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

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
Guest Editor
Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, RTP, 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 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.


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

Published Papers

This special issue is now open for submission, see below for planned papers.

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.

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