Special Issue "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 "Exposome".
Deadline for manuscript submissions: 17 December 2021.
Special Issue Editors
Interests: chemical mixtures; endocrine disrupting chemicals; metabolic health; adipogenesis; environmental toxicology; multiple stressors; obesogens
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 papers will be 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 1600 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
Planned Papers
The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.
Title: Protracted and impaired maternal metabolic effects induced by pregnancy exposure to a mixture of low dose endocrine disrupting chemicals
Authors: Alyssa K. Merrill 1, Timothy Anderson 1, Katherine Conrad 1, Elena Marvin 1, Tamarra James-Todd 2, Deborah A. Cory-Slechta 1, and Marissa Sobolewski 1
Affiliation: 1 Dept. of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY. 2 Dept. of Environmental Health, Harvard University, Boston, MA.
Abstract: Pregnancy is an understudied critical window of disease susceptibility for life-long maternal health. Epidemiological research has identified associations of exposures to multiple endocrine disrupting chemicals (EDCs) with an increased risk for metabolic disorders, obesity, and diabetes. Pregnancy is a period of rapid physiological changes coordinated by fluctuating steroid hormones that may be a target of EDC exposures. Animal models provide biological plausibility for epidemiological associations between EDC exposure with obesity and Type 2 diabetes. However, it’s unclear whether exposure to these EDCs in mixtures administered at low doses via a translationally relevant route of oral exposure alters long-term maternal metabolic disease risk. To address this possibility, mouse dams were exposed to relatively low doses of four EDCs alone (atrazine (10mg/kg), bisphenol-A (50µg/kg), perfluorooctanoic acid (0.1mg/kg), 2,3,7,8-tetrachlorodibenzo-p-dioxin (0.036µg/kg)), or in combination (MIX), from gestational day 7 until birth. Glucose intolerance, serum lipids, weight, and visceral adiposity were assessed in dams six months following birth. MIX produced hyperglycemia with a persistent and significant elevation in blood glucose two-hours after glucose administration in a glucose tolerance test. Correspondingly, MIX dams had elevated serum total cholesterol and low-density lipoprotein (LDL). No significant differences in weight occurred in dams across the six months, however, dams had a marginally significant increase in visceral fat with a 30% increase in visceral adipose volume. Collectively, these data provide biological plausibility for the epidemiological associations observed between pregnancy EDC exposures and highlight the importance of considering EDC mixtures for increased risk for adverse long-term maternal metabolic effects following pregnancy.
Title: Mixture-Induced Impacts of Chemicals in Everyday Household Environments
Authors: Celeste Carberry, Toby Turla, Lauren Koval, and Julia E Rager
Affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, NC, USA
Abstract: There are thousands of chemicals that humans can be exposed to in their everyday household environment, the majority of which lack substantial testing for potential exposure and toxicity. This study aimed to address this gap by implementing in silico methods to prioritize co-occurring chemicals that likely occur as mixtures in our everyday household environment, that also target a common molecular mediator, thus representing understudied mixtures that may exacerbate toxicity in humans. To detail, the Chemical Exposures Database (ChemExpoDB) was queried to identify which chemicals co-occur in everyday household exposure sources. Chemicals were pre-selected to include those that target a critical mediator involved in liver cell health and toxicity, namely, the peroxisome proliferator activated receptor gamma (PPARg). These co-occurring chemicals were thus hypothesized to exert synergistic effects on PPARg expression. To test this critical hypothesis, five commonly co-occurring chemicals were tested individually and in combination in human liver HepG2 cells. Findings support the potential synergy of these chemicals on PPARg expression, highlighting mixtures-induced changes that were amplified in comparison to individual chemical-induced changes. Together, this study demonstrates the utility of in silico-based methods to prioritize chemicals that co-occur in the environment for mixtures toxicity testing, and highlights relationships between understudied chemicals and changes in PPARg-associated signaling.
Title: Integrated Approach to Human Health Assessment of mixtures of per- and polyfluoroalkyl substances
Authors: Jason C. Lambert
Affiliation: United States Environmental Protection Agencydisabled, Washington, D.C., USA
Abstract: A diverse landscape of per- and polyfluoroalkyl substances (PFAS) co-occur in environmental media such as water, soil, and air. Indeed, biomonitoring data indicate mixtures of PFAS in randomized human serum samples. To date, Federal and State level human health assessments of PFAS have focused on the potential toxic effects of each species individually. However, based on health effects data primarily from experimental animal models, there are clear indications that many PFAS impact similar domains, such as liver, thyroid, and developmental/reproductive endpoints. Therefore it is imperative to evaluate the potential for joint toxicity of PFAS using toxicity data when and where available. Unfortunately, across the 100's to 1000's of PFAS present in commerce, virtually no toxicity data exists to inform human health assessment, with a few exceptions. As such, integrating the totality of information across traditional bioassay and new approach methodology (NAM)-based platforms will be key for advancing human health assessment of PFAS mixtures. This manuscript will provide a framing of how to assemble information across diverse data sources and platforms to: (1) conduct evidence-based grouping or subgrouping of "like" PFAS; and (2) conduct mixtures dose-response assessment to ascertain joint toxicity of PFAS mixtures.
Title: Is Mixtures Additivity Supported by Empirical Data? A Case Study of Developmental Toxicity of PFOS and 6:2FTS in Wildtype Zebrafish Embryos
Authors: M.O. Messak 1, C.M. Whipps 1, R.R. Razavi 1, and P.E. Goodrum 1,2
Affiliation: 1 State University of New York College of Environmental Science and Forestry 2 GSI Environmental, Inc.
Abstract: Per- and polyfluoroalkyl substances (PFAS) are now 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 remains important data gaps regarding the mode of action for toxicity of PFAS mixtures. The present study aimed to evaluate the developmental toxicity effects of two key components of aqueous film forming foam, perfluorosulfonic acid (PFOS) and 6:2 fluorotelomer sulfonic acid (6:2 FTS), on wildtype (AB) zebrafish embryos. Normal fertilized zebrafish embryos were exposed to either PFOS or a mixture of PFOS and 6:2 FTS from 48 to 120 hours post fertilization. Five treatment levels were selected to encompass environmentally relevant exposure levels. Experimental endpoints consisted of mortality and morphological anomalies such as larval body length, yolk sac area, and swim bladder inflation. A stereomicroscope was used to image morphological characteristics of the embryos over the course of the experiment. Dose response analysis focused on general effects, such as tail deformations and an uninflated swim bladder, as well as hatching rate and success. Whole transcriptome analysis was applied to both component and whole mixture study samples and mapped using the current zebrafish genome database. Results indicate that the assumption of additivity of PFAS mixtures may be supported for selected endpoints. Recommendations for additional investigations are provided to further our understanding of the toxicity of PFAS mixtures to aquatic organisms.
Title: The potential threat of nanoplastics in a changing world: a review on the effects of multiple stressors and complex mixtures on nanoplastics toxicity to aquatic species
Authors: Rafael Trevisan, Prabha Ranasinghe, Nishad Jayasundara, Richard Di Giulio
Affiliation: Department of Biochemistry, Federal University of Santa Catarina. Florianópolis, Brazil. Nicholas School of the Environment, Duke University. Durham, US.
Abstract: The production of plastics materials started in the early 1900s and one century later it has changed our way of life. But together with many of the innovations created by plastics, an enormous amount of plastic waste is generated every year, posing a real threat to the environment and human health. Recently, special attention is been called to the small plastic residues generated by the breakdown of larger particles, due to their ubiquitous presence and probability to cause adverse health effects. Among small plastic particles, plastics particles at the nanometer range (nanoplastics) are more easily absorbed, ingested, or inhaled and translocated to other tissues and organs. Nanoplastics were also shown to be transferred to the food web and between generations, to impact cellular function and physiology and to amplify infections and disease susceptibility. Due to our changing world scenario, nanoplastics in the environment are subjected to interactions with other chemicals, pollutants, and microorganisms, potentially acting as carriers of environmental pollutants and pathogens (the so-called Trojan Horse effect). For aquatic species, exposure to nanoplastics can happen in the presence of other environmental stressors, such as increased water temperature, ocean acidification, and hypoxic conditions. This review will address recent studies on the toxicity of nanoplastics to aquatic species in light of the potential effects of environmental complex mixtures and multiple stressors.
Title: Exposure to metal mixtures and cardiometabolic outcomes: systematic review
Authors: Gyeyoon Yim, Caitlin Howe and Megan Romano
Affiliation: Department of Epidemiology, Geisel School of Medicine at Dartmouth, NH, USA
Abstract: Cardiovascular disease (CVD) is the leading cause of death globally. Mounting evidence from human studies suggests that environmental exposure to toxic metals is associated with increased risk for CVD and related risk factors, such as hypertension and metabolic syndrome, even in early life. Several demographic and behavioral risk factors for cardiometabolic disorders have been observed, but a growing number of investigations suggest that environmental exposures, such as metals, may play a role in risk of cardiometabolic disorders. Recognizing that humans are exposed to multiple metals simultaneously, advanced statistical methods have been developed to overcome some of the challenges inherent to evaluating multiple correlated contaminants. However, to date no review has examined the current body of literature investigating associations between metal mixture exposures and cardiometabolic outcomes using multi-pollutant approaches. To address this gap, we will conduct a systematic review to summarize previous studies which applied environmental mixture approaches to investigate associations between multiple metal exposures and cardiometabolic outcomes (CVD, hypertension, type 2 diabetes mellitus, metabolic syndrome, obesity, pregnancy-induced hypertension, gestational hypertension, preeclampsia, gestational diabetes mellitus (GDM), hemolysis, elevated liver enzymes, and low platelet count (HELLP) Syndrome). We will systematically search commonly used electric database, such as PubMed and EMBASE, for published articles employing multi-pollutant statistical methods in the association of exposure to metal mixtures with cardiometabolic outcomes. Human population and English literature will be imposed as inclusion criteria. The quality of studies will be assessed using the Newcastle-Ottawa scale. The search results will be synthesized and reported following the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). General findings from the selected studies will be integrated/summarized, with the most commonly used statistical methods and consistently observed associations of individual metals within a mixture with cardiometabolic outcomes. Recommendations for future research on metal mixtures and cardiometabolic outcomes will be discussed.
Title: Prenatal exposure to a realistic EDC mixture (NeuroMix) affects brain and behavior in rats
Authors: Andrea C. Gore, Tatum Moore, Matthew Groom, Lindsay Thompson
Affiliation: The University of Texas at Austin
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 mixture designed to represent the real-world situation of multiple simultaneous exposure. The choice of EDCs for the mixture, which we refer to as “NeuroMix,” was informed by evidence for neurobiological effects in single-compound studies. 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 (social, anxiety-like) in adulthood. A subset of rats were also given a stress challenge in adolescence. Results showed a number of outcomes affected by prenatal NeuroMix exposure in a sex-specific manner. NeuroMix males, but not females, had decreased body weight and smaller anogenital index through life. Males also had a significant delay in the age at puberty. Several behavioral changes were observed, and these were influenced by adolescent stress [to elaborate]. Thus, a low-dose mixture of EDCs changes postnatal development and adult behaviors, as well as responses to stress. This finding is important and novel because it shows the interaction of two realistic environmental challenges on long-term outcomes.
Title: In vitro Toxicological Evaluation of Passive Air Sample Extracts from GAPS-Megacities in Avian Hepatocytes
Authors: Kelsey Ha 1,2, Xia Pu 2, Doug Crump 2,*, Amandeep Saini 3, Tom Harner 3, Jason O’Brien 2
Affiliation: 1 Department of Chemistry and Biomolecular Sciences, University of Ottawa 2 National Wildlife Research Centre, Environment and Climate Change Canada, Ottawa, Ontario, Canada 3 Air Quality Processes Research Section, Environment and Climate Change Canada, Toronto, Ontario
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 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 hours. Cell viability results indicate a high level of variability in cytotoxicity, with extracts from Toronto, Canada, having the lowest LC50 value. Partial least squares regression analysis was used to estimate LC50 values from OFR concentrations for each city. Estimated values had significant correlation with the actual measured LC50 values. 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. In general, OFR concentrations, LC50 values and gene expression dysregulation were not highly correlated; however, the in vitro approach shows promise in terms of evaluating effects of complex mixtures.