Systematic review and meta-analysis of birth weight and perfluorohexane sulfonate exposures: examination of sample timing and study confidence.

We examined the association between mean birth weight (BW) differences and perfluorohexane sulfonate (PFHxS) exposure biomarkers.We fit a random effects model to estimate the overall pooled effect and for different strata based on biomarker sample timing and overall study confidence. We also conducted an analysis to examine the impact of a continuous measure of gestational age sample timing on the overall pooled effect.We detected a -7.9 g (95% CI -15.0 to -0.7; pQ=0.85; I2=0%) BW decrease per ln ng/mL PFHxS increase based on 27 studies. The 11 medium confidence studies (ß=-10.0 g; 95% CI -21.1 to 1.1) showed larger deficits than 12 high (ß=-6.8 g; 95% CI -16.3 to 2.8) and 4 low confidence studies (ß=-1.5 g; 95% CI -51.6 to 48.7). 10 studies with mid-pregnancy to late-pregnancy sampling periods showed smaller deficits (ß=-3.9 g; 95% CI -17.7 to 9.9) than 5 post-partum studies (ß=-28.3 g; 95% CI -69.3 to 12.7) and 12 early sampling studies (ß=-7.6 g; 95% CI -16.2 to 1.1). 6 of 12 studies with the earliest sampling timing showed results closer to the null.Overall, we detected a small but statistically significant BW deficit across 27 studies. We saw comparable BW deficit magnitudes in both the medium and high confidence studies as well as the early pregnancy group. Despite no definitive pattern by sample timing, larger deficits were seen in postpartum studies. We also saw results closer to the null for a subset of studies restricted to the earliest biomarker collection times. Serial pregnancy sampling, improved precision in gestational age estimates and more standardised reporting of sample variation and exposure units in future epidemiologic research may offer a greater understanding of the relationship between PFHxS on BW and any potential impact of pregnancy haemodynamics.

Comparative susceptibility of children and adults to neurological effects of inhaled manganese: A review of the published literature.

BACKGROUND: Manganese (Mn) is neurotoxic in adults and children. Current assessments are based on the more extensive adult epidemiological data, but the potential for greater childhood susceptibility remains a concern. To better understand potential lifestage-based variations, we compared susceptibilities to neurotoxicity in children and adults using Mn biomarker data. METHODS: We developed a literature search strategy based on a Population, Exposures, Comparators, and Outcomes statement focusing on inhalation exposures and neurological outcomes in humans. Screening was performed using DistillerSR. Hair biomarker studies were selected for evaluation because studies with air measurements were unavailable or considered inadequate for children. Studies were paired based on concordant Mn source, biomarker, and outcome. Comparisons were made based on reported dose-response slopes (children vs. adults). Study evaluation was conducted to understand the confidence in our comparisons. RESULTS: We identified five studies evaluating seven pairings of hair Mn and neurological outcomes (cognition and motor effects) in children and adults matched on sources of environmental Mn inhalation exposure. Two Brazilian studies of children and one of adults reported intelligent quotient (IQ) effects; effects in both comparisons were stronger in children (1.21 to 2.03-fold difference). In paired analyses of children and adults from the United States, children exhibited both stronger and weaker effects compared to adults (0.37 to 1.75-fold differences) on postural sway metrics. CONCLUSION: There is limited information on the comparative susceptibility of children and adults to inhaled Mn. We report that children may be 0.37 to 2.03 times as susceptible as adults to neurotoxic effects of Mn, thereby providing a quantitative estimate for some aspects of lifestage variation. Due to the limited number of paired studies available in the literature, this quantitative estimate should be interpreted with caution. Our analyses do not account for other sources of inter-individual variation. Additional studies of Mn-exposed children with direct air concentration measurements would improve the evidence base.

Residential greenness, asthma, and lung function among children at high risk of allergic sensitization: a prospective cohort study.

BACKGROUND: While benefits of greenness to health have been reported, findings specific to child respiratory health are inconsistent. METHODS: We utilized a prospective birth cohort followed from birth to age 7 years (n = 617). Residential surrounding greenness was quantified via Normalized Difference Vegetation Index (NDVI) within 200, 400, and 800 m distances from geocoded home addresses at birth, age 7 years, and across childhood. Respiratory health outcomes were assessed at age 7 years, including asthma and lung function [percent predicted forced expiratory volume in the first second (%FEV1), percent predicted forced vital capacity (%FVC), and percent predicted ratio of forced expiratory volume in the first second to forced vital capacity (%FEV1/FVC)]. We assessed associations using linear and logistic regression models adjusted for community deprivation, household income, and traffic-related air pollution. We tested for effect measure modification by atopic status. RESULTS: We noted evidence of positive confounding as inverse associations were attenuated upon adjustment in the multivariable models. We found evidence of effect measure modification of NDVI and asthma within 400 m at age 7 years by atopic status (p = 0.04), whereby children sensitized to common allergens were more likely to develop asthma as exposure to greenness increased (OR = 1.3, 95% CI: 0.9, 2.0) versus children not sensitized to common allergens (OR = 0.8, 95% CI: 0.5, 1.2). We found consistently positive associations between NDVI and %FEV1 and %FVC which similarly evidenced positive confounding upon adjustment. In the adjusted regression models, NDVI at 7 years of age was associated with %FEV1 (200 m: ß = 2.1, 95% CI: 0.1, 3.3; 400 m: ß = 1.6, 95% CI: 0.3, 2.9) and %FVC (200 m: ß = 1.8, 95% CI: 0.7, 3.0; 400 m: ß = 1.6, 95% CI: 0.3, 2.8; 800 m: ß = 1.5, 95% CI: 0.1, 2.8). Adjusted results for %FEV1/FVC were non-significant except exposure at birth in the 400 m buffer (ß = 0.81, 95% CI: 0.1, 1.5). We found no evidence of effect measure modification of NDVI by atopic status for objective measures of lung function. CONCLUSION: Sensitivity to allergens may modify the effect of greenness on risk for asthma in children but greenness is likely beneficial for concurrent lung function regardless of allergic status.

Ambient ozone and fine particulate matter exposures and autism spectrum disorder in metropolitan Cincinnati, Ohio.

BACKGROUND: Epidemiological studies report fairly consistent associations between various air pollution metrics and autism spectrum disorder (ASD), with some elevated risks reported for different prenatal and postnatal periods. OBJECTIVES: To examine associations between ASD and ambient fine particulate matter (PM2.5) and ozone concentrations during the prenatal period through the second year of life in a case-control study. METHODS: ASD cases (n = 428) diagnosed at Cincinnati Children's Hospital Medical Center were frequency matched (15:1) to 6420 controls from Ohio birth records. We assigned daily PM2.5 and ozone estimates for 2005-2012 from US EPA's Fused Air Quality Surface Using Downscaling model to each participant for each day based on the mother's census tract of residence at birth. We calculated adjusted odds ratios (aORs) using logistic regression across continuous and categorical exposure window averages (trimesters, first and second postnatal years, and cumulative measure), adjusting for maternal- and birth-related confounders, both air pollutants, and multiple temporal exposure windows. RESULTS: We detected elevated aORs for PM2.5 during the 2nd trimester, 1st year of life, and a cumulative period from pregnancy through the 2nd year (aOR ranges across categories: 1.41-1.44, 1.54-1.84, and 1.41-1.52 respectively), and for ozone in the 2nd year of life (aOR range across categories: 1.29-1.42). Per each change in IQR, we observed elevated aORs for ozone in the 3rd trimester, 1st and 2nd years of life, and the cumulative period (aOR range: 1.19-1.27) and for PM2.5 in the 2nd trimester, 1st year of life, and the cumulative period (aOR range: 1.11-1.17). DISCUSSION: We saw limited evidence of linear exposure-response relationships for ASD with increasing air pollution, but the elevated aORs detected for PM2.5 in upper exposure categories and per IQR unit increases were similar in magnitude to those reported in previous studies, especially for postnatal exposures.

Exposure to disinfectant by-products and the risk of stillbirth in Massachusetts.

OBJECTIVES: We examined stillbirths in relation to disinfection by-product (DBP) exposures including chloroform, bromodichloromethane (BDCM), dibromochloromethane, bromoform, trichloroacetic acid, dichloroacetic acid (DCAA), monobromoacetic acid and summary DBP measures (trihalomethanes (THM4), haloacetic acids (HAA5), THMBr (brominated trihalomethanes) and DBP9 (sum of THM4 and HAA5)). METHODS: We randomly selected 10 controls for each of the 2460 stillbirth cases with complete quarterly 1997-2004 THM4 and HAA5 town-level drinking water data. Adjusted (aORs) were calculated based on weight-averaged second-trimester DBP exposures. RESULTS: We detected statistically significant associations for stillbirths and the upper DCAA quartiles (aOR range: 1.50-1.71). We also found positive associations for the upper four HAA5 quintiles and different stillbirth cause of death categories that were examined including unexplained stillbirth (aOR range: 1.24-1.72), compression of umbilical cord (aOR range: 1.08-1.94), prematurity (aOR range: 1.37-2.88), placental separation and haemorrhage (aOR range: 1.44-2.01) and asphyxia/hypoxia (aOR range: 1.52-1.97). Additionally, we found positive associations between stillbirths and chloroform exposure (aOR range: 1.29 - 1.36) and unexplained stillbirths and BDCM exposure (aOR range: 1.51 - 1.78). We saw no evidence of exposure-response relationships for any categorical DBP metrics. CONCLUSIONS: Consistent with some previous studies, we found associations between stillbirths and chloroform and unexplained stillbirth and BDCM exposures. These findings strengthen existing evidence of prenatal THM exposures increasing the risk of stillbirth. Additionally, we saw statistically significant associations between DCAA and stillbirth. Future research should examine cause-specific stillbirths in relation to narrower critical windows and additional DBP exposure metrics beyond trihalomethanes and haloacetic acids.

Characterizing Risk for Cumulative Risk Assessments.

In assessing environmental health risks, the risk characterization step synthesizes information gathered in evaluating exposures to stressors together with dose-response relationships, characteristics of the exposed population, and external environmental conditions. This article summarizes key steps of a cumulative risk assessment (CRA) followed by a discussion of considerations for characterizing cumulative risks. Cumulative risk characterizations differ considerably from single chemical- or single source-based risk characterization. CRAs typically focus on a specific population instead of a pollutant or pollutant source and should include an evaluation of all relevant sources contributing to the exposures in the population and other factors that influence dose-response relationships. Second, CRAs may include influential environmental and population-specific conditions, involving multiple chemical and nonchemical stressors. Third, a CRA could examine multiple health effects, reflecting joint toxicity and the potential for toxicological interactions. Fourth, the complexities often necessitate simplifying methods, including judgment-based and semi-quantitative indices that collapse disparate data into numerical scores. Fifth, because of the higher dimensionality and potentially large number of interactions, information needed to quantify risk is typically incomplete, necessitating an uncertainty analysis. Three approaches that could be used for characterizing risks in a CRA are presented: the multiroute hazard index, stressor grouping by exposure and toxicity, and indices for screening multiple factors and conditions. Other key roles of the risk characterization in CRAs are also described, mainly the translational aspect of including a characterization summary for lay readers (in addition to the technical analysis), and placing the results in the context of the likely risk-based decisions.

Swine exposure and methicillin-resistant Staphylococcus aureus infection among hospitalized patients with skin and soft tissue infections in Illinois: A ZIP code-level analysis.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA), a bacterial pathogen, is a predominant cause of skin and soft tissue infections (SSTI) in the United States. Swine-production facilities have been recognized as potential environmental reservoirs of MRSA. To better understand how swine production may contribute to MRSA infection, we evaluated the association between MRSA infection among SSTI inpatients and exposure measures derived from national swine inventory data. METHODS: Based on adjusted odds ratios from logistic regression models, we evaluated the association between swine exposure metrics and MRSA infections among all Illinois inpatient hospitalizations for SSTI from January 2008 through July 2011. We also assessed if swine exposures had greater association with suspected community-onset MRSA (CO-MRSA) compared to suspected hospital-onset MRSA (HO-MRSA). Exposures were estimated using the Farm Location and Agricultural Production Simulator, generating the number of farms with greater than 1000 swine per residential ZIP code and the residential ZIP code-level swine density (swine/km2). RESULTS: For every increase in 100 swine/km2 within a residential ZIP code, the adjusted OR (aOR) for MRSA infection was 1.36 (95% CI: 1.28-1.45). For every additional large farm (i.e., >1000 swine) per ZIP code, the aOR for MRSA infection was 1.06 (95% CI: 1.04-1.07). The aOR for ZIP codes with any large farms compared to those with no large farms was 1.24 (95% CI: 1.19-1.29). We saw no evidence of an increased association for CO-MRSA compared to HO-MRSA with either continuous exposure metric (aORs=0.99), and observed inconsistent results across exposure categories. CONCLUSIONS: These publicly-available, ecological exposure data demonstrated positive associations between swine exposure measures and individual-level MRSA infections among SSTI inpatients. Though it is difficult to draw definitive conclusions due to limitations of the data, these findings suggest that the risk of MRSA may increase based on indirect environmental exposure to swine production. Future research can address measurement error related to these data by improving exposure assessment precision, increased specification of MRSA strain, and better characterization of specific environmental exposure pathways.

Estimating Potential Increased Bladder Cancer Risk Due to Increased Bromide Concentrations in Sources of Disinfected Drinking Waters.

Public water systems are increasingly facing higher bromide levels in their source waters from anthropogenic contamination through coal-fired power plants, conventional oil and gas extraction, textile mills, and hydraulic fracturing. Climate change is likely to exacerbate this in coming years. We estimate bladder cancer risk from potential increased bromide levels in source waters of disinfecting public drinking water systems in the United States. Bladder cancer is the health end point used by the United States Environmental Protection Agency (EPA) in its benefits analysis for regulating disinfection byproducts in drinking water. We use estimated increases in the mass of the four regulated trihalomethanes (THM4) concentrations (due to increased bromide incorporation) as the surrogate disinfection byproduct (DBP) occurrence metric for informing potential bladder cancer risk. We estimate potential increased excess lifetime bladder cancer risk as a function of increased source water bromide levels. Results based on data from 201 drinking water treatment plants indicate that a bromide increase of 50 µg/L could result in a potential increase of between 10(-3) and 10(-4) excess lifetime bladder cancer risk in populations served by roughly 90% of these plants.

Risks of obstructive genitourinary birth defects in relation to trihalomethane and haloacetic acid exposures: expanding disinfection byproduct mixtures analyses using relative potency factors.

BACKGROUND: Some disinfection byproducts (DBPs) are teratogens based on toxicological evidence. Conventional use of predominant DBPs as proxies for complex mixtures may result in decreased ability to detect associations in epidemiological studies. OBJECTIVE: We assessed risks of obstructive genitourinary birth defects (OGDs) in relation to 12 DBP mixtures and 13 individual component DBPs. METHODS: We designed a nested registry-based case-control study (210 OGD cases; 2100 controls) in Massachusetts towns with complete quarterly 1999-2004 data on four trihalomethanes (THMs) and five haloacetic acids (HAAs). We estimated temporally-weighted average DBP exposures for the first trimester of pregnancy. We estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for OGD in relation to individual DBPs, unweighted mixtures, and weighted mixtures based on THM/HAA relative potency factors (RPF) from animal toxicology data for full-litter resorption, eye defects, and neural tube defects. RESULTS: We detected elevated aORs for OGDs for the highest of bromodichloromethane (aOR = 1.75; 95% CI: 1.15-2.65), dibromochloromethane (aOR = 1.71; 95% CI: 1.15-2.54), bromodichloroacetic acid (aOR = 1.56; 95%CI: 0.97-2.51), chlorodibromoacetic acid (aOR = 1.97, 95% CI: 1.23-3.15), and tribromoacetic acid (aOR = 1.90; 95%CI: 1.20-3.03). Across unweighted mixture sums, the highest aORs were for the sum of three brominated THMs (aOR = 1.74; 95% CI: 1.15-2.64), the sum of six brominated HAAs (aOR = 1.43; 95% CI: 0.89-2.31), and the sum of nine brominated DBPs (aOR = 1.80; 95% CI: 1.05-3.10). Comparing eight RPF-weighted to unweighted mixtures, the largest aOR differences were for two HAA metrics, which both were higher with RPF weighting; other metrics had reduced or minimally changed ORs in RPF-weighted models.

Comparison of Trihalomethane exposure assessment metrics in epidemiologic analyses of reproductive and developmental outcomes.

BACKGROUND: Researchers have developed exposure assessment metrics for disinfection by-products (DBPs) utilizing drinking water monitoring data and accounting for spatial and temporal variability, water consumption, and showering and bathing time with an expectation of decreasing exposure misclassification compared to the use of measured concentrations at public water supply (PWS) monitoring locations alone. OBJECTIVE: We used exposure data collected for a previous study of DBPs to evaluate how different sources of information impact trihalomethane (THM) exposure estimates. METHODS: We compared gestational exposure estimates to THMs based on water utility monitoring data alone, statistical imputation of daily concentrations to incorporate temporal variability, and personal water consumption and use (bathing and showering). We used Spearman correlation coefficients and ranked kappa statistics to compare exposure classifications. RESULTS: Exposure estimates based on measured or imputed daily THM concentrations, self-reported consumption, or bathing and showering differed substantially from estimates based solely on concentrations from PWS quarterly monitoring reports. Ranked exposure classifications, high to low quartiles or deciles, were generally consistent across each exposure metric (i.e., a subject with "high" exposure based on measured or imputed THM concentrations generally remained in the "high" category across exposure metrics.) The measured concentrations and imputed daily (i.e., spline regression) concentrations were highly correlated (r = 0.98). The weighted kappa statistics comparing exposure estimates using different exposure metrics ranged from 0.27 to 0.89, with the highest values for the ingestion + bathing/showering metrics compared to metrics for bathing/showering only (0.76 and 0.89). Bathing and showering contributed the most to "total" THM exposure estimates. IMPACT STATEMENT: We compare exposure metrics capturing temporal variability and multiple estimates of personal THM exposure with THM concentrations from PWS monitoring data. Our results show exposure estimates based on imputed daily concentrations accounting for temporal variability were very similar to the measured THM concentrations. We observed low agreement between imputed daily concentrations and ingestion-based estimates. Considering additional routes of exposure (e.g., inhalation and dermal) slightly increased agreement with the measured PWS exposure estimate in this population. Overall, the comparison of exposure assessment metrics allows researchers to understand the added value of additional data collection for future epidemiologic analyses of DBPs.

Maternal exposure to nitrosamines in drinking water during pregnancy and birth outcomes in a Chinese cohort.

Maternal exposure to regulated disinfection by-products (DBPs) during pregnancy has been linked with adverse birth outcomes. However, no human studies have focused on drinking water nitrosamines, a group of emerging unregulated nitrogenous DBPs that exhibits genotoxicity and developmental toxicity in experimental studies. This cohort study included 2457 mother-infant pairs from a single drinking water supply system in central China, and maternal trimester-specific and entire pregnancy exposure of drinking water nitrosamines were evaluated. Multivariable linear and Poisson regression models were used to estimate the associations between maternal exposure to nitrosamines in drinking water and birth outcomes [birth weight (BW), low birth weight (LBW), small for gestational age (SGA) and preterm delivery (PTD)]. Elevated maternal N-nitrosodimethylamine (NDMA) exposure in the second trimester and N-nitrosopiperidine (NPIP) exposure during the entire pregnancy were associated with decreased BW (e.g., ß = -88.6 g; 95% CI: -151.0, -26.1 for the highest vs. lowest tertile of NDMA; p for trend = 0.01) and increased risks of PTD [e.g., risk ratio (RR) = 2.16; 95% CI: 1.23, 3.79 for the highest vs. lowest tertile of NDMA; p for trend = 0.002]. Elevated maternal exposure of N-nitrosodiethylamine (NDEA) in the second trimester was associated with increased risk of SGA (RR = 1.80; 95% CI: 1.09, 2.98 for the highest vs. lowest tertile; p for trend = 0.01). Our study detected associations of maternal exposure to drinking water nitrosamines during pregnancy with decreased BW and increased risks of SGA and PTD. These findings are novel but require replication in other study populations.

Epidemiology Evidence for Health Effects of 150 per- and Polyfluoroalkyl Substances: A Systematic Evidence Map.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) comprise a large class of chemicals with widespread use and persistence in the environment and in humans; however, most of the epidemiology research has focused on a small subset. OBJECTIVES: The aim of this systematic evidence map (SEM) is to summarize the epidemiology evidence on approximately 150 lesser studied PFAS prioritized by the EPA for tiered toxicity testing, facilitating interpretation of those results as well as identification of priorities for risk assessment and data gaps for future research. METHODS: The Populations, Exposure, Comparators, and Outcomes (PECO) criteria were intentionally broad to identify studies of any health effects in humans with information on associations with exposure to the identified PFAS. Systematic review methods were used to search for literature that was screened using machine-learning software and manual review. Studies meeting the PECO criteria underwent quantitative data extraction and evaluation for risk of bias and sensitivity using the Integrated Risk Information System approach. RESULTS: 193 epidemiology studies were identified, which included information on 15 of the PFAS of interest. The most commonly studied health effect categories were metabolic (n=37), endocrine (n=30), cardiovascular (30), female reproductive (n=27), developmental (n=26), immune (n=22), nervous (n=21), male reproductive (n=14), cancer (n=12), and urinary (n=11) effects. In study evaluation, 120 (62%) studies were considered High/Medium confidence for at least one outcome. DISCUSSION: Most of the PFAS in this SEM have little to no epidemiology data available to inform evaluation of potential health effects. Although exposure to the 15 PFAS that had data was fairly low in most studies, these less-studied PFAS may be used as replacements for "legacy" PFAS, leading to potentially greater exposure. It is impractical to generate epidemiology evidence to fill the existing gaps for all potentially relevant PFAS. This SEM highlights some of the important research gaps that currently exist. https://doi.org/10.1289/EHP11185.

Identification of developmentally toxic drinking water disinfection byproducts and evaluation of data relevant to mode of action.

Reactions between chemicals used to disinfect drinking water and compounds present in source waters produce chemical mixtures containing hundreds of disinfection byproducts (DBPs). Although the results have been somewhat inconsistent, some epidemiological studies suggest associations may exist between DBP exposures and adverse developmental outcomes. The potencies of individual DBPs in rodent and rabbit developmental bioassays suggest that no individual DBP can account for the relative risk estimates reported in the positive epidemiologic studies, leading to the hypothesis that these outcomes could result from the toxicity of DBP mixtures. As a first step in a mixtures risk assessment for DBP developmental effects, this paper identifies developmentally toxic DBPs and examines data relevant to the mode of action (MOA) for DBP developmental toxicity. We identified 24 developmentally toxic DBPs and four adverse developmental outcomes associated with human DBP exposures: spontaneous abortion, cardiovascular defects, neural tube defects, and low birth weight infancy. A plausible MOA, involving hormonal disruption of pregnancy, is delineated for spontaneous abortion, which some epidemiologic studies associate with total trihalomethane and bromodichloromethane exposures. The DBP data for the other three outcomes were inadequate to define key MOA steps.

Temporal variability in trihalomethane and haloacetic acid concentrations in Massachusetts public drinking water systems.

Previous epidemiological studies in Massachusetts have reported a risk of adverse health outcomes in relation to disinfection by-product (DBP) exposures. Measurement error due to the use of indirect exposure surrogates can lead to misclassification bias in epidemiological studies; therefore, it is important to characterize exposure variability in these populations to assess the potential for exposure misclassification. We used 19,944 trihalomethane (THM) samples and 9291 haloacetic acid (HAA) samples collected in 201 public water systems (PWSs) in Massachusetts to examine temporal variability under different drinking water sources and disinfection types. Annual and seasonal variability was also examined in 46 PWSs with complete quarterly THM4 (i.e., the sum of 4 individual THMs) data from 1995 to 2004 and 19 PWSs with complete HAA5 (i.e., the sum of 5 individual HAAs) data from 2001 to 2004. The quarterly ratio of THM4 and HAA5 and correlations between THM4, HAA5 and individual DBP species were examined to determine the adequacy of using different exposure surrogates in epidemiological studies. Individual PWSs were used to examine monthly variability in relation to quarterly averages. Based on all available matched samples (n=9003) from 1995 to 2004 data, we found a correlation of 0.52 for THM4 and HAA5. The correlation was stronger among the 62 ground water systems (r(s)=0.62) compared to the 81 surface water (r(s)=0.45) and 40 mixed water (r(s)=0.39) systems. Mean THM4 levels were fairly stable over the 10-year study period for 46 PWSs including 39 PWSs that did not change disinfection. Large reductions (∼40 µg/L) in mean THM4 data were found among seven systems that switched from chlorination to alternative disinfectants. As expected, the highest mean THM4 values were detected for Quarter 3, while the lowest values were found in Quarter 1. The highest HAA5 values were detected in Quarters 2 and 3 and the lowest was found in Quarter 4. Data from four systems showed mean differences up to 66 µg/L (67% change) in successive months and by 46 µg/L compared to quarterly mean concentrations. Although longer-term disinfection by-product temporality may be minimal in this study population, the use of monthly average concentrations for exposure assessment may be needed for some PWSs to minimize misclassification of narrow critical periods of exposure in epidemiological studies.

Regression calibration for classical exposure measurement error in environmental epidemiology studies using multiple local surrogate exposures.

Environmental epidemiologic studies are often hierarchical in nature if they estimate individuals' personal exposures using ambient metrics. Local samples are indirect surrogate measures of true local pollutant concentrations which estimate true personal exposures. These ambient metrics include classical-type nondifferential measurement error. The authors simulated subjects' true exposures and their corresponding surrogate exposures as the mean of local samples and assessed the amount of bias attributable to classical and Berkson measurement error on odds ratios, assuming that the logit of risk depends on true individual-level exposure. The authors calibrated surrogate exposures using scalar transformation functions based on observed within- and between-locality variances and compared regression-calibrated results with naive results using surrogate exposures. The authors further assessed the performance of regression calibration in the presence of Berkson-type error. Following calibration, bias due to classical-type measurement error, resulting in as much as 50% attenuation in naive regression estimates, was eliminated. Berkson-type error appeared to attenuate logistic regression results less than 1%. This regression calibration method reduces effects of classical measurement error that are typical of epidemiologic studies using multiple local surrogate exposures as indirect surrogate exposures for unobserved individual exposures. Berkson-type error did not alter the performance of regression calibration. This regression calibration method does not require a supplemental validation study to compute an attenuation factor.

The relationship between water intake and foetal growth and preterm delivery in a prospective cohort study.

BACKGROUND: Interpretation of previous associations between water intake and adverse birth outcomes is challenging given that amount and type of water consumed can be non-specific markers of exposure or underlying behavioural characteristics. We examined the relationship between water intake measures and adverse birth outcomes in participants from three study sites in the United States. METHODS: Using a prospective cohort study, we examined daily intake of bottled, cold tap, total tap, and total water in relation to birth weight and risk of small-for-gestational-age (SGA) among term births and risk of preterm delivery. RESULTS: Based on water consumption data collected between 20-24 weeks of gestation, the adjusted mean birth weight was 27 (95% confidence interval [CI]: -34, 87), 39 (95% CI: -22, 99), and 50 (95% CI: -11, 110) grams higher for the upper three total water intake quartiles (> 51-78, > 78-114, and > 114 ounces/day) compared to the lowest quartile (≤ 51 ounces/day). Adjusted birth weight results were similar for bottled water, cold tap water, and total tap water intake. An exposure-response gradient was not detected for either preterm delivery or SGA with increasing total water intake and total tap water intake, but adjusted relative risks for all three upper quartiles were below 1.0 (range: 0.6-0.9) for SGA. CONCLUSION: These data suggest that high water intake may be associated with higher mean birth weight following adjustment for confounding.

Disinfection By-Product Exposures and the Risk of Musculoskeletal Birth Defects.

BACKGROUND: Epidemiological studies suggest that exposure to water disinfection by-products (DBPs) may increase the risk of certain birth defects. However, evidence for musculoskeletal defects (MSDs) is limited. Previous MSD studies have not examined DBPs beyond trihalomethanes (THMs) and have not separately examined limb or diaphragm defects which may have distinct developmental etiologies. METHODS: We calculated adjusted odds ratios (aORs) in a registry-based case-control study of birth defects in Massachusetts with complete quarterly 1999-2004 data on four THMs and five haloacetic acids (HAAs). We matched 10 controls each to 187 MSD cases based on week of conception. Weight-averaged town-level first-trimester DBP exposures were individually assigned based on residence at birth. We adjusted THM models for exposure to the sum of five HAAs (HAA5), and HAA models for the sum of four THMs (THM4). RESULTS: We detected positive exposure-response associations for all grouped MSDs with THM4 quintiles (aOR range: 1.90-3.18) and chloroform quartiles (aOR range: 1.30-2.21), and for reduction of upper or lower limbs with chloroform quartiles (aOR range: 2.39-3.52). We detected elevated aORs for diaphragmatic hernia with DBP9 (sum of THM4 and HAA5), and chloroform and bromodichloromethane tertiles and an exposure-response relationship for THM4 tertiles (aOR range: 1.67-1.80). CONCLUSIONS: This is the first epidemiological study to examine HAAs in relation to MSDs. Given the indirect nature of our exposure assessment data and small case numbers, the exposure-response relationships that we detected for THM4 and chloroform warrant further investigation.

Using high-resolution residential greenspace measures in an urban environment to assess risks of allergy outcomes in children.

Despite reported health benefits of urban greenspace (gs), the epidemiological evidence is less clear for allergic disease. To address a limitation of previous research, we examined the associations of medium- and high-resolution residential gs measures and tree and/or grass canopies with allergic outcomes for children enrolled in the longitudinal cincinnati childhood allergy and air pollution study (ccaaps). We estimated residential gs based on 400 m radial buffers around participant addresses (n = 478) using the normalized differential vegetation index (ndvi) and land cover-derived urban greenspace (ugs) (tree and grass coverage, combined and separate) at 30 m and 1.5-2.5 m resolution, respectively. Associations between outdoor aeroallergen sensitization and allergic rhinitis at age 7 and residential gs measures at different exposure windows were examined using multivariable logistic regression models. A 10% increase in ugs-derived grass coverage was associated with an increased risk of sensitization to grass pollens (adjusted odds ratio [aor]: 1.27; 95% confidence interval = 1.02-1.58). For each 10% increase in ugs-derived tree canopy coverage, nonstatistically significant decreased odds were found for grass pollen sensitization, tree pollen sensitization, and sensitization to either (aor range = 0.87-0.94). Results similar in magnitude to ugs-tree canopy coverage were detected for ndvi and allergic sensitizations. High-resolution (down to 1.5 m) gs measures of grass- and tree-covered areas showed associations in opposite directions for different allergy outcomes. These data suggest that measures strongly correlated with tree canopy (e.g., ndvi) may be insufficient to detect health effects associated with proximity to different types of vegetation or help elucidate mechanisms related to specific gs exposure pathways.

Development of outcome-specific criteria for study evaluation in systematic reviews of epidemiology studies.

INTRODUCTION AND OBJECTIVE: Systematic review tools that provide guidance on evaluating epidemiology studies are receiving increasing attention and support because their application facilitates improved quality of the review, consistency across reviewers, and transparency for readers. The U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) Program has developed an approach for systematic review of evidence of health effects from chemical exposures that includes structured approaches for literature search and screening, study evaluation, data extraction, and evidence synthesis and integration. This approach recognizes the need for developing outcome-specific criteria for study evaluation. Because studies are assessed at the outcome level, a study could be considered high quality for one investigated outcome, and low quality for another, due to differences in the outcome measures, analytic strategies, how relevant a certain bias is to the outcome, and how the exposure measure relates to the outcome. The objective of this paper is to illustrate the need for outcome-specific criteria in study evaluation or risk of bias evaluation, describe the process we used to develop the criteria, and summarize the resulting criteria. METHODS: We used a process of expert consultation to develop several sets of outcome-specific criteria to guide study reviewers, improve consistency, and ensure consideration of critical issues specific to the outcomes. The criteria were developed using the following domains: outcome assessment, exposure measurement (specifically timing of exposure in relation to outcome; other exposure measurement issues would be addressed in exposure-specific criteria), participant selection, confounding, analysis, and sensitivity (the study's ability to detect a true effect or hazard). RESULTS: We discuss the application of this process to pregnancy-related outcomes (preterm birth, spontaneous abortion), other reproductive-related outcomes (male reproductive hormones, sperm parameters, time to pregnancy, pubertal development), chronic disease (diabetes, insulin resistance), and acute or episodic conditions (asthma, allergies), and provide examples of the criteria developed. For each outcome the most influential methodological considerations are highlighted including biological sample collection and quality control, sensitivity and specificity of ascertainment tools, optimal timing for recruitment into the study (e.g., preconception, specific trimesters), the etiologically relevant window for exposure assessments, and important potential confounders. CONCLUSIONS: Outcome-specific criteria are an important part of a systematic review and will facilitate study evaluations by epidemiologists with experience in evaluating studies using systematic review methods who may not have extensive discipline-specific experience in the outcomes being reviewed.

Interpretation of biomonitoring data in clinical medicine and the exposure sciences.

Biomonitoring has become a fundamental tool in both exposure science and clinical medicine. Despite significant analytical advances, the clinical use of environmental biomarkers remains in its infancy. Clinical use of environmental biomarkers poses some complex scientific and ethical challenges. The purpose of this paper is compare how the clinical and exposure sciences differ with respect to their interpretation and use of biological data. Additionally, the clinical use of environmental biomonitoring data is discussed. A case study is used to illustrate the complexities of conducting biomonitoring research on highly vulnerable populations in a clinical setting.