Search

Informal electronic waste (e-waste) dismantling activities contribute to releasing hazardous compounds in the environment and potential exposure to humans and their health. These hazardous compounds include persistent organic pollutants (POPs), polycyclic aromatic hydrocarbons (PAHs) and heavy metals. This review searched papers addressing hazardous compounds emitted from e-waste recycling activities and their health effects in Vietnam. Based on the keywords searched in three electronic databases (PubMed, Psych Info, and Google scholar), we found 21 relevant studies in Vietnam. The review identifies extensive e-waste dismantling activities in Vietnam in the northern region. To measure the environmental exposure to hazardous compounds, samples such as e-waste recycling workshop dust, soil, air, and sediments were assessed, while human exposure levels were measured using participants’ hair, serum, or breast milk samples. Studies that compared levels of exposure in e-waste recycling sites and reference sites indicated higher levels of PBDEs, PCBs, and heavy metals were observed in both environmental and human samples from participants in e-waste recycling sites. Among environmental samples, hazardous chemicals were the most detected in dust from e-waste recycling sites. Considering both environmental and human samples, the highest exposure difference observed with PBDE ranged from 2-48-fold higher in e-waste processing sites than in the reference sites. PCBs showed nearly 3-fold higher levels in e-waste processing sites than in reference sites. In the e-waste processing sites, age-specific higher PCB levels were observed in older recycler’s serum samples. Among the heavy metals, Pb was highly detected in drinking water, indoor soil and human blood samples. While high detection of Ni in cooked rice, Mn in soil and diet, Zn in dust and As in urine were apparent. Exposure assessment from human biomonitoring showed participants, including children and mothers from the e-waste processing areas, had higher carcinogenic and non-carcinogenic risks than the reference sites. This review paper highlights the importance of further comprehensive studies on risk assessments of environmentally hazardous substances and their association with health outcomes at e-waste processing sites.

Objective: This study examined psychological status trajectories of mothers of infants with nonsyndromic orofacial clefts in Japan. Design: Prospective cohort study. Setting: Data from the Japan Environment and Children’s Study. Participants: Infants with a nonsyndromic cleft (N = 148) including cleft lip and palate (CLP; n = 72), cleft lip (CL; n = 46), and cleft palate (CP; n = 30). The control group included unaffected infants (N = 84 454). Main Outcome Measures: At 15 weeks and 27 weeks of pregnancy and 12 months after birth, the Kessler Psychological Distress Scale (clinical cutoff ≥5) was used. At 1 month and 6 months after birth, the Edinburgh Postnatal Depression Scale (clinical cutoff ≥9) was used. Results: Prenatal diagnosis rates were unavailable. Mothers of infants with CLP had higher psychological distress than controls at 27 weeks of pregnancy (prevalence ratio [PR] = 1.36, 95% CI: 1.06-1.74) and postnatal depression at 1 month after birth (PR = 2.21, 95% CI: 1.53-3.19). Mothers of infants with CP showed heightened psychological distress at 27 weeks of pregnancy (PR = 1.62, 95% CI: 1.21-2.17) and postnatal depression 6 months after birth (PR = 1.86, 95% CI: 1.01-3.43). There was no significant association between CL and maternal psychological status. At 12 months after birth, no differences in distress were found between mothers of infants with a cleft and controls. Conclusions: Mothers of infants with orofacial clefts may need psychosocial support, particularly during pregnancy and the first year after birth.

This prospective cohort study aimed to examine the associations between mold growth, type of stoves, and fragrance materials and early childhood wheezing and asthma, using data from the Japan Environment and Children's Study. Mold growth at home, usage of kerosene/gas stove, wood stove/fireplace, and air freshener/deodorizer were surveyed using a questionnaire at 1.5-year-old, and childhood wheezing and doctor-diagnosed asthma during the previous year were obtained using a 3-year-old questionnaire. Multilevel logistic regression analysis was performed to evaluate the association between exposure to childhood wheezing and asthma. A total of 60 529 children were included in the analysis. In multivariate analyses, mold growth and wood stove/fireplace had significantly higher odds ratios (ORs) for wheezing (mold growth: 1.13; 95% CI, 1.06-1.22; wood stove/fireplace: 1.23; 95% CI, 1.03-1.46). All four exposures had no significant ORs for childhood doctor-diagnosed asthma; however, in the supplemental analysis of northern regions, wood stove/fireplace had a significantly higher OR for asthma. Mold growth and wood stove/fireplace had significant associations with childhood wheezing in the northern regions. Mold elimination in the dwellings and use of clean heating (no air pollution emissions) should be taken into consideration to prevent and improve childhood wheezing and asthma.

Pets may play a role in the social-emotional development of children. In particular, some studies have suggested that family dog ownership is associated with better health outcomes. To date, no study has assessed child development in association with dog ownership of different time points. The purpose of the current study was primary to investigate whether “ever” family dog ownership was associated with early child development, and secondary to further examine whether associations between family dog ownership and early child development differ among family dog ownership of status, including “past only”, “current only”, and “always” groups, using the data of family dog ownership obtained at multiple time points. Associations between family dog ownership and infant development at 3 years of age were examined using data from a nationwide prospective birth cohort study, the Japan Environment and Children’s Study (n = 78,941). “Ever” family dog ownership was categorized to “past only”, “current only”, and “always”. We observed that children with “ever” family dog ownership showed a significantly decreased risk of developmental delay in the communication (odds ratio [OR] = 0.87, 95% confidence interval [CI]: 0.78, 0.96), gross motor (OR = 0.83, 95% CI: 0.76, 0.92), problem-solving (OR = 0.89, 95% CI: 0.83, 0.96) and personal-social (OR = 0.86, 95% CI: 0.72, 0.92) domains compared to children with “never” family dog ownership. Furthermore, a significantly decreased risk of developmental delay in gross motor function was observed in association with living with dogs in the “past only” (OR = 0.83, 95% CI: 0.73, 0.95) and “always” (OR = 0.86, 95% CI: 0.75, 0.98). In addition, a decreased risk of developmental delay in the problem-solving domain was associated with “past” family dog ownership (OR = 0.87, 95% CI: 0.79, 0.97) and in the personal-social domain was associated with “always” family dog ownership (OR = 0.81, 95% CI = 0.68, 0.95). Given the possible positive association between early life child development and family dog ownership, living with dogs may be an important factor to be considered when assessing child development.

BACKGROUND: Prenatal exposure to persistent organic pollutants, including polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), dioxin-like polychlorinated biphenyls (DL-PCBs), and nondioxin-like PCBs (NDL-PCBs), has been hypothesized to have a detrimental impact on neurodevelopment. However, the association of prenatal exposure to a dioxin and PCB mixture with neurodevelopment remains largely inconclusive partly because these chemical levels are correlated. OBJECTIVES: We aimed to elucidate the association of in utero exposure to a mixture of dioxins and PCBs with neurodevelopment measured at 6 months of age by applying multipollutant methods. METHODS: A total of 514 pregnant women were recruited between July 2002 and October 2005 in the Sapporo cohort, Hokkaido Study on Environment and Children’s Health. The concentrations of individual dioxin and PCB isomers were assessed in maternal peripheral blood during pregnancy. The mental and psychomotor development of the study participants’ infants was evaluated using the Bayley Scales of Infant Development-2nd Edition (n = 259). To determine both the joint and individual associations of prenatal exposure to a dioxin and PCB mixture with infant neurodevelopment, Bayesian kernel machine regression (BKMR) and quantile-based g-computation were employed. RESULTS: Suggestive inverse associations were observed between in utero exposure to a dioxin and PCB mixture and infant psychomotor development in both the BKMR and quantile g-computation models. In contrast, we found no association of a dioxin and PCB mixture with mental development. When group-specific posterior inclusion probabilities were estimated, BKMR suggested prenatal exposure to mono-ortho PCBs as the more important contributing factors to early psychomotor development compared with the other dioxin or PCB groups. No evidence of nonlinear exposure-outcome relationships or interactions among the chemical mixtures was detected. CONCLUSIONS: Applying the two complementary statistical methods for chemical mixture analysis, we demonstrated limited evidence of inverse associations of prenatal exposure to dioxins and PCBs with infant psychomotor development.

Organochlorine pesticides (OCPs) are environmental contaminants that persist in the environment and bioaccumulate through the food chain in humans and animals. Although previous studies have shown an association between prenatal OCP exposure and subsequent neurodevelopment, the levels of OCPs included in these studies were inconsistent. A hospital-based prospective birth cohort study was conducted to examine the associations between prenatal exposure to relatively low levels of OCPs and neurodevelopment in infants at 6 (n = 164) and 18 (n = 115) months of age. Blood samples were analyzed using gas chromatography/mass spectrometry techniques to quantify 29 OCPs. The Bayley Scales of Infant Development 2nd edition (BSID-II) was used to assess the Mental and Psychomotor Developmental Index. After controlling for confounders, we found an inverse association between prenatal exposure to cis-heptachlor epoxide and the Mental Developmental Index at 18 months of age. Furthermore, infants born to mothers with prenatal concentrations of cis-heptachlor epoxide in the highest quartile had Mental Developmental Index scores -9.8 (95% confidence interval: -16.4, -3.1) lower than that recorded for infants born to mothers with concentrations of cis-heptachlor epoxide in the first quartile (p for trend < 0.01). These results support the hypothesis that prenatal exposure to OCPs, especially cis-heptachlor epoxide, may have an adverse effect on the neurodevelopment of infants at specific ages, even at low levels.

Background: The influence of maternal psychological distress on infant congenital heart defects (CHDs) has not been thoroughly investigated. Furthermore, there have been no reports on the combined effect of maternal psychological distress and socioeconomic status on infant CHDs. This study aimed to examine whether maternal psychological distress, socioeconomic status, and their combinations were associated with CHD.Methods: We conducted a prospective cohort study using data from the Japan Environment and Children’s Study, which recruited pregnant women between 2011 and 2014. Maternal psychological distress was evaluated using the Kessler Psychological Distress Scale in the first trimester, while maternal education and household income were evaluated in the second and third trimesters. The outcome of infant CHD was determined using the medical records at 1 month of age and/or at birth. Crude and adjusted logistic regression analyses were performed to evaluate the association between maternal psychological distress and education and household income on infant CHD.Results: A total of 93,643 pairs of mothers and infants were analyzed, with 1.1% of infants having CHDs. Maternal psychological distress had a significantly higher odds ratio in the crude analysis but not in the adjusted analysis, while maternal education and household income were statistically insignificant. In the analysis of the combination variable of lowest education and psychological distress, the trend for p was statistically significant in the crude and adjusted analyses.Conclusions: The combination of maternal psychological distress and lower education may be a possible indicator of infant CHD.

Background Lower respiratory tract infections (LRTIs) are a cause of inpatient and outpatient care among children. Although orofacial clefts seem to be associated with LRTIs, epidemiological studies are scarce on this topic. This study aimed to examine whether infants with orofacial clefts were associated with LRTIs. Methods This prospective cohort study used data from the Japan Environment and Children's Study, whose baseline recruitment was conducted during 2011-2014. This study included 81,535 participants. The number of infants with cleft lip and palate (CLP), cleft lip (CL), and cleft palate only (CP) was 67, 49, and 36, respectively. We defined history of LRTIs until 12 months' age reported by their mothers as the dependent variable. Accumulated breastfeeding duration was used as potential mediators. Results The incidence proportion of LRTIs among the control group was 6.0%. The incidence proportion among infants with CLP, CL, and CP were 11.9%, 14.3%, and 5.6%, respectively. After adjusting for covariates, compared with the control group, infants with CLP and CL were associated with risk of LRTIs (incidence risk ratio [IRR] of CLP = 2.38 [95% confidence interval = 1.30, 4.36] and of CL = 2.73 [1.40, 5.33]) , but not ones with CP (1.08 [0.28, 4.15]). Accumulated breastfeeding duration decreased the IRR of CLP only (IRR of CLP = 2.16 [1.19, 3.93]). Conclusions Infants with orofacial clefts aged 1 year have a potentially high incidence proportion of LRTIs. Accumulated breastfeeding duration might mediate the associations of CLP.

Objectives Atopic dermatitis (AD) is a common childhood disease with an increasing prevalence, affecting the quality of life of afflicted children. The onset of AD at an early age may disrupt normal sleep patterns, behavior, and relationships. Increased behavioral and discipline problems associated with AD have been documented. However, there are insufficient studies on AD at early ages, especially in Japan. This study aimed to examine the association between AD and the mental and behavioral health of children of preschool age.Methods This study was a part of a prospective cohort study (n=20,926), and children born after April 2008 (n=7,386) were the target population of this study. Those who answered the Japanese version of the International Study of Asthma and Allergies in Childhood (ISAAC) at 4 years of age (n=4,228) and answered the Strength and Difficulties Questionnaire (SDQ) at 5 years of age were included in this study (n=3,862). The subscale scores of SDQ, namely, emotional symptoms, conduct problems, peer relationship problems, and hyperactivity/inattention, along with the sum of these 4 subscale scores, (total difficulties score (TDS), were investigated in relation to the prevalence of AD. SDQ scores were treated as continuous values for linear regression analysis and as dichotomized values for logistic regression analysis. The parental history of AD was adjusted in the final models.Results The prevalence of AD at 4 years of age was 20.7% (n=799). The mean scores of emotional symptoms, conduct problems, and TDS were significantly higher among children with AD than among those without AD. Linear regression analysis revealed increased scores for emotional symptoms, conduct problems, and TDS in association with AD. Logistic regression analysis revealed a significantly increased risk for conduct problems in children with AD.Conclusion This study found associations between AD at 4 years of age and emotional symptoms, conduct problems and TDS at 5 years of age. Further studies to assess the severity of AD and children's mental and behavioral problems at older ages are essential.

It has been known that pregnant women are exposed to a number of environmental chemicals and studies have reported that these environmental chemicals are detected from pregnant women of various population. Environmental exposures such as air pollution, pesticides, solvents, heavy metals, and chemicals including persistent organic pollutants (POPs) have implicated in adverse pregnancy-related outcomes. In addition to these environmental chemicals, phthalates and bisphenol A (BPA) are known as ubiquitous environmental chemicals and their endocrine disrupting effects have been reported from animal studies. These chemicals can impact the ability to become pregnant and sustain a healthy pregnancy. Taking trend of environmental chemical levels over the years into consideration is of cardinal importance for investigating adverse birth outcomes because oftentimes associations can be found at high exposure levels such as accidental or occupational settings. From individual studies and meta-analysis, systematic reviews of recent years, evidences on outdoor air pollution during pregnancy, and adverse birth outcomes have been strengthened. Especially, fairly good evidence for maternal exposure to PM2.5 pollution during pregnancy is associated with increased risk of adverse birth outcomes. Heavy metal exposures and PFOA exposure during pregnancy may moderately be associated with adverse birth outcomes; however, not sufficient investigation has been conducted for substitutions for PFOS and PFOA. Besides, it is important to consider concentrations of PFAS in association with adverse birth outcomes as PFOS concentration is decreasing since the Stockholm convention. Inconsistent findings have been reported for phthalates and BPA exposure during pregnancy and birth outcomes. Some of the studies mentioned different influence between male and female infants or sex-specific of environmental exposure on birth outcomes. Studies on genomic analysis, transcriptome analysis, proteome analysis, and epigenome analysis should be accelerated to elucidate mechanisms of observed results from epidemiological studies.

This chapter provides a general introduction to bisphenols and alkylphenols in toxicity, exposure assessment, biomonitoring, and epidemiological studies. Both bisphenols and alkylphenols are applied intensively to the majority of consumer products and are ubiquitous in environmental matrices. Bisphenol A (BPA), nonylphenol (NP), octylphenol (OP), triclosan (TCS), 3-benzophenone (BP-3), 2,4-dichlorophenol (2,4-DCP), and 2,5-dichlorophenol (2,5-DCP) have been proven as endocrine-disrupting chemicals (EDCs) and exhibited potential health effects on human, especially for vulnerable pregnant women and children. This chapter discusses human exposure source, pathway, metabolism, and possible effects of bisphenols and alkylphenols and provides various epidemiological evidences for human health risks.

Asia contains half of the world's children, and the countries of Asia are the most rapidly industrializing nations on the globe. Environmental threats to the health of children in Asia are myriad. Several birth cohorts were started in Asia in early 2000, and currently more than 30 cohorts in 13 countries have been established for study. Cohorts can contain from approximately 100-200 to 20,000-30,000 participants. Furthermore, national cohorts targeting over 100,000 participants have been launched in Japan and Korea. The aim of this manuscript is to discuss the importance of Asian cohorts, and the advantages and disadvantages of different-sized cohorts. As for case, one small-sized (n = 514) cohort indicate that even relatively low level exposure to dioxin in utero could alter birth size, neurodevelopment, and immune and hormonal functions. Several Asian cohorts focus prenatal exposure to perfluoroalkyo substances and reported associations with birth size, thyroid hormone levels, allergies and neurodevelopment. Inconsistent findings may possibly be explained by the differences in exposure levels and target chemicals, and by possible statistical errors. In a smaller cohort, novel hypotheses or preliminary examinations are more easily verifiable. In larger cohorts, the etiology of rare diseases, such as birth defects, can be analyzed; however, they require a large cost and significant human resources. Therefore, conducting studies in only one large cohort may not always be the best strategy. International collaborations, such as the Birth Cohort Consortium of Asia, would cover the inherent limitation of sample size in addition to heterogeneity of exposure, ethnicity, and socioeconomic conditions.

Bisphenol A and phthalates are widely detected in human urine, blood, breast milk, and amniotic fluid. Both bisphenol A and phthalates have been suggested as playing a role in obesity epidemics. Exposure to these chemicals during fetal development, and its consequences should be concerning because they can cross the placenta. Thus, this study aimed to assess the association between prenatal exposure to bisphenol A and phthalates, and cord blood metabolic-related biomarkers. Maternal serum was used during the first trimester, to determine prenatal exposure to bisphenol A and phthalates. Levels of metabolic-related biomarkers in the cord blood were also determined. Linear regression models were applied to the 365 participants with both, exposure and biomarker assessments, adjusted for maternal age, pre-pregnancy body mass index, parity, education, and sex of the child. The level of bisphenol A was negatively associated with the leptin level (β = -0.06, 95% confidence interval [CI]: -0.11, -0.01), but was positively associated with the high-molecular-weight adiponectin level, with marginal significance (β = 0.03, 95%CI: 0.00, 0.06). The mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-(2-ethylhexyl) phthalate (MEHP), and summation of MEHP and MECPP to represent DEHP exposure (∑DEHPm) levels were inversely associated with the leptin levels (β=-0.14, 95%CI: -0.27, -0.01; β = -0.12, 95%CI: -0.24, 0.00 with marginal significance; β=0.08, 95%CI: -0.14, -0.03; and β = -0.09, 95%CI: -0.16, -0.03, respectively). The present study provided some evidence that prenatal exposure to bisphenol A and certain phthalates may modify fetal adiponectin and leptin levels.

In recent years, the birthrate has been continuously declining in Japan. The main causes of the decline are social factors. On the other hand, there is increasing evidence that many environmental chemicals show endocrine disrupting properties. Thus, we hypothesized that exposure to these chemicals would also be a causal for the fertility crisis. In this review, we examined current evidence that focused on environmental chemical exposure in utero and its association with reproductive hormones in children. We have included the findings from a prospective birth cohorts, the Hokkaido Study on Environment and Children's Health Sapporo cohort. According to the literature, environmental chemical levels in utero, such as polychlorinated biphenyl, dioxins, perfluorinated chemical substances, phthalates, and bisphenol A were somewhat associated with the levels of reproductive hormones, such as testosterone, estradiol, progesterone, inhibin B, and insulin-like factor-3 in cord blood, in early childhood and adolescence. The literature also suggests the association between exposure to these chemicals and brain-sexual differentiation or the anogenital distance, which suggests the disruption of androgen shower during the developmental stage in the fetal period. There are still knowledge gaps on whether these hormones at an early stage affect the pubertal development and reproductive functions in later life. In addition, alternative chemicals are produced after banning one type. The health effects of alternative chemicals should be evaluated. Effects of exposure to a mixture of the chemicals should also be examined in future studies. In conclusion, the prevention of environmental chemical hazards in relation to human reproductive function is important. It would be one of the countermeasures to the falling birthrate caused by fertility issues.

Perfluoroalkyl substances (PFASs) are synthetic chemicals that persist in the environment and in humans. There is a possible association between prenatal PFASs exposure and both neonate adipokines and birth size, yet epidemiological studies are very limited. The objective of this study was to examine associations of prenatal exposure to PFASs with cord blood adipokines and birth size. We conducted birth cohort study, the Hokkaido Study. In this study, 168 mother-child pairs were included. Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) in maternal blood were determined by liquid chromatography tandem mass spectrometry. Cord blood adiponectin and leptin levels were measured by ELISA and RIA, respectively. Birth weight and ponderal index (PI) were obtained from birth record. The median maternal PFOS and PFOA were 5.1 and 1.4 ng/mL, respectively. The median total adiponectin and leptin levels were 19.4 μg/mL and 6.2 ng/mL, respectively. Adjusted linear regression analyses found that PFOS level was positively associated with total adiponectin levels (β=0.12, 95% CI:0.01, 0.22), contrary was negatively associated with PI (β=-2.25, 95% CI: -4.01, -0.50). PFOA level was negatively associated with birth weight (β=-197, 95% CI: -391, -3). Leptin levels were not associated with PFASs levels. PFOS and adiponectin levels showed marginal dose-response relationship and both PFOS and PFOA and birth size showed significant dose-response relationships. Results from this study suggested that prenatal PFASs exposure may alter cord blood adiponectin levels and may decrease birth size.

Di-2-ethylhexyl phthalate (DEHP) is one of the most widely used phthalates. Metabolites of DEHP are detectable in majority of the population. Findings on adverse health outcomes, particularly birth weight in association with prenatal exposure to DEHP remain equivocal. Besides, there is insufficient evidence to address influence on metabolic function from epidemiological studies. Thus, our objective was to investigate cord blood adipokine levels and birth size in association with prenatal DEHP exposure in prospective birth cohort study. Mono-2-methylhexyl phthalate (MEHP), primary metabolite of DEHP was determined as exposure by using maternal blood sample of 3rd trimester. Leptin and adiponectin levels in cord blood were measured as markers of metabolic function. Birth weight and length were obtained from birth record. Association between maternal MEHP levels and cord blood adiponectin and leptin levels, birth weight and ponderal index (PI) were examined for 167 mother-child pairs who had both MEHP and cord blood adipokine measurements. The median MEHP level was 8.81 ng/ml and the detection rate was 100%. There was no sex difference in MEHP levels. Both leptin and adiponectin levels were higher in girls than in boys. MEHP level was positively associated with adiponectin level among boys and was negatively associated with leptin level among girls. MEHP level were negatively associated with PI only in girls and this could be due to decreased leptin level. This study suggested that prenatal DEHP exposure may be associated with cord blood adipokine and birth size. The influence potentially be sex-specific and could be more significant in girls.

Exposure to bisphenol A (BPA) in utero is associated with adverse health outcome of the offspring. Differential DNA methylation at specific CpG sites may link BPA exposure to health impacts. We examined the association of prenatal BPA exposure with genome-wide DNA methylation changes in cord blood in 277 mother-child pairs in the Hokkaido Study on Environment and Children’s Health, using the Illumina HumanMethylation 450 BeadChip. We observed that a large portion of BPA-associated differentially methylated CpGs with p-value p

The Hokkaido Study on Environment and Children’s Health is an ongoing study of two birth cohorts: the Sapporo cohort and the Hokkaido cohort. Our primary goals are (1) to examine the possible effects of low-level environmental chemical exposures, (2) to follow childhood development through a longitudinal observation study, (3) to identify a high-risk group classified by genetic susceptibility, and (4) to identify any additive effects. Maternal and cord blood were collected for an environmental chemical exposure assessment of dioxins, polychlorinated biphenyls, organochlorine pesticides, perfluoroalkyl substances, phthalates, bisphenol A, and methylmercury. Assessments of health outcomes regarding birth size, neurodevelopment, asthma, allergies and infectious diseases, and hormone levels were conducted, along with observation of the children’s growth. Both genetic and epigenetic analyses were also conducted to examine the effects of environmental chemical exposures on a genetically susceptible population and on DNA methylation. Our study suggests that prenatal environmental chemical exposure affects birth size, hormone balance, neurodevelopment, and immune function, even at relatively low levels. Furthermore, specific genotypes may modify the effects of chemical exposure on health outcomes. Epigenetics, such as DNA methylation, may explain in part the mechanism of action.

Purpose of Review: Bisphenol A and phthalate have been found in the environment, as well as in humans. In this narrative review pre- and postnatal bisphenol A and phthalate exposures, their relationship to neurodevelopment, and the behavioral outcomes of children are elucidated, focusing in particular on the recent case-control, cross-sectional, and longitudinal studies. This review also introduces some of the possible mechanisms behind the observed associations between exposures and outcomes. Recent Findings: Although bisphenol A and phthalate exposure have been reported to influence neurobehavioral development in children, there are various kinds of test batteries for child neurodevelopmental assessment at different ages whose findings have been inconsistent among studies. In addition, the timing and number of exposure assessments have varied. Summary: Overall, this review suggests that prenatal exposure to bisphenol A and phthalates may contribute to neurobehavioral outcomes in children. The evidence is still limited; however, Attention Deficit Hyperactivity Disorder (ADHD) symptoms, especially among boys, constantly suggested association with both prenatal and concurrent exposure to bisphenol A. Although there is limited evidence on the adverse effects of prenatal and postnatal bisphenol A and phthalate exposures provided, pregnant women and young children should be protected from exposure based on a precautionary approach.

Background Finding associated factors with childhood behavioural problems as early as preschool age is important. Studies have revealed several factors including socioeconomic factors, which may vary among different cultural background and population. However, investigation in general Japanese population of preschool age has not been well demonstrated. Thus, the objective of this study was to examine associated factors of childhood behavioural problems using Strengths and Difficulties Questionnaire (SDQ) in a prospective birth cohort study. Methods Total 3813 SDQ were distributed between October 2014 and December 2015 to the subpopulation of prospective birth cohort study, the Hokkaido Study on Environment and Children's Health. The subpopulation consisted of participants who had reached age 5 and were born between April 2008 and December 2010. Baseline questionnaire filled at recruitment and birth record were used to obtain participant information. Children with total difficulties score ≧ 13 were defined as likelihood of behavioural problems. A total of 2553 children with valid answers were included into the analysis. The response rate was 67.1%. Results Number of children with likelihood of behavioural problems was 521 (20.4%). Boys showed more problematic scores than girls. Multivariate analysis found that maternal pre-pregnancy BMI ≧ 30 kg/m2, primipara, maternal education lower than high school, family income during pregnancy

Di (2-ethylhexyl) phthalate (DEHP) is commonly used phthalates and concerns of adverse effects of prenatal DEHP exposure on neonatal thyroid hormone (TH) and neurodevelopment are increasing. However, there is no report regarding association between prenatal DEHP exposure and infant neurodevelopment including TH levels in Japanese population. Thus the aim of present study was to evaluate the associations between prenatal DEHP exposure and mental and psychomotor development of infants 6 and 18 months along with investigating influence on neonatal free thyroxine (FT4) and thyroid stimulating hormone (TSH) levels in the prospective birth cohort study. Maternal blood samples collected between 23-41 weeks of gestation was analyzed for mono (2-ethylhexyl) phthalate (MEHP), metabolite of DEHP levels. Neonatal FT4 and TSH were obtained from mass screening data. Infant neurodevelopment was assessed by Bayley Scale of Infant Development second edition at 6 and 18 month of age. For the final analysis, 328 participants were included. The median levels of maternal MEHP was 10.6 ng/ml, neonatal TSH and FT4 was 2.20 μU/ml and 2.03 ng/ml, respectively. We did not find any associations between prenatal DEHP exposure and neonatal TH levels or infant mental and psychomotor development at 6 and 18 month. In this study, prenatal DEHP exposure did not show adverse effects on infant TH levels or mental and psychomotor development in early life stage. However, our previous study revealed negative effects of prenatal DEHP exposure on sex hormone levels, continuous investigation on neurodevelopment in later life in association with prenatal DEHP exposure is necessary.

Organochlorine pesticides (OCPs) are environmental contaminants with potentially adverse effects on neurodevelopment. Previous findings on the association between prenatal exposure to OCPs and the maternal or infant thyroid hormone system are inconsistent. Moreover, the influence of exposure to multiple OCPs and other chemical compounds is not clearly understood. Our study therefore aimed to examine the association between OCP exposure and both maternal and infant thyroid hormone systems. We also explored multiple exposure effects of OCPs and the influence of each compound using weighted quantile sum (WQS) methods. The study population included 514 participants in the Hokkaido study, recruited from 2002 to 2005 at one hospital in Sapporo, Japan. To quantify 29 OCPs, maternal blood samples were analyzed using gas chromatography/mass spectrometry. Blood samples for measuring thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from mothers during the early gestational stage (mean 11.4 weeks), and from infants between 7 and 43 days of age. The data of 333 mother child pairs with OCP and thyroid hormone measurements were included in the final analyses. Multivariate regression models showed a negative association between maternal FT4 and levels of o,p’-dichlorodiphenyldichloroethylene (DDE), o,p’-dichlorodiphenyltrichloroethane (DDT), and dieldrin. The WQS analysis showed that o,p’-DDT (48.6%), cis-heptachlorepoxide (22.8%), dieldrin (15.4%) were the primary contributors to the significant multiple exposure effect of OCPs on maternal FT4. For infants, we found a positive association between FT4 and cis-nonachlor and mirex. The most contributory compounds in the multiple exposure effect were trans-nonachlor (27.1%) and cis-nonachlor (13.8%), while several compounds contributed to the WQS via small weights (0.4-9.1%). These results indicate that OCPs, even at very low levels, may influence maternal and child thyroid hormone levels, which could modulate child development.

BACKGROUND Few previous studies have investigated the association between prenatal caffeine intake and birth size (small for gestational age [SGA], preterm birth, and birthweight Z-score) in Japan. OBJECTIVES We examined the dose-dependency of this association (prenatal caffeine consumption and birth size) as part of the Japan Environment and Children's Study. METHODS A prospective birth cohort included 94 876 fetuses in Japan. Participants were enrolled between January 2011 and March 2014. Adjusted multiple linear regression and Cox regression models were used to examine the association between prenatal caffeine levels and infant birth size. RESULTS The median estimated caffeine consumption during pregnancy was 125.5 mg/day, as determined by self-administered questionnaires. There were 7252 SGA infants (7.6%) and 4281 preterm birth infants (4.5%). Compared with infants of mothers whose caffeine consumption during pregnancy was in the lowest quartile (4.2 to

Introduction: Child exposure to environmental tobacco smoking (ETS) remains as a major issue, with adverse health consequences such as obesity, neurobehavioral disorders. This study aimed t...

Background Studies reported adverse behavioral development including internalizing and externalizing problems in association with prenatal exposure to bisphenol A (BPA) and phthalates; however, findings were not sufficient due to using different assessment tools and child ages among studies. This study aimed to examine associations between maternal serum levels of BPA and phthalate metabolites and behavioral problems at preschool age. Methods The Strengths and Difficulties Questionnaire (SDQ) was used to assess behavioral problems at 5 years of age. BPA and phthalate metabolite levels in the first trimester maternal serum was determined by LC-MS/MS for 458 children. Variables used for adjustment were parental ages, maternal cotinine levels, family income during pregnancy, child sex, birth order, and age at SDQ completed. Results The median concentrations of BPA, MnBP, MiBP, MEHP, and MECPP, primary and secondary metabolites of phthalates, were 0.062, 26.0, 7.0, 1.40, and 0.20 ng/ml, respectively. MECPP level was associated with increase conduct problem risk (OR = 2.78, 95% CI 1.36–5.68) overall and the association remained after child sex stratification, and odds ratios were increased with wider confidence interval (OR = 2.85, 95% CI 1.07–7.57 for boys, OR = 4.04, 95% CI 1.31–12.5 for girls, respectively). BPA, ∑DBPm (MnBP + MiBP), and ∑DEHPm (MEHP+MECPP) levels were not associated with any of the child behavioral problems. Conclusions Our analyses found no significant association between BPA or summation of phthalate metabolite levels and any of the behavioral problems at 5 years of age but suggested possible association between MECPP levels and increased risk of conduct problems. Electronic supplementary material The online version of this article (10.1186/s12199-018-0732-1) contains supplementary material, which is available to authorized users.

Background: Thyroid antibodies (TAs) are the most common cause of hypothyroidism during gestation. Although previous studies found that prenatal exposure to perfluoroalkyl substances (PFASs) disrupts thyroid hormones (THs) in humans, their effects on TAs during the perinatal period have not been investigated. Objective: To explore the associations between prenatal exposure to eleven different PFASs from two different groups (carboxylates and sulfonates) and the expression of THs and TAs in maternal and cord blood while considering maternal TA status. Methods: In a prospective birth cohort (the Hokkaido Study), we included 701 mother‑neonate pairs recruited in 2002–2005 for whom both prenatal maternal and cord blood samples were available. Eleven PFASs were measured in maternal plasma obtained at 28–32 weeks of gestation using ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. THs and TAs including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) were measured in maternal blood during early pregnancy (median 11 gestational weeks), and in cord blood at birth. Results: The median levels of TgAb and TPOAb in maternal serum were 15.0 and 6.0 IU/mL, respectively. The median TgAb level in neonates was 38.0 IU/mL, and TPOAb were detected in only 12.3% of samples. Maternal FT3 level was positively associated with PFAS levels in both TA-positive and TA-negative mothers. Maternal perfluorooctanoate was inversely associated with maternal TPOAb. Among boys, some maternal PFASs were associated with higher TSH and lower FT3 levels in maternal TA-negative group, while perfluorodecanoic acid was associated with lower TSH in maternal TA-positive group. Among girls, some PFAS of mothers showed associations with lower TSH and higher FT3 in maternal TA-negative group, while perfluorododecanoic acid was associated with lower FT4 in maternal TA-positive. Maternal PFASs showed associations with boy's TgAb inversely in maternal TA-negative group and with girl's TgAb positively in maternal TA-positive group. Conclusions: Our results suggest thyroid disrupting effects of PFAS exposure and susceptibility vary depending on maternal TA levels. Keywords: Perfluoroalkyl substances, Thyroid antibodies, Thyroid hormones, Prenatal exposure, Birth cohort

Recently, we have published a book containing evidence-based public health guidelines and a practical manual for the prevention of sick house syndrome. The manual is available through the homepage of the Ministry of Health, Labour and Welfare (http://www.mhlw.go.jp/file/06-Seisakujouhou-11130500-Shokuhinanzenbu/0000155147.pdf). It is an almost completely revised version of the 2009 version. The coauthors are 13 specialists in environmental epidemiology, exposure sciences, architecture, and risk communication. Since the 1970s, health problems caused by indoor chemicals, biological pollution, poor temperature control, humidity, and others in office buildings have been recognized as sick building syndrome (SBS) in Western countries, but in Japan it was not until the 1990s that people living in new or renovated homes started to describe a variety of nonspecific subjective symptoms such as eye, nose, and throat irritation, headache, and general fatigue. These symptoms resembled SBS and were designated "sick house syndrome (SHS)." To determine the strategy for prevention of SHS, we conducted a nationwide epidemiological study in six cities from 2003-2013 by randomly sampling 5,709 newly built houses. As a result 1,479 residents in 425 households agreed to environmental monitoring for indoor aldehydes and volatile organic compounds (VOCs). After adjustment for possible risk factors, some VOCs and formaldehyde were dose-dependently shown to be significant risk factors. We also studied the dampness of the houses, fungi, allergies, and others. This book is fully based on the scientific evidence collected through these studies and other newly obtained information, especially from the aspect of architectural engineering. In addition to SHS, we included chapters on recent information about "multi-chemical sensitivity."

Since "Our Stolen Future" by Theo Colborn was published in 1996, global interest on the impact of chemical substances, such as the endocrine-disrupting action of chemicals, has increased. In Japan, "The Hokkaido Study on Environment and Children's Health: Malformation, Development and Allergy" was launched in 2001. It was a model of Japan Environment and Children's Study of the Ministry of the Environment. In a large-scale, Hokkaido cohort, we obtained the consent of 20,926 mothers at the organogenesis stage with the cooperation of 37 obstetrics clinics in Hokkaido. We tracked the effects of endocrine disruptors on developmental disorders. In a small-scale Sapporo cohort, we observed in detail the neuropsychiatric development of children with the consent of 514 mothers in their late pregnancy. We examined how prenatal exposure to low concentrations of environmental chemicals affect the development of organs and the postnatal development of children. Maternal exposure to POPs, such as PCB/dioxins and perfluorinated alkyl substances, has affected not only children's birth size, thyroid functions, and sex hormone levels, but also postnatal neurodevelopment, infection, and allergy among others. The associations of short-half-life substances, such as DEHP and BPA, with obesity, ASD, and ADHD have been investigated. Gene-environment interactions have been found for smoking, caffeine, folic acid, and PCB/dioxin. In 2015, our center was officially designated as the WHO Collaborating Centre for Environmental Health and Prevention of Chemical Hazards, and we continue to the contribute to the global perspectives of child health.

Background Bisphenol A (BPA) is widely used and BPA exposure is nearly ubiquitous in developed countries. While animal studies have indicated adverse health effects of prenatal BPA exposure including reproductive dysfunction and thyroid function disruption possibly in a sex-specific manner, findings from epidemiologic studies have not been enough to prove these adverse effects. Given very limited research on human, the aim of this study was to investigate associations between cord blood BPA levels and reproductive and thyroid hormone levels of neonates and whether associations differed by neonate sex. Methods The study population included 514 participants of the Hokkaido study recruited from 2002 to 2005 at one hospital in Sapporo, Japan. The BPA level in cord blood was determined by ID-LC/MS/MS, and the limit of quantification was 0.040 ng/ml. We measured nine types of reproductive hormone levels in cord blood, and thyroid hormone levels were obtained from neonate mass screening test data. There were 283 subjects, who had both BPA and hormone levels measurements, included for the final analyses. Results The geometric mean of cord blood BPA was 0.051 ng/ml. After adjustment, BPA level was negatively associated with prolactin (PRL) (β = -0.38). There was an interaction between infant sex and BPA levels on PRL; a weak negative association was found in boys (β = -0.12), whereas a weak positive association was found in girls (β = 0.14). BPA level showed weak positive association with testosterone, estradiol, and progesterone levels in boys. No association was found between BPA and thyroid hormone levels. Conclusions Our findings suggested that fetal BPA levels might be associated with changes in certain reproductive hormone levels of neonates in a sex-specific manner, though further investigations are necessary.

The Hokkaido Study on Environment and Children’s Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary study goals are (1) to examine the effects of low-level environmental chemical exposures on birth outcomes, including birth defects and growth retardation; (2) to follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders and perform a longitudinal observation of child development; (3) to identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) to identify the additive effects of various chemicals, including tobacco smoking. The purpose of this report is to update the progress of the Hokkaido Study, to summarize the recent results, and to suggest future directions. In particular, this report provides the basic characteristics of the cohort populations, discusses the population remaining in the cohorts and those who were lost to follow-up at birth, and introduces the newly added follow-up studies and case-cohort study design. In the Sapporo cohort of 514 enrolled pregnant women, various specimens, including maternal and cord blood, maternal hair, and breast milk, were collected for the assessment of exposures to dioxins, polychlorinated biphenyls, organochlorine pesticides, perfluoroalkyl substances, phthalates, bisphenol A, and methylmercury. As follow-ups, face-to-face neurobehavioral developmental tests were conducted at several different ages. In the Hokkaido cohort of 20,926 enrolled pregnant women, the prevalence of complicated pregnancies and birth outcomes, such as miscarriage, stillbirth, low birth weight, preterm birth, and small for gestational age were examined. The levels of exposure to environmental chemicals were relatively low in these study populations compared to those reported previously. We also studied environmental chemical exposure in association with health outcomes, including birth size, neonatal hormone levels, neurobehavioral development, asthma, allergies, and infectious diseases. In addition, genetic and epigenetic analyses were conducted. The results of this study demonstrate the effects of environmental chemical exposures on genetically susceptible populations and on DNA methylation. Further study and continuous follow-up are necessary to elucidate the combined effects of chemical exposure on health outcomes.

Background Bisphenol A (BPA) is a ubiquitous environmental chemical which has been detected in various populations. There have been concerns that endocrine disrupting property of BPA may cause adverse health effects on neurodevelopmental and behavioral problems. Yet findings from prospective cohort studies to assess influence of prenatal exposure to BPA on child neural development were not conclusive. Especially, with relatively lower levels of exposure and its influence was not examined. Thus, the aim of this study was to evaluate child mental, psychomotor and behavioral problems at different ages in association with prenatal BPA exposures in the prospective birth cohort study. Method BPA level in cord blood was determined by ID-LC/MS/MS. Bayley Scales of Infant Development 2nd Edition was used to assess mental and motor development at 6 and 18 month of age. Kaufman Assessment Battery for Children to assess intelligence and Child Behavior Checklist (CBCL) to assess behavioral problems were used at 42 month of age. Out of 514 subjects in Sapporo cohort, 285 mother-child pairs with BPA measurement and child developmental assessments were included in this study. Results The median level of cord blood BPA was 0.051ng/ml. No association was found between BPA level and either mental or psychomotor development at 6 and 18 month of age. BPA level was positively associated with total, internalizing and externalizing problem scores of CBCL, respectively (β=4.77, 95% CI: -0.28, 9.82, β=4.35, 95% CI: -0.48, 9.18, β=4.33, 95% CI: -0.86, 9.25) with marginal significance. Cord blood BPA concentration was positively associated with development problems score (β=2.60, 95% CI: 0.15, 5.06) with significance. Conclusion Our findings suggested no association between cord blood BPA level and child mental, psychomotor, however, cord blood BPA level may be associated with child behavioral problems at early age.

Background: It is known that obesity is one of the risk factors for breast cancer although the association may differ between ethnic groups and with the menopausal status. Recently obesity-related risk factors including serum adiponectin and insulin levels have been analyzed together with BMI in association with breast cancer risk. Materials and Methods: We measured serum high molecular weight (HMW) adiponectin and insulin levels in a hospital based case-control study, including 66 sets of Japanese female breast cancer cases and age and menopausal status matched controls. Serum levels of HMW adiponectin, insulin levels and body mass index (BMI) were examined in association with breast cancer risk with adjustment for the various known risk factors by menopausal status. Results: Women in the highest HMW adiponectin levels showed significant reduced risk of breast cancer in both pre and postmenopausal women (odds ratio (OR), 0.01; 95% confidence interval (CI), 0.00-0.26 and 0.13; 0.03-0.57, respectively). Lower BMI showed decreased breast cancer risk in both pre and postmenopausal women (OR, 0.04; 95% CI, 0.00-0.69, OR, 0.28; 95% CI, 0.07-1.11, respectively). Conclusions: These results indicated that higher serum HMW adiponectin levels and lower BMI are associated with a decreased breast cancer risk in both pre and postmenopausal women in Japan, adding evidence for the obesity link.

Background: The age-adjusted incidence rate of prostate cancer (PCa) has been reported to be lower among Asians than Western populations. A traditional Japanese meal, high in soybean products or isoflavones, may be associated with a decreased risk of PCa. Equol, which is converted from daidzein by human intestinal flora, is biologically more active than any other isoflavone aglycone. Materials and Methods: We reviewed not only recent epidemiological studies on association of isoflavones with PCa risk, but also recent research on human intestinal bacteria responsible for converting daidzein into equol. Studies were systematically searched from the database published within the last 5 years of from 2008-2012. Results: Five out of 6 articles showed significant association of isoflavones with a decreased risk of PCa, and two of them consistently showed that equol-producers carry a significantly reduced risk of PCa. Furthermore, 5 human intestinal bacteria that can convert daidzein into equol were identified in the last 5 years. Conclusions: If equol can reduce risk of PCa, a possible strategy for reducing the risk of PCa may be to increase the proportion of equol-producers by changing the intestinal flora to carrying an equol-producing bacterium with dietary alteration or probiotic technology.

Introduction: Prenatal environment is considered to contribute childhood development and behavior. The aim of this study was to evaluate prenatal environmental factors including chemical exposures ...

Bisphenol A (BPA) is endocrine disrupting chemical that have been detected among general population. Exposure levels among pregnant women and their fetus are yet largely unknown among Japanese. We have developed a new method of measuring total BPA in whole blood samples by using isotopic dilution liquid chromatography-tandem mass spectrometry (ID-LC/MS/MS). For eliminating possible contaminations, we have used glass cartridge instead of polypropylene cartridge and successfully reduced background levels. Additionally gap retention technique was applied to improve sensitivity. We also confirmed no external contamination by measuring free BPA in the samples. The limit of quantification (LOQ) was 0.040 ng/ml. With this developed method, we determined total BPA concentrations of 59 maternal blood at delivery and 285 cord blood samples in prospective birth cohort study and investigated factors possibly related to total BPA levels. Total BPA levels ranged from below LOQ to 0.419 ng/ml and for maternal blood and from below LOQ to 0.217 ng/ml for cord blood, respectively. The geometric mean was 0.051 ng/ml for maternal blood and 0.046 ng/ml for cord blood, respectively. Although no correlation was observed between maternal and fetal blood levels of total BPA, our result suggested fetal exposure to BPA. We have found that younger mothers, frequent beef and pork consumption during pregnancy were positively associated with maternal total BPA levels. We confirmed in utero exposure to BPA, which highlights the importance of further studies of investing the effects of fetus BPA exposure on health outcomes.