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Despite numerous studies, the associations between per- and polyfluoroalkyl substances (PFAS) exposure and various lipid levels in pregnant women remain ambiguous, especially concerning the association with cord blood lipids. This analysis included 20,960 pregnant women enrolled in the Japan Environment and Children's Study, recruited between 2011 and 2014. Non-fasting plasma samples collected before 22 weeks of gestation were examined for PFAS concentrations. Additionally, non-fasting serum samples collected before, at and after 22 weeks of gestation, at birth, and from cord blood were used to measure total cholesterol (TC) and triglycerides (TG). Linear regression models were applied to quantify the association between each PFAS and various lipid metrics. Among the 28 PFAS analyzed, 7 were quantifiable in more than 80% of participants. Of these, 6 PFAS showed positive associations with TC in maternal blood before 22 weeks of gestation, a trend that remained mostly consistent for maternal blood samples in later stages. However, no associations were found with TC levels in cord blood. Regarding TG, 3 PFAS demonstrated a negative association with TG levels in maternal blood before 22 weeks of gestation, with these relationships generally persisting in later stages, while 4 PFAS were positively associated with TG in cord blood. In summary, this study identified associations between PFAS concentrations in maternal blood and lipid levels in both maternal and cord blood, with differing patterns observed between the two., Competing Interests: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier Inc.)

Background: Little is known about the relationship of healthy diets, which are widely recommended to prevent diseases in general populations, with the risk of hypertensive disorders of pregnancy (HDP), particular among non-Western populations with different dietary habits. We aimed to investigate the association between periconceptional diet quality and the risk of HDP among pregnant Japanese women., Methods and Results: Dietary intake over 1 year before the first trimester of pregnancy was assessed using a validated, self-administered food frequency questionnaire among 81 113 pregnant Japanese women who participated in a prospective cohort of the Japan Environment and Children's Study. Overall diet quality was assessed by the Balanced Diet Score (BDS) based on adherence to the country-specific dietary guidelines and the Dietary Approaches to Stop Hypertension (DASH) score. Cases of HDP were identified by medical record transcription. The association between diet quality and HDP risk was examined using Bayesian logistic regression models with monotonic effects. We identified 2383 (2.9%) cases of HDP. A higher BDS was associated with a lower risk of HDP. When comparing the highest with the lowest quintile of the BDS, the adjusted odds ratio (aOR) of HDP was 0.83 (95% credible interval [CrI], 0.73-0.94). The DASH score and HDP risk were inversely associated in a monotonic dose-response manner (aOR per 1-quintile increase in the DASH score, 0.92 [95% CrI, 0.89-0.95])., Conclusions: A high-quality diet, which is recommended for disease prevention in general populations, before conception may also reduce the risk of HDP among pregnant Japanese women.

Background: Although recent in vitro experimental results have raised the question of whether maternal exposure to per- and polyfluoroalkyl substances (PFAS) may be a potential environmental risk factor for chromosomal abnormalities, epidemiological studies investigating these associations are lacking., Objectives: This study examined whether prenatal PFAS exposure is associated with a higher prevalence of chromosomal abnormalities among offspring., Methods: We used data from the Japan Environment and Children's Study, a nationwide birth cohort study, and employed logistic regression models to examine the associations between maternal plasma PFAS concentrations in the first trimester and the diagnosis of chromosomal abnormalities in all births (artificial abortions, miscarriages, stillbirths, and live births) up to 2 years of age. In addition, we examined associations with mixtures of PFAS using multipollutant models., Results: The final sample consisted of 24,724 births with singleton pregnancies, of which 44 confirmed cases of chromosomal abnormalities were identified (prevalence: 17.8/10,000 births). When examined individually, exposure to perfluorononanoic acid (PFNA) and perfluorooctane sulfonic acid (PFOS) showed positive associations with any chromosomal abnormalities with age-adjusted odds ratios of 1.81 (95% CI: 1.26, 2.61) and 2.08 (95% CI: 1.41, 3.07) per doubling in concentration, respectively. These associations remained significant after Bonferroni correction, although they did not reach the adjusted significance threshold in certain sensitivity analyses. Furthermore, the doubling in all PFAS included as a mixture was associated with chromosomal abnormalities, indicating an age-adjusted odds ratio of 2.25 (95% CI: 1.34, 3.80), with PFOS as the predominant contributor, followed by PFNA, perfluoroundecanoic acid (PFUnA), and perfluorooctanoic acid (PFOA)., Discussion: The study findings suggested a potential association between maternal exposure to PFAS, particularly PFOS, and chromosomal abnormalities in offspring. However, the results should be interpreted cautiously, because selection bias arising from the recruitment of women in early pregnancy may explain the associations. https://doi.org/10.1289/EHP13617.

Per- and poly-fluoroalkyl substances (PFAS), which are long-lasting environmental contaminants that are released into the environment during the e-waste disassembly process, pose a threat to human health. Human milk is a complex and dynamic mixture of endogenous and exogenous substances, including steroid hormones and PFAS. Therefore, in this study, we aimed to investigate the association between PFAS and steroid hormones in human milk from women living close to an e-waste disassembly area. In 2021, we collected milk samples from 150 mothers within 4 weeks of delivery and analyzed them via liquid chromatography-tandem mass spectrometry to determine the levels of 21 perfluorinated compounds and five steroid hormones (estrone, estriol, testosterone, progesterone, and androstenedione [A-dione]). We also performed multiple linear regression analysis to clarify the association between maternal PFAS exposure and steroid hormone concentrations. Our results indicated that PFOA and PFOS were positively associated with estrone ( β , 0.23; 95% CI, 0.08-0.39) and A-dione ( β , 0.186; 95% CI, 0.016-0.357) concentrations in human milk, respectively. Further, the average estimated daily intake of PFOA and PFOS were 36.5 ng/kg bw/day (range, 0.52-291.7 ng/kg bw/day) and 5.21 ng/kg bw/day (range, 0.26-32.3 ng/kg bw/day), respectively. Of concern, the PFAS intake of breastfeeding infants in the study area was higher than the recommended threshold. These findings suggested that prenatal exposure to PFAS from the e-waste disassembly process can influence steroid hormones levels in human milk. Increased efforts to mitigate mother and infant exposure to environmental pollutants are also required., Competing Interests: The authors declare no conflicts of interest relevant to this study., (© 2024 The Author(s). GeoHealth published by Wiley Periodicals LLC on behalf of American Geophysical Union.)

Background: High low-density lipoprotein cholesterol levels (LDL-C) during pregnancy have been associated with adverse pregnancy and offspring outcomes. While previous studies have suggested a potential link between organophosphate pesticide (OPP) exposure and higher LDL-C in the general population and agricultural workers, the relationship in pregnant women and the effect of body mass index on this relationship remain unclear. We examined the association between the urinary concentrations of OPP metabolites (dialkylphosphates) and blood lipid levels in pregnant women., Methods: We used data from the Japan Environment and Children's Study, which included 5,169 pregnant women with urinary dialkylphosphate data. We examined the association between urinary concentrations of six dialkylphosphates (DEP, DETP, DEDTP, DMP, DMTP, DMDTP) and blood lipid levels (LDL-C, total cholesterol, high-density lipoprotein cholesterol, and triglycerides) during the first trimester using multiple linear regression under a Bayesian paradigm. We examined the association between high LDL-C, defined as ≥90th percentile of LDL-C, and urinary dialkylphosphate concentrations, using multiple logistic regression under a Bayesian paradigm. These analyses were repeated in underweight, normal-weight, and overweight participants., Results: DEP, DMP, and DMTP were detected in >50 % of the participants. Multiple linear regression analyses did not show associations between LDL-C and these dialkylphosphates. Stratified analyses showed a positive association between DEP and LDL-C in overweight women (beta coefficient = 2.13, 95 % credible interval = 0.86-3.38, probability of direction (PD) = 100 %); however, the association was not significant (percentage in region of practical equivalence (% in ROPE) = 84.0). Higher DEP was significantly associated with high LDL-C (odds ratio = 1.32, 95 % credible interval = 1.13-1.55, PD = 100 %, % in ROPE = 0.2)., Conclusions: Among overweight pregnant women in the first trimester, higher urinary DEP concentrations were associated with high LDL-C. The effects of OPP on blood lipid profiles merit further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The role of prenatal diet on childhood wheezing and subsequent risk of asthma is inconclusive, which may be partly due to the heterogeneity in wheezing phenotypes. We aimed to identify wheeze trajectories in early childhood and to examine their associations with periconceptional maternal diet quality., Methods: Data from 70,530 mother-child pairs of liveborn singletons from the Japan Environment and Children's Study were analysed. Wheezing was reported by caregivers using a modified International Study of Asthma and Allergies in Childhood questionnaire yearly from 1 to 4 years of age, from which trajectories were derived using group-based trajectory modelling. Maternal diet in the year preceding the first trimester of pregnancy was assessed using a validated food frequency questionnaire; overall diet quality was determined using the balanced diet score based on the Japanese Food Guide Spinning Top. Bayesian inference of multinomial logistic regression models was performed to examine the association between maternal diet quality and wheeze trajectory in early childhood., Results: We identified four wheeze trajectories: 'never/infrequent' (69.1%; reference group), 'early-childhood onset' (6.2%), 'transient early' (16.5%) and 'persistent' (8.2%). After adjustment for confounders, a higher quartile of maternal balanced diet score was associated with a lower risk of belonging to the 'transient early' and 'persistent' wheeze trajectories compared with the 'never/infrequent' wheeze trajectory by 10% of both. Maternal balanced diet score was not associated with belonging to the 'early-childhood onset' wheeze trajectory., Conclusion: Improving maternal diet quality prior to conception may reduce certain wheeze phenotypes in early childhood., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Environmental phenols are widely distributed in the environment and human samples, suggesting potential exposure to these chemicals. We designed an intervention trial with 30 participants over 6 days to assess the urinary concentrations and half-lives of environmental phenols in Japanese young people. The target environmental phenols include three parabens (methyl paraben, ethyl paraben, and propyl paraben), two benzophenones (benzophenone 1 and 3), two bisphenols (bisphenol F and bisphenol S), and triclosan. Throughout the intervention, the participants consumed the same food and drinks and used personal care products provided by the project. The target phenols were measured in urine from the participants using a liquid chromatography-tandem mass spectrometer. We compared the measured concentrations between the study periods to better understand the exposure tendency. Some statistically significant differences were observed. All target analytes were detected in more than 50% of samples collected on Day 0 (the day before the intervention). Methyl paraben was the dominant phenol detected in urine (1640 μg/g-creatinine), followed by ethyl paraben (119 μg/g-creatinine). Downward trends in creatinine-corrected concentrations were observed for all target analytes in some instances. Non-compartment analysis was performed to estimate urinary excretion parameters. The estimated half-lives ranged from 7.69 to 20.3 h. Use of paraben-free products during the intervention period reduced the body burden., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Tomohiko Isobe reports financial support was provided by Environmental Restoration and Conservation Agency. Tomohiko Isobe reports financial support was provided by Japan Society for the Promotion of Science., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Long-term exposure to inorganic arsenic (InAs) through arsenic (As)-contaminated drinking water poses serious health risks. However, epidemiological studies focusing on low-level dietary exposure to InAs are lacking. Furthermore, although toenail clippings are used as biomarkers for assessing As exposure in areas with contaminated drinking water, to date, no method has been developed for using toenails as a biomarker of long-term InAs exposure in individuals with lower exposure levels, e.g., from dietary sources including fish and seaweeds. Therefore, this study aimed to assess the feasibility of using toenails as biomarkers for estimating InAs exposure in Japanese adults., Methods: Three sets of 7-day diet records and toenail clipping samples were collected from 39 healthy adult participants at intervals of 1-6 months over 4-8 months, spanning from June 2019 to March 2020. The analysis sample sets comprised 113 sample sets obtained from 38 subjects: 56 samples from 19 males and 57 samples from 19 females. The speciation of As species in the toenail samples was performed using high-performance liquid chromatography-inductively coupled plasma mass spectrometry. The sum of the InAs and monomethylarsonic acid (MMA) or sum of As species (sum-As) concentrations in toenail samples was used as an index of InAs exposure., Results: The geometric mean (GM) concentration of InAs + MMA or sum-As in toenails was 0.180 µg As/g or 0.284 µg As/g. The estimated GM of daily dietary InAs exposure was 0.147 µg/kg/day. Log-transformed InAs + MMA or sum-As concentrations in toenails did not predict dietary InAs exposure levels from rice and hijiki consumption in both males and females. Similarly, toenail InAs + MMA or sum-As concentrations showed no correlation with dietary InAs exposure levels from rice or hijiki consumption., Conclusions: Our findings indicate that human toenail clippings are not a suitable biomarker for assessing long-term InAs exposure levels in Japanese individuals based on the observed range of InAs and its metabolite concentrations in toenails.

Background: Dioxin is an environmental pollutant as well as an endocrine disruptor in humans. Our longitudinal study wants to clarify the relationship between dioxin exposure and endocrine disorders in children living in the Vietnamese dioxin hotspot., Method: Seventeen congeners of polychlorinated dibenzo-p-dioxins/polychlorinated dibenzo-furans (PCDDs/PCDFs) in maternal breast milk and seven serum steroid hormones in children of 43 and 46 mothers and their 9-year-old children from the non-exposure and the hotspot areas were measured, respectively. The steroid metabolic enzyme ratios were calculated based on the hormone level ratio., Results: Most dioxin/furan congeners and toxic equivalents (TEQs) levels were significantly higher in the hotspot than in the non-exposure area, except for 2,4,7,8-TeCDF. The height and weight of girls from the hotspot area were substantially lower and inversely correlated with dioxin congener levels/total TEQs level dioxin. The dihydrotestosterone (DHT) levels in the hotspot were markedly lower than those in non-exposed in both genders. The cortisol concentrations were significantly higher in the hotspot than those from the non-exposure area only in the girls. The DHT/testosterone ratios that exhibited the 5α- or 5β-reductase activity declined by 50% in the hotspot area for both genders. The DHT levels showed strong inverse correlations with almost the PCDDs/PCDFs congeners and total TEQs dioxin in breast milk., Conclusions: This finding suggests that dioxin exposure in maternal breast milk might impact children's endocrine system until 9 years old, especially on the DHT biosynthesis.

Background: The developing brains are sensitive to methylmercury (MeHg). However, the exposure to MeHg in baby foods and toddler meals remains unknown. This study aimed to determine MeHg intake from baby food or toddler meals, and to investigate the relationship with child hair total mercury (THg)., Methods: A total of 3 days of 24-hour dietary diet and hair samples were collected from 260 consenting children aged 0-5 years. We measured the concentrations of THg and MeHg in the diet and THg in the hair., Results: The results of measuring THg were below both the method detection and method quantification limits or either of both in powdered milk (93.8%), 5-6 months (53.3%), and 7-8 months (39.5%). The median daily THg intake was 20.3 (95% confidence interval 0.72-232.5) ng/kgbw. MeHg was not detected in 213 samples with dietary THg concentrations below 1 ng/g. The MeHg concentration with THg concentrations of 1 ng/g or higher was 1.70 (0.87-6.21) ng/g, and MeHg percentage in THg was 90.0%. To estimate MeHg intake, we multiplied the THg concentration by 90.0%, resulting in an estimated MeHg intake of 18.3 (0.65-209.2) ng/kgbw/day. The THg in children's hair was 1.05 (0.31-3.96) ppm, and a weak positive correlation was observed between hair THg and dietary MeHg (r = 0.170)., Conclusions: This study highlights the accurate estimation of MeHg intake in children using a duplicate method. Japanese children consume fish, the MeHg intakes exceeded the reference dose and/or provisional tolerable weekly intake in several children. Further discussion based on epidemiological data is required.

Seasonal variations of chemical compounds in indoor air and outdoor air and personal exposure to these chemicals were continuously monitored for 6 years using four types of passive sampling devices: PSD-BPE/DNPH packed with 2,4-dinitrophenylhydrazine and trans-1,2-bis(2-pyridyl)ethylene coated silica for ozone and carbonyls; PSD-VOC packed with Carboxen 572 or Active Carbon Beads particles for volatile organic compounds; PSD-TEA packed with triethanolamine impregnated silica for acid gases; and PSD-TEA packed with phosphoric acid impregnated silica for basic gases. Many chemical compounds except for nitrogen dioxide, formic acid, and benzene showed seasonal variations with high concentrations in summer and low concentrations in winter. In particular, formaldehyde, nonanal, 2-ethyl-1-hexanol, 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate, and ammonia concentrations showed remarkable seasonal variation. For example, the concentration of formaldehyde in February and August was 5.9 and 40 μg/m 3 , respectively, a difference of about 7 times. Although there were large differences in the concentrations in each house, the fluctuation pattern was almost the same every year in each house. By contrast, nitrogen dioxide, formic acid, and benzene concentrations were low in summer and high in winter. These compounds were generated by kerosine and gas stoves in winter. Long-term continuous monitoring revealed that annual mean concentrations could be estimated using data from February and August. Personal exposure concentrations could be classified into four patterns: chemicals affected by the indoor environment such as formaldehyde, chemicals affected by the outdoor environment such as ozone, chemicals affected by the occupational environment such as hexane, and background level chemicals such as benzene (without kerosine and gas stoves). Indoor and outdoor measurements are means to investigate the "health" of each environment. Personal exposure measurement using PSD-samplers is suitable for assessing the health risk of chemical compounds to humans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Kawasaki disease (KD) is common among pediatric patients and is associated with an increased risk of later cardiovascular complications, though the precise pathophysiology of KD remains unknown. Per- and polyfluoroalkyl substances (PFAS) have gathered notoriety as the causal pathogens of numerous diseases as well as for their immunosuppressive effects. The present epidemiological study aims to assess whether PFAS may affect KD risk. We evaluated research participants included in the ongoing prospective nationwide birth cohort of the Japan Environment and Children's Study (JECS). Among the over 100,000 pregnant women enrolled in the JECS study, 28 types of PFAS were measured in pregnancy in a subset of participants (N = 25,040). The JECS followed their children born between 2011 and 2014 (n total infants = 25,256; n Kawasaki disease infants = 271), up to age four. Among the 28 types of PFAS, those which were detected in >60 % of participants at levels above the method reporting limit (MRL) were eligible for analyses. Multivariable logistic regressions were implemented on the seven eligible PFAS, adjusting for multiple comparison effects. Finally, we conducted Weighted Quantile Sum (WQS) and Bayesian kernel machine regression (BKMR) to assess the effects of the PFAS mixture on KD. Therefore, we ran the BKMR model using kernel mechanical regression equations to examine PFAS exposure and the outcomes of KD. Upon analysis, the adjusted multivariable regression results did not reach statistical significance for the seven eligible substances on KD, while odds ratios were all under 1.0. WQS regression was used to estimate the mixture effect of the seven eligible PFAS, revealing a negative correlation with KD incidence; similarly, BKMR implied an inverse association between the PFAS mixture effect and KD incidence. In conclusion, PFAS exposure was not associated with increased KD incidence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The effects of early-life exposure to per- and polyfluoroalkyl substances (PFAS) on the onset of asthma in children have been unclear. We examined the association between prenatal PFAS exposure and wheezing and asthma symptoms among 4-year-old children in a total of 17,856 mother-child pairs from the Japan Environment and Children's Study. Maternal first-trimester serum concentrations of six PFAS were used for the exposure assessment. We defined "wheeze ever," "current wheeze," "current symptoms of severe asthma," and "asthma ever" at the age of 4 years by the responses to the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, and "doctor-diagnosed asthma" by the response to a corresponding question. Multivariate logistic regression models were used to examine exposure-outcome associations. Our findings revealed that doubling of the PFOA concentration was associated with a reduced occurrence of "wheeze ever," yielding an adjusted odds ratio of 0.94 (95% CI: 0.90-0.98). Also, doubling in the concentrations of PFOA and PFHxS was associated with a decreased prevalence of "asthma ever," with adjusted odds ratios of 0.94 (95% CI: 0.88-1.00) and 0.95 (95% CI: 0.90-0.99), respectively. However, these associations were not significant after applying the Bonferroni correction. The estimated exposure-response curves were nearly linear with a subtle or flat slope. When stratified by the child's sex or the mother's history of asthma, most of the estimated confidence intervals were overlapped between each pair of strata. Regional stratification analysis indicated low-to-moderate heterogeneity in 12 exposure-outcome pairs and moderate-to-high heterogeneity in 9 out of the 30 examined pairs. This study found no clear associations between prenatal PFAS exposure and the prevalence of wheezing and asthma among children at the age of 4 years., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Humans are exposed to various bisphenols, alkylphenols and nitrophenols through dietary intake, food packaging and container materials, indoor and outdoor air/dust. This study aimed to evaluate exposure of Japanese pregnant women to environmental phenols by measuring target compounds in urine samples. From a cohort of the Japan Environment and Children's Study, 4577 pregnant women were selected. Bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF), bisphenol AF (BPAF), para-nitrophenol (PNP), 3-methyl-4-nitrophenol (PNMC), branched 4-nonylphenol (4-NP), linear 4-nonylphenol and 4-tert-octylphenol (4-t-OP) were analysed using a high-performance liquid chromatograph coupled to a triple-quadrupole mass spectrometer. The urinary metabolite data were combined with a questionnaire to examine the determinants of phenol exposure by machine learning. The estimated daily intake (EDI) and hazard quotient (HQ) of BPA were calculated. PNP (68.2%) and BPA (71.5%) had the highest detection frequencies, with median concentrations of 0.76 and 0.46 μg/g creatinine, respectively. PNMC, BPS, BPF and 4-NP were determined in 24.9%, 11.9%, 1.3% and 0.4% of samples, respectively, whereas BPAF (0.02%) and 4-t-OP (0.02%) were only determined in a few samples. The PNP concentrations measured in this study were comparable with those reported in previous studies, whereas the BPA concentrations were lower than those reported previously worldwide. The EDI of BPA was 0.014 μg/kg body weight/day. Compared with the tolerable daily intake set by the German Federal Institute for Risk Assessment, the median (95th percentile) HQ was 0.044 (0.2). This indicates that the observed levels of BPA exposure pose a negligible health risk to Japanese pregnant women. Determinants of bisphenol and nitrophenol exposure could not be identified by analysing the questionnaire solely, suggesting that biological measurement is necessary to assess exposure of pregnant women to bisphenols and nitrophenols. This is the first study to report environmental phenol exposure of Japanese pregnant women on a nationwide scale., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Electronic waste that has not been properly treated can lead to environmental contamination including of heavy metals, which can pose risks to human health. Infants, a sensitive group, are highly susceptible to heavy metals exposure. The aim of this study was to investigate the association between prenatal heavy metal exposure and infant birth outcomes in an e-waste recycling area in China. We analyzed cadmium (Cd), chromium (Cr), manganese (Mn), lead (Pb), copper (Cu), and arsenic (As) concentrations in 102 human milk samples collected 4 weeks after delivery. The results showed that 34.3% of participants for Cr, which exceeds the World Health Organization (WHO) guidelines, as well as the mean exposure of Cr exceeded the WHO guidelines. We collected data on the birth weight (BW) and length of infants and analyzed the association between metal concentration in human milk and birth outcomes using multivariable linear regression. We observed a significant negative association between the Cd concentration in maternal milk and BW in female infants ( β  = -162.72, 95% CI = -303.16, -22.25). In contrast, heavy metals did not associate with birth outcomes in male infants. In this study, we found that 34.3% of participants in an e-waste recycling area had a Cr concentration that exceeded WHO guidelines, and there was a significant negative association between prenatal exposure to the Cd and infant BW in females. These results suggest that prenatal exposure to heavy metals in e-waste recycling areas may lead to adverse birth outcomes, especially for female infants., Competing Interests: The authors declare no conflicts of interest relevant to this study., (© 2023 The Authors. GeoHealth published by Wiley Periodicals LLC on behalf of American Geophysical Union.)

Background: Prenatal exposure to multiple heavy metals can interfere with early neurodevelopment, lead to changes in sex hormone concentrations in children, and affect female reproductive health. To date, the influence of prenatal exposure to heavy metals on the endocrine system of children in Chinese electronic waste (e-waste) recycling areas has not been elucidated., Methods: Four weeks after delivery, 10 mL of human milk was collected for analysis of three heavy metals (lead (Pb), cadmium (Cd), and mercury (Hg)) via inductively coupled plasma mass spectrometry (ICP-MS). Four serum steroid hormones, including progesterone, testosterone, androstenedione (A-dione), and dehydroepiandrosterone (DHEA), were analyzed in 4-year-old children (25 boys and 17 girls). A multiple linear regression (MLR) model was implemented to investigate the association between each individual metal and serum steroid hormone. The exposure-response relationships were explored by generalized additive models (GAMs). Additionally, a Bayesian kernel machine regression (BKMR) model was used to assess the effects of multiple heavy metal exposures on each steroid hormone., Results: The MLR results show a significant positive association between a natural log unit increase in Hg and DHEA levels after adjusting for confounders (β = 65.50, 95% confidence interval (CI) = 4.37, 126.62). According to the GAM, the univariate exposure-response relationship of Hg on DHEA was almost linear. However, this association was attenuated based on the multiple metal MLR and BKMR results after accounting for multiple heavy metal exposures., Significance: Prenatal Hg exposure may affect sex hormones in children by affecting DHEA levels., Impact Statement: Prenatal maternal exposure to Hg may have long-term effects on the next generation. Hence, regulatory measures to reduce Hg exposure and long-term monitoring of children's health in e-waste areas are needed., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Recent studies have reported the effect of neonicotinoid (NEO) exposures on development in human. However, information about the risk of childhood development delays due to NEO exposures is limited., Objectives: The study aimed to examine the association between NEO exposure and child development up to 4 years of age using data of the Japan Environment and Children's Study., Methods: The study employed urinary NEO and metabolite concentrations in the first and second or third trimesters; the Japanese translation of the Ages and Stages Questionnaire (third edition; J-ASQ-3) scores on developmental delay in five domains, namely communication, gross motor skills, fine motor skills, problem solving, and personal-social characteristics from 6 months to 4 years of age; and self-reported questionnaire data. The associations between urinary NEO concentrations and J-ASQ-3 results were analysed using the treed distributed lag mixture model. A total of 8538 participants were included in statistical analyses., Results: The determination rates of urinary acetamiprid-N-desmethyl (dm-ACE), clothianidin (CLO), dinotefuran (DIN) and thiamethoxam (THX) were greater than 50%. Median urinary dm-ACE, CLO, DIN and THX concentrations were 0.34, 0.14, 0.22 and 0.05 ng/ml, respectively, in samples collected during gestational weeks < 23, and 0.28, 0.12, 0.18 and 0.04 ng/ml, respectively, in those collected during gestational weeks ≥ 23. The binomial scores divided by the cut-off values of the J-ASQ were used in the treed distributed lag mixture model. The highest percentage for a domain with a value less than the cut-off value was 'problem solving' at 6 months of age among all the J-ASQ-3 scores (10.5%). There was no statistically significant association between maternal urinary dm-ACE, CLO, DIN and THX concentrations during pregnancy and the J-ASQ-3 results up to 4 years of age. Objective assessment of child development in different populations may be warranted to confirm our findings., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Exposure to low doses of neonicotinoid (NEO) insecticides during pregnancy may have a negative impact on the neurodevelopment of children. Biomarkers are frequently used to investigate the exposure and its health effects in environmental epidemiology. In the present study, we aimed to evaluate the utility of urinary biomarkers of NEO exposure by calculating intra-class correlation coefficients (ICCs). Urine samples were collected from 30 pregnant women who were non-smokers and living in a central part of Japan, between 12 and 22 weeks of gestation. We collected first morning voided (FMV) urine and afternoon spot (PM) urine samples on the same day on five occasions within a 2-week period. The urinary concentrations of NEO and their metabolites (NEO/m) were measured by liquid chromatography-tandem mass spectrometry. Normalisation to the specific gravity and creatinine concentration was used in the calculation of ICC. The number of urine samples required to obtain a reliable biomarker estimate of NEO exposure was calculated. The most frequently detected NEO/m was N-desmethyl-acetamiprid (N-dm-ACE), followed by clothianidin (CLO), thiamethoxam (THX) and dinotefuran (DIN), in both FMV and PM urine samples. The ICC calculations showed poor reproducibility for the measurement of CLO and THX concentrations (ICCs ≤0.25) in both FMV and PM urine samples and for DIN (ICC ≤0.29) in the FMV urine samples, and moderate reproducibility was identified for N-dm-ACE (ICC >0.60) in both FMV and PM urine samples and for DIN (ICC >0.40) in the PM urine samples. A minimum of 1-19 spot urine samples per individual was required to provide a reliable biomarker estimate over a 2 week period. These results suggest that pregnant Japanese women are frequently exposed to NEOs, and that, with the exception of urinary N-dm-ACE, a single measurement of urinary NEO concentrations may not be an appropriate method of characterising overall exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Numerous studies suggest that sex steroids might play a role in sex disparity observed in allergic diseases in adults. However, whether sex hormones influence allergic diseases in children remains unclear. The aim of the present study was to examine the association of sex steroid hormones with allergic disease in Japanese children., Methods: The present cross-sectional study included 145 6-year-old children participating in a pilot birth cohort study in the Japan Environment and Children's Study. Data on allergic diseases were obtained from questionnaires, and serum levels of sex steroid hormones and allergen-specific IgE were measured. Logistic regression was performed to evaluate the association of sex hormones with allergic diseases., Results: After adjusted sex, amount of body fat at 6 years, parental history of allergic disease, and exposure to tobacco smoke, serum dehydroepiandrosterone sulfate level was significantly associated with reduced odds of any allergic disease (adjusted odds ratio, 0.58; 95% confidence interval, 0.36-0.93; P = 0.024) and serum follicle-stimulating hormone level was significantly associated with increased odds of any allergic disease (adjusted odds ratio, 2.04; 95% confidence interval, 1.01-4.11, P = 0.046). Dehydroepiandrosterone sulfate level showed a significant association with number of allergic diseases., Conclusions: The current study findings suggest that sex hormones may play an important role in the development of allergic diseases in prepubertal children., (© 2023. BioMed Central Ltd., part of Springer Nature.)

As 3,3',5-triiodothyroacetic acid (TRIAC), a metabolite of thyroid hormones (THs), was previously detected in sewage effluent, we aimed to investigate exogenous TRIAC's potential for endocrine disruption. We administered either TRIAC or 3,3',5-triiodo-L-thyronine (LT3) to euthyroid mice and 6-propyl-2-thiouracil-induced hypothyroid mice. In hypothyroid mice, TRIAC administration suppressed the hypothalamus-pituitary-thyroid (HPT) axis and upregulated TH-responsive genes in the pituitary gland, the liver, and the heart. We observed that, unlike LT3, TRIAC administration did not upregulate cerebral TH-responsive genes. Measurement of TRIAC contents suggested that TRIAC was not efficiently trafficked into the cerebrum. By analyzing euthyroid mice, we found that cerebral TRIAC content did not increase despite TRIAC administration at higher concentrations, whereas serum levels and cerebral contents of THs were substantially decreased. Disruption by TRIAC is due to the additive effects of circulating endogenous THs being depleted via a negative feedback loop involving the HPT axis and heterogeneous distribution of TRIAC among different organs., Competing Interests: The authors declare no competing financial interests., (© 2023 The Author(s).)

Background: Diets contain toxic chemical contaminants as well as essential nutrients, both of which influence the intrauterine environment for foetal growth. However, whether a high-quality diet that is nutritionally healthy also results in lower exposure to chemical contaminants is unknown., Objective: We examined associations between periconceptional maternal diet quality and circulating concentrations of heavy metals during pregnancy., Design: Dietary intake over the year prior to the first trimester of pregnancy was assessed using a validated, self-administered food frequency questionnaire among 81,104 pregnant Japanese women who participated in the Japan Environment and Children's Study. Overall diet quality was determined using the Balanced Diet Score (BDS) based on the Japanese Food Guide Spinning Top, the Healthy Eating Index-2015 (HEI-2015), the Dietary Approaches to Stop Hypertension (DASH) score and the Mediterranean diet score (MDS). We measured whole-blood concentrations of mercury (Hg), lead (Pb) and cadmium (Cd) during the second or third trimester of pregnancy., Results: After controlling for confounders, all diet quality scores were positively associated with blood Hg concentrations. By contrast, higher BDS, HEI-2015 and DASH scores were associated with lower concentrations of Pb and Cd. Although the MDS was positively associated with concentrations of Pb and Cd, when dairy products were classified as a beneficial (rather than detrimental) food component, these associations were attenuated., Conclusion: A high-quality diet may reduce exposure to Pb and Cd but not Hg. Further studies are required to determine the optimal balance between mercury exposure risk and nutritional benefits of high-quality diets prior to pregnancy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Long-term air pollution exposure has been linked to increased lung cancer mortality. However, little is known about whether day-to-day fluctuations in air pollution levels are in relation to lung cancer mortality, particularly in low-exposure settings. This study aimed to evaluate the short-term associations between air pollution and lung cancer mortality. Daily data on lung cancer mortality, fine particulate matter (PM 2.5 ), nitrogen dioxide (NO 2 ), sulfur dioxide (SO 2 ), carbon monoxide (CO), and weather conditions were collected from Osaka Prefecture, Japan, from 2010 to 2014. Generalized linear models were combined with quasi-Poisson regression were applied to evaluate the associations between each air pollutant and lung cancer mortality after adjusting for potential confounders. Mean (standard deviation) concentrations of PM 2.5 , NO 2 , SO 2 , and CO were 16.7 (8.6) μg/m 3 , 36.8 (14.2) μg/m 3 , 11.1 (4.0) μg/m 3 , and 0.51 (0.16) mg/m 3 , respectively. Interquartile range increases in concentrations of PM 2.5 , NO 2 , SO 2 , and CO (2-d moving average) were associated with 2.65% (95% confidence intervals [CIs]: 0.96%-4.37%), 4.28% (95% CIs: 2.24%-6.36%), 3.35% (95% CIs: 1.03%-5.73%), and 4.60% (95% CIs: 2.19%-7.05%) increased risk of lung cancer mortality, respectively. Stratified analyses showed that the associations were strongest in the older population and men. Exposure‒response curves showed a continuously increasing mortality risk from lung cancer with elevation of air pollution levels, without discernible thresholds. In summary, we found evidence of increased lung cancer mortality in relation to short-term elevations in ambient air pollution. These findings may merit further research to better understand this issue., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A simultaneous, high-throughput and sensitive method for analysing nine neonicotinoid pesticides (NEOs) and four metabolites (NEOms) in urine using a liquid chromatography-tandem mass spectrometry (LC-MSMS) was developed. The method detection limit (MDL) and lowest concentration minimum reporting limit (LCMRL) of the nine NEOs were 0.0013-0.048 ng/ml and 0.0050-0.17 ng/ml, respectively. The MDL and LCMRL of the four NEOms were 0.0052-0.52 ng/ml and 0.011-1.6 ng/ml, respectively. Intermediate precision for the nine NEOs and four NEOms was 7.5-12.5% and 7.4-10.9%, respectively. Accuracy for the nine NEOs and four NEOms was 3.83-5.60% and 3.01-29.2%, respectively. The developed method was applied to analyse urine samples collected from participants of a large-scale birth cohort study, namely, the Japan Environment and Children's Study (JECS). •The NEO and NEOm concentrations in 100 µl urine samples were analysed using a highly sensitive LC-MSMS.•Automated solid phase extraction in a 96-well plate was utilised to achieve high-throughput analysis.•Intermediate precision and accuracy were less than 12.5% and 94.8-99.1%, respectively., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Background: Both poor maternal nutrition and toxic heavy metal exposure influence foetal growth and development. However, whether consumption of a variety of healthy foods modifies the association between prenatal heavy metal exposure and foetal growth is unknown., Objective: We examined whether long-term maternal diet quality in periconception modifies the associations between maternal circulating concentrations of heavy metals and foetal growth., Design: Data of 72,317 Japanese women who delivered singleton infants was extracted from the Japan Environment and Children's Study. Maternal diet over a 1-year before the first trimester of pregnancy was assessed using a validated food frequency questionnaire, and overall diet quality was determined using the balanced diet score based on the Japanese Food Guide Spinning Top. Maternal whole-blood concentrations of mercury (Hg), lead (Pb) and cadmium (Cd) were measured during the second/third trimester of pregnancy. Bayesian inference of multiple linear regression analysis was performed to evaluate the relationships between maternal diet quality and the blood concentrations of heavy metals; Bayesian logistic regression was used to analyse the risk of low birth weight (LBW; <2,500 g)., Results: After controlling for confounders, a high maternal balanced diet score was associated with low concentrations of blood Pb and Cd and high Hg. While all heavy metals assessed were positively associated with LBW risk, a higher maternal balanced diet score was negatively associated with LBW risk. A high-quality maternal diet attenuated the effect of Pb on LBW, an effect that was more marked at high blood Pb concentrations., Conclusion: A high-quality, 'well-balanced' diet prior to conception may reduce exposure to some heavy metals and mitigate the elevated risk of LBW associated with prenatal Pb exposure in Japanese mother-child pairs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: The risk of premature infants in neonatal incubators exposed to evaporated alcohol from alcohol-based disinfectants (ABDs) is unknown., Objective: To assess alcohol concentrations in the peripheral blood of premature infants and neonatal incubators., Design, Setting, and Participants: A quality improvement study comparing 2 different populations before and after introduction of ABD practice (ABD-PRAC) was conducted in a neonatal intensive care unit of a single tertiary hospital in Japan. Participants included premature infants who were born before 34 weeks of gestational age and received medical care in neonatal incubators. The study consisted of 3 periods: (1) September 1, 2020, to August 1, 2021 (prospective observation of pre-ABD-PRAC, (2) August 2 to August 22, 2021 (introduction of ABD-PRAC to medical staff and parents in the neonatal intensive care unit), and (3) August 23, 2021, to March 31, 2022 (prospective observation of post-ABD-PRAC). No follow-up studies were initiated., Interventions: An ABD-PRAC that aimed to reduce alcohol evaporation from ABDs inside neonatal incubators was instituted: (1) place alcohol preps in the incubator just before use and remove them from the incubator as soon as possible and (2) withhold placing hands into the incubators until 60 seconds after using ABDs for disinfection (applied only to family members)., Main Outcomes and Measures: Blood alcohol concentration and evaporated alcohol concentrations in neonatal incubators., Results: Disinfectant practice was assessed among 28 infants during the pre-ABD-PRAC (17 infants [10 girls]; median gestational age at birth, 29.4 [IQR, 26.3-30.3] weeks) and post-ABD-PRAC (11 infants [3 girls]; median gestational age at birth, 30.0 [IQR, 25.3-32.2] weeks) study periods. The median blood alcohol concentration was 7.0 (IQR, 5.4-9.3) mg/dL pre-ABD-PRAC and 4.2 (IQR, 2.5-7.2) mg/dL post-ABD-PRAC. The median evaporated alcohol concentration inside neonatal incubators during pre-ABD-PRAC during the day was 23.6 (IQR, 15.9-36.5) ppm and, at night, was 13.2 (IQR, 8.9-19.4) ppm; during post-ABD-PRAC, the concentration was 9.4 (IQR, 6.0-16.0) ppm during the day and 5.7 (IQR, 3.6-9.7) ppm at night. The introduction of ABD-PRAC at 22 weeks' corrected gestational age was associated with a lower blood alcohol concentration in premature infants: regression coefficient value, -8.3 (95% CI, -12.0 to -4.7)., Conclusions and Relevance: In this study, alcohol evaporated from ABDs was absorbed by premature infants in neonatal incubators. The findings suggest that introduction of ABD-PRAC was associated with lower alcohol concentrations in neonatal incubators and in the blood of premature infants.

Human biomonitoring (HBM) data measured in specific contexts or populations provide information for comparing population exposures. There are numerous health-based biomonitoring guidance values, but to locate these values, interested parties need to seek them out individually from publications, governmental reports, websites and other sources. Until now, there has been no central, international repository for this information. Thus, a tool is needed to help researchers, public health professionals, risk assessors, and regulatory decision makers to quickly locate relevant values on numerous environmental chemicals. A free, on-line repository for international health-based guidance values to facilitate the interpretation of HBM data is now available. The repository is referred to as the "Human Biomonitoring Health-Based Guidance Value (HB2GV) Dashboard". The Dashboard represents the efforts of the International Human Biomonitoring Working Group (i-HBM), affiliated with the International Society of Exposure Science. The i-HBM's mission is to promote the use of population-level HBM data to inform public health decision-making by developing harmonized resources to facilitate the interpretation of HBM data in a health-based context. This paper describes the methods used to compile the human biomonitoring health-based guidance values, how the values can be accessed and used, and caveats with using the Dashboard for interpreting HBM data. To our knowledge, the HB2GV Dashboard is the first open-access, curated database of HBM guidance values developed for use in interpreting HBM data. This new resource can assist global HBM data users such as risk assessors, risk managers and biomonitoring programs with a readily available compilation of guidance values., Competing Interests: Conflict of interest The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC) or U.S. Environmental Protection Agency (USEPA). The findings and conclusions in this report are from a research perspective and do not necessarily represent the official position of Health Canada. The research presented was not performed or funded by US EPA and was not subject to US EPA's quality system requirements. Health Canada support is acknowledged for this publication., (Crown Copyright © 2022. Published by Elsevier GmbH. All rights reserved.)

Urinary biomarkers are commonly used in epidemiological studies as surrogates or indicators of exposure to chemical substances. Evaluating the reliability of a biomarker is highly important because use of an unreliable marker may lead to misclassification and attenuation bias, resulting in flawed interpretations and conclusions. Although intraclass correlation coefficient (ICC) is regarded as a typical index of test reliability, methods for determining the ICCs of urinary biomarkers have not been standardised, and different methods have been used. This study evaluated different imputation methods for left-censored data, i.e., four imputation or one substitution methods, before calculating ICCs, and at the same time mathematically assessed the impact of the left-censoring proportion on the estimated ICCs. Biomarkers of exposure to organophosphate pesticides, i.e., dialkylphosphates, were used as an example. The Gibbs sampler-based left-censored missing value imputation approach had the best performance for imputation of values below reporting limits, with lower values on Kolmogorov-Smirnov test statistics than other imputation/substitution methods, i.e., a univariate distribution fitting approach, multiple imputation by chained equation, a bootstrap expectation-maximisation algorithm approach, and a single value substitution. In all imputation methods, however, ICCs decreased as censoring rates increased. We propose a method to estimate true ICCs based on mathematical estimation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Autism spectrum disorder (ASD) is a neurodevelopmental condition diagnosed in approximately 2% of children. Reliance on the emergence of clinically observable behavioral patterns only delays the mean age of diagnosis to approximately 4 years. However, neural pathways critical to language and social functions develop during infancy, and current diagnostic protocols miss the age when therapy would be most effective. We developed non-invasive ASD biomarkers using mass spectrometry analyses of elemental metabolism in single hair strands, coupled with machine learning. We undertook a national prospective study in Japan, where hair samples were collected at 1 month and clinical diagnosis was undertaken at 4 years. Next, we analyzed a national sample of Swedish twins and, in our third study, participants from a specialist ASD center in the US. In a blinded analysis, a predictive algorithm detected ASD risk as early as 1 month with 96.4% sensitivity, 75.4% specificity, and 81.4% accuracy ( n = 486; 175 cases). These findings emphasize that the dynamics in elemental metabolism are systemically dysregulated in autism, and these signatures can be detected and leveraged in hair samples to predict the emergence of ASD as early as 1 month of age.

Background: Low birth weight (LBW), which is considered a birth weight of <2500  g, poses significant health problems for children. However, population attributable fraction (PAF) of risk factors for LBW have not been well studied., Objective: We aimed to re-evaluate associations between risk factors for LBW reported in previous studies that used the Japan Environment and Children's Study (JECS) data, and to estimate the magnitude of risk using PAF., Methods: Data including 91,559 mother-child dyads were obtained from JECS. Risk factors identified by previous studies that used JECS data were used to calculate odds ratios for LBW using a Bayesian logistic regression model. Based on calculated odds ratios, the PAF was calculated., Results: Parity, history of adenomyosis, hypertension disorder of pregnancy, maternal age at birth, prepregnancy body mass index, gestational weight gain (GWG), maternal smoking and lead (Pb) exposure were all significantly associated with LBW. The sum of the PAF of all factors was 79.4 %, with the largest PAF among single risk factors being GWG (16.5 %); the environmental portion of the PAF (Pb exposure, 14.6 % + maternal smoking, 12.1 %) surpassed the PAF of GWG., Conclusion: Our findings suggest that the number of births classified as LBW can be reduced by approximately 27% if Pb exposure is reduced to the lowest quartile and maternal smoking is eliminated. Further investigations are needed to identify unknown risk factors for LBW., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: To our knowledge, the association of maternal exposure to metallic elements with weight trajectory pattern from the neonatal period has not been investigated., Objectives: The goals of this study were to identify infant growth trajectories in weight in the first 3 y of life and to determine the associations of maternal blood levels of lead, cadmium, mercury, selenium, and manganese with growth trajectory., Methods: This longitudinal study, part of the Japan Environment and Children Study, enrolled 103,099 pregnant women at 15 Regional Centres across Japan between 2011 and 2014. Lead, cadmium, mercury, selenium, and manganese levels were measured in blood samples collected in the second (14-27 wk gestational age) or third trimester ( ≥ 28 wk ). Growth trajectory of 99,014 children was followed until age 3 y. Raw weight values were transformed to age- and sex-specific weight standard deviation (SD) scores, and latent-class group-based trajectory models were estimated to determine weight trajectories. Associations between maternal metallic element levels and weight trajectory were examined using multinomial logistic regression models after confounder adjustment., Results: We identified 5 trajectory patterns based on weight SD score: 4.74% of infants were classified in Group I, very small to small; 31.26% in Group II, moderately small; 21.91% in Group III, moderately small to moderately large; 28.06% in Group IV, moderately large to normal; and 14.03% in Group V, moderately large to large. On multinomial logistic regression, higher maternal lead and selenium levels tended to be associated with increased odds ratios (ORs) of poor weight SD score trajectories (Groups I and II), in comparison with Group III. Higher levels of mercury were associated with decreased ORs, whereas higher levels of manganese were associated with increased ORs of "moderately large" trajectories (Groups IV and V)., Discussion: Maternal lead, mercury, selenium, and manganese blood levels affect infant growth trajectory pattern in the first 3 y of life. https://doi.org/10.1289/EHP10321.

This study is the first to assess postnatal exposure to heavy metals using breast milk in an electronic waste (e-waste) recycling area. From January to April 2021, 102 and 97 breastfeeding women were recruited from an e-waste recycling area and a control area, respectively. Four weeks after delivery, medical staff collected 20 mL of breast milk from each participant. The breast milk was tested for six heavy metals (lead, cadmium, chromium, arsenic, copper, and manganese) using inductively coupled plasma mass spectrometry (ICP-MS). The estimated daily intake (EDI) of infants during breastfeeding was calculated to assess the impact of postnatal exposure to heavy metals on infant health. The concentrations of chromium and lead in the breast milk were significantly higher in the e-waste recycling area than in the control area. Chromium concentrations in breast milk was 34.3%, exceeding the permissible limits set by the World Health Organization (WHO), in the e-waste recycling area, which is 16 times higher than that in the control areas. The EDIs of lead and chromium in the e-waste area were twice as those in the control area. This strongly indicates that the potential impact of postnatal exposure to lead and chromium on infant and child health in e-waste recycling areas cannot be ignored. Infants and children in e-waste recycling areas are at risk of long-term exposure to heavy metals. Therefore, ongoing health monitoring is necessary., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Few studies have investigated personal exposure concentrations of not only some volatile organic compounds but also more types of chemicals including acidic gases and acrolein. We measured the personal exposure concentrations of 35 chemicals including these chemicals in indoor and outdoor air in Chiba-shi, Japan, for 7 days in summer and winter to assess the associated health risks in 22 people. The personal exposure concentrations of nitrogen dioxide were higher in winter than in summer, and those of formaldehyde, p -dichlorobenzene, and tetradecane were higher in summer than in winter. The personal exposure concentrations were mostly equal to or lower than the concentrations in indoor air, contrary to the results of a lot of previous studies. The high-risk chemicals based on personal exposure concentrations were identified as acrolein (max. 0.43 μg/m 3 ), benzene (max. 3.1 μg/m 3 ), and hexane (max. 220 μg/m 3 ) in summer, and acrolein (max. 0.31 μg/m 3 ), nitrogen dioxide (max. 320 μg/m 3 ), benzene (max. 5.2 μg/m 3 ), formic acid (max. 70 μg/m 3 ), and hexane (max. 290 μg/m 3 ) in winter. In addition, we estimated personal exposure concentrations according to the time spent at home and the chemical concentrations in indoor and outdoor air. We found that the estimated concentrations of some participants largely differed from the measured ones indicating that it is difficult to estimate personal exposure concentrations based on only these data.

3,3',5-Triiodothyroacetic acid (TRIAC) was identified as a major contributor to the activity of thyroid hormone receptor (TR) agonists in environmental water. TRIAC contributed 60-148% of the TR-agonist activity in effluents from sewage treatment plants (STPs). Meanwhile, the contributions of 3,5,3'-triiodothyronine (T3), 3,3',5,5'-tetraiodothyronine (T4), and analogues were <1%. TRIAC concentrations in the range of 0.30-4.2 ng/L are likely enough to cause disruption of the thyroid system in living aquatic organisms. The origin of TRIAC in the STP effluents was investigated by analyzing both STP influents and effluents. Relatively high concentrations of T3 and T4 (2.5 and 6.3 ng/L, respectively) were found only in the influents. TRIAC was identified only in the effluents. These findings suggested that T3 and T4 in STP influents were potentially converted into TRIAC during activated sludge treatment or by other means. The evaluation of TRIAC at relevant environmental concentrations by in vivo assays and an appropriate treatment to reduce the TR activity in sewage are needed.

Combustible cigarette smoking impacts fetal growth during pregnancy. However, the risk associated with heated tobacco products (HTPs) remains unclear. This nationwide cross-sectional study investigated whether HTP use during pregnancy is associated with small for gestational age (SGA) outcomes among 5647 post-delivery women with singleton pregnancies, which were divided into four groups: lifetime never-smokers, former smokers before pregnancy, and current smokers for each of the tobacco products during pregnancy (sole HTP and sole combustion smokers). Information on the prevalence of SGA, defined as birth weight and height below the 10th percentile, was retrieved from the Maternal and Child Health Handbooks of post-delivery women. Using logistic regression, the association between sole HTP smokers during pregnancy and SGA, adjusted for covariates, with lifetime never-smokers as reference, was investigated. The prevalence was: current sole HTP smokers during pregnancy, 1.8% (102/5647); and SGA, 2.9% (164/5647). Sole HTP smokers during pregnancy had a higher prevalence of SGA (5.9% [6/102] vs. 2.7% [111/4144]) with an adjusted odds ratio (OR) of 2.50 (95% confidence interval [CI], 1.03-6.05) than lifetime never-smokers. Among sole combustion smokers, the adjusted OR for SGA was 1.95 (95% CI, 0.81-4.67). In Japan, HTP smoking during pregnancy may be associated with an increased risk for SGA., Competing Interests: The authors declare no conflict of interest.

Compared with the relatively well-investigated effects of childhood exposure to lead on neurocognitive deficits, those of prenatal exposure remain relatively inconclusive. We aimed to investigate the association between prenatal blood lead levels and neurodevelopmental delay during the first three years of life. From a prospective cohort of the Japan Environment and Children's Study, we analyzed a total of 80,759 children. The exposure factors were prenatal lead concentrations measured from maternal whole blood in the second/third trimesters and umbilical cord blood at birth. Neurodevelopment was assessed at 6, 12, 18, 24, 30, and 36 months old using a screening tool, the Ages and Stages Questionnaires, third edition (ASQ). The outcome measures were any suspected neurodevelopmental delay (sNDD) identified via the ASQ during the first (sNDD-1Y), second (sNDD-2Y), and third (sNDD-3Y) years of life. sNDD-1Y, 2Y, and 3Y were identified in 18.0%, 16.2%, and 17.2% of children, respectively. The geometric means of blood lead concentration in this study were much lower (0.62 μg/dL in maternal blood and 0.50 μg/dL in cord blood) than previously investigated levels. Multivariable regression models revealed that there were no associations between maternal blood lead and sNDD-1Y and 2Y and between cord blood lead and sNDD-1Y, 2Y, and 3Y. Although a higher maternal blood lead was associated with a reduced risk of sNDD-3Y (adjusted relative risk: 0.84, 95% confidence interval 0.75-0.94, per 1 increase in common logarithm of lead concentration), there were no dose-response relationships in the analysis using quintiles of lead concentrations. Using a large-scale data set, the present study demonstrated no convincing evidence for an inverse association between levels of prenatal blood lead and neurodevelopment in early childhood. Longitudinal measurements of prenatal and postnatal lead levels are needed to understand the relationship between lead exposure and neurocognitive development., (© 2022. The Author(s).)

Background: Exposure to several metallic elements has been suggested as a risk factor for gestational diabetes mellitus (GDM), but inconsistent findings have been reported. This study aimed to examine the association between the maternal whole blood concentration of metallic elements (Hg, Pb, Cd, Mn, and Se) and GDM using the dataset of the Japan Environment and Children's Study (JECS), a nationwide birth cohort study, which was designed to examine the adverse effects of pre/post-natal exposure to hazardous environment., Methods: The data of 78,964 pregnant women who were participants of JECS were used. Blood samples were collected from the pregnant women at second/third trimester of gestation. We employed logistic regression analysis, quantile g-computation (QGC) and a distributed lag nonlinear model (DLNM) to examine the association between the blood concentration of metallic elements and the risk of GDM., Results: The prevalence of GDM was 2.1%. In the logistic regression analyses, maternal blood Hg was associated with an increased risk of GDM. In QGC analysis, although metallic elements mixtures were not related to an increased risk of GDM, Hg (52.6%) may be the main contributor. According to the results of DLNM, for maternal exposure to Hg, 4.99 ng/g was identified as its susceptible minimum window for elevated risk of GDM., Conclusions: Our findings highlighted an association between Hg exposure and an increased risk of GDM. Studies of the underlying mechanisms and potential contributing factors, including fish intake, of this association are warranted., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Allergen-specific immunoglobulins have a crucial role in allergic diseases. Most wheeze episodes develop before school age, and allergic rhinitis later develops during early elementary school years. However, the clinical background and cytokine/chemokine profiles associated with changes in immunoglobulins during early school-age are poorly understood., Methods: This study used blood samples from children participating in the JECS Pilot Study. We examined nineteen kinds of aeroallergen-specific immunoglobulins (IgE, IgG1, IgG4, and IgA) levels in patients at age 6 and age 8. Fluctuations of Der f 1- and Cry j 1-specific immunoglobulins levels during the two periods were compared to assess the frequency of allergic statuses and clusters of cytokine/chemokine profiles., Results: The medians of aeroallergen-specific IgE levels did not fluctuate, and almost all IgG1 and IgG4 decreased. In IgA, four (e.g., Der f 1) increased, whereas the other four (e.g., Cry j 1) decreased. The ratio of the Der f 1-specific IgG1 level at age 8 to that at age 6 was higher in children with poor asthma control than in children with better asthma control. Moreover, the cytokine/chemokine cluster with relatively lower IL-33 and higher CXCL7/NAP2 was associated with lower Der f 1- and Cry j 1-specific IgG4 levels, but not IgE levels., Conclusions: The cluster of cytokine/chemokine profiles characterized by lower IL-33 and higher CXCL7/NAP2 was associated with the maintenance of aeroallergen-specific IgG4 levels. This result provides a basis for considering the control of aeroallergen-specific immunoglobulins., (Copyright © 2022 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Growth restriction in the prenatal period is a significant public health concern. Metals can negatively affect birth size, and pregnant women may be exposed to metal mixtures. Comprehensive studies analyzing the effects of combined metal exposure with accurate individual blood metal concentrations are limited. The current study investigated the associations between maternal metal exposure and birth size in a large, nationwide Japanese cohort using individual and mixed model approaches., Methods: Lead, cadmium, mercury, selenium, and manganese blood concentrations were measured in pregnant women in the Japan Environment and Children's Study (JECS). Measurements of infant birth size-including body weight, body length, and head and chest circumference-were collected. Linear and logistic regressions were used for birth size measurements and the odds of an infant being small in size for gestational age, respectively. Associations between combined metal mixtures and measurements at birth were evaluated using quantile g-computation and Bayesian kernel machine regression (BKMR)., Results: Of the 103,060 JECS pregnancies, 93,739 mother-infant pairs were analyzed. The linear regression models showed that lead, selenium, cadmium, and manganese-but not mercury-were associated with body weight. Cadmium was associated with length and chest circumference and mercury was associated with head circumference. Quantile g-computation revealed that manganese increased infant birth weight, length, head circumference, and chest circumference. Lead was the strongest negative factor for infant birth weight, length, head circumference, and chest circumference. The BKMR analysis revealed that the metals had an additive, rather than a synergistic effect., Conclusion: Metal exposure is associated with infant birth size, with lead and manganese playing a more significant role in Japan. The effects of prenatal combined metal exposure at low levels warrant public health attention., (Copyright © 2022. Published by Elsevier Ltd.)

We conducted a follow-up observational study on the effects of dioxin exposure on the synthesis of steroid hormones in infants during the perinatal period. The participants included 42 pairs of mothers and infants that were previously studied in 2015. We analyzed four types of steroid hormones including progesterone, testosterone, androstenedione (A-dione), and dehydroepiandrosterone (DHEA) in the serum samples of 6-year-olds and the concentration of dioxins in breast milk. A multivariate linear regression was performed to associate steroid hormones (dependent variables) and dioxins with the body mass index (BMI), sex, age, and residence of participants (independent variables). The results were reported as β (standardized coefficient) and p-values. We found that dioxins have a significant negative correlation with DHEA and A-dione but no significant relationship with progesterone and testosterone. However, in previous studies, we found that testosterone and progesterone levels were significantly related to dioxins in 4-year-olds. We concluded that dioxins can affect the level of steroid hormones, but their effects fluctuate, and the harm caused by dioxins in children requires further long-term monitoring., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The Japan Environment and Children's Study (JECS) is a nationwide birth cohort study investigating environmental effects on children's health and development. A Sub-Cohort Study has begun, conducting extended exposure and outcome measurements by targeting a subgroup randomly selected from the JECS Main Study. We report the Sub-Cohort Study methodology and participants' baseline profiles., Methods: Of 100,148 children in the JECS Main Study, children born after April 1, 2013 who met eligibility criteria ([1] all questionnaire and medical record data from children and their mothers collected from the first trimester to 6 months of age, [2] biospecimens [except umbilical cord blood] from children and their mothers collected at first to second/third trimester and delivery) were randomly selected for each Regional Centre at regular intervals. Face-to-face assessment of neuropsychiatric development, body measurement, paediatrician's examination, blood/urine collection for clinical testing and chemical analysis, and home visits (ambient and indoor air measurement and dust collection) are conducted. Participants are followed up at 1.5 and 3 years old for home visits, and 2, 4, 6, and 8 years old for developmental/medical examination. The details of protocols after age 10 are under discussion., Results: Of 10,302 selected children, 5,017 participated. The profiles of the participating mothers, fathers and children did not substantially differ between the Main Study and Sub-Cohort Study., Conclusion: The JECS Sub-Cohort Study offers a platform for investigating associations between environmental exposure and outcomes.

A decline in the proportion of male births (secondary sex ratio, SSR) has been seen in several countries including Japan in recent years. Although previous studies have reported that the SSR is affected by exposure to chemical substances such as dioxins and polychlorinated biphenyls, as well as heavy metals such as methylmercury, the effects of lead exposure on the SSR have been little studied. The aim of this study was to determine the association between maternal lead exposure and SSR. In a large-scale nationwide birth cohort study, maternal blood lead level (BLL) was determined using whole blood from the second or third trimester of pregnancy. The association between SSR and maternal BLL was estimated using multivariable logistic models. Binomial distribution was applied to examine the differences in SSR by dividing the participants into five groups based on BLL. The primary outcome was SSR, and the child sex was obtained from the medical record transcripts. Of 104,062 fetal records, 85,171 were examined for analysis. The median maternal BLL was 5.85 ng/g (5th-95th percentile 3.45-10.6 ng/g). The overall proportion of males among participating infants was 0.512. In logistic regression models adjusted for covariates, the analysis revealed an increased odds ratio for SSR with higher blood lead concentrations [Group 2: adjusted OR 1.082, 95% confidence interval 1.037 to 1.129, Group 3: 1.122, 1.074 to 1.171, Group 4: 1.214, 1.163 to 1.268, Group 5: 1.279, 1.224 to 1.336]. Compared to the general birth probability in Japan, the group with low BLL had a lower SSR and the group with high BLL had a higher SSR. Higher maternal lead exposures during pregnancy were associated with increased SSR. Further investigations including assessment of paternal lead exposure are necessary to understand the association between lead exposure and SSR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Background: Reluctance of people to receive recommended vaccines is a growing concern, as distribution of vaccines is considered critical to ending the COVID-19 pandemic. There is little information regarding pregnant women's views toward coronavirus vaccination in Japan. Therefore, we investigated the vaccination rate and reasons for vaccination and vaccine hesitancy among pregnant women in Japan., Methods: We conducted a cross-sectional study involving 1,791 pregnant women using data from the Japan "COVID-19 and Society" Internet Survey, conducted from July to August 2021, and valid response from 1,621 respondents were analyzed. We defined participants with vaccine hesitancy as those who identified with the statement "I do not want to be vaccinated" or "I want to 'wait and see' before getting vaccinated." Multivariate Poisson regression analysis was used to investigate the factors contributing to vaccine hesitancy., Results: The prevalence of vaccination and vaccine hesitancy among pregnant women was 13.4% (n = 217) and 50.9% (n = 825), respectively. The main reasons for hesitancy were concerns about adverse reactions and negative effects on the fetus and breastfeeding. Vaccine hesitancy was significantly associated with the lack of trust in the government (adjusted prevalence ratio, 1.26; 95% confidence interval, 1.03-1.54). Other factors, such as age, educational attainment, and state of emergency declaration, were not associated with vaccine hesitancy., Conclusions: COVID-19 vaccination is not widespread among pregnant women in Japan, although many vaccines have been shown to be safe in pregnancy. Accurate information dissemination and boosting trust in the government may be important to address vaccine hesitancy among pregnant women.

hER-MIP is a molecularly imprinted polymer (MIP) that has been shown to selectively collect human estrogen receptor (hER) binding active substances. However, environmental samples contain various chemicals depending on the location and regional differences, and the hER binding activity depends on the sample type. Thus, the general applicability of hER-MIP to actual environmental samples must be elucidated. In this study, 48 environmental samples were collected and screened with hER-MIP, and a yeast assay was performed to evaluate the adsorption characteristics of the samples according to the adsorption and elution fractions. The results showed that hER-MIP collects hER binding active substances almost selectively but does not collect constitutive androstane receptor (CAR) binding active substances selectively. CAR binding activity was detected in the adsorbed fraction because several hER binding active substances also demonstrate CAR binding activity., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The Japan Environment and Children's Study (JECS) is a nationwide birth cohort study of environmental factors affecting children's health and development. We summarize the complete blood count and chemistry panel statistical data from pregnant women enrolled in JECS., Methods: Statistical data of up to 58,056 mother's sample in their first (gestational age ≤ 13 weeks) and second trimester (22-27 weeks) were calculated., Results: Mean (SD) values in the first trimester were: white blood cell count, 7866 (1906)/μL; red blood cell count, 417 (33) 10 4 /μL; hemoglobin, 12.4 (1.0) g/dL; hematocrit, 37.1 (2.6)%; mean corpuscular volume, 89.2 (4.7) fL; mean corpuscular hemoglobin, 29.8 (1.9) pg; mean corpuscular hemoglobin concentration, 33.3 (0.9)%; platelet count, 24.8 (5.2) 10 4 /μL; HbA1c, 5.26 (0.26)%; total cholesterol, 181 (28) mg/dL; low density lipoprotein cholesterol, 95 (23) mg/dL; high density lipoprotein cholesterol, 73 (13) mg/dL; free cholesterol, 41 (7) mg/dL; triglycerides, 109 (47) mg/dL; total protein, 6.9 (0.4) g/dL; and albumin, 4.1 (0.2) g/dL. Mean values (SD) in the second trimester were: total cholesterol, 246 (38) mg/dL; free cholesterol, 61 (9) mg/dL; triglycerides, 183 (70) mg/dL; total protein, 6.5 (0.4) g/dL; and albumin, 3.6 (0.2) g/dL., Conclusions: These data will be useful for future JECS studies.

Background: Maternal prepregnancy body mass index (BMI) may influence allergic diseases in the children who are the product of those pregnancies., Objective: The purpose of our study was to investigate the association between mothers' prepregnancy BMI and the risk of physician-diagnosed asthma, food allergy (FA), and atopic dermatitis (AD) in their children during the first 3 years of life., Methods: Data on mothers' prepregnancy BMI and physician-diagnosed asthma, FA, and AD in their children until the age of 3 years were obtained from the Japan Environment and Children's Study, a nationwide birth cohort study that has recruited 103,099 pregnant women between 2011 and 2014. Logistic regression analysis was used to analyze the results., Results: We analyzed 67,204 mother-child pairs with available information on physician-diagnosed allergic diseases. The risk of asthma was significantly higher in children born to overweight mothers (adjusted OR [aOR] =1.17 [95% CI = 1.07-1.28]) and obese mothers (aOR = 1.28 [95% CI = 1.08-1.50]), whereas the risk of FA, cow's milk allergy, and egg allergy decreased significantly in children born to overweight mothers (aOR = 0.84 [95% CI = 0.76-0.92]; aOR = 0.78 [95% CI = 0.64-0.93]; and aOR = 0.83 [95% CI = 0.74-0.94]) and obese mothers (aOR = 0.81 [95% CI = 0.67-0.97]; aOR = 0.58 [95% CI = 0.36-0.87]; and aOR = 0.73 [95% CI = 0.56-0.93]) compared with in children born to normal weight mothers, respectively. Associations between AD and maternal BMI were not detected., Conclusion: Our study showed that an increase in mothers' prepregnancy BMI was associated with an increase in asthma prevalence and a decrease in FA prevalence in their children. Further studies are needed to reveal the mechanisms associated with maternal BMI and pediatric allergic diseases., (© 2022 The Author(s).)

Background: Manganese (Mn) is an essential trace metal and a neurotoxicant. Adverse effects of Mn exposure on the neurodevelopment of children have been reported. However, there is limited information on the effects of maternal exposure during pregnancy., Objectives: We aimed to investigate the association between maternal and cord blood Mn levels and neurodevelopment in children aged between 6 months and 3 years using data from a Japanese nationwide birth cohort study., Methods: We used the data of 63,767 mother-child pairs with maternal blood Mn measurements recorded during the second and third trimester and of 3,787 mother-child pairs with cord blood Mn measurements. Neurodevelopment was assessed using the Japanese version of the Ages and Stages Questionnaires, third edition (J-ASQ-3), which was completed by parents or guardians at 6 months, 1 year, 1.5 years, 2 years, 2.5 years, and 3 years of age., Results: The median maternal and cord blood Mn levels were 15.2 and 44.5 ng/g, respectively. After adjusting for covariates, both maternal and cord blood Mn levels were negatively associated with J-ASQ-3 scores. Maternal blood Mn levels were negatively associated with gross motor function scores at all ages except for that at 1.5 years (adjusted β: -0.55 to -1.23 for a two-fold increase in maternal Mn levels). The risk of developmental delay (score below the cut-off) in gross motor function increased at the same time points (adjusted odds ratio: 1.08 to 1.13). In the subgroup, cord blood Mn levels were negatively associated with gross motor function scores at 1, 2, and 2.5 years (adjusted β: -1.84 to -3.27)., Discussion: Maternal blood Mn levels during pregnancy and cord blood Mn levels were negatively associated with neurodevelopment in children up to 3 years of age. Excessive maternal and fetal exposure to Mn may have adverse effects on neuromotor function in children., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)