in diet. Total serum PCBs (ng/g lipid) [geometric mean (geometric standard deviation)] were similar in the 1980 [163.0 (1.7)] and the 1995 [142.6 (2.0)] surveys. In contrast, dietary intake (ng/day) between 1980 and 1995 decreased significantly, from 522.8 (2.5) to 165.9 (3.3), respectively, (P<0.05). We classified the participants by birth year-before 1941 (older generation) and equal to or after 1941 (younger generation). Serum PCB levels decreased significantly in the younger generation, from 179.1 (1.8) in the 1980 survey to 115.4 (2.0) in the 1995 survey (P<0.05). However, in the older generation, serum levels (ng/g lipid) did not change: 150.4 (1.6) in the 1980 survey and 180 (1.8) in the 1995 survey. Total PBDE serum levels (ng/g lipid) increased significantly during the 15 years, from 0.5 (3.5) to 1.8 (3.7) (P<0.05). At the Shimane site, PBDE serum levels (ng/g lipid) increased 20-fold, from 1.3 (4.8) to 26.0 (5.0). The serum levels of PCBs decreased in the younger generation but not in the older, although levels in daily intakes decreased significantly. Exposure levels of PBDEs appear to be increasing in an area-specific manner.

Secular trends and geographical variations in the dietary intake of polybrominated diphenyl ethers (PBDEs) using archived samples from the early 1980s and mid 1990s in Japan.

A retrospective exposure assessment among the general population for polybrominated diphenyl ethers (PBDEs) was conducted using dietary surveys. We analyzed samples of food duplicate portions collected in the early 1980s (1980 survey: N=40) and the mid 1990s (1995 survey: N=39) from female subjects (5 participants from each of 8 sites per survey except for one site) living throughout Japan, from the north (Hokkaido) to the south (Okinawa). The study populations in the 1980 and 1995 surveys were different, but lived in the same communities. We measured four PBDE congeners [2,2',4,4'-tetrabrominated diphenyl ether (tetraBDE): #47; 2,2',4,4',5-pentaBDE: #99; 2,2',4,4',6-pentaBDE: #100; and 2,2',4,4',5,5'-hexaBDE: #153] in the diet. #99 was the most abundant congener in the diet (49% of the total PBDEs), followed by #47 (33%), #100 (12%) and #153 (6%). Regional variations found in the 1980 survey decreased in the 1995 survey. The total daily intake of PBDEs (ng/d) [GM (GSD)] in the 1980 survey [91.4 (4.1)] was not significantly different from that in the 1995 survey [93.8 (3.4)] for the total population, nor did it differ among the sites including Shimane, in which a 20-fold increase in serum concentrations was observed in the same population1). In consideration of the significant increases in the serum concentration, inhalation may be more important than food ingestion as the route of human exposure to PBDEs.

Free water 3H concentrations in serum samples collected during 1969-1992 in Akita, Japan.

The measurements for human and environmental samples from the 1960's and 1970's are important to understand the long-term transfer of 3H from the environment to the human body. The authors have previously reported 3H concentrations in diet samples collected in Akita Prefecture during 1969-1988. Serum samples from persons living in Akita Prefecture during 1969-1992 were recently obtained. The samples were originally gathered for medical examinations and stored in freezers at -20 degrees C. Composite samples from 100 persons on average were made for analysis. The free water 3H (FWT) concentrations in those samples were determined and compared with 3H concentrations in diet samples and precipitation. The long-term variation pattern of the FWT concentrations in the serum samples was similar to patterns in the diet samples and precipitation, but the FWT concentrations in the serum samples were slightly higher than those in the latter two. A single compartment model calculation showed that the apparent mean residence time of serum FWT was 1.4 y using precipitation as an input to the compartment.

Current hair mercury levels in Japanese: survey in five districts.

To understand the current Japanese hair mercury levels, we planned a survey of hair mercury among the general populations of different regions in Japan. The present paper, as the first report of the survey, summarized the results obtained in five districts, Minamata, Kumamoto, Tottori, Wakayama and Chiba. Hair samples were collected at beauty salons, barbershops and primary schools in each district with questionnaires on age, sex, amount and species of fish usually consumed, hair-dyed and artificial hair waving "permanent wave." The total mercury levels of 3686 hair samples collected were analyzed by an oxygen combustion-gold amalgamation method. The geometric mean of the total mercury concentration was significantly higher in males than in females, i.e., 2.55 microg/g and 1.43 microg/g, respectively. The sex difference was also observed on hair samples without artificial waving, i.e., 2.64 microg/g and 1.64 microg/g, respectively. The geometric mean in each district varied from 2.23 to 4.79 microg/g for males and from 1.23 to 2.50 microg/g for females. The average hair mercury levels were highest in Chiba among the five districts both in males and females. A multiple regression analysis revealed a significant correlation of the mercury level with age, sex, amount of daily fish consumption, tuna and bonito as usually consumed fish, artificial waving and Chiba as a residential area. In the laboratory experiment, we found that the treatment of hair samples with a lotion for artificial waving caused a 30%-reduction in the mercury content. Furthermore, longitudinal hair analysis showed a marked difference in the concentration between the hair root and the tip of the hair taken from artificially waved females; higher values were observed at the hair root. These results suggested that artificial waving significantly removes hair mercury and that hair analysis at the hair root should be necessary to estimate an accurate methylmercury exposure for waved persons.