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Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple...
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Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors

A special issue of Toxics (ISSN 2305-6304). This special issue belongs to the section "Novel Methods in Toxicology Research".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 47064

Special Issue Editors

Dr. Christopher Kassotis

E-Mail Website
Guest Editor
Institute of Environmental Health Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48202, USA
Interests: chemical mixtures; endocrine disrupting chemicals; metabolic health; adipogenesis; environmental toxicology; multiple stressors; obesogens
Dr. Allison Phillips

E-Mail Website
Guest Editor
Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, RTP, Omaha, NC, USA
Interests: chemical mixtures; human health risk assessment; environmental chemistry; toxicology; high resolution mass spectrometry; non-targeted analysis; flame retardants

Special Issue Information

Dear Colleagues, 

We are pleased to invite you to contribute an article to the Toxics Special Issue “Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors.” Humans are chronically exposed to complex mixtures of inorganic and organic contaminants and diverse external stressors (stress, sleep, diet, etc.). The composition of complex mixtures that are encountered in the environment often differ substantially from those that are released into the environment due to intricate fate and transport processes. Real-life exposures to complex mixtures of environmental chemicals occur both sequentially and concurrently, and through multiple pathways. After an initial exposure, these chemical mixtures can interact at biological sites and elicit effects through similar or dissimilar modes of action. These factors, along with inherent difficulties associated with comprehensive characterization of complex mixtures, make assessing cumulative risk exceptionally challenging. Yet, new and emerging methods are advancing our knowledge of the exposome and will underpin research-driven decision making on the management of chemical mixtures. Analytical approaches are allowing for a more complete understanding of the chemical milieu that exist in exposure settings and require further assessment through toxicological assays. Innovative toxicological approaches are facilitating more in-depth assessments of the interplay between environmental toxicants and various external factors that may mediate toxicant effects.

This Special Issue aims to bring together novel approaches and established experts in the areas of mixture toxicology and exposure science to foster a better understanding of potential adverse health effects from exposure to complex contaminant mixtures and/or multiple stressors. We believe that this is accomplished through contributions from environmental chemists characterizing realistic environmental mixtures of all types, toxicologists conducting controlled experiments in vitro and/or in vivo to understand health outcomes and/or underlying mechanistic effects from exposure to mixtures and/or multiple stressors, and public health researchers performing mixture analyses to define the associations between complex contaminant mixture exposures and human health outcomes at varying stages of development. Our hope is that through bringing together these contributions we will foster a better understanding of the complexity of mixtures analyses and more clearly outline a path forward for this field of research.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but not limited to) the following: new methods for assessing cumulative risk, compositional characterization of chemical mixtures, toxicological evaluation of environmental mixtures using modelling approaches, in vitro models, and in vivo model organisms, computational approaches to defining mixtures exposure and hazard, and epidemiological assessments of joint effects of mixtures on human health outcomes.

Dr. Christopher Kassotis
Dr. Allison Phillips
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Toxics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mixtures
  • multiple stressors
  • cumulative hazard
  • UVCBs
  • exposome
  • synergism
  • antagonism
  • dose addition
  • independent action
  • interaction

Published Papers (15 papers)

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Editorial

Jump to: Research, Review, Other

6 pages, 218 KiB  
Editorial
Complex Mixtures and Multiple Stressors: Evaluating Combined Chemical Exposures and Cumulative Toxicity
by Christopher D. Kassotis and Allison L. Phillips
Toxics 2023, 11(6), 487; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics11060487 - 26 May 2023
Viewed by 1064
Abstract
The problem of chemical mixtures in the environment encompasses biological, analytical, logistical, and regulatory challenges, among others [...] Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)

Research

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20 pages, 1584 KiB  
Article
Adverse Outcome Pathway ‘Footprinting’: A Novel Approach to the Integration of 21st Century Toxicology Information into Chemical Mixtures Risk Assessment
by Jason C. Lambert
Toxics 2023, 11(1), 37; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics11010037 - 30 Dec 2022
Cited by 3 | Viewed by 2196
Abstract
For over a decade, New Approach Methodologies (NAMs) such as structure-activity/read-across, -omics technologies, and Adverse Outcome Pathway (AOP), have been considered within regulatory communities as alternative sources of chemical and biological information potentially relevant to human health risk assessment. Integration of NAMs into [...] Read more.
For over a decade, New Approach Methodologies (NAMs) such as structure-activity/read-across, -omics technologies, and Adverse Outcome Pathway (AOP), have been considered within regulatory communities as alternative sources of chemical and biological information potentially relevant to human health risk assessment. Integration of NAMs into applications such as chemical mixtures risk assessment has been limited due to the lack of validation of qualitative and quantitative application to adverse health outcomes in vivo, and acceptance by risk assessors. However, leveraging existent hazard and dose–response information, including NAM-based data, for mixture component chemicals across one or more levels of biological organization using novel approaches such as AOP ‘footprinting’ proposed herein, may significantly advance mixtures risk assessment. AOP footprinting entails the systematic stepwise profiling and comparison of all known or suspected AOPs involved in a toxicological effect at the level of key event (KE). The goal is to identify key event(s) most proximal to an adverse outcome within each AOP suspected of contributing to a given health outcome at which similarity between mixture chemicals can be confidently determined. These key events are identified as the ‘footprint’ for a given AOP. This work presents the general concept, and a hypothetical example application, of AOP footprinting as a key methodology for the integration of NAM data into mixtures risk assessment. Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)
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17 pages, 2881 KiB  
Article
Is Mixtures’ Additivity Supported by Empirical Data? A Case Study of Developmental Toxicity of PFOS and 6:2 FTS in Wildtype Zebrafish Embryos
by Megan E. Fey, Philip E. Goodrum, N. Roxanna Razavi, Christopher M. Whipps, Sujan Fernando and Janet K. Anderson
Toxics 2022, 10(8), 418; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics10080418 - 25 Jul 2022
Cited by 3 | Viewed by 2243
Abstract
Per- and polyfluoroalkyl substances (PFASs) are a major priority for many federal and state regulatory agencies charged with monitoring levels of emerging contaminants in environmental media and setting health-protective benchmarks to guide risk assessments. While screening levels and toxicity reference values have been [...] Read more.
Per- and polyfluoroalkyl substances (PFASs) are a major priority for many federal and state regulatory agencies charged with monitoring levels of emerging contaminants in environmental media and setting health-protective benchmarks to guide risk assessments. While screening levels and toxicity reference values have been developed for numerous individual PFAS compounds, there remain important data gaps regarding the mode of action for toxicity of PFAS mixtures. The present study aims to contribute whole-mixture toxicity data and advance the methods for evaluating mixtures of two key components of aqueous film-forming foams: perfluorooctanesulfonic acid (PFOS), and 6:2 fluorotelomer sulfonic acid (6:2 FTS). Wildtype (AB) zebrafish embryos were exposed to PFOS and 6:2 FTS, both as individual components and as binary mixtures, from 2 to 122 h post-fertilization. Five treatment levels were selected to encompass environmentally relevant exposure levels. Experimental endpoints consisted of mortality, hatching, and developmental endpoints, including swim bladder inflation, yolk sac area, and larval body length. Results from dose–response analysis indicate that the assumption of additivity using conventional points of departure (e.g., NOAEL, LOAEL) is not supported for critical effect endpoints with these PFAS mixtures, and that the interactions vary as a function of the dose range. Alternative methods for quantifying relative potency are proposed, and recommendations for additional investigations are provided to further advance assessments of the toxicity of PFAS mixtures to aquatic organisms. Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)
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15 pages, 2093 KiB  
Article
The Mixture of Bisphenol-A and Its Substitutes Bisphenol-S and Bisphenol-F Exerts Obesogenic Activity on Human Adipose-Derived Stem Cells
by Iris Reina-Pérez, Alicia Olivas-Martínez, Vicente Mustieles, Elena Salamanca-Fernández, José Manuel Molina-Molina, Nicolás Olea and Mariana F. Fernández
Toxics 2022, 10(6), 287; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics10060287 - 27 May 2022
Cited by 6 | Viewed by 2590
Abstract
Bisphenol A (BPA) and its substitutes, bisphenol F (BPF) and S (BPS), have previously shown in vitro obesogenic activity. This study was designed to investigate their combined effect on the adipogenic differentiation of human adipose-derived stem cells (hASCs). Cells were exposed for 14 [...] Read more.
Bisphenol A (BPA) and its substitutes, bisphenol F (BPF) and S (BPS), have previously shown in vitro obesogenic activity. This study was designed to investigate their combined effect on the adipogenic differentiation of human adipose-derived stem cells (hASCs). Cells were exposed for 14 days to an equimolar mixture of bisphenols (MIX) (range 10 nM–10 µM). Oil Red staining was used to measure intracellular lipid accumulation, quantitative real-time polymerase chain reaction (qRT-PCR) to study gene expression of adipogenic markers (PPARγ, C/EBPα, LPL, and FABP4), and Western Blot to determine their corresponding proteins. The MIX promoted intracellular lipid accumulation in a dose-dependent manner with a maximal response at 10 µM. Co-incubation with pure antiestrogen (ICI 182,780) inhibited lipid accumulation, suggesting that the effect was mediated by the estrogen receptor. The MIX also significantly altered the expression of PPARγ, C/EBPα, LPL, and FABP4 markers, observing a non-monotonic (U-shaped) dose-response, with maximal gene expression at 10 nM and 10 µM and lesser expression at 1 µM. This pattern was not observed when bisphenols were tested individually. Exposure to MIX (1–10 µM) also increased all encoded proteins except for FABP4, which showed no changes. Evaluation of the combined effect of relevant chemical mixtures is needed rather than single chemical testing. Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)
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20 pages, 3645 KiB  
Article
Individual and Combined Effects of Paternal Deprivation and Developmental Exposure to Firemaster 550 on Socio-Emotional Behavior in Prairie Voles
by Sagi Enicole A. Gillera, William P. Marinello, Mason A. Nelson, Brian M. Horman and Heather B. Patisaul
Toxics 2022, 10(5), 268; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics10050268 - 22 May 2022
Cited by 9 | Viewed by 2243
Abstract
The prevalence of neurodevelopmental disorders (NDDs) is rapidly rising, suggesting a confluence of environmental factors that are likely contributing, including developmental exposure to environmental contaminants. Unfortunately, chemical exposures and social stressors frequently occur simultaneously in many communities, yet very few studies have sought [...] Read more.
The prevalence of neurodevelopmental disorders (NDDs) is rapidly rising, suggesting a confluence of environmental factors that are likely contributing, including developmental exposure to environmental contaminants. Unfortunately, chemical exposures and social stressors frequently occur simultaneously in many communities, yet very few studies have sought to establish the combined effects on neurodevelopment or behavior. Social deficits are common to many NDDs, and we and others have shown that exposure to the chemical flame retardant mixture, Firemaster 550 (FM 550), or paternal deprivation impairs social behavior and neural function. Here, we used a spontaneously prosocial animal model, the prairie vole (Microtus ochrogaster), to explore the effects of perinatal chemical (FM 550) exposure alone or in combination with an early life stressor (paternal absence) on prosocial behavior. Dams were exposed to vehicle (sesame oil) or 1000 µg FM 550 orally via food treats from conception through weaning and the paternal absence groups were generated by removing the sires the day after birth. Adult offspring of both sexes were then subjected to open-field, sociability, and a partner preference test. Paternal deprivation (PD)-related effects included increased anxiety, decreased sociability, and impaired pair-bonding in both sexes. FM 550 effects include heightened anxiety and partner preference in females but reduced partner preference in males. The combination of FM 550 exposure and PD did not exacerbate any behaviors in either sex except for distance traveled by females in the partner preference test and, to a lesser extent, time spent with, and the number of visits to the non-social stimulus by males in the sociability test. FM 550 ameliorated the impacts of parental deprivation on partner preference behaviors in both sexes. This study is significant because it provides evidence that chemical and social stressors can have unique behavioral effects that differ by sex but may not produce worse outcomes in combination. Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)
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18 pages, 3159 KiB  
Article
Chemical Mixtures in Household Environments: In Silico Predictions and In Vitro Testing of Potential Joint Action on PPARγ in Human Liver Cells
by Celeste K. Carberry, Toby Turla, Lauren E. Koval, Hadley Hartwell, Rebecca C. Fry and Julia E. Rager
Toxics 2022, 10(5), 199; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics10050199 - 19 Apr 2022
Cited by 4 | Viewed by 2664
Abstract
There are thousands of chemicals that humans can be exposed to in their everyday environments, the majority of which are currently understudied and lack substantial testing for potential exposure and toxicity. This study aimed to implement in silico methods to characterize the chemicals [...] Read more.
There are thousands of chemicals that humans can be exposed to in their everyday environments, the majority of which are currently understudied and lack substantial testing for potential exposure and toxicity. This study aimed to implement in silico methods to characterize the chemicals that co-occur across chemical and product uses in our everyday household environments that also target a common molecular mediator, thus representing understudied mixtures that may exacerbate toxicity in humans. To detail, the Chemical and Products Database (CPDat) was queried to identify which chemicals co-occur across common exposure sources. Chemicals were preselected to include those that target an important mediator of cell health and toxicity, the peroxisome proliferator activated receptor gamma (PPARγ), in liver cells that were identified through query of the ToxCast/Tox21 database. These co-occurring chemicals were thus hypothesized to exert potential joint effects on PPARγ. To test this hypothesis, five commonly co-occurring chemicals (namely, benzyl cinnamate, butyl paraben, decanoic acid, eugenol, and sodium dodecyl sulfate) were tested individually and in combination for changes in the expression of PPARγ and its downstream target, insulin receptor (INSR), in human liver HepG2 cells. Results showed that these likely co-occurring chemicals in household environments increased both PPARγ and INSR expression more significantly when the exposures occurred as mixtures vs. as individual chemicals. Future studies will evaluate such chemical combinations across more doses, allowing for further quantification of the types of joint action while leveraging this method of chemical combination prioritization. This study demonstrates the utility of in silico-based methods to identify chemicals that co-occur in the environment for mixtures toxicity testing and highlights relationships between understudied chemicals and changes in PPARγ-associated signaling. Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)
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23 pages, 1992 KiB  
Article
Prenatal Exposure to an EDC Mixture, NeuroMix: Effects on Brain, Behavior, and Stress Responsiveness in Rats
by Andrea C. Gore, Tatum Moore, Matthew J. Groom and Lindsay M. Thompson
Toxics 2022, 10(3), 122; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics10030122 - 03 Mar 2022
Cited by 9 | Viewed by 3065
Abstract
Humans and wildlife are exposed to endocrine-disrupting chemicals (EDCs) throughout their lives. Environmental EDCs are implicated in a range of diseases/disorders with developmental origins, including neurodevelopment and behavior. EDCs are most often studied one by one; here, we assessed outcomes induced by a [...] Read more.
Humans and wildlife are exposed to endocrine-disrupting chemicals (EDCs) throughout their lives. Environmental EDCs are implicated in a range of diseases/disorders with developmental origins, including neurodevelopment and behavior. EDCs are most often studied one by one; here, we assessed outcomes induced by a mixture designed to represent the real-world situation of multiple simultaneous exposures. The choice of EDCs, which we refer to as “NeuroMix,” was informed by evidence for neurobiological effects in single-compound studies and included bisphenols, phthalates, vinclozolin, and perfluorinated, polybrominated, and polychlorinated compounds. Pregnant Sprague Dawley rats were fed the NeuroMix or vehicle, and then offspring of both sexes were assessed for effects on postnatal development and behaviors and gene expression in the brain in adulthood. In order to determine whether early-life EDCs predisposed to subsequent vulnerability to postnatal life challenges, a subset of rats were also given a stress challenge in adolescence. Prenatal NeuroMix exposure decreased body weight and delayed puberty in males but not females. In adulthood, NeuroMix caused changes in anxiety-like, social, and mate preference behaviors only in females. Effects of stress were predominantly observed in males. Several interactions of NeuroMix and stress were found, especially for the mate preference behavior and gene expression in the brain. These findings provide novel insights into how two realistic environmental challenges lead to developmental and neurobehavioral deficits, both alone and in combination, in a sex-specific manner. Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)
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20 pages, 4384 KiB  
Article
Nonylphenol Polyethoxylates Enhance Adipose Deposition in Developmentally Exposed Zebrafish
by Christopher D. Kassotis, Matthew K. LeFauve, Yu-Ting Tiffany Chiang, Megan M. Knuth, Stacy Schkoda and Seth W. Kullman
Toxics 2022, 10(2), 99; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics10020099 - 20 Feb 2022
Cited by 6 | Viewed by 3047 | Correction
Abstract
Alkylphenol polyethoxylates (APEOs), such as nonylphenol ethoxylates (NPEOs), are high-production-volume surfactants used in laundry detergents, hard-surface cleaners, pesticide formulations, textile production, oils, paints, and other products. NPEOs comprise −80% of the total production of APEOs and are widely reported across diverse environmental matrices. [...] Read more.
Alkylphenol polyethoxylates (APEOs), such as nonylphenol ethoxylates (NPEOs), are high-production-volume surfactants used in laundry detergents, hard-surface cleaners, pesticide formulations, textile production, oils, paints, and other products. NPEOs comprise −80% of the total production of APEOs and are widely reported across diverse environmental matrices. Despite a growing push for replacement products, APEOs continue to be released into the environment through wastewater at significant levels. Research into related nonionic surfactants from varying sources has reported metabolic health impacts, and we have previously demonstrated that diverse APEOs and alcohol polyethoxylates promote adipogenesis in the murine 3T3-L1 pre-adipocyte model. These effects appeared to be independent of the base alkylphenol and related to the ethoxylate chain length, though limited research has evaluated NPEO exposures in animal models. The goals of this study were to assess the potential of NPEOs to promote adiposity (Nile red fluorescence quantification) and alter growth and/or development (toxicity, length, weight, and energy expenditure) of developmentally exposed zebrafish (Danio rerio). We also sought to expand our understanding of the ability to promote adiposity through evaluation in human mesenchymal stem cells. Herein, we demonstrated consistent adipogenic effects in two separate human bone-marrow-derived mesenchymal stem cell models, and that nonylphenol and its ethoxylates promoted weight gain and increased adipose deposition in developmentally exposed zebrafish. Notably, across both cell and zebrafish models we report increasing adipogenic/obesogenic activity with increasing ethoxylate chain lengths up to maximums around NPEO-6 and then decreasing activity with the longest ethoxylate chain lengths. This research suggests metabolic health concerns for these common obesogens, suggesting further need to assess molecular mechanisms and better characterize environmental concentrations for human health risk assessments. Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)
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17 pages, 1724 KiB  
Article
Protracted Impairment of Maternal Metabolic Health in Mouse Dams Following Pregnancy Exposure to a Mixture of Low Dose Endocrine-Disrupting Chemicals, a Pilot Study
by Alyssa K. Merrill, Timothy Anderson, Katherine Conrad, Elena Marvin, Tamarra James-Todd, Deborah A. Cory-Slechta and Marissa Sobolewski
Toxics 2021, 9(12), 346; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics9120346 - 09 Dec 2021
Cited by 6 | Viewed by 3212
Abstract
Pregnancy, a period of increased metabolic demands coordinated by fluctuating steroid hormones, is an understudied critical window of disease susceptibility for later-life maternal metabolic health. Epidemiological studies have identified associations between exposures to various endocrine-disrupting chemicals (EDCs) with an increased risk for metabolic [...] Read more.
Pregnancy, a period of increased metabolic demands coordinated by fluctuating steroid hormones, is an understudied critical window of disease susceptibility for later-life maternal metabolic health. Epidemiological studies have identified associations between exposures to various endocrine-disrupting chemicals (EDCs) with an increased risk for metabolic syndrome, obesity, and diabetes. Whether such adverse outcomes would be heightened by concurrent exposures to multiple EDCs during pregnancy, consistent with the reality that human exposures are to EDC mixtures, was examined in the current pilot study. Mouse dams were orally exposed to relatively low doses of four EDCs: (atrazine (10 mg/kg), bisphenol-A (50 µg/kg), perfluorooctanoic acid (0.1 mg/kg), 2,3,7,8-tetrachlorodibenzo-p-dioxin (0.036 µg/kg)), or the combination (MIX), from gestational day 7 until birth or for an equivalent 12 days in non-pregnant females. Glucose intolerance, serum lipids, weight, and visceral adiposity were assessed six months later. MIX-exposed dams exhibited hyperglycemia with a persistent elevation in blood glucose two hours after glucose administration in a glucose tolerance test, whereas no such effects were observed in MIX-exposed non-pregnant females. Correspondingly, MIX dams showed elevated serum low-density lipoprotein (LDL). There were no statistically significant differences in weight or visceral adipose; MIX dams showed an average visceral adipose volume to body volume ratio of 0.09, while the vehicle dams had an average ratio of 0.07. Collectively, these findings provide biological plausibility for the epidemiological associations observed between EDC exposures during pregnancy and subsequent maternal metabolic dyshomeostasis, and proof of concept data that highlight the importance of considering complex EDC mixtures based of off common health outcomes, e.g., for increased risk for later-life maternal metabolic effects following pregnancy. Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)
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14 pages, 1477 KiB  
Article
Cytotoxic and Transcriptomic Effects in Avian Hepatocytes Exposed to a Complex Mixture from Air Samples, and Their Relation to the Organic Flame Retardant Signature
by Kelsey Ha, Pu Xia, Doug Crump, Amandeep Saini, Tom Harner and Jason O’Brien
Toxics 2021, 9(12), 324; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics9120324 - 30 Nov 2021
Cited by 2 | Viewed by 2315
Abstract
Assessing complex environmental mixtures and their effects is challenging. In this study, we evaluate the utility of an avian in vitro screening approach to determine the effects of passive air sampler extracts collected from different global megacities on cytotoxicity and gene expression. Concentrations [...] Read more.
Assessing complex environmental mixtures and their effects is challenging. In this study, we evaluate the utility of an avian in vitro screening approach to determine the effects of passive air sampler extracts collected from different global megacities on cytotoxicity and gene expression. Concentrations of a suite of organic flame retardants (OFRs) were quantified in extracts from a total of 19 megacities/major cities in an earlier study, and levels were highly variable across sites. Chicken embryonic hepatocytes were exposed to serial dilutions of extracts from the 19 cities for 24 h. Cell viability results indicate a high level of variability in cytotoxicity, with extracts from Toronto, Canada, having the lowest LC50 value. Partial least squares (PLS) regression analysis was used to estimate LC50 values from OFR concentrations. PLS modeling of OFRs was moderately predictive of LC50 (p-value = 0.0003, r2 = 0.66, slope = 0.76, when comparing predicted LC50 to actual values), although only after one outlier city was removed from the analysis. A chicken ToxChip PCR array, comprising 43 target genes, was used to determine effects on gene expression, and similar to results for cell viability, gene expression profiles were highly variable among the megacities. PLS modeling was used to determine if gene expression was related to the OFR profiles of the extracts. Weak relationships to the ToxChip expression profiles could be detected for only three of the 35 OFRs (indicated by regression slopes between 0.6 and 0.5 when comparing predicted to actual OFR concentrations). While this in vitro approach shows promise in terms of evaluating effects of complex mixtures, we also identified several limitations that, if addressed in future studies, might improve its performance. Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)
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Review

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30 pages, 2058 KiB  
Review
Nanoplastics in Aquatic Environments: Impacts on Aquatic Species and Interactions with Environmental Factors and Pollutants
by Rafael Trevisan, Prabha Ranasinghe, Nishad Jayasundara and Richard T. Di Giulio
Toxics 2022, 10(6), 326; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics10060326 - 15 Jun 2022
Cited by 30 | Viewed by 7944
Abstract
Plastic production began in the early 1900s and it has transformed our way of life. Despite the many advantages of plastics, a massive amount of plastic waste is generated each year, threatening the environment and human health. Because of their pervasiveness and potential [...] Read more.
Plastic production began in the early 1900s and it has transformed our way of life. Despite the many advantages of plastics, a massive amount of plastic waste is generated each year, threatening the environment and human health. Because of their pervasiveness and potential for health consequences, small plastic residues produced by the breakdown of larger particles have recently received considerable attention. Plastic particles at the nanometer scale (nanoplastics) are more easily absorbed, ingested, or inhaled and translocated to other tissues and organs than larger particles. Nanoplastics can also be transferred through the food web and between generations, have an influence on cellular function and physiology, and increase infections and disease susceptibility. This review will focus on current research on the toxicity of nanoplastics to aquatic species, taking into account their interactive effects with complex environmental mixtures and multiple stressors. It intends to summarize the cellular and molecular effects of nanoplastics on aquatic species; discuss the carrier effect of nanoplastics in the presence of single or complex environmental pollutants, pathogens, and weathering/aging processes; and include environmental stressors, such as temperature, salinity, pH, organic matter, and food availability, as factors influencing nanoplastic toxicity. Microplastics studies were also included in the discussion when the data with NPs were limited. Finally, this review will address knowledge gaps and critical questions in plastics’ ecotoxicity to contribute to future research in the field. Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)
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22 pages, 1067 KiB  
Review
Effects of Phthalate Mixtures on Ovarian Folliculogenesis and Steroidogenesis
by Endia J. Fletcher, Ramsés Santacruz-Márquez, Vasiliki E. Mourikes, Alison M. Neff, Mary J. Laws and Jodi A. Flaws
Toxics 2022, 10(5), 251; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics10050251 - 16 May 2022
Cited by 22 | Viewed by 5184 | Correction
Abstract
The female reproductive system is dependent upon the health of the ovaries. The ovaries are responsible for regulating reproduction and endocrine function. Throughout a female’s reproductive lifespan, the ovaries undergo continual structural changes that are crucial for the maturation of ovarian follicles and [...] Read more.
The female reproductive system is dependent upon the health of the ovaries. The ovaries are responsible for regulating reproduction and endocrine function. Throughout a female’s reproductive lifespan, the ovaries undergo continual structural changes that are crucial for the maturation of ovarian follicles and the production of sex steroid hormones. Phthalates are known to target the ovaries at critical time points and to disrupt normal reproductive function. The US population is constantly exposed to measurable levels of phthalates. Phthalates can also pass placental barriers and affect the developing offspring. Phthalates are frequently prevalent as mixtures; however, most previous studies have focused on the effects of single phthalates on the ovary and female reproduction. Thus, the effects of exposure to phthalate mixtures on ovarian function and the female reproductive system remain unclear. Following a brief introduction to the ovary and its major roles, this review covers what is currently known about the effects of phthalate mixtures on the ovary, focusing primarily on their effects on folliculogenesis and steroidogenesis. Furthermore, this review focuses on the effects of phthalate mixtures on female reproductive outcomes. Finally, this review emphasizes the need for future research on the effects of environmentally relevant phthalate mixtures on the ovary and female reproduction. Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)
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Other

1 pages, 539 KiB  
Correction
Correction: Fletcher et al. Effects of Phthalate Mixtures on Ovarian Folliculogenesis and Steroidogenesis. Toxics 2022, 10, 251
by Endia J. Fletcher, Ramsés Santacruz-Márquez, Vasiliki E. Mourikes, Alison M. Neff, Mary J. Laws and Jodi A. Flaws
Toxics 2022, 10(10), 562; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics10100562 - 26 Sep 2022
Cited by 2 | Viewed by 1389
Abstract
The authors wish to make the following corrections to this paper [...] Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)
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2 pages, 3190 KiB  
Correction
Correction: Kassotis et al. Nonylphenol Polyethoxylates Enhance Adipose Deposition in Developmentally Exposed Zebrafish. Toxics 2022, 10, 99
by Christopher D. Kassotis, Matthew K. LeFauve, Yu-Ting Tiffany Chiang, Megan M. Knuth, Stacy Schkoda and Seth W. Kullman
Toxics 2022, 10(7), 345; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics10070345 - 22 Jun 2022
Viewed by 1017
Abstract
In the original publication [...] Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)
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32 pages, 1209 KiB  
Systematic Review
Exposure to Metal Mixtures in Association with Cardiovascular Risk Factors and Outcomes: A Scoping Review
by Gyeyoon Yim, Yuting Wang, Caitlin G. Howe and Megan E. Romano
Toxics 2022, 10(3), 116; https://0-doi-org.brum.beds.ac.uk/10.3390/toxics10030116 - 01 Mar 2022
Cited by 20 | Viewed by 4890
Abstract
Since the National Institute of Environmental Health Sciences (NIEHS) declared conducting combined exposure research as a priority area, literature on chemical mixtures has grown dramatically. However, a systematic evaluation of the current literature investigating the impacts of metal mixtures on cardiovascular disease (CVD) [...] Read more.
Since the National Institute of Environmental Health Sciences (NIEHS) declared conducting combined exposure research as a priority area, literature on chemical mixtures has grown dramatically. However, a systematic evaluation of the current literature investigating the impacts of metal mixtures on cardiovascular disease (CVD) risk factors and outcomes has thus far not been performed. This scoping review aims to summarize published epidemiology literature on the cardiotoxicity of exposure to multiple metals. We performed systematic searches of MEDLINE (PubMed), Scopus, and Web of Science to identify peer-reviewed studies employing statistical mixture analysis methods to evaluate the impact of metal mixtures on CVD risk factors and outcomes among nonoccupationally exposed populations. The search was limited to papers published on or after 1998, when the first dedicated funding for mixtures research was granted by NIEHS, through 1 October 2021. Twenty-nine original research studies were identified for review. A notable increase in relevant mixtures publications was observed starting in 2019. The majority of eligible studies were conducted in the United States (n = 10) and China (n = 9). Sample sizes ranged from 127 to 10,818. Many of the included studies were cross-sectional in design. Four primary focus areas included: (i) blood pressure and/or diagnosis of hypertension (n = 15), (ii) risk of preeclampsia (n = 3), (iii) dyslipidemia and/or serum lipid markers (n = 5), and (iv) CVD outcomes, including stroke incidence or coronary heart disease (n = 8). The most frequently investigated metals included cadmium, lead, arsenic, and cobalt, which were typically measured in blood (n = 15). The most commonly utilized multipollutant analysis approaches were Bayesian kernel machine regression (BKMR), weighted quantile sum regression (WQSR), and principal component analysis (PCA). To our knowledge, this is the first scoping review to assess exposure to metal mixtures in relation to CVD risk factors and outcomes. Recommendations for future studies evaluating the associations of exposure to metal mixtures with risk of CVDs and related risk factors include extending environmental mixtures epidemiologic studies to populations with wider metals exposure ranges, including other CVD risk factors or outcomes outside hypertension or dyslipidemia, using repeated measurement of metals to detect windows of susceptibility, and further examining the impacts of potential effect modifiers and confounding factors, such as fish and seafood intake. Full article
(This article belongs to the Special Issue Evaluating Chemical Exposures and Toxicity of Complex Mixtures and Multiple Stressors)
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