Prenatal exposure to fluoride and neuropsychological development in early childhood: 1-to 4 years old children.

BACKGROUND: Cross-sectional and prospective studies have provided evidence of the neurotoxic effect of early exposure to fluoride (F) in pregnancy. It has been negatively associated with cognitive development during childhood, with most research conducted in areas with high F levels in community drinking water (CDW). METHOD: Data from 316 to 248 mother-child pairs from the Infancia y Medio Ambiente (Childhood and Environment, INMA) birth cohort project with maternal urinary F level adjusted for creatinine (MUFcr) measurements in the first and third trimesters of pregnancy. Children's cognitive domains and intelligence indexes were evaluated using the Bayley Scales (age of 1) and the McCarthy Scales (age of 4). Multiple linear regression analyses were carried out adjusting for a wide range of covariates related to the child, mother, family context and other potential neurotoxicants. RESULTS: No association was found between MUFcr levels and Bayley Mental Development Index score. Nevertheless, regarding the McCarthy scales, it was found that per unit (mg/g) of MUFcr across the whole pregnancy, scores in boys were greater for the verbal, performance, numeric and memory domains (ß = 13.86, CI 95%: 3.91, 23.82), (ß = 5.86, CI 95%: 0.32, 11.39), (ß = 6.22, CI 95%: 0.65, 11.79) and (ß = 11.63, CI 95%: 2.62, 20.63) respectively and for General Cognitive Index (ß = 15.4, CI 95%: 6.32, 24.48). For girls there was not any cognitive score significantly associated with MUFcr, being the sex-F interactions significant (P interaction <0.05). Including other toxicants levels, quality of family context or deprivation index did not substantially change the results. CONCLUSIONS: In boys, positive associations were observed between MUFcr and scores in cognitive domains at the age of 4. These findings are inconsistent with those from some previous studies and indicate the need for other population-based studies to confirm or overturn these results at low levels of F in CDW.

Bisphenol-A in the European Prospective Investigation into Cancer and Nutrition cohort in Spain: Levels at recruitment and associated dietary factors.

Bisphenol A (BPA) is considered an endocrine disruptor and it is present in numerous products of daily use. The aim of this study was to analyze serum BPA concentrations in a subcohort of the Spanish European Prospective Investigation into Cancer and Nutrition (EPIC), as well as to identify potential predictors of the exposure. The population consisted on 3553 subjects from 4 EPIC-Spain centres and BPA levels were measured in serum samples by UHPLC-MS/MS. Almost 70% of the participants showed detectable BPA values (>0.2 ng/ml), with a geometric mean of 1.19 ng/ml (95% CI: 1.12-1.25). By sex, detectable percentages were similar (p = 0.56) but with higher serum levels in men (1.27 vs 1.11 ng/ml, p = 0.01). Based on the adjusted regression models, a 50 g/day increase in the consumption of added fats and oils were associated with 43% lower BPA serum levels, while sugar and confectionary was associated with 25% higher levels of serum BPA. We evidenced differential exposure levels by province, sex and age, but not by anthropometric or lifestyle characteristics. Further investigation is needed to understand the influence of diet in BPA exposure.

Associations of Maternal Cell-Phone Use During Pregnancy With Pregnancy Duration and Fetal Growth in 4 Birth Cohorts.

Results from studies evaluating potential effects of prenatal exposure to radio-frequency electromagnetic fields from cell phones on birth outcomes have been inconsistent. Using data on 55,507 pregnant women and their children from Denmark (1996-2002), the Netherlands (2003-2004), Spain (2003-2008), and South Korea (2006-2011), we explored whether maternal cell-phone use was associated with pregnancy duration and fetal growth. On the basis of self-reported number of cell-phone calls per day, exposure was grouped as none, low (referent), intermediate, or high. We examined pregnancy duration (gestational age at birth, preterm/postterm birth), fetal growth (birth weight ratio, small/large size for gestational age), and birth weight variables (birth weight, low/high birth weight) and meta-analyzed cohort-specific estimates. The intermediate exposure group had a higher risk of giving birth at a lower gestational age (hazard ratio = 1.04, 95% confidence interval: 1.01, 1.07), and exposure-response relationships were found for shorter pregnancy duration (P < 0.001) and preterm birth (P = 0.003). We observed no association with fetal growth or birth weight. Maternal cell-phone use during pregnancy may be associated with shorter pregnancy duration and increased risk of preterm birth, but these results should be interpreted with caution, since they may reflect stress during pregnancy or other residual confounding rather than a direct effect of cell-phone exposure.

The Association of Mediterranean Diet during Pregnancy with Longitudinal Body Mass Index Trajectories and Cardiometabolic Risk in Early Childhood.

OBJECTIVE: To evaluate the associations between maternal adherence to the Mediterranean diet during pregnancy and their offspring's longitudinal body mass index (BMI) trajectories and cardiometabolic risk in early childhood. STUDY DESIGN: We included mother-child pairs from the Infancia y Medio Ambiente (INMA) longitudinal cohort study in Spain. We measured dietary intake during pregnancy using a validated food frequency questionnaire and calculated the relative Mediterranean diet score (rMED). We estimated offspring's BMI z score trajectories from birth to age 4 years using latent class growth analyses (n = 2195 mother-child pairs). We measured blood pressure, waist circumference, and cardiometabolic biomarkers to construct a cardiometabolic risk score at 4 years (n = 697 mother-child pairs). We used multivariable adjusted linear and multinomial regression models. RESULTS: A higher maternal rMED in pregnancy was associated with a lower risk in offspring of larger birth size, followed by accelerated BMI gain (reference trajectory group: children with average birth size and subsequent slower BMI gain) (relative risk of high vs low rMED score, 0.68; 95% CI, 0.47-0.99). rMED score during pregnancy was not associated with the cardiometabolic risk score, its components, or related biomarkers. CONCLUSIONS: Higher adherence to the Mediterranean diet in pregnancy was associated with lower risk of having offspring with an accelerated growth pattern. This dietary pattern was not associated with the offspring's cardiometabolic risk at 4 years.

Exposure and health risks perception of extremely low frequency and radiofrequency electromagnetic fields and the effect of providing information.

Given that regardless of actual exposure levels, high-risk perceptions of electromagnetic fields of non-ionizing radiation (EMF-NIR) may cause health effects, it is important to understand the mechanisms behind perceptions in the general population. The aims of this study were to assess perceptions of both exposure and health-risk among mothers of the INMA (Environment and childhood)-Gipuzkoa child cohort; to explore possible determinants that explain such perceptions; and to evaluate whether providing information on exposure levels has any effect on perceptions. Overall, 387 mothers completed a questionnaire composed of four questions on perceived exposure and perceived health-risk of exposure to extremely low frequency (ELF) and radiofrequency (RF) fields answered on a Likert-type scale from 0 to 10. Later, measurements of ELF and RF fields were conducted in the houses of a subsample of 104 participants. All measured levels were far below the levels established by the European Council recommendation. This was explained in the individual reports sent to the families. After reading the results, mothers completed the aforementioned questionnaire a second time, plus two additional questions regarding the role of public health bodies in risk communication. The association between perceived and measured levels as categorical variables was assessed with a chi-square test. Multiple linear regressions were conducted for each of the questions related to perceived exposure and health-risk perceptions. Wilcoxon signed-rank test was conducted to assess the effect of receiving information. Both exposure and health risk were perceived to be very high for both ELF and RF fields, with mean and medians of 7 on a 10-point scale. Reporting higher perception levels was not associated with higher levels of exposure measured at home. Variables that were repeatedly associated with higher perceptions included: manual social class, not having the feeling of living in a good neighborhood, difficulty getting by financially, not having a television antenna within 600 m, being younger and having fewer devices at home. Providing information on EMF-NIR exposure levels at home did not alter health-risk perceptions, but mean perceived RF exposure decreased significantly (by 0.7 points). Most of the participants claimed to have received no or insufficient information regarding exposure and health-risks of EMF-NIR from public bodies and considered it very important that they should.

Poor mothers, unhealthy children: the transmission of health inequalities in the INMA study, Spain.

BACKGROUND: The health of pregnant women and their fetuses are especially sensitive to socioeconomic conditions. This study analyzes the impact of maternal socioeconomic status (SES), evaluated by occupation and maternal education level, in preterm births (PTBs) and in small for gestational age (SGA) fetuses, considering the effect of the potential mediating factors on the SES and birth outcomes. METHODS: A total of 2497 mother/newborn dyads from the INMA-Spain project were studied. We examined maternal occupation and education in relation to PTB and SGA along with covariate data, using logistic regression analysis. Adjusted models for each of the outcome variables in relation to SES indicators were estimated, considering potential mediating factors. RESULTS: About 4.7% of babies were PTB and 9.7% SGA. Full adjusted logistic regression models showed similar odds ratio (OR) for SGA in both SES indicators. Manual working women or without university studies had higher risk of SGA than their counterpart groups (OR = 1.39% CI = 1.03-1.88 and OR = 1.39% CI = 1.00-2.00, respectively). Likewise, mothers with a manual occupation were at more risk of PTB than those with a non-manual occupation (OR = 1.74 95% CI = 1.13-2.74), but there was no association between education and PTB. Smoking, pre-pregnancy BMI and underweight gain during pregnancy were significantly associated to SGA births. The mother's age, presence of complications and overweight gain during pregnancy were related to PTB. CONCLUSION: The mother's socioeconomic disadvantage was consistently associated with birth outcomes giving rise to intergenerational transmission of health inequalities. Reducing inequalities requires eliminating the upstream causes of poverty itself.

Exposure to extremely low and intermediate-frequency magnetic and electric fields among children from the INMA-Gipuzkoa cohort.

Detailed assessment of exposure to extremely low frequency (ELF) and intermediate frequency (IF) fields is essential in order to conduct informative epidemiological studies of the health effects from exposure to these fields. There is limited information available regarding ELF electric fields and on both magnetic and electric field exposures of children in the IF range. The aim of this study was to characterize ELF and IF exposure of children in the Spanish INMA cohort. A combination of spot and fixed measurements was carried out in 104 homes, 26 schools and their playgrounds and 105 parks. Low levels of ELF magnetic fields (ELF-MF) were observed (with the highest 24-h time-weighted average (TWA) exposure being 0.15µT in one home). The interquartile range (IQR) of ELF electric fields (ELF-EF) ranged from 1 to 15V/m indoors and from 0.3 to 1.1V/m outdoors and a maximum value observed was 55.5V/m in one school playground. IQR ranges for IF magnetic and electric fields were between 0.02 and 0.23µT and 0.2 and 0.5V/m respectively and maximum values were 0.03µT and 1.51V/m in homes. Correlations between magnetic and electric fields were weak for ELF (Spearman 0.04-0.36 in different settings) and moderate for IF (between 0.28 and 0.75). Children of INMA-Gipuzkoa cohort were exposed to very low levels of ELF-MF in all settings and to similar levels of ELF-EF compared to the range of previously reported levels, although somewhat higher exposures occurred at home. Children enrolled to our study were similarly exposed to IF in all settings.

Characterisation of exposure to non-ionising electromagnetic fields in the Spanish INMA birth cohort: study protocol.

BACKGROUND: Analysis of the association between exposure to electromagnetic fields of non-ionising radiation (EMF-NIR) and health in children and adolescents is hindered by the limited availability of data, mainly due to the difficulties on the exposure assessment. This study protocol describes the methodologies used for characterising exposure of children to EMF-NIR in the INMA (INfancia y Medio Ambiente- Environment and Childhood) Project, a prospective cohort study. METHODS/DESIGN: Indirect (proximity to emission sources, questionnaires on sources use and geospatial propagation models) and direct methods (spot and fixed longer-term measurements and personal measurements) were conducted in order to assess exposure levels of study participants aged between 7 and 18 years old. The methodology used varies depending on the frequency of the EMF-NIR and the environment (homes, schools and parks). Questionnaires assessed the use of sources contributing both to Extremely Low Frequency (ELF) and Radiofrequency (RF) exposure levels. Geospatial propagation models (NISMap) are implemented and validated for environmental outdoor sources of RFs using spot measurements. Spot and fixed longer-term ELF and RF measurements were done in the environments where children spend most of the time. Moreover, personal measurements were taken in order to assess individual exposure to RF. The exposure data are used to explore their relationships with proximity and/or use of EMF-NIR sources. DISCUSSION: Characterisation of the EMF-NIR exposure by this combination of methods is intended to overcome problems encountered in other research. The assessment of exposure of INMA cohort children and adolescents living in different regions of Spain to the full frequency range of EMF-NIR extends the characterisation of environmental exposures in this cohort. Together with other data obtained in the project, on socioeconomic and family characteristics and development of the children and adolescents, this will enable to evaluate the complex interaction between health outcomes in children and adolescents and the various environmental factors that surround them.

Water hardness and eczema at 1 and 4 y of age in the INMA birth cohort.

BACKGROUND: Exposure to hard water has been suggested as a risk factor for eczema in childhood, based on limited evidence from two ecologic and two cross-sectional studies. OBJECTIVES: We evaluate this hypothesis for the first time in early infancy using prospective data from a mother-child cohort study. METHODS: We used data from the INMA cohorts in Gipuzkoa, Sabadell and Valencia, Spain (N=1638). Current and ever eczema, bathing frequency and duration and covariables were collected by questionnaires at 14 months (14 m) and 4 years (4 y). Calcium carbonate (CaCO3) level in municipal water was assigned to home addresses at birth, 14 m and 4 y. We calculated Odds Ratio (OR) of eczema related to CaCO3 at home, bath exposure and a combination of both. RESULTS: Prevalence of eczema ever was 18.4% at 14 m and 33.4% at 4 y. Mean CaCO3 ranged from 51.6 to 272.8 mg/L among areas. No association was detected between water hardness at home and current or ever eczema. Adjusted OR was 0.79 (95%CI=0.45, 1.39) at 14 m and 0.93 (0.56, 1.52) at 4 y among children in the highest vs. lowest tertiles of CaCO3. Bath exposure alone or in combination with water hardness did not increase the OR of eczema at 14 m or 4 y either. CONCLUSIONS: We did not find an association between eczema and water hardness at home or bathing exposure during the first four years of life. This first cohort study in a critical age period with improved exposure assessment does not confirm the association suggested among children by previous studies.

Relationship between exposure to parabens and benzophenones and prostate cancer risk in the EPIC-Spain cohort.

The etiology of prostate cancer is not fully elucidated. Among environmental risk factors, endocrine-disrupting chemicals (EDCs) deserve special mention, as they alter metabolic pathways involved in hormone-dependent cancers. Epidemiological evidence assessing the carcinogenicity of EDCs is scarce. The aim of this study was to analyze the relationship between exposure to parabens and benzophenones and prostate cancer risk. We conducted a case-cohort study nested within the EPIC-Spain prospective multi-center cohort. Study population comprised 1,838 sub-cohort participants and 467 non-sub-cohort prostate cancer cases. Serum concentrations of four parabens and two benzophenones were assessed at recruitment. Covariates included age, physical activity, tobacco smoking, alcohol consumption, body mass index, educational level and diabetes. Borgan II weighted Cox proportional hazard models stratified by study center were applied. Median follow-up time was 18.6 years (range = 1.0-21.7 years). Most sub-cohort participants reached primary education at most (65.5%), were overweight (57.7%) and had a low level of physical activity (51.3%). Detection percentages varied widely, being lowest for butyl-paraben (11.3%) and highest for methyl-paraben (80.7%), which also showed the highest geometric mean (0.95 ng/ml). Cases showed significantly higher concentrations of methyl-paraben (p = 0.041) and propyl-paraben (p < 0.001). In the multivariable analysis, methyl-paraben - log-transformed (HR = 1.07; 95%CI = 1.01-1.12) and categorized into tertiles (HR = 1.60 for T3; 95%CI = 1.16-2.20) -, butyl-paraben - linear (HR = 1.19; 95%CI = 1.14-1.23) and log-transformed (HR = 1.17; 95%CI = 1.01-1.35) - and total parabens - log-transformed (HR = 1.09; 95%CI = 1.02-1.17) and categorized into tertiles (HR = 1.62 for T3; 95%CI = 1.10-2.40) - were associated with an increased prostate cancer risk. In this study, higher concentrations of methyl-, butyl-, and total parabens were positively associated with prostate cancer risk. Further research is warranted to confirm these findings.

Breast cancer risk for the joint exposure to metals and metalloids in women: Results from the EPIC-Spain cohort.

Environmental factors play a role in breast cancer development. While metals and metalloids (MMs) include some carcinogens, their association with breast cancer depends on the element studied. Most studies focus on individual MMs, but the combined effects of metal mixtures remain unclear. The aim of this study was to analyze the relationship between the joint exposure to MMs and the risk of developing female breast cancer. We conducted a case-control study within the multicenter prospective EPIC-Spain cohort. Study population comprised 292 incident cases and 286 controls. Plasma concentrations of 16 MMs were quantified at recruitment. Potential confounders were collected using a questionnaire and anthropometric measurements. Mixed-effects logistic regression models were built to explore the effect of individual MMs. Quantile-based g computation models were applied to identify the main mixture components and to estimate the joint effect of the metal mixture. The geometric means were highest for Cu (845.6 ng/ml) and Zn (604.8 ng/ml). Cases had significantly higher Cu concentrations (p = 0.010) and significantly lower Zn concentrations (p < 0.001). Cu (+0.42) and Mn (+0.13) showed the highest positive weights, whereas Zn (-0.61) and W (-0.16) showed the highest negative weights. The joint effect of the metal mixture was estimated at an OR = 4.51 (95%CI = 2.32-8.79), suggesting a dose-response relationship. No evidence of non-linearity or non-additivity was found. An unfavorable exposure profile, primarily characterized by high Cu and low Zn levels, could lead to a significant increase in the risk of developing female breast cancer. Further studies are warranted to confirm these findings.

Circadian clock gene variants and their link with chronotype, chrononutrition, sleeping patterns and obesity in the European prospective investigation into cancer and nutrition (EPIC) study.

BACKGROUND & AIMS: The circadian clock is involved in the control of daily rhythms and is related to the individual's chronotype, i.e., the morningness-eveneningness preference. Knowledge is limited on the relationship between circadian genes, chronotype, sleeping patterns, chronutrition and obesity. The aim was to explore these associations within the EPIC-Spain cohort study. METHODS: There were 3183 subjects with information on twelve genetic variants of six genes (PER1, PER2, PER3, CRY1, NR1D1, CLOCK). Their association was evaluated with: chronotype and sleeping duration/quality (assessed by questionnaires), chrononutrition (number of meals and timing of intake assessed by a diet history), and also anthropometric measures of obesity at early and late adulthood (in two points in time), such as weight and waist circumference (assessed by physical measurements). Multivariable logistic and linear regression as well as additive genetic models were applied. Odds ratios (ORs), ß coefficients, and p-values corrected for multiple comparisons were estimated. Genetic risk scores (GRS) were built to test gene-outcome associations further. RESULTS: At nominal significance level, the variant rs2735611 (PER1 gene) was associated with a 11.6% decrease in long-term weight gain (per-allele ß = -0.12), whereas three CLOCK gene variants (rs12649507, rs3749474 and rs4864548), were associated with a ∼20% decrease in waist circumference gain (per-allele ߠ∼ -0.19). These and other associations with body measures did not hold after multiple testing correction, except waist-to-hip ratio and rs1801260, rs2070062 and rs4580704 (CLOCK gene). Associations with chrononutrition variables, chronotype and sleep duration/quality failed to reach statistical significance. Conversely, a weighted GRS was associated with the evening/late chronotype and with all other outcomes (p < 0.05). The chronotype-GRS was associated with an increased overweight/obesity risk (vs normal weight) in both early and late adulthood (OR = 2.2; p = 0.004, and OR = 2.1; p = 0.02, respectively). CONCLUSION: Genetic variants of some circadian clock genes could explain the link between genetic susceptibility to the individual's chronotype and obesity risk.

Association between maternal thyroid function and risk of gestational hypertension and pre-eclampsia: a systematic review and individual-participant data meta-analysis.

BACKGROUND: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia. METHODS: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585. FINDINGS: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT4 concentrations and TPO antibody status) to be classified according to their thyroid function status. Of these women, 1275 (3·2%) had subclinical hypothyroidism, 933 (2·3%) had isolated hypothyroxinaemia, 619 (1·6%) had subclinical hyperthyroidism, and 337 (0·8%) had overt hyperthyroidism. Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia (2·1% vs 3·6%; OR 1·53 [95% CI 1·09-2·15]). Subclinical hyperthyroidism, isolated hypothyroxinaemia, or TPO antibody positivity were not associated with gestational hypertension or pre-eclampsia. In continuous analyses, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia (p=0·0001). FT4 concentrations were not associated with the outcomes measured. INTERPRETATION: Compared with euthyroidism, subclinical hypothyroidism during pregnancy was associated with a higher risk of pre-eclampsia. There was a U-shaped association of TSH with pre-eclampsia. These results quantify the risks of gestational hypertension or pre-eclampsia in women with thyroid function test abnormalities, adding to the total body of evidence on the risk of adverse maternal and fetal outcomes of thyroid dysfunction during pregnancy. These findings have potential implications for defining the optimal treatment target in women treated with levothyroxine during pregnancy, which needs to be assessed in future interventional studies. FUNDING: Arkansas Biosciences Institute and Netherlands Organization for Scientific Research.

Association of maternal thyroid function with birthweight: a systematic review and individual-participant data meta-analysis.

BACKGROUND: Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight. METHODS: In this systematic review and individual-participant data meta-analysis, we searched MEDLINE (Ovid), Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to Oct 15, 2019, for prospective cohort studies with data on maternal thyroid function during pregnancy and birthweight, and we issued open invitations to identify study authors to join the Consortium on Thyroid and Pregnancy. We excluded participants with multiple pregnancies, in-vitro fertilisation, pre-existing thyroid disease or thyroid medication usage, miscarriages, and stillbirths. The main outcomes assessed were small for gestational age (SGA) neonates, large for gestational age neonates, and newborn birthweight. We analysed individual-participant data using mixed-effects regression models adjusting for maternal age, BMI, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex, and gestational age at birth. The study protocol was pre-registered at the International Prospective Register of Systematic Reviews, CRD42016043496. FINDINGS: We identified 2526 published reports, from which 36 cohorts met the inclusion criteria. The study authors for 15 of these cohorts agreed to participate, and five more unpublished datasets were added, giving a study population of 48 145 mother-child pairs after exclusions, of whom 1275 (3·1%) had subclinical hypothyroidism (increased thyroid stimulating hormone [TSH] with normal free thyroxine [FT4]) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT4 with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA than was euthyroidism (11·8% vs 10·0%; adjusted risk difference 2·43%, 95% CI 0·43 to 4·81; odds ratio [OR] 1·24, 1·04 to 1·48; p=0·015) and lower mean birthweight (mean difference -38 g, -61 to -15; p=0·0015), with a higher effect estimate for measurement in the third trimester than in the first or second. Isolated hypothyroxinaemia was associated with a lower risk of SGA than was euthyroidism (7·3% vs 10·0%, adjusted risk difference -2·91, -4·49 to -0·88; OR 0·70, 0·55 to 0·91; p=0·0073) and higher mean birthweight (mean difference 45 g, 18 to 73; p=0·0012). Each 1 SD increase in maternal TSH concentration was associated with a 6 g lower birthweight (-10 to -2; p=0·0030), with higher effect estimates in women who were thyroid peroxidase antibody positive than for women who were negative (pinteraction=0·10). Each 1 SD increase in FT4 concentration was associated with a 21 g lower birthweight (-25 to -17; p<0·0001), with a higher effect estimate for measurement in the third trimester than the first or second. INTERPRETATION: Maternal subclinical hypothyroidism in pregnancy is associated with a higher risk of SGA and lower birthweight, whereas isolated hypothyroxinaemia is associated with lower risk of SGA and higher birthweight. There was an inverse, dose-response association of maternal TSH and FT4 (even within the normal range) with birthweight. These results advance our understanding of the complex relationships between maternal thyroid function and fetal outcomes, and they should prompt careful consideration of potential risks and benefits of levothyroxine therapy during pregnancy. FUNDING: Netherlands Organization for Scientific Research (grant 401.16.020).

Children's exposure assessment of radiofrequency fields: Comparison between spot and personal measurements.

INTRODUCTION: Radiofrequency (RF) fields are widely used and, while it is still unknown whether children are more vulnerable to this type of exposure, it is essential to explore their level of exposure in order to conduct adequate epidemiological studies. Personal measurements provide individualized information, but they are costly in terms of time and resources, especially in large epidemiological studies. Other approaches, such as estimation of time-weighted averages (TWAs) based on spot measurements could simplify the work. OBJECTIVES: The aims of this study were to assess RF exposure in the Spanish INMA birth cohort by spot measurements and by personal measurements in the settings where children tend to spend most of their time, i.e., homes, schools and parks; to identify the settings and sources that contribute most to that exposure; and to explore if exposure assessment based on spot measurements is a valid proxy for personal exposure. METHODS: When children were 8 years old, spot measurements were conducted in the principal settings of 104 participants: homes (104), schools and their playgrounds (26) and parks (79). At the same time, personal measurements were taken for a subsample of 50 children during 3 days. Exposure assessment based on personal and on spot measurements were compared both in terms of mean exposures and in exposure-dependent categories by means of Bland-Altman plots, Cohen's kappa and McNemar test. RESULTS: Median exposure levels ranged from 29.73 (in children's bedrooms) to 200.10 µW/m2 (in school playgrounds) for spot measurements and were higher outdoors than indoors. Median personal exposure was 52.13 µW/m2 and median levels of assessments based on spot measurements ranged from 25.46 to 123.21 µW/m2. Based on spot measurements, the sources that contributed most to the exposure were FM radio, mobile phone downlink and Digital Video Broadcasting-Terrestrial, while indoor and personal sources contributed very little (altogether <20%). Similar distribution was observed with personal measurements. There was a bias proportional to power density between personal measurements and estimates based on spot measurements, with the latter providing higher exposure estimates. Nevertheless, there were no systematic differences between those methodologies when classifying subjects into exposure categories. Personal measurements of total RF exposure showed low to moderate agreement with home and bedroom spot measurements and agreed better, though moderately, with TWA based on spot measurements in the main settings where children spend time (homes, schools and parks; Kappa = 0.46). CONCLUSIONS: Exposure assessment based on spot measurements could be a feasible proxy to rank personal RF exposure in children population, providing that all relevant locations are being measured.

[Fluoride intake through consumption of water from municipal network in the INMA-Gipuzkoa cohort]. / Ingesta de flúor a través del consumo de agua de abastecimiento público en la cohorte INMA-Gipuzkoa.

OBJECTIVE: To estimate fluoride intake through consumption of water from the municipal network in pregnant women and their children from the INMA-Gipuzkoa cohort and to compare these intakes with recommended levels. In Euskadi (Spain), fluoridation of drinking water is compulsory in water supplies for more than 30,000 inhabitants. METHOD: 575 pregnant women (recruitment, 2006-2008) and 424 4-year-old children (follow-up, 2010-2012) have been included. Fluoride levels in drinking water were obtained from the water consumption information system of the Basque Country (EKUIS). Water consumption habits and socioeconomic variables were obtained by questionnaire. RESULTS: 74.9% and 87.7% of women and children consumed water from the municipal network. Average fluoride levels in fluoridated water were 0.805 (SD: 0.194) mg/L during baseline recruitment and 0.843 (SD: 0.080) mg/L during follow up, at 4 years old of the children. Average and 95th percentile of fluoride intake were 0.015 and 0.026mg/kg per day in women and 0.033 and 0.059mg/kg per day in children. Considering only fluoride provided by drinking water, 8.71% of children living in fluoridated areas exceeded intake level recommended by the European Food Safety Authority, consisting in 0.05mg/kg per day. CONCLUSION: The results show that ingested levels of fluoride through consumption of municipal water can exceed the recommended levels in children and encourages further studies that will help in fluoridation policies of drinking water in the future.

Long-term exposure to trihalomethanes in drinking water and breast cancer in the Spanish multicase-control study on cancer (MCC-SPAIN).

BACKGROUND: Exposure to trihalomethanes (THMs) in drinking water has consistently been associated with an increased risk of bladder cancer, but evidence on other cancers including the breast is very limited. OBJECTIVES: We assessed long-term exposure to THMs to evaluate the association with female breast cancer (BC) risk. METHODS: A multi case-control study was conducted in Spain from 2008 to 2013. We included 1003 incident BC cases (women 20-85years old) recruited from 14 hospitals and 1458 population controls. Subjects were interviewed to ascertain residential histories and major recognized risk factors for BC. Mean residential levels of chloroform, brominated THMs (Br-THMs) and the sum of both as total THM (TTHMs) during the adult-lifetime were calculated. RESULTS: Mean adult-lifetime residential levels ranged from 0.8 to 145.7µg/L for TTHM (median=30.8), from 0.2 to 62.4µg/L for chloroform (median=19.7) and from 0.3 to 126.0µg/L for Br-THMs (median=9.7). Adult-lifetime residential chloroform was associated with BC (adjusted OR=1.47; 95%CI=1.05, 2.06 for the highest (>24µg/L) vs. lowest (<8µg/L) quartile; p-trend=0.024). No association was detected for residential Br-THMs (OR=0.91; 95%CI=0.68, 1.23 for >31µg/L vs. <6µg/L) or TTHMs (OR=1.14; 95%CI=0.83, 1.57 for >48µg/L vs. <22µg/L). CONCLUSIONS: At common levels in Europe, long-term residential total THMs were not related to female breast cancer. A moderate association with chloroform was suggested at the highest exposure category. This large epidemiological study with extensive exposure assessment overcomes several limitations of previous studies but further studies are needed to confirm these results.

Spatial and temporal variability of personal environmental exposure to radio frequency electromagnetic fields in children in Europe.

BACKGROUND: Exposure to radiofrequency electromagnetic fields (RF-EMF) has rapidly increased and little is known about exposure levels in children. This study describes personal RF-EMF environmental exposure levels from handheld devices and fixed site transmitters in European children, the determinants of this, and the day-to-day and year-to-year repeatability of these exposure levels. METHODS: Personal environmental RF-EMF exposure (µW/m2, power flux density) was measured in 529 children (ages 8-18 years) in Denmark, the Netherlands, Slovenia, Switzerland, and Spain using personal portable exposure meters for a period of up to three days between 2014 and 2016, and repeated in a subsample of 28 children one year later. The meters captured 16 frequency bands every 4 s and incorporated a GPS. Activity diaries and questionnaires were used to collect children's location, use of handheld devices, and presence of indoor RF-EMF sources. Six general frequency bands were defined: total, digital enhanced cordless telecommunications (DECT), television and radio antennas (broadcast), mobile phones (uplink), mobile phone base stations (downlink), and Wireless Fidelity (WiFi). We used adjusted mixed effects models with region random effects to estimate associations of handheld device use habits and indoor RF-EMF sources with personal RF-EMF exposure. Day-to-day and year-to-year repeatability of personal RF-EMF exposure were calculated through intraclass correlations (ICC). RESULTS: Median total personal RF-EMF exposure was 75.5 µW/m2. Downlink was the largest contributor to total exposure (median: 27.2 µW/m2) followed by broadcast (9.9 µW/m2). Exposure from uplink (4.7 µW/m2) was lower. WiFi and DECT contributed very little to exposure levels. Exposure was higher during day (94.2 µW/m2) than night (23.0 µW/m2), and slightly higher during weekends than weekdays, although varying across regions. Median exposures were highest while children were outside (157.0 µW/m2) or traveling (171.3 µW/m2), and much lower at home (33.0 µW/m2) or in school (35.1 µW/m2). Children living in urban environments had higher exposure than children in rural environments. Older children and users of mobile phones had higher uplink exposure but not total exposure, compared to younger children and those that did not use mobile phones. Day-to-day repeatability was moderate to high for most of the general frequency bands (ICCs between 0.43 and 0.85), as well as for total, broadcast, and downlink for the year-to-year repeatability (ICCs between 0.49 and 0.80) in a small subsample. CONCLUSION: The largest contributors to total personal environmental RF-EMF exposure were downlink and broadcast, and these exposures showed high repeatability. Urbanicity was the most important determinant of total exposure and mobile phone use was the most important determinant of uplink exposure. It is important to continue evaluating RF-EMF exposure in children as device use habits, exposure levels, and main contributing sources may change.

Ingesta de flúor a través del consumo de agua de abastecimiento público en la cohorte INMA-Gipuzkoa / Fluoride intake through consumption of water from municipal network in the INMA-Gipuzkoa cohort

Objetivo: Estimar la ingesta de flúor en mujeres embarazadas y sus hijos/as de la cohorte INMA-Gipuzkoa a través del consumo de agua de la red municipal y comparar estas ingestas con los valores recomendados. En Euskadi, la fluoración del agua de consumo es obligatoria en abastecimientos de más de 30.000 habitantes. Método: Se han incluido 575 mujeres embarazadas (reclutamiento en 2006-2008) y 424 niños/as de 4 años (seguimiento en 2010-2012). Las concentraciones de fluoruros en el agua se obtuvieron del sistema de información de aguas de consumo de Euskadi (EKUIS). Los hábitos de consumo de agua y las variables socioeconómicas se obtuvieron mediante cuestionario. Resultados: El 74,9% de las mujeres y el 87,7% de los/las niños/as consumían agua de red municipal. En agua fluorada, el valor medio de fluoruro fue de 0,805mg/l (desviación estándar [DE]: 0,194) durante el periodo de reclutamiento, y de 0,843mg/l (DE: 0,080) durante el seguimiento de los/las niños/as. La ingesta media de flúor y el percentil 95 en las zonas fluoradas fueron de 0,015 y 0,026mg/kg al día en las mujeres y de 0,033 y 0,059mg/kg al día en los/las niños/as. Considerando solo el flúor aportado por el agua, el 8,71% de los/las niños/as residentes en zonas con fluoración superaban la ingesta de 0,05mg/kg al día recomendada por la European Food Safety Authority. Conclusión: Los resultados obtenidos muestran que las ingestas de flúor a través del agua de consumo pueden superar lo recomendado en población infantil, y propician futuros estudios que aporten evidencias que puedan ayudar en las políticas de fluoración de las aguas de consumo público

Objective: To estimate fluoride intake through consumption of water from the municipal network in pregnant women and their children from the INMA-Gipuzkoa cohort and to compare these intakes with recommended levels. In Euskadi (Spain), fluoridation of drinking water is compulsory in water supplies for more than 30,000 inhabitants. Method: 575 pregnant women (recruitment, 2006-2008) and 424 4-year-old children (follow-up, 2010-2012) have been included. Fluoride levels in drinking water were obtained from the water consumption information system of the Basque Country (EKUIS). Water consumption habits and socioeconomic variables were obtained by questionnaire. Results: 74.9% and 87.7% of women and children consumed water from the municipal network. Average fluoride levels in fluoridated water were 0.805 (SD: 0.194) mg/L during baseline recruitment and 0.843 (SD: 0.080) mg/L during follow up, at 4 years old of the children. Average and 95th percentile of fluoride intake were 0.015 and 0.026mg/kg per day in women and 0.033 and 0.059mg/kg per day in children. Considering only fluoride provided by drinking water, 8.71% of children living in fluoridated areas exceeded intake level recommended by the European Food Safety Authority, consisting in 0.05mg/kg per day. Conclusion: The results show that ingested levels of fluoride through consumption of municipal water can exceed the recommended levels in children and encourages further studies that will help in fluoridation policies of drinking water in the future

[Situation of environmental and food area disinfectants registered in Spain under directive 98/8/CE]. / Situación de los desinfectantes de uso ambiental y en industria alimentaria registrados en España tras la publicación de la directiva 98/8/CE.

BACKGROUND: Directive 98/8/EC harmonizes and regulates in the European market authorization and registration of biocides and establishes a period of 14 years for review of active substances. This study analyzes the most significant changes produced in the registry of biocides used as disinfectants registered since the publication of the Directive. METHOD: Information was obtained from the registry of biocides published in the website of the Ministry of Health, Social Policy and Equality in May 2010. We used an Excel data base for the dump and data processing. RESULTS: There are 1575 biocides with intended use as environmental and food area disinfectants registered in Spain (1137 formulas and 438 active ingredients). Formulas are composed of 56 active sustances which are being assessed for their inclusion in the Community list of authorized substances. 54% of the formulas are registered as both bactericide and fungicide, 79% are contact disinfectants, 42% of the formulas correspond to those composed of quaternary ammonium compounds and 67.9% are made with a single active substance. Regarding hazardous properties 45.3% are corrosive, 25.7% irritant, 9.8% harmful, 1.1% toxic , and 33.1% are dangerous to the environment. CONCLUSIONS: The Spanish registry of biocides has complied with the provisions of the Directive cancelling the registrations of the formulas containing substances not included in the list. Of all the substances which are under review in Europe, 58% of environmental disinfectants and 76.4% of food area disinfectants are authorized in Spain.