Grantee Research Project Results
2020 Progress Report: Center for Research on Early Childhood Exposure and Development in Puerto Rico
EPA Grant Number: R836155Center: Center for Research on Early Childhood Exposure and Development in Puerto Rico
Center Director: Alshawabkeh, Akram
Title: Center for Research on Early Childhood Exposure and Development in Puerto Rico
Investigators: Alshawabkeh, Akram
Current Investigators: Alshawabkeh, Akram , Suh, Helen H. , Cordero, Jose , Manjourides, Justin , Zimmerman, Emily , Gu, April , Meeker, John D.
Institution: Northeastern University
EPA Project Officer: Callan, Richard
Project Period: September 1, 2015 through August 31, 2019 (Extended to August 31, 2022)
Project Period Covered by this Report: September 1, 2019 through August 31,2020
Project Amount: $2,099,537
RFA: Children's Environmental Health and Disease Prevention Research Centers (2014) RFA Text | Recipients Lists
Research Category: Human Health , Children's Health
Objective:
The Center for Research on Early Childhood Exposure and Development in Puerto Rico (CRECE) investigates the impact of a mixture of environmental exposures and modifying factors on fetal and early childhood health and development in this under-served, highly-exposed population. Since 2010, our interdisciplinary research team has been conducting a highly productive NIEHS-funded pregnancy study of a cohort of 1800 pregnant women in Puerto Rico to investigate links between exposure to groundwater contamination and the unusually high preterm birth rate on the island (PROTECT, P42ES017198). The CRECE Center leverages this rich dataset and the infrastructure established to study a cohort of 600 mothers and follow up on 510 children whose prenatal exposures were documented in the PROTECT study, tracking them through age four.
CRECE research projects couple air-pollution epidemiology (Project 1), high throughput toxicity screening of multi-media pollutant mixtures (Project 2), and biomarker epidemiology (Project 3) to analyze the impacts of early life exposure (both specific stressors and mixture effects) on fetal/child health and development, taking into account environmental, clinical, social, demographic, behavioral, dietary, and other factors. Through CRECE’s centralized Human Subjects Core (facility/service core), observed, self-reported, and biological measures are collected, providing new information characterizing the early life exposures to air and water pollution, including contaminants of emerging concern (CECs).
Project 1: Assessing the Impact of Air Pollution on Adverse Birth Outcomes and Child Development
Our study will provide new evidence of the impacts of air pollution on neonatal and early childhood development for infants and children living in Puerto Rico along with the factors that affect susceptibility to air pollution’s harmful impacts. We will do so by leveraging the success of PROTECT, our cohort study of 1800 pregnant women in Puerto Rico for whom a rich dataset of environmental, health, social, demographic, and behavioral factors are being collected. We will add to these data measurements of air pollution exposures, early childhood development, and non-nutritive suck (NNS)--a measure of newborn central nervous system function that has not yet been used to assess neonatal development in environmental epidemiology. We will use these data to achieve three aims: to (1) assess the association of air pollution on adverse birth outcomes; (2) determine the impact of air pollution on child development; and (3) examine effect modification of the air pollution–adverse health relationship by social and personal factors, including socio-economic status, maternal stress, birth outcomes, other pollutant exposures, and housing characteristics.
Project 2: Toxicogenomics-based Mechanistic Multimedia Exposure Assessment and Child Development
Project 2 employs novel in vitro, high throughput screening (HTS) assays to yield new toxicity information needed to reveal the impacts of exposure to complex pollutant mixtures on pathways relevant to neonatal and early childhood development. Significant challenges remain in understanding the complex risks that pollutant mixtures and their metabolites pose for human health. These challenges motivate a new paradigm for toxicity evaluation that is based on an in vitro mechanistic and genetic pathway-based approach that allows combinations of exposures and outcomes to be tested comprehensively yet feasibly. To address this need, we have developed an approach that uses in vitro HTS to measure translational changes in targeted genetic pathways occurring in response to pollutants and pollutant mixtures. Importantly, these pollutants and mixtures are drawn directly from environmental sources, such as water and air, and also from biological matrices like urine. They are then passed through in vitro preparations of human and non-human cells, where we measure biomarkers of oxidative stress, DNA damage and inflammation. These pathways and biomarkers were selected based on their established association with CRECE-relevant neonatal and early childhood health outcomes, and because the biomarkers are found at measurable concentrations in the urine and sera of exposed individuals. Through this approach, we are able to provide pathway- and sample-specific fingerprints of pollutant exposures and their effects that can inform environmental epidemiological studies and even be used themselves as biomarkers of exposure in these studies. Through close collaboration with CRECE’s other two projects, this project will inform epidemiological studies of our cohort of 600 Puerto Rican children. These studies leverage data and infrastructure established under PROTECT, a highly productive NIEHS-funded pregnancy study of a cohort of 1800 pregnant women from Puerto Rico’s northern coast. This project will provide its HTS findings and exposure biomarker measures to Projects 1 and 3, thus allowing those projects to perform health effect analyses for pollutant mixtures identified as toxic by the HTS, and to examine the association of exposure biomarkers with neonatal and early childhood health outcomes.
Project 3: Biomarker Epidemiology of In Utero Environmental Exposures and Child Development
It has been documented that there are particularly high rates for a number of developmental conditions, as well as elevated exposure to environmental contaminants, in Puerto Rico. Most human studies to date on environmental exposures and child health have focused on metals or persistent organic pollutants, but there is a great need for more data on emerging chemicals of concern, such as those currently used in a wide array of industrial and consumer applications. Chemicals such as phenols and parabens disrupt endocrine function, induce oxidative stress, and cause other alterations that may result in reduced fetal or child growth, preterm birth, neurodevelopmental delays, reproductive tract anomalies, obesity, allergies/asthma, and others. While near-ubiquitous exposures to these chemicals have been documented among pregnant women, well-designed human studies are greatly needed to determine whether developmental impacts are related to early life in utero exposure. In addition, few studies have addressed the real life situation of considering multiple exposures and susceptibility factors. To fill these gaps, we will use state-of-the-art epidemiologic approaches among an underserved and potentially highly exposed population. We will leverage an ongoing NIH-funded pregnancy cohort study in Puerto Rico (P42ES017198) that is building a rich dataset on environmental, clinical, social, demographic, behavioral, dietary and other factors among 1800 pregnant women on the island’s Northern coast. The study will follow 600 children born into the cohort through the age of 4 years. This project will link with Project 1 to test the impacts of exposure to multi-pollutant mixtures, and Project 2 to exchange information about mechanisms and test mixtures for our biomarker epidemiology study and their toxicity screening study.
Progress Summary:
The association between maternal exposure to fine particulate matter in Puerto Rico and birth outcomes and child neurodevelopment
We also completed an analysis of PM2.5 exposures and preterm birth using data from our PROTECT cohort. Specifically, we used data on maternal characteristics and behaviors and PTB and other birth outcomes for women participating in PROTECT. For each of these women, we assessed prenatal PM2.5 exposures for each infant based on the nearest US Environmental Protection Agency monitor. We estimated prenatal phthalate exposures as the geometric mean of urinary measurements obtained during pregnancy. We then examined the association between PM2.5 and PTB using modified Poisson regression and further assessed modification of the association by phthalate exposure levels and demographic factors such as maternal age and infant gender. Among 1,092 singleton births, we found 9.1% of infants were born preterm and 92.9% of mothers had at least a high school education. Mothers had a mean (standard deviation) age of 26.9 (5.5) years and a median (range) of 2.0 (1.0-8.0) pregnancies. Median (range) prenatal PM2.5 concentrations were 6.0 (3.1-19.8) g/m3. Median (interquartile range) prenatal phthalate levels were 14.9 (8.9–26.0) and 14.5 (8.4–26.0), respectively, for di-n-butyl phthalate (DBP) and di-isobutyl phthalate (DiBP). An interquartile range increase in PM2.5 was associated with a 1.2% (95% CI 0.4%, 2.1%) higher risk of PTB. There was little difference in PTB risk in strata of infant sex, mother’s age, family income, history of adverse birth outcome, parity, and pre-pregnancy body mass index. Pregnancy urinary phthalate metabolite levels did not modify the PM2.5-PTB association. A paper detailing our findings is currently under review at the journal Environmental Health.
Toxicity of chemicals in Puerto Rican drinking water
This year, we have analyzed 36 tap water samples collected according to the two sampling schemes: (1) Eighteen samples were collected from the households of recruited pregnant women in Northern Puerto Rico (PR) from April 2016 to February 2018 within the cohort; (2) another eighteen tap water samples were collected from nine locations across PR (including collaborating university laboratories and hotels) at two time points (December 2017 and February 2018). Organic compounds from all 36 tap water samples were enriched via porous extraction paddle (PEP) immediately after sample collection in collaborating laboratories at the University of Puerto Rico (UPR) and subjected to both chemical analysis and toxicity assays. The 21 acidified water samples were analyzed for 18 trace elements on ICP-MS at NU, while all 36 organic extracts eluted from PEP were subjected to targeted and suspect screening for 234 organic micropollutants including PR human exposure-relevant chemicals on high-resolution LC-MS at Cornell University. In parallel, a HTS quantitative toxicogenomics assay with GFP-fused yeast reporters library (74 biomarkers) targeting genotoxicity, oxidative, protein, chemical, and general stress, and a RT-qPCR assay with human A549 cells targeting inflammation, genotoxicity, oxidative stress, endocrine disruption (ED), aryl hydrocarbon receptor (AHR) and apoptosis effects, were employed for toxicity assessment. Based on the initial assay sensitivity and reproducibility test for tap water analysis, the relative enrichment factor (REF) for all tap water samples was selected to be 200 times. In this past year, we have finished all the data analysis for these 36 tap water samples and the results have been published.
Gestational length and prenatal exposure to parabens and triclocarban in Puerto Rico
We found that associations between triclocarban, bisphenol-S, methyl- and propylparaben in relation to gestational length were stronger among women with negative Total scores on the Life Experiences Survey (LES). Among women with negative Total LES scores, bisphenol-S and triclocarban were associated with a 3-5 day decrease in gestational length [(-3.15; 95% CI:-6.06, -0.24); (-4.68; 95% CI: -8.47, -0.89)], whereas methylparaben and propylparaben were associated with a 2-3 day increase in gestational length [(2.21; 95% CI: 0.02, 4.40); (2.92; 95% CI: 0.58, 5.26)]. Significant interactions were driven by negative life events, but the association with triclocarban was driven by fewer positive life events. In summary, associations between exposure biomarkers and gestational length were stronger in the presence of negative life events. This provides evidence supporting the hypothesis that stress makes the body more vulnerable to chemical exposure; we will continue investigating these interactions as we explore associations between
phenol/paraben exposures and child developmental measures.
Prenatal air pollution and chemical exposures and child neurodevelopment outcomes
We examined the association of air pollution exposures and non-nutritive suck (NNS) using data from 2017-2019 for 198 infants aged 0-3 months enrolled in CRECE. We measured NNS using a pacifier attached to a pressure transducer, allowing for real-time visualization of NNS amplitude, frequency, duration, cycles/burst, cycles/min and bursts/min. These data were linked to 9-month average prenatal concentrations of PM2.5 and its components, measured at three community monitoring sites. We used linear regression to examine the PM2.5-NNS association in single pollutant models, controlling for household smoke exposure, maternal age, residential location, infant sex, age at testing, NNS duration, and gestational age. We found the average NNS amplitude and burst duration to equal 17.1 cmH2O and 6.13 seconds, respectively. Decreased NNS amplitude was consistently and significantly associated with 9-month average exposure to sulfur (-1.03 ± 0.51), zinc (-1.09 ± 0.50), copper (1.10 ± 0.54) vanadium (-1.16 ± 0.54), and nickel (-1.53 ± 0.50). Decrements in NNS frequency were associated with sulfur exposure (0.036 ± 0.02), but not other examined PM components. Together our findings suggest that prenatal maternal exposure to PM components was associated with lower NNS amplitude and frequency for Puerto Rican infants soon after birth.
We also have a new paper that has been submitted and is currently in peer review that represents the first to investigate chemical exposures in pregnancy in relation to non-nutritive suck (NNS) parameters. NNS is an innovative measure of early infant brain function. Urinary phthalate metabolite levels were measured in women at up to three time points in pregnancy as a measure of in utero exposure to the child. Infants had their NNS sampled using our custom research pacifier between 4-6 (± 2 weeks) weeks of age, yielding the following NNS dependent measures: cycles/burst, frequency, amplitude, bursts/min, and cycles/min. We used multiple linear regression to assess associations between individual phthalate metabolites and NNS measurements, adjusting for infant sex, birthweight, and urinary specific gravity. An interquartile range (IQR) increase in mono carboxyisononyl phthalate across pregnancy was associated with 3.5% (95%CI: -6.2, -0.8%) lower NNS frequency and 8.9% (0.6, 17.3%) higher NNS amplitude. Similarly, an IQR increase in mono-2-ethylhexyl phthalate was also associated with 3.4% (-6.5, -0.2%) lower NNS frequency, while an IQR increase in di-2-ethylhexyl terephthalate metabolites was associated with 11.2% (2.9, 19.5%) higher NNS amplitude. Gestational exposure to phthalates may alter NNS amplitude and frequency in full-term infants. These findings indicate that the infants may be increasing their NNS amplitude to compensate for their slower NNS frequency. These preliminary findings could have important clinical implications for earlier detection of exposure-related deficits in neurofunction as well as implications for subsequent neurodevelopment and related interventions.
Project 1: Our major activities this reporting period focused on analyses of the impact of fine particle (PM2.5) and PM2.5-associated black carbon (BC) and metal exposures on adverse birth outcomes. We did so through two main analyses. The first was aimed at examining the association of air pollutant exposures on preterm birth using data from PROTECT (Aim 1 of CRECE). This paper was published in Environmental Epidemiology in 2019. We also completed an analysis of PM2.5 exposures and preterm birth using data from our PROTECT cohort.
Specifically, we used data on maternal characteristics and behaviors and PTB and other birth outcomes for women participating in PROTECT. For each of these women, we assessed prenatal PM2.5 exposures for each infant based on the nearest US Environmental Protection Agency monitor. We estimated prenatal phthalate exposures as the geometric mean of urinary measurements obtained during pregnancy. We then examined the association between PM2.5 and PTB using modified Poisson regression and further assessed modification of the association by phthalate exposure levels and demographic factors such as maternal age and infant gender. Among 1,092 singleton births, we found 9.1% of infants were born preterm and 92.9% of mothers had at least a high school education. Mothers had a mean (standard deviation) age of 26.9 (5.5) years and a median (range) of 2.0 (1.0-8.0) pregnancies. Median (range) prenatal PM2.5 concentrations were 6.0 (3.1-19.8) g/m3. Median (interquartile range) prenatal phthalate levels were 14.9 (8.9–26.0) and 14.5 (8.4–26.0), respectively, for di-n-butyl phthalate (DBP) and di-isobutyl phthalate (DiBP). An interquartile range increase in PM2.5 was associated with a 1.2% (95% CI 0.4%, 2.1%) higher risk of PTB. There was little difference in PTB risk in strata of infant sex, mother’s age, family income, history of adverse birth outcome, parity, and pre-pregnancy body mass index. Pregnancy urinary phthalate metabolite levels did not modify the PM2.5-PTB association. A paper detailing our findings is currently under review at the journal Environmental Health. Additionally, we examined the association of air pollution exposures and non-nutritive suck (NNS) using data from 2017-2019 for 198 infants aged 0-3 months enrolled in CRECE. We measured NNS using a pacifier attached to a pressure transducer, allowing for real-time visualization of NNS amplitude, frequency, duration, cycles/burst, cycles/min and bursts/min. These data were linked to 9-month average prenatal concentrations of PM2.5 and its components, measured at three community monitoring sites. We used linear regression to examine the PM2.5-NNS association in single pollutant models, controlling for household smoke exposure, maternal age, residential location, infant sex, age at testing, NNS duration, and gestational age. We found the average NNS amplitude and burst duration to equal 17.1 cmH2O and 6.13 seconds, respectively. Decreased NNS amplitude was consistently and significantly associated with 9-month average exposure to sulfur (-1.03 ± 0.51), zinc (-1.09 ± 0.50), copper (1.10 ± 0.54) vanadium (-1.16 ± 0.54), and nickel (-1.53 ± 0.50). Decrements in NNS frequency were associated with sulfur exposure (0.036 ± 0.02), but not other examined PM components. Together our findings suggest that prenatal maternal exposure to PM components was associated with lower NNS amplitude and frequency for Puerto Rican infants soon after birth.
Project 2: Toxicity of Pollutant Mixtures in Puerto Rican Drinking Water: This year, we have analyzed 36 tap water samples collected according to the two sampling schemes: (1) Eighteen samples were collected from the households of recruited pregnant women in Northern Puerto Rico (PR) from April 2016 to February 2018 within the cohort; (2) another eighteen tap water samples were collected from nine locations across PR (including collaborating university laboratories and hotels) at two time points (December 2017 and February 2018). Organic compounds from all 36 tap water samples were enriched via porous extraction paddle (PEP) immediately after sample collection in collaborating laboratories at the University of Puerto Rico (UPR) and subjected to both chemical analysis and toxicity assays. The 21 acidified water samples were analyzed for 18 trace elements on ICP-MS at NU, while all 36 organic extracts eluted from PEP were subjected to targeted and suspect screening for 234 organic micropollutants including PR human exposure-relevant chemicals on high-resolution LC-MS at Cornell University. In parallel, a HTS quantitative toxicogenomics assay with GFP-fused yeast reporters library (74 biomarkers) targeting genotoxicity, oxidative, protein, chemical, and general stress, and a RT-qPCR assay with human A549 cells targeting inflammation, genotoxicity, oxidative stress, endocrine disruption (ED), aryl hydrocarbon receptor (AHR) and apoptosis effects, were employed for toxicity assessment. Based on the initial assay sensitivity and reproducibility test for tap water analysis, the relative enrichment factor (REF) for all tap water samples was selected to be 200 times. In this past year, we have finished all the data analysis for these 36 tap water samples and the results have been published. In order to investigate the lasting impact of Hurricane Maria on drinking water quality in PR, 60 more tap water samples were collected from Mar. 2018 to Jan. 2019 during the second round of sampling events following the same protocol, and analyzed for inorganic and organic trace pollutants and molecular-level toxicity effects. In this past year, we have finished all the samples analysis and data processing. Covid-19 led to lab shutdown for over 3 months from March until July. According to the chemical analyses, a total of 18 trace elements and 38 organic micropollutants were detected in at least one of the 60 water samples measured, with the concentrations all below the corresponding health-based benchmark levels (MCLs or HBSLs if available). For inorganic trace elements specifically, the top three elements with the highest average concentrations were Sr (322 μg/L), Cu (73 μg/L), and Ba (25 μg/L). The average contamination levels of trace elements decreased from February to May 2018 after HM, slightly increased from June to August when entering the wet season featuring heavier storms and rainfalls, and finally approached equal or below the average pre-HM levels
(except for Cr, Ni, Sr, U, and Zn) in early 2019. A similar temporal trend has been observed for most organic micropollutants, while all reduced to the pre-HM contamination levels in early 2019. Collectively, these temporal trends indicate the sweeping and lasting impact of HM on the drinking water quality in PR that would take almost one year to recover to the pre-hurricane background levels. It should be recognized that other impacting factors such as storm seasons and background spatial changes in water sources may also complexify the recovery process of the water quality. In addition, compared to the post-HM samples collected from December 2017 to February 2018, 15 new organic micropollutants were detected in at least one of the 60 water samples during the 2nd round of sampling; among which 26.7% were biocides, 40% were pharmaceutical residues, and another 26.7% were degradation products or metabolites of pesticides or drugs. Therefore, more concerns may need to put on these persistent pollutants during the follow-up monitoring and remediation actions due to their potential for long-range transport, persistence in the environment, ability to bio-magnify and bio-accumulate in ecosystems, as well as their significant negative effects on human health and the environment. According to the yeast toxicogenomics-based assay targeting oxidative and DNA stress response pathways, exposure to tap water samples collected in April 2018 induced overall higher oxidative stress at the relative enrichment factor of 400 compared to later sampling months from May to October; whereas for DNA stress, no obvious temporal trend was observed, with the highest PELI value induced by the PS5-CY sample collected in August 2018 at Cayey, PR. The pathway perturbations were complicated by the cocktails of different chemical contaminants for different sampling sites and time points; thus more efforts are currently undergoing on statistical data analysis to explore potential connections between trace pollutants and molecular toxicity effects.
Toxicity of Puerto Rican Air Pollutant Mixtures:
In this past year, we have finished the data analysis for the air samples and are in the process of preparing a manuscript. To investigate the toxicity of Puerto Rican ambient air pollutant mixtures, PM2.5 sampling was conducted in the northern coast of Puerto Rico by Prof. Helen Suh’s group (Project 1) at Tufts University. After sampling, metal mixtures were extracted by hot acid (5.55% HNO3/16.75% HCl) from Teflon filters and neutralized to pH7 before subject to the toxicity evaluation of a yeast HTS toxicogenomics assay and a human A549 cell RT-qPCR assay. To achieve the minimum sample weight requirement for the toxicogenomics assay, air pollutant mixtures collected through 5-6 weeks were combined together as 1 sample. A total of 8 combined samples were analyzed.
The sample-specific impacts of air sample extracts were assessed using the yeast HTS toxicogenomics-based assay (76 biomarkers) for the evaluation of oxidative stress, DNA damage, protein stress, chemical stress and general stress, with results reported as quantitative pathway-specific biomarker measures and toxicity fingerprints. Dose-response relationships were established through four concentrations (0.2, 1, 5, 25 mg/L). The values of overall toxicity endpoint 1/EC-PELI1.5 generated from dose-response curves ranged from 0.06 to 0.85 for all eight air samples, with samples collected in winter displaying higher toxicity compared to other seasons through the sampling year. Similar trends with toxicity fingerprints at the concentration of 25 mg/L showed that the toxicity of air samples collected in Dec 2016 was the highest. The toxicity screening results revealed the distinct pathway-specific toxicity profiles of PR air samples at different time points. Higher up-regulation of biomarkers that represent chemical and protein stresses were detected in most of the samples, while enhanced oxidative and DNA stresses were observed in samples collected around Dec 2016.
Correspondence analysis was conducted to investigate the patterns of the toxicity profiles of the PR air samples, showing that at the concentration of 25 mg/L, samples in Dec 2016 were separated more by DNA stress on X-axis, and that chemical and protein stresses separated most samples on Y-axis. Meanwhile, transcription levels of 13 genes representing oxidative, inflammation, DNA stresses and apoptosis were investigated in response to air sample extracts (25 mg/L) in human A549 cells using a RT-qPCR assay. All biomarkers showed differential expression (fold change>2 or <0.5) relative to untreated control in at least one of the eight samples, with GPX in oxidative pathway and NFKB2 in inflammation pathway showing the highest average fold change (I). Similar to yeast assay results, samples collected from Oct 2016 to Jan 2017 induced more expression of stress-response genes, especially genes related to inflammation and oxidative stress.
Toxicity of Chemicals and Metabolites Found in Urine:
We planned to collect more urine samples in Spring and summer 2020; however, covid-19 led to lab shutdown and we were not able to obtain more urine samples as planned. We have conducted more correlations analysis between the urine sample profiling results from our assay with metabolites concentrations and preterm variables or gestational age after all the postpartum information collected within the CRECE center from other teams. In order to investigate the potential relationships between the pregnancy exposome and adverse pregnancy outcomes, urine samples of accumulated first morning voids were collected from the households of recruited pregnant women in Northern Puerto Rico. The chemicals and metabolites from urine samples were enriched via a Porous Extraction Paddle (PEP) device immediately after sample collection in collaborating laboratories at the University of Puerto Rico (UPR), and then were subject to the evaluation of a pathway-specific toxicogenomics assay that targets five stress response pathways (i.e. oxidative stress, DNA damage, protein stress, chemical stress and general stress). Since urine volume and solute concentrations vary widely based upon water consumption and other physiological and pathophysiological factors, urine concentration normalization is critical. Samples were normalized according to their specific gravities measured by a refractometer. β-glucuronidase/sulfatase was added to urine samples before conducting the toxicogenomics assay to deconjugate metabolites. Based on the initial assay sensibility and reproducibility test, the relative enrichment factor for all urine samples was selected to be 1X (the original concentration). Quantitative pathway-specific toxicity endpoints and toxicity fingerprints were obtained for 76 biomarkers within the five stress-response pathways. All biomarkers showed differential up-regulation levels (PELI>1.5) in exposure to at least 3 out of the 13 urine samples. Integrated up-regulated responses of all five stress-response pathways were shown in all 13 samples. DNA damage or chemical stress showed the highest up-regulation levels compared to other stress-response pathways among 11 out of 13 urine samples; general stress showed the highest up-regulation levels in the other 2 samples. The toxicity screening results from the yeast toxicogenomics-based assay revealed the distinct toxicity profiles among urine samples of different individuals.
Project 3: This past year we have published numerous papers from the project in relation to our specific aims. One to highlight is our analysis on the interaction between phenol/paraben exposure and social determinants of health on pregnancy outcomes that has now been published (Aker et al. 2020; Science of the Total Environment). We found that associations between triclocarban, bisphenol-S, methyl- and propylparaben in relation to gestational length were stronger among women with negative Total scores on the Life Experiences Survey (LES). Among women with negative Total LES scores, bisphenol-S and triclocarban were associated with a 3-5 day decrease in gestational length [(-3.15; 95% CI:-6.06, -0.24); (-4.68; 95% CI: -8.47, -0.89)], whereas methylparaben and propylparaben were associated with a 2-3 day increase in gestational length [(2.21; 95% CI: 0.02, 4.40); (2.92; 95% CI: 0.58, 5.26)]. Significant interactions were driven by negative life events, but the association with triclocarban was driven by fewer positive life events. In summary, associations between exposure biomarkers and gestational length were stronger in the presence of negative life events. This provides evidence supporting the hypothesis that stress makes the body more vulnerable to chemical exposure; we will continue investigating these interactions as we explore associations between phenol/paraben exposures and child developmental measures.
We also have a new paper that has been submitted and is currently in peer review that represents the first to investigate chemical exposures in pregnancy in relation to non-nutritive suck (NNS) parameters. NNS is an innovative measure of early infant brain function. Urinary phthalate metabolite levels were measured in women at up to three time points in pregnancy as a measure of in utero exposure to the child. Infants had their NNS sampled using our custom research pacifier between 4-6 (± 2 weeks) weeks of age, yielding the following NNS dependent measures: cycles/burst, frequency, amplitude, bursts/min, and cycles/min. We used multiple linear regression to assess associations between individual phthalate metabolites and NNS measurements, adjusting for infant sex, birthweight, and urinary specific gravity. An interquartile range (IQR) increase in mono carboxyisononyl phthalate across pregnancy was associated with 3.5% (95%CI: -6.2, -0.8%) lower NNS frequency and 8.9% (0.6, 17.3%) higher NNS amplitude. Similarly, an IQR increase in mono-2-ethylhexyl phthalate was also associated with 3.4% (-6.5, -0.2%) lower NNS frequency, while an IQR increase in di-2-ethylhexyl terephthalate metabolites was associated with 11.2% (2.9, 19.5%) higher NNS amplitude. Gestational exposure to phthalates may alter NNS amplitude and frequency in full-term infants. These findings indicate that the infants may be increasing their NNS amplitude to compensate for their slower NNS frequency. These preliminary findings could have important clinical implications for earlier detection of exposure-related deficits in neurofunction as well as implications for subsequent neurodevelopment and related interventions.
Future Activities:
During the final period of the project, we will continue to focus on data analysis, with a particular emphasis on linking environmental exposure data with child health outcomes such as size/growth, Non-Nutritive Suck, anogenital distance, and neurodevelopmental measures such as the Ages & Stages Questionnaire (ASQ) or Batelle Developmental Inventory (BDI). The team will focus on publishing results of these analyses in addition to presenting at conferences and to stakeholders and the community.
Journal Articles: 47 Displayed | Download in RIS Format
Other center views: | All 68 publications | 47 publications in selected types | All 47 journal articles |
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Aker AM, Watkins DJ, Johns LE, Ferguson KK, Soldin OP, Anzalota Del Toro LV, Alshawabkeh AN, Cordero JF, Meeker JD. Phenols and parabens in relation to reproductive and thyroid hormones in pregnant women. Environmental Research 2016;151:30-37. |
R836155 (2017) R836155 (2020) R836155C003 (2017) |
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Aker AM, Johns L, McElrath TF, Cantonwine DE, Mukherjee B, Meeker JD. Associations between maternal phenol and paraben urinary biomarkers and maternal hormones during pregnancy: a repeated measures study. Environment International 2018;113:341-349. |
R836155 (2018) R836155 (2019) R836155 (2020) |
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Aker AM, Ferguson KK, Rosario ZY, Mukherjee B, Alshawabkeh AN, Cordero JF, Meeker JD. The associations between prenatal exposure to triclocarban, phenols and parabens with gestational age and birth weight in northern Puerto Rico. Environmental Research 2019;169:41-51. |
R836155 (2019) R836155 (2020) |
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Aung MT, Johns LE, Ferguson KK, Mukherjee B, McElrath TF, Meeker JD. Thyroid hormone parameters during pregnancy in relation to urinary bisphenol A concentrations: a repeated measures study. Environment International 2017;104:33-40. |
R836155 (2018) R836155 (2019) R836155 (2020) |
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Aung MT, Ferguson KK, Cantonwine DE, McElrath TF, Meeker JD. Preterm birth in relation to the bisphenol A replacement, bisphenol S, and other phenols and parabens. Environmental Research 2019;169:131-138. |
R836155 (2019) R836155 (2020) |
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Bedrosian LD, Ferguson KK, Cantonwine DE, McElrath TF, Meeker JD. Urinary phthalate metabolite concentrations in relation to levels of circulating matrix metalloproteinases in pregnant women. Science of the Total Environment 2018;613-614:1349-1352. |
R836155 (2018) R836155 (2019) R836155 (2020) |
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Cantonwine DE, Ferguson KK, Mukherjee B, McElrath TF, Meeker JD. Urinary bisphenol A levels during pregnancy and risk of preterm birth. Environmental Health Perspectives 2015;123(9):895-901. |
R836155 (2020) R836155C003 (2017) |
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Cathey A, Ferguson KK, McElrath TF, Cantonwine DE, Pace G, Alshawabkeh A, Cordero JF, Meeker JD. Distribution and predictors of urinary polycyclic aromatic hydrocarbon metabolites in two pregnancy cohort studies. Environmental Pollution 2018;232:556-562. |
R836155 (2018) R836155 (2019) R836155 (2020) |
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Ferguson KK, Cantonwine DE, McElrath TF, Mukherjee B, Meeker JD. Repeated measures analysis of associations between urinary bisphenol-A concentrations and biomarkers of inflammation and oxidative stress in pregnancy. Reproductive Toxicology 2016;66:93-98. |
R836155 (2017) R836155 (2020) R836155C003 (2017) |
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Ferguson KK, Meeker JD, Cantonwine DE, Chen Y-H, Mukherjee B, McElrath TF. Urinary phthalate metabolite and bisphenol A associations with ultrasound and delivery indices of fetal growth. Environment International 2016;94:531-537. |
R836155 (2017) R836155 (2020) R836155C003 (2017) R834513 (Final) R835436 (2016) R835436 (2017) |
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Ferguson KK, McElrath TF, Pace GG, Weller D, Zeng L, Pennathur S, Cantonwine DE, Meeker JD. Urinary polycyclic aromatic hydrocarbon metabolite associations with biomarkers of inflammation, angiogenesis, and oxidative stress in pregnant women. Environmental Science & Technology 2017;51(8):4652-4660. |
R836155 (2018) R836155 (2019) R836155 (2020) |
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Johns LE, Ferguson KK, Meeker JD. Relationships between urinary phthalate metabolite and bisphenol A concentrations and vitamin D levels in U.S. adults: National Health and Nutrition Examination Survey (NHANES), 2005-2010. Journal of Clinical Endocrinology and Metabolism 2016;101(11):4062-4069. |
R836155 (2017) R836155 (2020) R836155C003 (2017) |
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Lan J, Gou N, Rahman SM, Gao C, He M, Gu AZ. A quantitative toxicogenomics assay for high-throughput and mechanistic genotoxicity assessment and screening of environmental pollutants. Environmental Science & Technology 2016;50(6):3202-3214. |
R836155 (2020) R836155C002 (2016) |
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Lewis RC, Johns LE, Meeker JD. Serum biomarkers of exposure to perfluoroalkyl substances in relation to serum testosterone and measures of thyroid function among adults and adolescents from NHANES 2011-2012. International Journal of Environmental Research and Public Health 2015;12(6):6098-6114. |
R836155 (2020) R836155C003 (2017) R835436 (2014) R835436 (2015) R835436 (2017) |
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Watkins DJ, Fortenberry GZ, Sanchez BN, Barr DB, Panuwet P, Schnaas L, Osorio-Valencia E, Solano-Gonzalez M, Ettinger AS, Hernandez-Avila M, Hu H, Tellez-Rojo MM, Meeker JD. Urinary 3-phenoxybenzoic acid (3-PBA) levels among pregnant women in Mexico City: distribution and relationships with child neurodevelopment. Environmental Research 2016;147:307-313. |
R836155 (2017) R836155 (2020) R836155C003 (2017) R835436 (2015) R835436 (2016) R835436 (2017) |
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Yuan Y, Meeker JD, Ferguson KK. Serum polybrominated diphenyl ether (PBDE) concentrations in relation to biomarkers of oxidative stress and inflammation: the National Health and Nutrition Examination Survey 2003-2004. Science of the Total Environment 2017;575:400-405. |
R836155 (2017) R836155 (2018) R836155 (2020) R836155C003 (2017) |
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Watkins DJ, Ferguson KK, Anzalota Del Toro LV, Alshawabkeh AN, Cordero JF, Meeker JD. Associations between urinary phenol and paraben concentrations and markers of oxidative stress and inflammation among pregnant women in Puerto Rico. International Journal of Hygiene and Environmental Health 2015;218(2):212-219. |
R836155 (2020) R836155C003 (2017) |
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Ashrap P, Watkins DJ, Calafat AM, Ye X, Rosario Z, Brown P, Velez-Vega CM, Alshawabkeh A, Cordero JF, Meeker JD. Elevated concentrations of urinary triclocarban, phenol and paraben among pregnant women in northern Puerto Rico:predictors and trends. Environment International 2018;121:990-1002. |
R836155 (2019) R836155 (2020) |
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Ferguson KK, Meeker JD, Cantonwine DE, Mukherjee B, Pace GG, Weller D, McElrath TF. Environmental phenol associations with ultrasound and delivery measures of fetal growth. Environment International 2018;112:243-250. |
R836155 (2019) R836155 (2020) |
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Lan J, Rahman SM, Gou N, Jiang T, Plewa MJ, Alshawabkeh A, Gu AZ. Genotoxicity assessment of drinking water disinfection byproducts by DNA damage and repair pathway profiling analysis. Environmental Science & Technology 2018;52(11):6565-6675. |
R836155 (2019) R836155 (2020) |
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Zhang Y, Gu AZ, Xie S, Li X, Cen T, Li D, Chen J. Nano-metal oxides induce antimicrobial resistance via radical-mediated mutagenesis. Environment International 2018;121:1162-1171. |
R836155 (2019) R836155 (2020) |
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Aker AM, Ferguson KK, Rosario ZY, Mukherjee B, Alshawabkeh AN, Calafat AM, Cordero JF, Meeker JD. A repeated measures study of phenol, paraben and Triclocarban urinary biomarkers and circulating maternal hormones during gestation in the Puerto Rico PROTECT cohort. Environmental Health 2019;18(1):28. |
R836155 (2019) R836155 (2020) |
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Li D, Gu AZ. Antimicrobial resistance:a new threat from disinfection byproducts and disinfection of drinking water?. Current Opinion in Environmental Science & Health 2019;7:83-91. |
R836155 (2019) R836155 (2020) |
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Aung MT, Ferguson KK, Cantonwine DE, Bakulski KM, Mukherjee B, Loch-Caruso R, McElrath TF, Meeker JD. Associations between maternal plasma measurements of inflammatory markers and urinary levels of phenols and parabens during pregnancy:a repeated measures study. Science of The Total Environment 2019;650:1131-1140. |
R836155 (2019) R836155 (2020) |
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Eick SM, Meeker JD, Brown P, Swartzendruber A, Rios-McConnell R, Shen Y, Milne GL, Vega CV, Rosario Z, Alshawabkeh A, Cordero JF. Associations between socioeconomic status, psychosocial stress, and urinary levels of 8-iso-prostaglandin-F2α during pregnancy in Puerto Rico. Free Radical Biology and Medicine 2019;143:95-100. |
R836155 (2020) |
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Cathey AL, Watkins D, Rosario ZY, Vélez C, Alshawabkeh AN, Cordero JF, Meeker JD. Associations of phthalates and phthalate replacements with CRH and other hormones among pregnant women in puerto rico. Journal of the Endocrine Society 2019;3(6):1127-49. |
R836155 (2020) |
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Ferguson KK, Rosario Z, McElrath TF, Vélez Vega C, Cordero JF, Alshawabkeh A, Meeker JD. Demographic risk factors for adverse birth outcomes in Puerto Rico in the PROTECT cohort. PloS one 2019;14(6):e0217770.. |
R836155 (2020) |
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Ferguson KK, Rosen EM, Rosario Z, Feric Z, Calafat AM, McElrath TF, Vega CV, Cordero JF, Alshawabkeh A, Meeker JD. Environmental phthalate exposure and preterm birth in the PROTECT birth cohort. Environment international 2019;132:105099. |
R836155 (2020) |
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Boss J, Mukherjee B, Ferguson KK, Aker A, Alshawabkeh AN, Cordero JF, Meeker JD, Kim S. Estimating outcome-exposure associations when exposure biomarker detection limits vary across batches. Epidemiology 2019;30(5):746-55. |
R836155 (2020) |
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Kirwa K, McConnell-Rios R, Manjourides J, Cordero J, Alshawabekeh A, Suh HH. Low birth weight and PM2. 5 in Puerto Rico. Environmental epidemiology 2019;3(4). |
R836155 (2020) |
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Aung MT, Yu Y, Ferguson KK, Cantonwine DE, Zeng L, McElrath TF, Pennathur S, Mukherjee B, Meeker JD. Prediction and associations of preterm birth and its subtypes with eicosanoid enzymatic pathways and inflammatory markers. Scientific reports 2019;9(1):1-7. |
R836155 (2020) |
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Xie S, Gu AZ, Cen T, Li D, Chen J. The effect and mechanism of urban fine particulate matter (PM2. 5) on horizontal transfer of plasmid-mediated antimicrobial resistance genes. Science of the Total Environment 2019;683:116-23. |
R836155 (2020) |
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Ingle ME, Watkins D, Rosario Z, VélezVega CM, Calafat AM, Ospina M, Ferguson KK, Cordero JF, Alshawabkeh A, Meeker JD. An exploratory analysis of urinary organophosphate ester metabolites and oxidative stress among pregnant women in Puerto Rico. Science of the Total Environment 2020;703:134798. |
R836155 (2020) |
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Manjourides J, Zimmerman E, Watkins DJ, Carpenito T, Vélez-Vega CM, Huerta-Montañez G, Rosario Z, Ayala I, Vergara C, Feric Z, Ondras M. Cohort profile:Center for Research on Early Childhood Exposure and Development in Puerto Rico. BMJ open 2020;10(7):e036389. |
R836155 (2020) |
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Lin Y, Sevillano-Rivera M, Jiang T, Li G, Cotto I, Vosloo S, Carpenter CM, Larese-Casanova P, Giese RW, Helbling DE, Padilla IY. Impact of Hurricane Maria on Drinking Water Quality in Puerto Rico. Environmental Science & Technology 2020;54(15):9495-509. |
R836155 (2020) |
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Welton M, Vega CM, Murphy CB, Rosario Z, Torres H, Russell E, Brown P, Huerta-Montanez G, Watkins D, Meeker JD, Alshawabkeh A. Impact of Hurricanes Irma and Maria on Puerto Rico Maternal and Child Health Research Programs. Maternal and child health journal 2020;24(1):22-9. |
R836155 (2020) |
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Aker A, McConnell RE, Loch-Caruso R, Park SK, Mukherjee B, Rosario ZY, Vélez-Vega CM, Huerta-Montanez G, Alshawabkeh AN, Cordero JF, Meeker JD. Interactions between chemicals and non-chemical stressors:the modifying effect of life events on the association between triclocarban, phenols and parabens with gestational length in a Puerto Rican cohort. Science of The Total Environment 2020;708:134719. |
R836155 (2019) R836155 (2020) |
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Eick SM, Ferguson KK, Milne GL, Rios-McConnell R, Vélez-Vega C, Rosario Z, Alshawabkeh A, Cordero JF, Meeker JD. Repeated measures of urinary oxidative stress biomarkers and preterm birth in Puerto Rico. Free Radical Biology and Medicine 2020;146:299-305. |
R836155 (2020) |
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Zimmerman E, Watkins DJ, Huerta-Montanez G, Pabon ZR, Feric Z, Manjourides J, Velez-Vega CM, Figueroa A, Hines M, Martens A, Cordero J. Associations of gestational phthalate exposure and non-nutritive suck among infants from the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) birth cohort study. Environment international 2021;152:106480. |
R836155 (2021) |
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Jiang T, Lin Y, Amadei CA, Gou N, Rahman SM, Lan J, Vecitis CD, Gu AZ. Comparative and mechanistic toxicity assessment of structure-dependent toxicity of carbon-based nanomaterials. Journal of Hazardous Materials 2021;418:126282. |
R836155 (2021) |
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Aung MT, Ashrap P, Watkins DJ, Mukherjee B, Rosario Z, Vélez-Vega CM, Alshawabkeh AN, Cordero JF, Meeker JD. Maternal lipidomic signatures in relation to spontaneous preterm birth and large-for-gestational age neonates. Scientific reports 2021;11(1):1-1. |
R836155 (2021) |
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Morton S, Honda T, Zimmerman E, Kirwa K, Huerta-Montanez G, Martens A, Hines M, Ondras M, Eum KD, Cordero JF, Alshawabekeh A. Non-nutritive suck and airborne metal exposures among Puerto Rican infants. Science of The Total Environment 2021;789:148008. |
R836155 (2021) |
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Silver MK, Fernandez J, Tang J, McDade A, Sabino J, Rosario Z, Vélez Vega C, Alshawabkeh A, Cordero JF, Meeker JD. Prenatal exposure to glyphosate and its environmental degradate, aminomethylphosphonic acid (AMPA), and preterm birth:a nested case–control study in the PROTECT cohort (Puerto Rico). Environmental health perspectives 2021;129(5):057011. |
R836155 (2021) |
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Kirwa K, Feric Z, Manjourides J, Alshawabekeh A, Vega CM, Cordero JF, Meeker JD, Suh HH. Preterm birth and PM2. 5 in Puerto Rico:evidence from the PROTECT birth cohort. Environmental Health 2021;20(1):1-1.. |
R836155 (2021) |
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Ashrap P, Aker A, Watkins DJ, Mukherjee B, Rosario-Pabón Z, Vélez-Vega CM, Alshawabkeh A, Cordero JF, Meeker JD. Psychosocial status modifies the effect of maternal blood metal and metalloid concentrations on birth outcomes. Environment International 2021;149:106418. |
R836155 (2021) |
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Park S, Zimmerman E, Huerta-Montañez G, Rosario-Pabón Z, Vélez-Vega CM, Cordero JF, Alshwabekah A, Meeker JD, Watkins DJ. Gestational exposure to phthalates and phthalate replacements in relation to neurodevelopmental delays in early childhood. Toxics 2023;11(1):65. |
R836155 (Final) |
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Muenter MM, Aiken A, Akanji JO, Baig S, Bellou S, Carlson A, Conway C, Cowell CM, DeLateur NA, Hester A, Joshi C. The response of Escherichia coli to the alkylating agents chloroacetaldehyde and styrene oxide. Mutation Research/Genetic Toxicology and Environmental Mutagenesis 2019;840:1-10. |
R836155 (2019) R836155 (2020) |
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Supplemental Keywords:
air pollution, metals, neurodevelopment, adverse birth outcomes, toxicogenomics, environmental exposure, biomarkers, pathway-specific effects, biomarkers, environmental exposure, phenols, parabens, endocrine disruptersRelevant Websites:
Progress and Final Reports:
Original Abstract Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R836155C001 Air Pollution Impacts on Neonatal and Early Childhood Development
R836155C002 Toxicogenomics-based Mechanistic Multimedia Exposure Assessment and Child Development
R836155C003 Biomarker Epidemiology of In Utero Environmental Exposures and Child Development
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- Final Report
- 2021 Progress Report
- 2019 Progress Report
- 2018 Progress Report
- 2017 Progress Report
- 2016 Progress Report
- Original Abstract
47 journal articles for this center