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A special issue of International Journal of Environmental Research and Public Health (ISSN 1660-4601). This special issue belongs to the section "Environmental Health".

Deadline for manuscript submissions: closed (11 July 2023) | Viewed by 33806

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Special Issue Editors

Dr. Danielle J. Carlin

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Guest Editor

National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709, USA
Interests: chemical mixtures; combined exposures; metals; inhalation toxicology; xenobiotic metabolism
Special Issues, Collections and Topics in MDPI journals

Dr. Cynthia V. Rider

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Guest Editor

National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
Interests: combined exposures; mixtures; toxicology; polycyclic aromatic compounds

Special Issue Information

Dear Colleagues,

Continued evaluation of single chemical associations with disease risk is inadequate for identifying the complex factors that contribute to disease development. Rather, multiple environmental chemical exposures along with non-chemical stressors that occur simultaneously and over time (i.e., combined exposures/mixtures) require consideration.

This Special Issue will focus on the health effects of combined exposures/mixtures (CEM) and will bring together experts to present original articles on the state-of-the-science associated with CEM. Specifically, experts are invited to contribute papers to this Special Issue that discuss relevant CEM studies, which may include cell-based models, animal models, 3-D tissue culture models, epidemiological studies, new statistical methods for CEM research, risk analysis, regulatory considerations, exposure modeling and measurement, and prevention/intervention strategies with the ultimate goal of highlighting the latest CEM science. In addition, papers that include studies involving the engagement with community partners that are disproportionately affected by CEM and the combination of CEM and nonchemical stressors (e.g., noise, temperature, humidity, stress from the built environment, social factors, and lack of health care, and environmental justice) are highly encouraged. The goals of this Special Issue will be to advance the field of CEM, determine relevant CEMs that contribute to disease, uncover research gaps, and propose future directions for research in CEM.

Dr. Danielle J. Carlin
Dr. Cynthia V. Rider
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Environmental Research and Public Health is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

mixtures
combined exposures
chemical interactions
non-chemical stressors
cumulative risk
joint toxicity fxposome dose addition response addition
relative potency
toxic equivalency
chemicals
biomarkers
epidemiology
health impact
emerging contaminants
exposure assessment
multiroute exposure
risk assessment
risk management
risk communication

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Published Papers (9 papers)

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Research

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25 pages, 885 KiB

Open AccessArticle

The Long Goodbye: Finally Moving on from the Relative Potency Approach to a Mixtures Approach for Polycyclic Aromatic Hydrocarbons (PAHs)

by Lynne T. Haber, Alison M. Pecquet, Melissa J. Vincent and Louise M. White

Int. J. Environ. Res. Public Health 2022, 19(15), 9490; https://doi.org/10.3390/ijerph19159490 - 2 Aug 2022

Cited by 8 | Viewed by 2109

Abstract

For the past several decades, a relative potency approach has been used to estimate the human health risks from exposure to polycyclic aromatic hydrocarbon (PAH) mixtures. Risk estimates are derived using potency equivalence factors (PEFs; also called relative potency factors [RPFs]), based on the ratio of selected PAHs to benzo[a]pyrene (BaP), expressed qualitatively by orders of magnitude. To quantify PEFs for 18 selected carcinogenic PAHs, a systematic approach with a priori and dose response criteria was developed, building on draft work by the US EPA in 2010 and its review by US EPA Science Advisory Board (SAB) in 2011. An exhaustive search for carcinogenicity studies that included both target PAHs and BaP with environmentally relevant exposure routes found only 48 animal bioassay datasets (mostly pre-1992 based on skin painting). Only eight datasets provided adequate low-response data, and of these only four datasets were appropriate for modeling to estimate PEFs; only benzo[b]fluoranthene and cyclopenta[c,d]pyrene had a PEF that could be quantified. Thus, current knowledge of PAH carcinogenicity is insufficient to support quantitative PEFs for PAH mixtures. This highlights the long-acknowledged need for an interdisciplinary approach to estimate risks from PAH mixtures. Use of alternative and short-term toxicity testing methods, improved mixture characterization, understanding the fate and bioavailability of PAH mixtures, and understanding exposure route-related differences in carcinogenicity are discussed as ways to improve the understanding of the risks of PAHs. Full article

(This article belongs to the Special Issue Combined Environmental Exposures/ Chemical Mixtures)

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14 pages, 2099 KiB

Open AccessArticle

Competitive Metabolism of Polycyclic Aromatic Hydrocarbons (PAHs): An Assessment Using In Vitro Metabolism and Physiologically Based Pharmacokinetic (PBPK) Modeling

by Jordan N. Smith, Kari A. Gaither and Paritosh Pande

Int. J. Environ. Res. Public Health 2022, 19(14), 8266; https://doi.org/10.3390/ijerph19148266 - 6 Jul 2022

Cited by 9 | Viewed by 2520

Abstract

Humans are routinely exposed to complex mixtures such as polycyclic aromatic hydrocarbons (PAHs) rather than to single compounds, as are often assessed for hazards. Cytochrome P450 enzymes (CYPs) metabolize PAHs, and multiple PAHs found in mixtures can compete as substrates for individual CYPs (e.g., CYP1A1, CYP1B1, etc.). The objective of this study was to assess competitive inhibition of metabolism of PAH mixtures in humans and evaluate a key assumption of the Relative Potency Factor approach that common human exposures will not cause interactions among mixture components. To test this objective, we co-incubated binary mixtures of benzo[a]pyrene (BaP) and dibenzo[def,p]chrysene (DBC) in human hepatic microsomes and measured rates of enzymatic BaP and DBC disappearance. We observed competitive inhibition of BaP and DBC metabolism and measured inhibition coefficients (K_i), observing that BaP inhibited DBC metabolism more potently than DBC inhibited BaP metabolism (0.061 vs. 0.44 µM K_i, respectively). We developed a physiologically based pharmacokinetic (PBPK) interaction model by integrating PBPK models of DBC and BaP and incorporating measured metabolism inhibition coefficients. The PBPK model predicts significant increases in BaP and DBC concentrations in blood AUCs following high oral doses of PAHs (≥100 mg), five orders of magnitude higher than typical human exposures. We also measured inhibition coefficients of Supermix-10, a mixture of the most abundant PAHs measured at the Portland Harbor Superfund Site, on BaP and DBC metabolism. We observed similar potencies of inhibition coefficients of Supermix-10 compared to BaP and DBC. Overall, results of this study demonstrate that these PAHs compete for the same enzymes and, at high doses, inhibit metabolism and alter internal dosimetry of exposed PAHs. This approach predicts that BaP and DBC exposures required to observe metabolic interaction are much higher than typical human exposures, consistent with assumptions used when applying the Relative Potency Factor approach for PAH mixture risk assessment. Full article

(This article belongs to the Special Issue Combined Environmental Exposures/ Chemical Mixtures)

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18 pages, 721 KiB

Open AccessArticle

Chemical Mixtures in the EU Population: Composition and Potential Risks

by Sebastian Socianu, Stephanie K. Bopp, Eva Govarts, Liese Gilles, Jurgen Buekers, Marike Kolossa-Gehring, Thomas Backhaus and Antonio Franco

Int. J. Environ. Res. Public Health 2022, 19(10), 6121; https://doi.org/10.3390/ijerph19106121 - 18 May 2022

Cited by 27 | Viewed by 4380

Abstract

Regulating chemical mixtures is a complex scientific and policy task. The aim of this study was to investigate typical mixtures and their potential risks based on internal exposure levels in the European population. Based on human biomonitoring (HBM) data made available via the HBM4EU project, we derived generic mixtures representative of a median (P50) and a worst-case scenario (P95) for adults and children. We performed a mixture risk assessment based on HBM concentrations, health-based guidance values (HBGVs) as internal thresholds of concern, and the conservative assumption of concentration addition applied across different toxicological endpoints. Maximum cumulative ratios (MCRs) were calculated to characterize the mixture risk. The mixtures comprise 136 biomarkers for adults and 84 for children, although concentration levels could be quantified only for a fraction of these. Due to limited availability of HBGVs, the mixture risk was assessed for a subset of 20 substance-biomarker pairs for adults and 17 for children. The mixture hazard index ranged from 2.8 (P50, children) to 9.2 (P95, adults). Six to seven substances contributed to over 95% of the total risk. MCR values ranged between 2.6 and 5.5, which is in a similar range as in previous studies based on human external exposures assessments. The limited coverage of substances included in the calculations and the application of a hazard index across toxicological endpoints argue for caution in the interpretation of the results. Nonetheless the analyses of MCR and MAF_ceiling can help inform a possible mixture assessment factor (MAF) applicable to single substance risk assessment to account for exposure to unintentional mixtures. Full article

(This article belongs to the Special Issue Combined Environmental Exposures/ Chemical Mixtures)

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23 pages, 19828 KiB

Open AccessArticle

A Comparative Multi-System Approach to Characterizing Bioactivity of Commonly Occurring Chemicals

by Brianna N. Rivera, Lindsay B. Wilson, Doo Nam Kim, Paritosh Pande, Kim A. Anderson, Susan C. Tilton and Robyn L. Tanguay

Int. J. Environ. Res. Public Health 2022, 19(7), 3829; https://doi.org/10.3390/ijerph19073829 - 23 Mar 2022

Cited by 2 | Viewed by 3524

Abstract

A 2019 retrospective study analyzed wristband personal samplers from fourteen different communities across three different continents for over 1530 organic chemicals. Investigators identified fourteen chemicals (G14) detected in over 50% of personal samplers. The G14 represent a group of chemicals that individuals are commonly exposed to, and are mainly associated with consumer products including plasticizers, fragrances, flame retardants, and pesticides. The high frequency of exposure to these chemicals raises questions of their potential adverse human health effects. Additionally, the possibility of exposure to mixtures of these chemicals is likely due to their co-occurrence; thus, the potential for mixtures to induce differential bioactivity warrants further investigation. This study describes a novel approach to broadly evaluate the hazards of personal chemical exposures by coupling data from personal sampling devices with high-throughput bioactivity screenings using in vitro and non-mammalian in vivo models. To account for species and sensitivity differences, screening was conducted using primary normal human bronchial epithelial (NHBE) cells and early life-stage zebrafish. Mixtures of the G14 and most potent G14 chemicals were created to assess potential mixture effects. Chemical bioactivity was dependent on the model system, with five and eleven chemicals deemed bioactive in NHBE and zebrafish, respectively, supporting the use of a multi-system approach for bioactivity testing and highlighting sensitivity differences between the models. In both NHBE and zebrafish, mixture effects were observed when screening mixtures of the most potent chemicals. Observations of BMC-based mixtures in NHBE (NHBE BMC Mix) and zebrafish (ZF BMC Mix) suggested antagonistic effects. In this study, consumer product-related chemicals were prioritized for bioactivity screening using personal exposure data. High-throughput high-content screening was utilized to assess the chemical bioactivity and mixture effects of the most potent chemicals. Full article

(This article belongs to the Special Issue Combined Environmental Exposures/ Chemical Mixtures)

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16 pages, 1040 KiB

Open AccessArticle

Statistical Methods for Assessing the Explained Variation of a Health Outcome by a Mixture of Exposures

by Hua Yun Chen, Hesen Li, Maria Argos, Victoria W. Persky and Mary E. Turyk

Int. J. Environ. Res. Public Health 2022, 19(5), 2693; https://doi.org/10.3390/ijerph19052693 - 25 Feb 2022

Cited by 3 | Viewed by 2021

Abstract

Exposures to environmental pollutants are often composed of mixtures of chemicals that can be highly correlated because of similar sources and/or chemical structures. The effect of an individual chemical on a health outcome can be weak and difficult to detect because of the relatively low level of exposures to many environmental pollutants. To tackle the challenging problem of assessing the health risk of exposure to a mixture of environmental pollutants, we propose a statistical approach to assessing the proportion of the variation of an outcome explained by a mixture of pollutants. The proposed approach avoids the difficult task of identifying specific pollutants that are responsible for the effects and may also be used to assess interactions among exposures. Extensive simulation results demonstrate that the proposed approach has very good performance. Application of the proposed approach is illustrated by investigating the main and interaction effects of the chemical pollutants on systolic and diastolic blood pressure in participants from the National Health and Nutrition Examination Survey. Full article

(This article belongs to the Special Issue Combined Environmental Exposures/ Chemical Mixtures)

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15 pages, 1618 KiB

Open AccessArticle

Using Metrics of a Mixture Effect and Nutrition from an Observational Study for Consideration towards Causal Inference

by Chris Gennings, Katherine Svensson, Alicja Wolk, Christian Lindh, Hannu Kiviranta and Carl-Gustaf Bornehag

Int. J. Environ. Res. Public Health 2022, 19(4), 2273; https://doi.org/10.3390/ijerph19042273 - 17 Feb 2022

Cited by 7 | Viewed by 3300

Abstract

Environmental exposures to a myriad of chemicals are associated with adverse health effects in humans, while good nutrition is associated with improved health. Single chemical in vivo and in vitro studies demonstrate causal links between the chemicals and outcomes, but such studies do not represent human exposure to environmental mixtures. One way of summarizing the effect of the joint action of chemical mixtures is through an empirically weighted index using weighted quantile sum (WQS) regression. My Nutrition Index (MNI) is a metric of overall dietary nutrition based on guideline values, including for pregnant women. Our objective is to demonstrate the use of an index as a metric for more causally linking human exposure to health outcomes using observational data. We use both a WQS index of 26 endocrine-disrupting chemicals (EDCs) and MNI using data from the SELMA pregnancy cohort to conduct causal inference using g-computation with counterfactuals for assumed either reduced prenatal EDC exposures or improved prenatal nutrition. Reducing the EDC exposure using the WQS index as a metric or improving dietary nutrition using MNI as a metric, the counterfactuals in a causal inference with one SD change indicate significant improvement in cognitive function. Evaluation of such a strategy may support decision makers for risk management of EDCs and individual choices for improving dietary nutrition. Full article

(This article belongs to the Special Issue Combined Environmental Exposures/ Chemical Mixtures)

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18 pages, 3092 KiB

Open AccessArticle

Spatial and Temporal Analysis of Impacts of Hurricane Florence on Criteria Air Pollutants and Air Toxics in Eastern North Carolina

by Sharmila Bhandari, Gaston Casillas, Noor A. Aly, Rui Zhu, Galen Newman, Fred A. Wright, Anthony Miller, Gabriela Adler, Ivan Rusyn and Weihsueh A. Chiu

Int. J. Environ. Res. Public Health 2022, 19(3), 1757; https://doi.org/10.3390/ijerph19031757 - 3 Feb 2022

Cited by 6 | Viewed by 3610

Abstract

Natural and anthropogenic disasters are associated with air quality concerns due to the potential redistribution of pollutants in the environment. Our objective was to conduct a spatiotemporal analysis of air concentrations of benzene, toluene, ethylbenzne, and xylene (BTEX) and criteria air pollutants in North Carolina during and after Hurricane Florence. Three sampling campaigns were carried out immediately after the storm (September 2018) and at four-month intervals. BTEX were measured along major roads. Concurrent criteria air pollutant concentrations were predicted from modeling. Correlation between air pollutants and possible point sources was conducted using spatial regression. Exceedances of ambient air criteria were observed for benzene (in all sampling periods) and PM2.5 (mostly immediately after Florence). For both, there was an association between higher concentrations and fueling stations, particularly immediately after Florence. For other pollutants, concentrations were generally below levels of regulatory concern. Through characterization of air quality under both disaster and “normal” conditions, this study demonstrates spatial and temporal variation in air pollutants. We found that only benzene and PM2.5 were present at levels of potential concern, and there were localized increases immediately after the hurricane. These substances warrant particular attention in future disaster response research (DR2) investigations. Full article

(This article belongs to the Special Issue Combined Environmental Exposures/ Chemical Mixtures)

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16 pages, 3993 KiB

Open AccessArticle

Potential Human Health Hazard of Post-Hurricane Harvey Sediments in Galveston Bay and Houston Ship Channel: A Case Study of Using In Vitro Bioactivity Data to Inform Risk Management Decisions

by Zunwei Chen, Suji Jang, James M. Kaihatu, Yi-Hui Zhou, Fred A. Wright, Weihsueh A. Chiu and Ivan Rusyn

Int. J. Environ. Res. Public Health 2021, 18(24), 13378; https://doi.org/10.3390/ijerph182413378 - 19 Dec 2021

Cited by 11 | Viewed by 3147

Abstract

Natural and anthropogenic disasters may be associated with redistribution of chemical contaminants in the environment; however, current methods for assessing hazards and risks of complex mixtures are not suitable for disaster response. This study investigated the suitability of in vitro toxicity testing methods as a rapid means of identifying areas of potential human health concern. We used sediment samples (n = 46) from Galveston Bay and the Houston Ship Channel (GB/HSC) areas after hurricane Harvey, a disaster event that led to broad redistribution of chemically-contaminated sediments, including deposition of the sediment on shore due to flooding. Samples were extracted with cyclohexane and dimethyl sulfoxide and screened in a compendium of human primary or induced pluripotent stem cell (iPSC)-derived cell lines from different tissues (hepatocytes, neuronal, cardiomyocytes, and endothelial) to test for concentration-dependent effects on various functional and cytotoxicity phenotypes (n = 34). Bioactivity data were used to map areas of potential concern and the results compared to the data on concentrations of polycyclic aromatic hydrocarbons (PAHs) in the same samples. We found that setting remediation goals based on reducing bioactivity is protective of both “known” risks associated with PAHs and “unknown” risks associated with bioactivity, but the converse was not true for remediation based on PAH risks alone. Overall, we found that in vitro bioactivity can be used as a comprehensive indicator of potential hazards and is an example of a new approach method (NAM) to inform risk management decisions on site cleanup. Full article

(This article belongs to the Special Issue Combined Environmental Exposures/ Chemical Mixtures)

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Review

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24 pages, 1292 KiB

Open AccessEditor’s ChoiceReview

Powering Research through Innovative Methods for Mixtures in Epidemiology (PRIME) Program: Novel and Expanded Statistical Methods

by Bonnie R. Joubert, Marianthi-Anna Kioumourtzoglou, Toccara Chamberlain, Hua Yun Chen, Chris Gennings, Mary E. Turyk, Marie Lynn Miranda, Thomas F. Webster, Katherine B. Ensor, David B. Dunson and Brent A. Coull

Int. J. Environ. Res. Public Health 2022, 19(3), 1378; https://doi.org/10.3390/ijerph19031378 - 26 Jan 2022

Cited by 39 | Viewed by 7224

Abstract

Humans are exposed to a diverse mixture of chemical and non-chemical exposures across their lifetimes. Well-designed epidemiology studies as well as sophisticated exposure science and related technologies enable the investigation of the health impacts of mixtures. While existing statistical methods can address the most basic questions related to the association between environmental mixtures and health endpoints, there were gaps in our ability to learn from mixtures data in several common epidemiologic scenarios, including high correlation among health and exposure measures in space and/or time, the presence of missing observations, the violation of important modeling assumptions, and the presence of computational challenges incurred by current implementations. To address these and other challenges, NIEHS initiated the Powering Research through Innovative methods for Mixtures in Epidemiology (PRIME) program, to support work on the development and expansion of statistical methods for mixtures. Six independent projects supported by PRIME have been highly productive but their methods have not yet been described collectively in a way that would inform application. We review 37 new methods from PRIME projects and summarize the work across previously published research questions, to inform methods selection and increase awareness of these new methods. We highlight important statistical advancements considering data science strategies, exposure-response estimation, timing of exposures, epidemiological methods, the incorporation of toxicity/chemical information, spatiotemporal data, risk assessment, and model performance, efficiency, and interpretation. Importantly, we link to software to encourage application and testing on other datasets. This review can enable more informed analyses of environmental mixtures. We stress training for early career scientists as well as innovation in statistical methodology as an ongoing need. Ultimately, we direct efforts to the common goal of reducing harmful exposures to improve public health. Full article

(This article belongs to the Special Issue Combined Environmental Exposures/ Chemical Mixtures)

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