Publications by authors named "Tracey J Woodruff"

137 Publications

Defining the Scope of Exposome Studies and Research Needs from a Multidisciplinary Perspective.

Environ Sci Technol Lett 2021 Oct 7;8(10):839-852. Epub 2021 Sep 7.

Gunma University Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Gunma 371-8511, Japan.

The concept of the exposome was introduced over 15 years ago to reflect the important role that the environment exerts on health and disease. While originally viewed as a call-to-arms to develop more comprehensive exposure assessment methods applicable at the individual level and throughout the life course, the scope of the exposome has now expanded to include the associated biological response. In order to explore these concepts, a workshop was hosted by the Gunma University Initiative for Advanced Research (GIAR, Japan) to discuss the scope of exposomics from an international and multidisciplinary perspective. This Global Perspective is a summary of the discussions with emphasis on (1) top-down, bottom-up, and functional approaches to exposomics, (2) the need for integration and standardization of LC- and GC-based high-resolution mass spectrometry methods for untargeted exposome analyses, (3) the design of an exposomics study, (4) the requirement for open science workflows including mass spectral libraries and public databases, (5) the necessity for large investments in mass spectrometry infrastructure in order to sequence the exposome, and (6) the role of the exposome in precision medicine and nutrition to create personalized environmental exposure profiles. Recommendations are made on key issues to encourage continued advancement and cooperation in exposomics.
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http://dx.doi.org/10.1021/acs.estlett.1c00648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515788PMC
October 2021

Dietary predictors of prenatal per- and poly-fluoroalkyl substances exposure.

J Expo Sci Environ Epidemiol 2021 Oct 6. Epub 2021 Oct 6.

Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.

Background: Per- and poly-fluoroalkyl substances (PFAS) are commonly detected in a variety of foods and food packaging materials. However, few studies have examined diet as a potential source of PFAS exposure during pregnancy. In the present cross-sectional study, we examined prenatal PFAS levels in relation to self-reported consumption of meats, dairy products, and processed foods during pregnancy.

Methods: Participants were enrolled in the Chemicals in Our Bodies study, a demographically diverse pregnancy cohort in San Francisco, CA (N = 509). Diet was assessed using a self-reported interview questionnaire administered during the second trimester. Participants were asked on average how many times a day, week, or month they ate 11 different foods since becoming pregnant. Responses were categorized as at least once a week or less than once a week and foods were grouped into three categories: processed foods, dairy products, and meats. Twelve PFAS (ng/mL) were measured in second trimester serum samples. We investigated relationships between consumption of individual dairy products, meats, and processed foods and natural log-transformed PFAS using separate linear regression models adjusted for maternal age, education, race/ethnicity, and nativity.

Results: Seven PFAS were detected in ≥65% of participants. Consumption of dairy milk and cheese at least once per week was moderately associated with elevated levels of perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDeA) relative to those who ate dairy products less than once week. The strongest associations observed were with PFDeA for dairy milk (β = 0.2, 95% confidence interval [CI] = 0.02, 0.39) and PFNA for cheese (β = 0.22, 95% CI = 0.02, 0.41). Eating fish, poultry, and red meat at least once per week was associated with higher levels of perfluoroundecanoic acid, PFDeA, PFNA, and perflucorooctane sulfonic acid.

Conclusions: Results indicate that consumption of animal products may contribute to elevated prenatal PFAS levels.
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http://dx.doi.org/10.1038/s41370-021-00386-6DOI Listing
October 2021

Large-Scale Implementation and Flaw Investigation of Human Serum Suspect Screening Analysis for Industrial Chemicals.

J Am Soc Mass Spectrom 2021 Sep 19;32(9):2425-2435. Epub 2021 Aug 19.

Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California 94158, United States.

Non-targeted analysis (NTA), including both suspect screening analysis (SSA) and unknown compound analysis, has gained increasing popularity in various fields for its capability in identifying new compounds of interests. Current major challenges for NTA SSA are that (1) tremendous effort and resources are needed for large-scale identification and confirmation of suspect chemicals and (2) suspect chemicals generally show low matching rates during identification and confirmation processes. To narrow the gap between these challenges and smooth implementation of NTA SSA methodology in the biomonitoring field, we present a thorough SSA workflow for the large-scale screen, identification, and confirmation of industrial chemicals that may pose adverse health effects in pregnant women and newborns. The workflow was established in a study of 30 paired maternal and umbilical cord serum samples collected at delivery in the San Francisco Bay area. By analyzing LC-HRMS and MS/MS data, together with the assistance of a combination of resources including online MS/MS spectra libraries, online in silico fragmentation tools, and the EPA CompTox Chemicals Dashboard, we confirmed the identities of 17 chemicals, among which monoethylhexyl phthalate, 4-nitrophenol, tridecanedioic acid, and octadecanedioic acid are especially interesting due to possible toxicities and their high-volume use in industrial manufacturing. Similar to other previous studies in the SSA field, the suspect compounds show relatively low MS/MS identification (16%) and standard confirmation (8%) rates. Therefore, we also investigated origins of false positive features and unidentifiable suspected features, as well as technical obstacles encountered during the confirmation process, which would promote a better understanding of the flaw of low confirmation rate and encourage gaining more effective tools for tackling this issue in NTA SSA.
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http://dx.doi.org/10.1021/jasms.1c00135DOI Listing
September 2021

A Comprehensive Non-targeted Analysis Study of the Prenatal Exposome.

Environ Sci Technol 2021 08 14;55(15):10542-10557. Epub 2021 Jul 14.

Department of Obstetrics, Gynecology and Reproductive Sciences, Program on Reproductive Health and the Environment, University of California San Francisco, San Francisco 94143, California, United States.

Recent technological advances in mass spectrometry have enabled us to screen biological samples for a very broad spectrum of chemical compounds allowing us to more comprehensively characterize the human exposome in critical periods of development. The goal of this study was three-fold: (1) to analyze 590 matched maternal and cord blood samples (total 295 pairs) using non-targeted analysis (NTA); (2) to examine the differences in chemical abundance between maternal and cord blood samples; and (3) to examine the associations between exogenous chemicals and endogenous metabolites. We analyzed all samples with high-resolution mass spectrometry using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) in both positive and negative electrospray ionization modes (ESI+ and ESI-) and in soft ionization (MS) and fragmentation (MS/MS) modes for prioritized features. We confirmed 19 unique compounds with analytical standards, we tentatively identified 73 compounds with MS/MS spectra matching, and we annotated 98 compounds using an annotation algorithm. We observed 103 significant associations in maternal and 128 in cord samples between compounds annotated as endogenous and compounds annotated as exogenous. An example of these relationships was an association between three poly and perfluoroalkyl substances (PFASs) and endogenous fatty acids in both the maternal and cord samples indicating potential interactions between PFASs and fatty acid regulating proteins.
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http://dx.doi.org/10.1021/acs.est.1c01010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338910PMC
August 2021

Mixture effects of prenatal exposure to per- and polyfluoroalkyl substances and polybrominated diphenyl ethers on maternal and newborn telomere length.

Environ Health 2021 06 30;20(1):76. Epub 2021 Jun 30.

Program On Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, USA.

Background: Per- and polyfluoroalkyl substances (PFAS) and polybrominated diphenyl ethers (PBDEs) are endocrine disrupting chemicals with widespread exposures across the U.S. given their abundance in consumer products. PFAS and PBDEs are associated with reproductive toxicity and adverse health outcomes, including certain cancers. PFAS and PBDEs may affect health through alternations in telomere length. In this study, we examined joint associations between prenatal exposure to PFAS, PBDEs, and maternal and newborn telomere length using mixture analyses, to characterize effects of cumulative environmental chemical exposures.

Methods: Study participants were enrolled in the Chemicals in Our Bodies (CIOB) study, a demographically diverse cohort of pregnant people and children in San Francisco, CA. Seven PFAS (ng/mL) and four PBDEs (ng/g lipid) were measured in second trimester maternal serum samples. Telomere length (T/S ratio) was measured in delivery cord blood of 292 newborns and 110 second trimester maternal whole blood samples. Quantile g-computation was used to assess the joint associations between groups of PFAS and PBDEs and newborn and maternal telomere length. Groups considered were: (1) all PFAS and PBDEs combined, (2) PFAS, and (3) PBDEs. Maternal and newborn telomere length were modeled as separate outcomes.

Results: T/S ratios in newborn cord and maternal whole blood were moderately correlated (Spearman ρ = 0.31). In mixtures analyses, a simultaneous one quartile increase in all PFAS and PBDEs was associated with a small increase in newborn (mean change per quartile increase = 0.03, 95% confidence interval [CI] = -0.03, 0.08) and maternal telomere length (mean change per quartile increase = 0.03 (95% CI = -0.03, 0.09). When restricted to maternal-fetal paired samples (N = 76), increasing all PFAS and PBDEs combined was associated with a strong, positive increase in newborn telomere length (mean change per quartile increase = 0.16, 95% CI = 0.03, 0.28). These associations were primarily driven by PFAS (mean change per quartile increase = 0.11 [95% CI = 0.01, 0.22]). No associations were observed with maternal telomere length among paired samples.

Conclusions: Our findings suggest that PFAS and PBDEs may be positively associated with newborn telomere length.
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http://dx.doi.org/10.1186/s12940-021-00765-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247076PMC
June 2021

Improving the quality of toxicology and environmental health systematic reviews: What journal editors can do.

ALTEX 2021 22;38(3):513-522. Epub 2021 Jun 22.

Program on Reproductive Health and the Environment, University of California San Francisco, San Francisco, CA, USA.

Systematic reviews are fast increasing in prevalence in the toxicology and environmental health literature. However, how well these complex research projects are being conducted and reported is unclear. Since editors have an essential role in ensuring the scientific quality of manuscripts being published in their journals, a workshop was convened where editors, systematic review practitioners, and research quality control experts could discuss what editors can do to ensure the systematic reviews they publish are of sufficient scientific quality. Interventions were explored along four themes: setting standards; reviewing protocols; optimizing editorial workflows; and measuring the effectiveness of editorial interventions. In total, 58 editorial interventions were proposed. Of these, 26 were shortlisted for being potentially effective, and 5 were prioritized as short-term actions that editors could relatively easily take to improve the quality of published systematic reviews. Recent progress in improving systematic reviews is summarized, and outstanding challenges to further progress are highlighted.
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http://dx.doi.org/10.14573/altex.2106111DOI Listing
June 2021

Global, regional, and national burdens of ischemic heart disease and stroke attributable to exposure to long working hours for 194 countries, 2000-2016: A systematic analysis from the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury.

Environ Int 2021 09 17;154:106595. Epub 2021 May 17.

Program on Reproductive Health and the Environment, University of California San Francisco, San Francisco, CA, USA.

Background: World Health Organization (WHO) and International Labour Organization (ILO) systematic reviews reported sufficient evidence for higher risks of ischemic heart disease and stroke amongst people working long hours (≥55 hours/week), compared with people working standard hours (35-40 hours/week). This article presents WHO/ILO Joint Estimates of global, regional, and national exposure to long working hours, for 194 countries, and the attributable burdens of ischemic heart disease and stroke, for 183 countries, by sex and age, for 2000, 2010, and 2016.

Methods And Findings: We calculated population-attributable fractions from estimates of the population exposed to long working hours and relative risks of exposure on the diseases from the systematic reviews. The exposed population was modelled using data from 2324 cross-sectional surveys and 1742 quarterly survey datasets. Attributable disease burdens were estimated by applying the population-attributable fractions to WHO's Global Health Estimates of total disease burdens.

Results: In 2016, 488 million people (95% uncertainty range: 472-503 million), or 8.9% (8.6-9.1) of the global population, were exposed to working long hours (≥55 hours/week). An estimated 745,194 deaths (705,786-784,601) and 23.3 million disability-adjusted life years (22.2-24.4) from ischemic heart disease and stroke combined were attributable to this exposure. The population-attributable fractions for deaths were 3.7% (3.4-4.0) for ischemic heart disease and 6.9% for stroke (6.4-7.5); for disability-adjusted life years they were 5.3% (4.9-5.6) for ischemic heart disease and 9.3% (8.7-9.9) for stroke.

Conclusions: WHO and ILO estimate exposure to long working hours (≥55 hours/week) is common and causes large attributable burdens of ischemic heart disease and stroke. Protecting and promoting occupational and workers' safety and health requires interventions to reduce hazardous long working hours.
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http://dx.doi.org/10.1016/j.envint.2021.106595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204267PMC
September 2021

Drinking water contaminants in California and hypertensive disorders in pregnancy.

Environ Epidemiol 2021 Apr 2;5(2):e149. Epub 2021 Apr 2.

Department of Environmental Science, Policy and Management & School of Public Health, University of California, Berkeley, Berkeley, California.

Environmental pollutants have been associated with hypertensive disorders in pregnancy including gestational hypertension, preeclampsia, and eclampsia, though few have focused on drinking water contamination. Water pollution can be an important source of exposures that may contribute to adverse pregnancy outcomes.

Methods: We linked water quality data on 13 contaminants and two violations from the California Communities Environmental Health Screening Tool to birth records from vital statistics and hospital discharge records (2007-2012) to examine the relationship between drinking water contamination and hypertensive disorders in pregnancy. We examined contaminants in single- and multipollutant models. Additionally, we examined if the relationship between water contamination and hypertensive disorders in pregnancy differed by neighborhood poverty, individual socioeconomic status, and race/ethnicity.

Results: Arsenic, nitrate, trihalomethane, hexavalent chromium, and uranium were detected in a majority of water systems. Increased risk of hypertensive disorders in pregnancy was modestly associated with exposure to cadmium, lead, trihalomethane, and hexavalent chromium in drinking water after adjusting for covariates in single pollutant models with odds ratios ranging from 1.01 to 1.08. In multipollutant models, cadmium was consistent, lead and trihalomethane were stronger, and additional contaminants were associated with hypertensive disorders in pregnancy including trichloroethylene, 1,2-Dibromo-3-chloropropane, nitrate, and tetrachloroethylene. Other contaminants either showed null results or modest inverse associations. The relationship between water contaminants and hypertensive disorders in pregnancy did not differ by neighborhood poverty.

Conclusions: We found increased risk of hypertensive disorders in pregnancy associated with exposure to several contaminants in drinking water in California. Results for cadmium, lead, trihalomethane, and hexavalent chromium were robust in multipollutant models.
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http://dx.doi.org/10.1097/EE9.0000000000000149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043732PMC
April 2021

Response to "Comment on 'Identifying and Prioritizing Chemicals with Uncertain Burden of Exposure: Opportunities for Biomonitoring and Health-Related Research' and 'Beyond the Light under the Lamppost: New Chemical Candidates for Biomonitoring in Young Children'".

Environ Health Perspect 2021 04 7;129(4):48002. Epub 2021 Apr 7.

Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California, USA.

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http://dx.doi.org/10.1289/EHP9192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041267PMC
April 2021

Joint effects of prenatal exposure to per- and poly-fluoroalkyl substances and psychosocial stressors on corticotropin-releasing hormone during pregnancy.

J Expo Sci Environ Epidemiol 2021 Apr 6. Epub 2021 Apr 6.

Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.

Background: Prenatal exposure to per- and poly-fluoroalkyl substances (PFAS) and psychosocial stressors has been associated with adverse pregnancy outcomes, including preterm birth. Previous studies have suggested that joint exposure to environmental chemical and social stressors may be contributing to disparities observed in preterm birth. Elevated corticotropin-releasing hormone (CRH) during mid-gestation may represent one biologic mechanism linking chemical and nonchemical stress exposures to preterm birth.

Methods: Using data from a prospective birth cohort (N = 497), we examined the cross-sectional associations between five individual PFAS (ng/mL; PFNA, PFOA, PFOS, PFHxS, and Me-PFOSA-AcOH) and CRH (pg/mL) using linear regression. PFAS and CRH were measured during the second trimester in serum and plasma, respectively. Coefficients were standardized to reflect change in CRH associated with an interquartile range (IQR) increase in natural log-transformed PFAS. We additionally examined if the relationship between PFAS and CRH was modified by psychosocial stress using stratified models. Self-reported depression, stressful life events, perceived stress, food insecurity, and financial strain were assessed using validated questionnaires during the second trimester and included as binary indicators of psychosocial stress.

Results: An IQR increase in PFNA was associated with elevated CRH (β = 5.17, 95% confidence interval [CI] = 1.79, 8.55). Increased concentrations of PFOA were also moderately associated with CRH (β = 3.62, 95% CI = -0.42, 7.66). The relationship between PFNA and CRH was stronger among women who experienced stressful life events, depression, food insecurity, and financial strain compared to women who did not experience these stressors.

Conclusions: This cross-sectional study is the first to examine the relationship between PFAS exposure and CRH levels in mid-gestation. We found that these associations were stronger among women who experienced stress, which aligns with previous findings that chemical and nonchemical stressor exposures can have joint effects on health outcomes.
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http://dx.doi.org/10.1038/s41370-021-00322-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492777PMC
April 2021

Reviews in environmental health: How systematic are they?

Environ Int 2021 07 30;152:106473. Epub 2021 Mar 30.

UCSF Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology & Reproductive Sciences, Box 0132, 490 Illinois Street, Floor 10, San Francisco, CA 94143, United States. Electronic address:

Background: Synthesizing environmental health science is crucial to taking action to protect public health. Procedures for evidence evaluation and integration are transitioning from "expert-based narrative" to "systematic" review methods. However, little is known about the methodology being utilized for either type of review.

Objectives: To appraise the methodological strengths and weaknesses of a sample of "expert-based narrative" and "systematic" reviews in environmental health.

Methods: We conducted a comprehensive search of multiple databases and identified relevant reviews using pre-specified eligibility criteria. We applied a modified version of the Literature Review Appraisal Toolkit (LRAT) to three environmental health topics that assessed the utility, validity and transparency of reviews.

Results: We identified 29 reviews published between 2003 and 2019, of which 13 (45%) were self-identified as systematic reviews. Across every LRAT domain, systematic reviews received a higher percentage of "satisfactory" ratings compared to non-systematic reviews. In eight of these domains, there was a statistically significant difference observed between the two types of reviews and "satisfactory" ratings. Non-systematic reviews performed poorly with the majority receiving an "unsatisfactory" or "unclear" rating in 11 of the 12 domains. Systematic reviews performed poorly in six of the 12 domains; 10 (77%) did not state the reviews objectives or develop a protocol; eight (62%) did not state the roles and contribution of the authors, or evaluate the internal validity of the included evidence consistently using a valid method; and only seven (54%) stated a pre-defined definition of the evidence bar on which their conclusions were based, or had an author disclosure of interest statement.

Discussion: Systematic reviews produced more useful, valid, and transparent conclusions compared to non-systematic reviews, but poorly conducted systematic reviews were prevalent. Ongoing development and implementation of empirically based systematic review methods are required in environmental health to ensure transparent and timely decision making to protect the public's health.
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http://dx.doi.org/10.1016/j.envint.2021.106473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118386PMC
July 2021

Exposure to formaldehyde and asthma outcomes: A systematic review, meta-analysis, and economic assessment.

PLoS One 2021 31;16(3):e0248258. Epub 2021 Mar 31.

University of California San Francisco, Program on Reproductive Health and the Environment, San Francisco, California, United States of America.

Background: Every major federal regulation in the United States requires an economic analysis estimating its benefits and costs. Benefit-cost analyses related to regulations on formaldehyde exposure have not included asthma in part due to lack of clarity in the strength of the evidence.

Objectives: 1) To conduct a systematic review of evidence regarding human exposure to formaldehyde and diagnosis, signs, symptoms, exacerbations, or other measures of asthma in humans; and 2) quantify the annual economic benefit for decreases in formaldehyde exposure.

Methods: We developed and registered a protocol in PROSPERO (Record ID #38766, CRD 42016038766). We conducted a comprehensive search of articles published up to April 1, 2020. We evaluated potential risk of bias for included studies, identified a subset of studies to combine in a meta-analysis, and rated the overall quality and strength of the evidence. We quantified economics benefit to children from a decrease in formaldehyde exposure using assumptions consistent with EPA's proposed formaldehyde rule.

Results: We screened 4,821 total references and identified 150 human studies that met inclusion criteria; of these, we focused on 90 studies reporting asthma status of all participants with quantified measures of formaldehyde directly relevant to our study question. Ten studies were combinable in a meta-analysis for childhood asthma diagnosis and five combinable for exacerbation of childhood asthma (wheezing and shortness of breath). Studies had low to probably-low risk of bias across most domains. A 10-μg/m3 increase in formaldehyde exposure was associated with increased childhood asthma diagnosis (OR = 1.20, 95% CI: [1.02, 1.41]). We also found a positive association with exacerbation of childhood asthma (OR = 1.08, 95% CI: [0.92, 1.28]). The overall quality and strength of the evidence was rated as "moderate" quality and "sufficient" for asthma diagnosis and asthma symptom exacerbation in both children and adults. We estimated that EPA's proposed rule on pressed wood products would result in 2,805 fewer asthma cases and total economic benefit of $210 million annually.

Conclusion: We concluded there was "sufficient evidence of toxicity" for associations between exposure to formaldehyde and asthma diagnosis and asthma symptoms in both children and adults. Our research documented that when exposures are ubiquitous, excluding health outcomes from benefit-cost analysis can underestimate the true benefits to health from environmental regulations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248258PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011796PMC
October 2021

Suspect Screening, Prioritization, and Confirmation of Environmental Chemicals in Maternal-Newborn Pairs from San Francisco.

Environ Sci Technol 2021 04 16;55(8):5037-5049. Epub 2021 Mar 16.

Department of Obstetrics, Gynecology and Reproductive Sciences, Program on Reproductive Health and the Environment, University of California, San Francisco, San Francisco, California 94143, United States.

Our proof-of-concept study develops a suspect screening workflow to identify and prioritize potentially ubiquitous chemical exposures in matched maternal/cord blood samples, a critical period of development for future health risks. We applied liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-QTOF/MS) to perform suspect screening for ∼3500 industrial chemicals on pilot data from 30 paired maternal and cord serum samples ( = 60). We matched 662 suspect features in positive ionization mode and 788 in negative ionization mode (557 unique formulas overall) to compounds in our database, and selected 208 of these for fragmentation analysis based on detection frequency, correlation in feature intensity between maternal and cord samples, and peak area differences by demographic characteristics. We tentatively identified 73 suspects through fragmentation spectra matching and confirmed 17 chemical features (15 unique compounds) using analytical standards. We tentatively identified 55 compounds not previously reported in the literature, the majority which have limited to no information about their sources or uses. Examples include (i) 1-(1-acetyl-2,2,6,6-tetramethylpiperidin-4-yl)-3-dodecylpyrrolidine-2,5-dione (known high production volume chemical) (ii) methyl perfluoroundecanoate and 2-perfluorooctyl ethanoic acid (two PFAS compounds); and (iii) Sumilizer GA 80 (plasticizer). Thus, our workflow demonstrates an approach to evaluating the chemical exposome to identify and prioritize chemical exposures during a critical period of development.
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http://dx.doi.org/10.1021/acs.est.0c05984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114949PMC
April 2021

Organophosphate Flame Retardants, Highly Fluorinated Chemicals, and Biomarkers of Placental Development and Disease During Mid-Gestation.

Toxicol Sci 2021 05;181(2):215-228

Program on Reproductive Health and the Environment, University of California, San Francisco (UCSF), San Francisco, California 94158.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) and organophosphate flame retardants (OPFRs) are chemicals that may contribute to placenta-mediated complications and adverse maternal-fetal health risks. Few studies have investigated these chemicals in relation to biomarkers of effect during pregnancy. We measured 12 PFASs and four urinary OPFR metabolites in 132 healthy pregnant women during mid-gestation and examined a subset with biomarkers of placental development and disease (n = 62). Molecular biomarkers included integrin alpha-1 (ITGA1), vascular endothelial-cadherin (CDH5), and matrix metalloproteinase-1 (MMP1). Morphological endpoints included potential indicators of placental stress and the extent of cytotrophoblast (CTB)-mediated uterine artery remodeling. Serum PFASs and urinary OPFR metabolites were detected in ∼50%-100% of samples. The most prevalent PFASs were perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonic acid (PFOS), with geometric mean (GM) levels of ∼1.3-2.8 (95% confidence limits from 1.2-3.1) ng/ml compared to ≤0.5 ng/ml for other PFASs. Diphenyl phosphate (DPhP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were the most prevalent OPFR metabolites, with GMs of 2.9 (95% CI: 2.5-3.4) and 3.6 (95% CI: 2.2-3.1) ng/ml, respectively, compared to <1 ng/ml for bis(2-chloroethyl) phosphate (BCEP) and bis(1-chloro-2-propyl) phosphate (BCIPP). We found inverse associations of PFASs or OPFRs with ITGA1 or CDH5 immunoreactivity and positive associations with indicators of placental stress in multiple basal plate regions, indicating these chemicals may contribute to abnormal placentation and future health risks. Associations with blood pressure and lipid concentrations warrant further examination. This is the first study of these chemicals with placental biomarkers measured directly in human tissues and suggests specific biomarkers are sensitive indicators of exposure during a vulnerable developmental period.
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http://dx.doi.org/10.1093/toxsci/kfab028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163039PMC
May 2021

Associations of Maternal Stress, Prenatal Exposure to Per- and Polyfluoroalkyl Substances (PFAS), and Demographic Risk Factors with Birth Outcomes and Offspring Neurodevelopment: An Overview of the ECHO.CA.IL Prospective Birth Cohorts.

Int J Environ Res Public Health 2021 01 16;18(2). Epub 2021 Jan 16.

Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA.

Background: Infants whose mothers experience greater psychosocial stress and environmental chemical exposures during pregnancy may face greater rates of preterm birth, lower birth weight, and impaired neurodevelopment.

Methods: ECHO.CA.IL is composed of two cohorts, Chemicals in Our Bodies (CIOB; = 822 pregnant women and = 286 infants) and Illinois Kids Development Study (IKIDS; = 565 mother-infant pairs), which recruit pregnant women from San Francisco, CA and Urbana-Champaign, IL, respectively. We examined associations between demographic characteristics and gestational age, birth weight z-scores, and cognition at 7.5 months across these two cohorts using linear models. We also examined differences in biomarkers of exposure to per- and polyfluoroalkyl substances (PFAS), measured in second-trimester serum, and psychosocial stressors by cohort and participant demographics.

Results: To date, these cohorts have recruited over 1300 pregnant women combined. IKIDS has mothers who are majority white (80%), whereas CIOB mothers are racially and ethnically diverse (38% white, 34% Hispanic, 17% Asian/Pacific Islander). Compared to CIOB, median levels of PFOS, a specific PFAS congener, are higher in IKIDS (2.45 ng/mL versus 1.94 ng/mL), while psychosocial stressors are higher among CIOB. Across both cohorts, women who were non-white and single had lower birth weight z-scores relative to white women and married women, respectively. Demographic characteristics are not associated with cognitive outcomes at 7.5 months.

Conclusions: This profile of the ECHO.CA.IL cohort found that mothers and their infants who vary in terms of socioeconomic status, race/ethnicity, and geographic location are similar in many of our measures of exposures and cognitive outcomes. Similar to past work, we found that non-white and single women had lower birth weight infants than white and married women. We also found differences in levels of PFOS and psychosocial stressors based on geographic location.
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http://dx.doi.org/10.3390/ijerph18020742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830765PMC
January 2021

The association of maternal psychosocial stress with newborn telomere length.

PLoS One 2020 10;15(12):e0242064. Epub 2020 Dec 10.

Department of Environmental Science, Policy and Management and School of Public Health, University of California, Berkeley, CA, United States of America.

Background: Telomere length in early life predicts later length, and shortened telomere length among adults and children has been linked to increased risk of chronic disease and mortality. Maternal stress during pregnancy may impact telomere length of the newborn.

Methods: In a diverse cohort of 355 pregnant women receiving prenatal and delivery care services at two hospitals in San Francisco, California, we investigated the relationship between self-reported maternal psychosocial stressors during the 2nd trimester of pregnancy and telomere length (T/S ratio) in newborn umbilical cord blood leukocytes. We examined financial strain, food insecurity, high job strain, poor neighborhood quality, low standing in one's community, experience of stressful/traumatic life events, caregiving for a dependent family member, perceived stress, and unplanned pregnancy. We used linear regression and Targeted Minimum Loss-Based Estimation (TMLE) to evaluate the change in the T/S ratio associated with exposure to each stressor controlling for maternal age, education, parity, race/ethnicity, and delivery hospital.

Results: In TMLE analyses, low community standing (-0.09; 95% confidence interval [CI]-0.19 to 0.00) and perceived stress (-0.07; 95% CI -0.15 to 0.021 was marginally associated with shorter newborn telomere length, but the associations were not significant after adjusting for multiple comparisons. All linear regression estimates were not statistically significant. Our results also suggest that the association between some maternal stressors and newborn telomere length varies by race/ethnicity and infant sex.

Conclusions: This study is the first to examine the joint effect of multiple stressors during pregnancy on newborn TL using a flexible modeling approach.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242064PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728273PMC
January 2021

Assessing risk of bias in human environmental epidemiology studies using three tools: different conclusions from different tools.

Syst Rev 2020 10 29;9(1):249. Epub 2020 Oct 29.

Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, USA.

Background: Systematic reviews are increasingly prevalent in environmental health due to their ability to synthesize evidence while reducing bias. Different systematic review methods have been developed by the US National Toxicology Program's Office of Health Assessment and Translation (OHAT), the US Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS), and by the US EPA under the Toxic Substances Control Act (TSCA), including the approach to assess risk of bias (ROB), one of the most vital steps which is used to evaluate internal validity of the studies. Our objective was to compare the performance of three tools (OHAT, IRIS, TSCA) in assessing ROB.

Methods: We selected a systematic review on polybrominated diphenyl ethers and intelligence quotient and/or attention deficit hyperactivity disorder because it had been endorsed by the National Academy of Sciences. Two reviewers followed verbatim instructions from the tools and independently applied each tool to assess ROB in 15 studies previously identified. We documented the time to apply each tool and the impact the ROB ratings for each tool had on the final rating of the quality of the overall body of evidence.

Results: The time to complete the ROB assessments varied widely (mean = 20, 32, and 40 min per study for the OHAT, IRIS, and TSCA tools, respectively). All studies were rated overall "low" or "uninformative" using IRIS, due to "deficient" or "critically deficient" ratings in one or two domains. Similarly, all studies were rated "unacceptable" using the TSCA tool because of one "unacceptable" rating in a metric related to statistical power. Approximately half of the studies had "low" or "probably low ROB" ratings across all domains with the OHAT and Navigation Guide tools.

Conclusions: Tools that use overall ROB or study quality ratings, such as IRIS and TSCA, may reduce the available evidence to assess the harms of environmental exposures by erroneously excluding studies, which leads to inaccurate conclusions about the quality of the body of evidence. We recommend using ROB tools that circumvents these issues, such as OHAT and Navigation Guide.

Systematic Review Registration: This review has not been registered as it is not a systematic review.
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http://dx.doi.org/10.1186/s13643-020-01490-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596989PMC
October 2020

Maternal Experience of Multiple Hardships and Fetal Growth: Extending Environmental Mixtures Methodology to Social Exposures.

Epidemiology 2021 01;32(1):18-26

Department of Environmental Science, Policy, and Management & School of Public Health, University of California, Berkeley, CA.

Background: Women can be exposed to a multitude of hardships before and during pregnancy that may affect fetal growth, but previous approaches have not analyzed them jointly as social exposure mixtures.

Methods: We evaluated the independent, mutually adjusted, and pairwise joint associations between self-reported hardships and birthweight for gestational age z-scores in the Chemicals in Our Bodies-2 prospective birth cohort (N = 510) using G-computation. We examined financial hardship, food insecurity, job strain, poor neighborhood environment, low community standing, caregiving, high burden of stressful life events, and unplanned pregnancy collected via questionnaire administered in the second trimester of pregnancy. We used propensity scores to ensure our analyses had sufficient data support and estimated absolute differences in outcomes.

Results: Food insecurity was most strongly associated with reduced birthweight for gestational age z-scores individually, with an absolute difference of -0.16, 95% confidence interval (CI) -0.45, 0.14. We observed an unexpected increase in z-scores associated with poor perceived neighborhood environment (0.18, 95% CI -0.04, 0.41). Accounting for coexposures resulted in similar findings. The pairwise joint effects were strongest for food insecurity in combination with unplanned pregnancy (-0.45, 95% CI -0.93, 0.02) and stressful life events (-0.42, 95% CI -0.90, 0.05). Poor neighborhood environment in combination with caregiving was associated with an increase in z-scores (0.47, 95% CI -0.01, 0.95).

Conclusions: Our results are consistent with the hypothesis that experiencing food insecurity during pregnancy, alone and in combination with stressful life events and unplanned pregnancy, may affect fetal growth.
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http://dx.doi.org/10.1097/EDE.0000000000001272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708528PMC
January 2021

Associations between prenatal maternal exposure to per- and polyfluoroalkyl substances (PFAS) and polybrominated diphenyl ethers (PBDEs) and birth outcomes among pregnant women in San Francisco.

Environ Health 2020 09 16;19(1):100. Epub 2020 Sep 16.

Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA, USA.

Background: Perfluoroalkyl substances (PFAS) and polybrominated diphenyl ethers (PBDEs) are used in consumer products for their water repellent and flame retardant properties, respectively. However, there is widespread prenatal exposure and concern about their potential harm to the developing fetus. Here, we utilized data from a demographically diverse cohort of women in San Francisco, CA to examine associations between prenatal exposure to PFAS and PBDEs with gestational age and birth weight for gestational age z-scores.

Methods: Women included in this analysis were enrolled in the Chemicals in our Bodies (CIOB) cohort study (N = 506). PFAS and PBDEs were measured in serum obtained during the second trimester of pregnancy. Linear regression models were used to calculate crude and adjusted β coefficients for the association between PFAS and PBDE concentrations in tertiles and gestational age and birth weight z-scores. Individual PFAS and PBDE concentrations, as well as their sums, were examined in separate models.

Results: The highest compared to lowest tertile of BDE-47 was associated with shorter gestational age (β = - 0.49, 95% confidence interval [CI] = - 0.95, - 0.02). Additionally, exposure to BDE-47 and BDE-99 in the middle tertile was also associated with a reduction in birth weight z-scores (β = - 0.26, 95% CI = -0.48, - 0.04; β = - 0.25, 95% CI = -0.47, - 0.04, respectively) compared to those in the lowest tertile of exposure. No consistent associations were observed between increasing PFAS concentrations and gestational age or birth weight z-scores.

Discussion: Among a diverse group of pregnant women in the San Francisco Bay Area, we found non-linear associations between prenatal exposure to PBDEs during the second trimester of pregnancy and birth weight z-scores. However, most PFAS congeners were not associated with adverse birth outcomes. PFAS and PBDE concentrations were lower in our cohort relative to other studies. Future research should assess the effects of emerging and persistent PFAS and PBDEs on birth outcomes, as some congeners are being phased out and replaced by chemically similar structures.
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http://dx.doi.org/10.1186/s12940-020-00654-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495899PMC
September 2020

Differences in cytochrome p450 enzyme expression and activity in fetal and adult tissues.

Placenta 2020 10 6;100:35-44. Epub 2020 Aug 6.

Program on Reproductive Health and the Environment, University of California, San Francisco (UCSF), San Francisco, CA, USA.

Introduction: Human cytochrome p450 (CYP) enzyme expression and activity is lower in the fetus as compared to the adult; however, limited quantitative data exists regarding the specific differences in magnitude or the degree of inducibility due to environmental factors.

Methods: We utilized a combination of in silico- and molecular-based approaches to profile and compare CYP expression/activity in human adult liver and fetal tissues. Using public datasets, we evaluated human CYP expression between: 1) placenta vs. adult livers; 2) fetal vs. adult livers; or 3) five compartments of the human placenta. We generated new experimental data, characterizing expression levels of nine CYPs in placenta/fetal liver vs. adult liver. In a subset of samples, we evaluated CYP3A4 activity. Finally, we summarized evidence of human fetal CYP expression/activity and environmental exposures during pregnancy.

Results: In silico, CYPs were predominately expressed at higher levels in the adult liver vs. fetal tissues, with a few noted exceptions. Sixty percent of CYP enzymes were expressed at nominal levels in the placenta. In wet-lab analyses, we observed significant CYP-specific differences in expression/activity between adult and fetal tissues; CYP2E1 and -3A4 were expressed significantly lower in fetal vs. adult livers, while CYP2J2 levels were similar.

Discussion: We provide a qualitative review of the expression of the CYP enzyme family in critical sites of xenobiotic distribution during human pregnancy and novel quantitative data regarding fetal CYP expression and activity during mid-gestation. Data outputs may be a resource for modeling predictions of chemical distribution and sensitivity.
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http://dx.doi.org/10.1016/j.placenta.2020.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021394PMC
October 2020

Racial/ethnic and geographic differences in polybrominated diphenyl ether (PBDE) levels across maternal, placental, and fetal tissues during mid-gestation.

Sci Rep 2020 07 22;10(1):12247. Epub 2020 Jul 22.

Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, Mailstop 0132, 550 16th Street, 7th Floor, San Francisco, CA, 94143, USA.

Prenatal polybrominated diphenyl ether (PBDE) exposures are a public health concern due to their persistence and potential for reproductive and developmental harm. However, we have little information about the extent of fetal exposures during critical developmental periods and the variation in exposures for groups that may be more highly exposed, such as communities of color and lower socioeconomic status (SES). To characterize maternal-fetal PBDE exposures among potentially vulnerable groups, PBDE levels were examined in the largest sample of matched maternal serum, placenta, and fetal liver tissues during mid-gestation among a geographically, racially/ethnically, and socially diverse population of pregnant women from Northern California and the Central Valley (n = 180; 2014-16). Maternal-fetal PBDE levels were compared to population characteristics using censored Kendall's tau correlation and linear regression. PBDEs were commonly detected in all biomatrices. Before lipid adjustment, wet-weight levels of all four PBDE congeners were highest in the fetal liver (p < 0.001), whereas median PBDE levels were significantly higher in maternal serum than in the fetal liver or placenta after lipid-adjustment (p < 0.001). We also found evidence of racial/ethnic disparities in PBDE exposures (Non-Hispanic Black > Latina/Hispanic > Non-Hispanic White > Asian/Pacific Islander/Other; p < 0.01), with higher levels of BDE-100 and BDE-153 among non-Hispanic Black women compared to the referent group (Latina/Hispanic women). In addition, participants living in Fresno/South Central Valley had 34% (95% CI: - 2.4 to 84%, p = 0.07) higher wet-weight levels of BDE-47 than residents living in the San Francisco Bay Area. PBDEs are widely detected and differentially distributed in maternal-fetal compartments. Non-Hispanic Black pregnant women and women from Southern Central Valley geographical populations may be more highly exposed to PBDEs. Further research is needed to identify sources that may be contributing to differential exposures and associated health risks among these vulnerable populations.
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http://dx.doi.org/10.1038/s41598-020-69067-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376153PMC
July 2020

Relationships between psychosocial stressors among pregnant women in San Francisco: A path analysis.

PLoS One 2020 12;15(6):e0234579. Epub 2020 Jun 12.

Department of Obstetrics, Gynecology and Reproductive Sciences, Program on Reproductive Health and the Environment, University of California, San Francisco, San Francisco, California, United States of America.

Pregnant women who experience psychosocial stressors, such as stressful life events, poor neighborhood quality, and financial hardship, are at an increased risk for adverse pregnancy outcomes. Yet, few studies have examined associations between multiple stressors from different sources, which may be helpful to better inform causal pathways leading to adverse birth outcomes. Using path analysis, we examined associations between multiple self-reported stressor exposures during and before pregnancy in the Chemicals in Our Bodies-2 study (N = 510), a demographically diverse cohort of pregnant women in San Francisco. We examined associations between eight self-reported exposures to stressors and three responses to stress which were assessed via interview questionnaire at the 2nd trimester. Stressors included: neighborhood quality, stressful life events, caregiving, discrimination, financial strain, job strain, food insecurity, and unplanned pregnancy. Perceived stress, depression, and perceived community status were included as indicators of self-reported stress response. Our model indicated that women who experienced discrimination and food insecurity had a 3.76 (95% confidence interval [CI] = 1.60, 5.85) and 2.67 (95% CI = 1.31, 4.04) increase in depression scale scores compared to women who did not experience discrimination and food insecurity, respectively. We additionally identified job strain and caregiving for an ill family member as strong predictors of increased depressive symptoms (β = 1.63, 95% CI = 0.29, 3.07; β = 1.48, 95% CI = 0.19, 2.70, respectively). Discrimination, food insecurity, and job strain also influenced depression indirectly through the mediating pathway of increasing perceived stress, although indirect effects were less precise. In our study population, women who experienced discrimination, food insecurity, job strain and caregiving for an ill family member had an increased number of depressive symptoms compared to women who did not experience these stressors. Results from our study highlight the complex relationships between stressors and stress responses and may help to identify possible mediating pathways leading to adverse pregnancy outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234579PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292353PMC
August 2020

The effect of exposure to long working hours on ischaemic heart disease: A systematic review and meta-analysis from the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury.

Environ Int 2020 09 5;142:105739. Epub 2020 Jun 5.

Life Science Centre, University of Düsseldorf, Merowingerplatz 1a, Düsseldorf 40225, Germany. Electronic address:

Background: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing Joint Estimates of the work-related burden of disease and injury (WHO/ILO Joint Estimates), with contributions from a large network of experts. Evidence from mechanistic data suggests that exposure to long working hours may cause ischaemic heart disease (IHD). In this paper, we present a systematic review and meta-analysis of parameters for estimating the number of deaths and disability-adjusted life years from IHD that are attributable to exposure to long working hours, for the development of the WHO/ILO Joint Estimates.

Objectives: We aimed to systematically review and meta-analyse estimates of the effect of exposure to long working hours (three categories: 41-48, 49-54 and ≥55 h/week), compared with exposure to standard working hours (35-40 h/week), on IHD (three outcomes: prevalence, incidence and mortality).

Data Sources: We developed and published a protocol, applying the Navigation Guide as an organizing systematic review framework where feasible. We searched electronic databases for potentially relevant records from published and unpublished studies, including MEDLINE, Scopus, Web of Science, CISDOC, PsycINFO, and WHO ICTRP. We also searched grey literature databases, Internet search engines and organizational websites; hand-searched reference lists of previous systematic reviews; and consulted additional experts.

Study Eligibility And Criteria: We included working-age (≥15 years) workers in the formal and informal economy in any WHO and/or ILO Member State but excluded children (aged < 15 years) and unpaid domestic workers. We included randomized controlled trials, cohort studies, case-control studies and other non-randomized intervention studies which contained an estimate of the effect of exposure to long working hours (41-48, 49-54 and ≥55 h/week), compared with exposure to standard working hours (35-40 h/week), on IHD (prevalence, incidence or mortality).

Study Appraisal And Synthesis Methods: At least two review authors independently screened titles and abstracts against the eligibility criteria at a first stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. Missing data were requested from principal study authors. We combined relative risks using random-effect meta-analysis. Two or more review authors assessed the risk of bias, quality of evidence and strength of evidence, using Navigation Guide and GRADE tools and approaches adapted to this project.

Results: Thirty-seven studies (26 prospective cohort studies and 11 case-control studies) met the inclusion criteria, comprising a total of 768,751 participants (310,954 females) in 13 countries in three WHO regions (Americas, Europe and Western Pacific). The exposure was measured using self-reports in all studies, and the outcome was assessed with administrative health records (30 studies) or self-reported physician diagnosis (7 studies). The outcome was defined as incident non-fatal IHD event in 19 studies (8 cohort studies, 11 case-control studies), incident fatal IHD event in two studies (both cohort studies), and incident non-fatal or fatal ("mixed") event in 16 studies (all cohort studies). Because we judged cohort studies to have a relatively lower risk of bias, we prioritized evidence from these studies and treated evidence from case-control studies as supporting evidence. For the bodies of evidence for both outcomes with any eligible studies (i.e. IHD incidence and mortality), we did not have serious concerns for risk of bias (at least for the cohort studies). No eligible study was found on the effect of long working hours on IHD prevalence. Compared with working 35-40 h/week, we are uncertain about the effect on acquiring (or incidence of) IHD of working 41-48 h/week (relative risk (RR) 0.98, 95% confidence interval (CI) 0.91 to 1.07, 20 studies, 312,209 participants, I 0%, low quality of evidence) and 49-54 h/week (RR 1.05, 95% CI 0.94 to 1.17, 18 studies, 308,405 participants, I 0%, low quality of evidence). Compared with working 35-40 h/week, working ≥55 h/week may have led to a moderately, clinically meaningful increase in the risk of acquiring IHD, when followed up between one year and 20 years (RR 1.13, 95% CI 1.02 to 1.26, 22 studies, 339,680 participants, I 5%, moderate quality of evidence). Compared with working 35-40 h/week, we are very uncertain about the effect on dying (mortality) from IHD of working 41-48 h/week (RR 0.99, 95% CI 0.88 to 1.12, 13 studies, 288,278 participants, I 8%, low quality of evidence) and 49-54 h/week (RR 1.01, 95% CI 0.82 to 1.25, 11 studies, 284,474 participants, I 13%, low quality of evidence). Compared with working 35-40 h/week, working ≥55 h/week may have led to a moderate, clinically meaningful increase in the risk of dying from IHD when followed up between eight and 30 years (RR 1.17, 95% CI 1.05 to 1.31, 16 studies, 726,803 participants, I 0%, moderate quality of evidence). Subgroup analyses found no evidence for differences by WHO region and sex, but RRs were higher among persons with lower SES. Sensitivity analyses found no differences by outcome definition (exclusively non-fatal or fatal versus "mixed"), outcome measurement (health records versus self-reports) and risk of bias ("high"/"probably high" ratings in any domain versus "low"/"probably low" in all domains).

Conclusions: We judged the existing bodies of evidence for human evidence as "inadequate evidence for harmfulness" for the exposure categories 41-48 and 49-54 h/week for IHD prevalence, incidence and mortality, and for the exposure category ≥55 h/week for IHD prevalence. Evidence on exposure to working ≥55 h/week was judged as "sufficient evidence of harmfulness" for IHD incidence and mortality. Producing estimates for the burden of IHD attributable to exposure to working ≥55 h/week appears evidence-based, and the pooled effect estimates presented in this systematic review could be used as input data for the WHO/ILO Joint Estimates.
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http://dx.doi.org/10.1016/j.envint.2020.105739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339147PMC
September 2020

Association of polybrominated diphenyl ether (PBDE) levels with biomarkers of placental development and disease during mid-gestation.

Environ Health 2020 06 3;19(1):61. Epub 2020 Jun 3.

Program on Reproductive Health and the Environment, UCSF Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, Mailstop 0132, 550 16th Street, 7th Floor, San Francisco, CA, 94143, USA.

Background: Polybrominated diphenyl ether (PBDE) exposures have been associated with adverse pregnancy outcomes. A hypothesized mechanism is via alterations in placental development and function. However, we lack biomarkers that can be used as early indicators of maternal/fetal response to PBDE exposures and/or perturbations in placental development or function.

Methods: To evaluate the relationship between PBDE levels and placental biomarkers during mid-gestation of human pregnancy (n = 62), we immunolocalized three molecules that play key roles in cytotrophoblast (CTB) differentiation and interstitial/endovascular uterine invasion-integrin alpha-1 (ITGA1), vascular endothelial-cadherin (CDH5), and metalloproteinase-1 (MMP1)-and assessed three morphological parameters as potential indicators of pathological alterations using H&E-stained tissues-leukocyte infiltration, fibrinoid deposition, and CTB endovascular invasion. We evaluated associations between placental PBDE levels and of biomarkers of placental development and disease using censored Kendall's tau correlation and linear regression methods.

Results: PBDEs were detected in all placental samples. We observed substantial variation in antigen expression and morphological endpoints across placental regions. We observed an association between PBDE concentrations and immunoreactivity of endovascular CTB staining with anti-ITGA1 (inverse) or interstitial CTBs staining with anti-CDH5 (positive).

Conclusions: We found several molecular markers that may be sensitive placental indicators of PBDE exposure. Further, this indicates that placental biomarkers of development and disease could be useful barometers of exposure to PBDEs, a paradigm that could be extended to other environmental chemicals and placental stage-specific antigens.
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http://dx.doi.org/10.1186/s12940-020-00617-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268484PMC
June 2020

Applications of Machine Learning to In Silico Quantification of Chemicals without Analytical Standards.

J Chem Inf Model 2020 06 20;60(6):2718-2727. Epub 2020 May 20.

Program on Reproductive Health and the Environment, Department of Obstetrics and Gynecology, University of California, San Francisco, California 94158, United States.

Non-targeted analysis provides a comprehensive approach to analyze environmental and biological samples for nearly all chemicals present. One of the main shortcomings of current analytical methods and workflows is that they are unable to provide any quantitative information constituting an important obstacle in understanding environmental fate and human exposure. Herein, we present an in silico quantification method using mahine-learning for chemicals analyzed using electrospray ionization (ESI). We considered three data sets from different instrumental setups: (i) capillary electrophoresis electrospray ionization-mass spectrometry (CE-MS) in positive ionization mode (ESI+), (ii) liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) in ESI+ and (iii) LC-QTOF/MS in negative ionization mode (ESI-). We developed and applied two different machine-learning algorithms: a random forest (RF) and an artificial neural network (ANN) to predict the relative response factors (RRFs) of different chemicals based on their physicochemical properties. Chemical concentrations can then be calculated by dividing the measured abundance of a chemical, as peak area or peak height, by its corresponding RRF. We evaluated our models and tested their predictive power using 5-fold cross-validation (CV) and  randomization. Both the RF and the ANN models showed great promise in predicting RRFs. However, the accuracy of the predictions was dependent on the data set composition and the experimental setup. For the CE-MS ESI+ data set, the best model predicted measured RRFs with a mean absolute error (MAE) of 0.19 log units and a cross-validation coefficient of determination () of 0.84 for the testing set. For the LC-QTOF/MS ESI+ data set, the best model predicted measured RRFs with an MAE of 0.32 and a of 0.40. For the LC-QTOF/MS ESI- data set, the best model predicted measured RRFs with a MAE of 0.50 and a of 0.20. Our findings suggest that machine-learning algorithms can be used for predicting concentrations of nontargeted chemicals with reasonable uncertainties, especially in ESI+, while the application on ESI- remains a more challenging problem.
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http://dx.doi.org/10.1021/acs.jcim.9b01096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328371PMC
June 2020

Maternal and fetal exposures to fluoride during mid-gestation among pregnant women in northern California.

Environ Health 2020 04 6;19(1):38. Epub 2020 Apr 6.

Department of Orofacial Sciences, School of Dentistry, University of California, San Francisco, San Francisco, California, USA.

Background: Previous studies have shown a correlation between fluoride concentrations in urine and community water fluoride concentrations. However, there are no studies of the relationship between community water fluoridation, urine, serum, and amniotic fluid fluoride concentrations in pregnant women in the US. The aim of this study was to determine the relationship between maternal urine fluoride (MUF), maternal urine fluoride adjusted for specific gravity (MUF), maternal serum fluoride (MSF), amniotic fluid fluoride (AFF) concentrations during pregnancy, and community water fluoridation in Northern California.

Methods: Archived samples of urine, serum and amniotic fluid collected from second trimester pregnant women in Northern California from 47 different communities in Northern California and one from Montana (n = 48), were analyzed for fluoride using an ion specific electrode following acid microdiffusion. Women's addresses were matched to publicly reported water fluoride concentrations. We examined whether fluoride concentrations in biospecimens differed by fluoridation status of the community water, and determined the association between water fluoride concentrations and biospecimen fluoride concentrations using linear regression models adjusted for maternal age, smoking, Body Mass Index (BMI), race/ethnicity, and gestational age at sample collection.

Results: Fluoride concentrations in the community water supplies ranged from 0.02 to 1.00 mg/L. MUF, MSF , and AFF concentrations were significantly higher in pregnant women living in communities adhering to the U.S. recommended water fluoride concentration (0.7 mg/L), as compared with communities with less than 0.7 mg/L fluoride in drinking water. When adjusted for maternal age, smoking status, BMI, race/ethnicity, and gestational age at sample collection, a 0.1 mg/L increase in community water fluoride concentration was positively associated with higher concentrations of MUF (B = 0.052, 95% CI:0.019,0.085), MUF (B = 0.028, 95% CI: -0.006, 0.062), MSF (B = 0.001, 95% CI: 0.000, 0.003) and AFF (B = 0.001, 95% CI: 0.000, 0.002).

Conclusions: We found universal exposure to fluoride in pregnant women and to the fetus via the amniotic fluid. Fluoride concentrations in urine, serum, and amniotic fluid from women were positively correlated to public records of community water fluoridation. Community water fluoridation remains a major source of fluoride exposure for pregnant women living in Northern California.
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http://dx.doi.org/10.1186/s12940-020-00581-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132865PMC
April 2020

Opportunities for evaluating chemical exposures and child health in the United States: the Environmental influences on Child Health Outcomes (ECHO) Program.

J Expo Sci Environ Epidemiol 2020 05 17;30(3):397-419. Epub 2020 Feb 17.

Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA, USA.

The Environmental Influences on Child Health Outcomes (ECHO) Program will evaluate environmental factors affecting children's health (perinatal, neurodevelopmental, obesity, respiratory, and positive health outcomes) by pooling cohorts composed of >50,000 children in the largest US study of its kind. Our objective was to identify opportunities for studying chemicals and child health using existing or future ECHO chemical exposure data. We described chemical-related information collected by ECHO cohorts and reviewed ECHO-relevant literature on exposure routes, sources, and environmental and human monitoring. Fifty-six ECHO cohorts have existing or planned chemical biomonitoring data for mothers or children. Environmental phenols/parabens, phthalates, metals/metalloids, and tobacco biomarkers are each being measured by ≥15 cohorts, predominantly during pregnancy and childhood, indicating ample opportunities to study child health outcomes. Cohorts are collecting questionnaire data on multiple exposure sources and conducting environmental monitoring including air, dust, and water sample collection that could be used for exposure assessment studies. To supplement existing chemical data, we recommend biomonitoring of emerging chemicals, nontargeted analysis to identify novel chemicals, and expanded measurement of chemicals in alternative biological matrices and dust samples. ECHO's rich data and samples represent an unprecedented opportunity to accelerate environmental chemical research to improve the health of US children.
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http://dx.doi.org/10.1038/s41370-020-0211-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183426PMC
May 2020

RoB-SPEO: A tool for assessing risk of bias in studies estimating the prevalence of exposure to occupational risk factors from the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury.

Environ Int 2020 02 18;135:105039. Epub 2019 Dec 18.

Cesare Maltoni Cancer Research Center, Ramazzini Institute, Bologna, Italy.

Background: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing joint estimates of the work-related burden of disease and injury (WHO/ILO Joint Estimates). For this, systematic reviews of studies estimating the prevalence of exposure to selected occupational risk factors will be conducted to provide input data for estimations of the number of exposed workers. A critical part of systematic review methods is to assess risk of bias (RoB) of individual studies. In this article, we present and describe the development of such a tool, called the Risk of Bias in Studies estimating Prevalence of Exposure to Occupational risk factors (RoB-SPEO) tool; report results from RoB-SPEO's pilot testing; note RoB-SPEO's limitations; and suggest how the tool might be tested and developed further.

Methods: Selected existing RoB tools used in environmental and occupational health systematic reviews were reviewed and analysed. From existing tools, we identified domains for the new tool and, if necessary, added new domains. For each domain, we then identified and integrated components from the existing tools (i.e. instructions, domains, guiding questions, considerations, ratings and rating criteria), and, if necessary, we developed new components. Finally, we elicited feedback from other systematic review methodologists and exposure scientists and agreed upon RoB-SPEO. Nine experts pilot tested RoB-SPEO, and we calculated a raw measure of inter-rater agreement (P) for each of its domain, rating P < 0.4 as poor, 0.4 ≤ P ≥ 0.8 as substantial and P > 0.80 as almost perfect agreement.

Results: Our review found no standard tool for assessing RoB in prevalence studies of exposure to occupational risk factors. We identified six existing tools for environmental and occupational health systematic reviews and found that their components for assessing RoB differ considerably. With the new RoB-SPEO tool, assessors judge RoB for each of eight domains: (1) bias in selection of participants into the study; (2) bias due to a lack of blinding of study personnel; (3) bias due to exposure misclassification; (4) bias due to incomplete exposure data; (5) bias due to conflict of interest; (6) bias due to selective reporting of exposures; (7) bias due to difference in numerator and denominator; and (8) other bias. The RoB-SPEO's ratings are low, probably low, probably high, high or no information. Pilot testing of the RoB-SPEO tool found substantial inter-rater agreement for six domains (range of P for these domains: 0.51-0.80), but poor agreement for two domains (i.e. P of 0.31 and 0.33 for biases due to incomplete exposure data and in selection of participants into the study, respectively). Limitations of RoB-SPEO include that it has not yet been fully performance-tested.

Conclusions: We developed the RoB-SPEO tool for assessing RoB in prevalence studies of exposure to occupational risk factors. The tool will be applied and its performance tested in the ongoing systematic reviews for the WHO/ILO Joint Estimates.
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http://dx.doi.org/10.1016/j.envint.2019.105039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479507PMC
February 2020
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