Toxic Mixtures Evaluation and Management

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 (31 December 2023) | Viewed by 13833

Special Issue Editor

Science Advisor, Agency for Toxic Substances and Disease Registry (ATSDR), Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA
Interests: risk assessment; mixtures toxicity; methods development; predictive toxicology and alternatives testing methods

Special Issue Information

Dear Colleagues,

Complex exposures to mixtures, chemical and non-chemical, are prevalent in our lives. Often such exposures are unintentional, even though they inherit a potential to cause adverse health effects. Incidentally the food we eat, the water we drink, and the air we breathe all contribute to this phenomenon. For the past several decades, there has been a demand and a growing emphasis on studies to address scientific issues and uncertainties in the evaluation of mixtures. Some of these studies have clarified our understanding of the basics of mixtures toxicology, potential role of non-interactive or interactive mechanisms, and manifestation of their pathways to cause health effects. Hence, risk assessors and decision makers should be cognizant of this knowledge-base to protect our communities from mixtures exposures. This special issue will highlight the recent findiings, identify and encourage innovative methods development that must be undertaken as influx of new mixtures continues in our communities.  Authors are welcome to submit original research papers, short communications, or review articles. We are looking forward to your contributions to make this an outstanding Special Issue that will capture the current literature.  

Dr. M. Moiz Mumtaz
Guest Editor

Manuscript Submission Information

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Keywords

  • mixtures assessments/case studies
  • adverse outcome pathways (AOP)
  • drugs and emerging pollutants
  • innovative/predictive approaches
  • guideline and frameworks
  • computational tools
  • modeling and artificial intelligence

Published Papers (10 papers)

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Research

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25 pages, 1643 KiB  
Article
Evaluation of a Proportional Response Addition Approach to Mixture Risk Assessment and Predictive Toxicology Using Data on Four Trihalomethanes from the U.S. EPA’s Multiple-Purpose Design Study
by Linda K. Teuschler, Richard C. Hertzberg, Anthony McDonald, Yusupha Mahtarr Sey and Jane Ellen Simmons
Toxics 2024, 12(4), 240; https://doi.org/10.3390/toxics12040240 - 25 Mar 2024
Viewed by 324
Abstract
In this study, proportional response addition (Prop-RA), a model for predicting response from chemical mixture exposure, is demonstrated and evaluated by statistically analyzing data on all possible binary combinations of the four regulated trihalomethanes (THMs). These THMs were the subject of a multipurpose [...] Read more.
In this study, proportional response addition (Prop-RA), a model for predicting response from chemical mixture exposure, is demonstrated and evaluated by statistically analyzing data on all possible binary combinations of the four regulated trihalomethanes (THMs). These THMs were the subject of a multipurpose toxicology study specifically designed to evaluate Prop-RA. The experimental design used a set of doses common to all components and mixtures, providing hepatotoxicity data on the four single THMs and the binary combinations. In Prop-RA, the contribution of each component to mixture toxicity is proportional to its fraction in the mixture based on its response at the total mixture dose. The primary analysis consisted of 160 evaluations. Statistically significant departures from the Prop-RA prediction were found for seven evaluations, with three predications that were greater than and four that were less than the predicted response; interaction magnitudes (n-fold difference in response vs. prediction) ranged from 1.3 to 1.4 for the former and 2.6 to 3.8 for the latter. These predictions support the idea that Prop-RA works best with chemicals where the effective dose ranges overlap. Prop-RA does not assume the similarity of toxic action or independence, but it can be applied to a mixture of components that affect the same organ/system, with perhaps unknown toxic modes of action. Full article
(This article belongs to the Special Issue Toxic Mixtures Evaluation and Management)
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12 pages, 884 KiB  
Article
In Vitro Toxicity Screening of Fifty Complex Mixtures in HepG2 Cells
by Sunmi Kim, Kyounghee Kang, Haena Kim and Myungwon Seo
Toxics 2024, 12(2), 126; https://doi.org/10.3390/toxics12020126 - 02 Feb 2024
Viewed by 742
Abstract
To develop the risk prediction technology for mixture toxicity, a reliable and extensive dataset of experimental results is required. However, most published literature only provides data on combinations containing two or three substances, resulting in a limited dataset for predicting the toxicity of [...] Read more.
To develop the risk prediction technology for mixture toxicity, a reliable and extensive dataset of experimental results is required. However, most published literature only provides data on combinations containing two or three substances, resulting in a limited dataset for predicting the toxicity of complex mixtures. Complex mixtures may have different mode of actions (MoAs) due to their varied composition, posing difficulty in the prediction using conventional toxicity prediction models, such as the concentration addition (CA) and independent action (IA) models. The aim of this study was to generate an experimental dataset comprising complex mixtures. To identify the target complex mixtures, we referred to the findings of the HBM4EU project. We identified three groups of seven to ten components that were commonly detected together in human bodies, namely environmental phenols, perfluorinated compounds, and heavy metal compounds, assuming these chemicals to have different MoAs. In addition, a separate mixture was added consisting of seven organophosphate flame retardants (OPFRs), which may have similar chemical structures. All target substances were tested for cytotoxicity using HepG2 cell lines, and subsequently 50 different complex mixtures were randomly generated with equitoxic mixtures of EC10 levels. To determine the interaction effect, we calculated the model deviation ratio (MDR) by comparing the observed EC10 with the predicted EC10 from the CA model, then categorized three types of interactions: antagonism, additivity, and synergism. Dose–response curves and EC values were calculated for all complex mixtures. Out of 50 mixtures, none demonstrated synergism, while six mixtures exhibited an antagonistic effect. The remaining mixtures exhibited additivity with MDRs ranging from 0.50 to 1.34. Our experimental data have been formatted to and constructed for the database. They will be utilized for further research aimed at developing the combined CA/IA approaches to support mixture risk assessment. Full article
(This article belongs to the Special Issue Toxic Mixtures Evaluation and Management)
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26 pages, 6389 KiB  
Article
Integrative Chemical–Biological Grouping of Complex High Production Volume Substances from Lower Olefin Manufacturing Streams
by Alexandra C. Cordova, William D. Klaren, Lucie C. Ford, Fabian A. Grimm, Erin S. Baker, Yi-Hui Zhou, Fred A. Wright and Ivan Rusyn
Toxics 2023, 11(7), 586; https://doi.org/10.3390/toxics11070586 - 05 Jul 2023
Cited by 1 | Viewed by 1249
Abstract
Human cell-based test methods can be used to evaluate potential hazards of mixtures and products of petroleum refining (“unknown or variable composition, complex reaction products, or biological materials” substances, UVCBs). Analyses of bioactivity and detailed chemical characterization of petroleum UVCBs were used separately [...] Read more.
Human cell-based test methods can be used to evaluate potential hazards of mixtures and products of petroleum refining (“unknown or variable composition, complex reaction products, or biological materials” substances, UVCBs). Analyses of bioactivity and detailed chemical characterization of petroleum UVCBs were used separately for grouping these substances; a combination of the approaches has not been undertaken. Therefore, we used a case example of representative high production volume categories of petroleum UVCBs, 25 lower olefin substances from low benzene naphtha and resin oils categories, to determine whether existing manufacturing-based category grouping can be supported. We collected two types of data: nontarget ion mobility spectrometry-mass spectrometry of both neat substances and their organic extracts and in vitro bioactivity of the organic extracts in five human cell types: umbilical vein endothelial cells and induced pluripotent stem cell-derived hepatocytes, endothelial cells, neurons, and cardiomyocytes. We found that while similarity in composition and bioactivity can be observed for some substances, existing categories are largely heterogeneous. Strong relationships between composition and bioactivity were observed, and individual constituents that determine these associations were identified. Overall, this study showed a promising approach that combines chemical composition and bioactivity data to better characterize the variability within manufacturing categories of petroleum UVCBs. Full article
(This article belongs to the Special Issue Toxic Mixtures Evaluation and Management)
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14 pages, 2818 KiB  
Article
In Vitro Genotoxicity Evaluation of PAHs in Mixtures Using Experimental Design
by Rebecca Castel, Virginie Tassistro, Magalie Claeys-Bruno, Laure Malleret and Thierry Orsière
Toxics 2023, 11(5), 470; https://doi.org/10.3390/toxics11050470 - 19 May 2023
Cited by 3 | Viewed by 921
Abstract
Settled dusts are sinks for environmental pollutants, including Polycyclic Aromatic Hydrocarbons (PAHs) that are ubiquitous, persistent, and carcinogenic. To assess their toxicity in mixtures, Toxic Equivalent Factors (TEFs) are routinely used and based on the hypothesis of additive effects, although PAH interactions may [...] Read more.
Settled dusts are sinks for environmental pollutants, including Polycyclic Aromatic Hydrocarbons (PAHs) that are ubiquitous, persistent, and carcinogenic. To assess their toxicity in mixtures, Toxic Equivalent Factors (TEFs) are routinely used and based on the hypothesis of additive effects, although PAH interactions may occur and remain an open issue. This study investigated genotoxic binary interaction effects for six PAHs in mixtures using two in vitro assays and estimated Genotoxic Equivalent Factors (GEFs) to roughly predict the genotoxicity of PAH in mixtures. The Design of the Experiment approach was used with the micronucleus assay for cytostasis and micronuclei frequency and the alkaline comet assay for DNA damage. GEFs were determined for each PAH independently and in a mixture. For the cytostasis endpoint, no PAHs interaction was noted. BbF and BaP had a synergistic effect on DNA damage. All the PAH interacted between them regarding chromosomal damage. Although the calculated GEFs were similar to the TEFs, the latter may underestimate the genotoxic potential of a PAH mixture. GEFs calculated for PAH alone were lower than GEFs for PAHs in mixtures; thus, mixtures induce greater DNA/chromosomal damage than expected. This research helps to advance the challenging issue of contaminant mixtures’ effects on human health. Full article
(This article belongs to the Special Issue Toxic Mixtures Evaluation and Management)
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14 pages, 944 KiB  
Article
Unknown Organofluorine Mixtures in U.S. Adult Serum:Contribution from Pharmaceuticals?
by Emily H. Pennoyer, Wendy Heiger-Bernays, Rudolf Aro, Leo W. Y. Yeung, Jennifer J. Schlezinger and Thomas F. Webster
Toxics 2023, 11(5), 416; https://doi.org/10.3390/toxics11050416 - 27 Apr 2023
Cited by 1 | Viewed by 1954
Abstract
Organofluorines occur in human serum as complex mixtures of known and unidentified compounds. Human biomonitoring traditionally uses targeted analysis to measure the presence of known and quantifiable per- and polyfluoroalkyl substances (PFAS) in serum, yet characterization of exposure to and quantification of PFAS [...] Read more.
Organofluorines occur in human serum as complex mixtures of known and unidentified compounds. Human biomonitoring traditionally uses targeted analysis to measure the presence of known and quantifiable per- and polyfluoroalkyl substances (PFAS) in serum, yet characterization of exposure to and quantification of PFAS are limited by the availability of methods and analytical standards. Studies comparing extractable organofluorine (EOF) in serum to measured PFAS using organofluorine mass balance show that measurable PFAS only explain a fraction of EOF in human serum and that other sources of organofluorine may exist. The gap in fluorine mass balance has important implications for human biomonitoring because the total body burden of PFAS cannot be characterized and the chemical species that make up unidentified EOF are unknown. Many highly prescribed pharmaceuticals contain organofluorine (e.g., Lipitor, Prozac) and are prescribed with dosing regimens designed to maintain a therapeutic range of concentrations in serum. Therefore, we hypothesize organofluorine pharmaceuticals contribute to EOF in serum. We use combustion ion chromatography to measure EOF in commercial serum from U.S. blood donors. Using fluorine mass balance, we assess differences in unexplained organofluorine (UOF) associated with pharmaceutical use and compare them with concentrations of organofluorine predicted based on the pharmacokinetic properties of each drug. Pharmacokinetic estimates of organofluorine attributable to pharmaceuticals ranged from 0.1 to 55.6 ng F/mL. Analysis of 44 target PFAS and EOF in samples of commercial serum (n = 20) shows the fraction of EOF not explained by Σ44 PFAS ranged from 15% to 86%. Self-reported use of organofluorine pharmaceuticals is associated with a 0.36 ng F/mL (95% CL: −1.26 to 1.97) increase in UOF, on average, compared to those who report not taking organofluorine pharmaceuticals. Our study is the first to assess sources of UOF in U.S. serum and examine whether organofluorine pharmaceuticals contribute to EOF. Discrepancies between pharmacokinetic estimates and EOF may be partly explained by differences in analytical measurements. Future analyses using EOF should consider multiple extraction methods to include cations and zwitterions. Whether organofluorine pharmaceuticals are classified as PFAS depends on the definition of PFAS. Full article
(This article belongs to the Special Issue Toxic Mixtures Evaluation and Management)
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10 pages, 307 KiB  
Article
From Cohort to Cohort: A Similar Mixture Approach (SMACH) to Evaluate Exposures to a Mixture Leading to Thyroid-Mediated Neurodevelopmental Effects Using NHANES Data
by Maria Sapounidou, Patrik L. Andersson, Michelle Leemans, Jean-Baptiste Fini, Barbara Demeneix, Joëlle Rüegg, Carl-Gustaf Bornehag and Chris Gennings
Toxics 2023, 11(4), 331; https://doi.org/10.3390/toxics11040331 - 31 Mar 2023
Cited by 1 | Viewed by 1466
Abstract
Prenatal exposure to a mixture (MIX N) of eight endocrine-disrupting chemicals has been associated with language delay in children in a Swedish pregnancy cohort. A novel approach was proposed linking this epidemiological association with experimental evidence, where the effect of MIX N on [...] Read more.
Prenatal exposure to a mixture (MIX N) of eight endocrine-disrupting chemicals has been associated with language delay in children in a Swedish pregnancy cohort. A novel approach was proposed linking this epidemiological association with experimental evidence, where the effect of MIX N on thyroid hormone signaling was assessed using the Xenopus eleuthero-embryonic thyroid assay (XETA OECD TG248). From this experimental data, a point of departure (PoD) was derived based on OECD guidance. Our aim in the current study was to use updated toxicokinetic models to compare exposures of women of reproductive age in the US population to MIX N using a Similar Mixture Approach (SMACH). Based on our findings, 66% of women of reproductive age in the US (roughly 38 million women) had exposures sufficiently similar to MIX N. For this subset, a Similar Mixture Risk Index (SMRIHI) was calculated comparing their exposures to the PoD. Women with SMRIHI > 1 represent 1.1 million women of reproductive age. Older women, Mexican American and other/multi race women were less likely to have high SMRIHI values compared to Non-Hispanic White women. These findings indicate that a reference mixture of chemicals identified in a Swedish cohort—and tested in an experimental model for establishment of (PoDs)—is also of health relevance in a US population. Full article
(This article belongs to the Special Issue Toxic Mixtures Evaluation and Management)
20 pages, 4685 KiB  
Article
Complex Mixtures: Array PBPK Modeling of Jet Fuel Components
by Teresa R. Sterner, Tammie R. Covington and David R. Mattie
Toxics 2023, 11(2), 187; https://doi.org/10.3390/toxics11020187 - 17 Feb 2023
Cited by 1 | Viewed by 1459
Abstract
An array physiologically-based pharmacokinetic (PBPK) model represents a streamlined method to simultaneously quantify dosimetry of multiple compounds. To predict internal dosimetry of jet fuel components simultaneously, an array PBPK model was coded to simulate inhalation exposures to one or more selected compounds: toluene, [...] Read more.
An array physiologically-based pharmacokinetic (PBPK) model represents a streamlined method to simultaneously quantify dosimetry of multiple compounds. To predict internal dosimetry of jet fuel components simultaneously, an array PBPK model was coded to simulate inhalation exposures to one or more selected compounds: toluene, ethylbenzene, xylenes, n-nonane, n-decane, and naphthalene. The model structure accounts for metabolism of compounds in the lung and liver, as well as kinetics of each compound in multiple tissues, including the cochlea and brain regions associated with auditory signaling (brainstem and temporal lobe). The model can accommodate either diffusion-limited or flow-limited kinetics (or a combination), allowing the same structure to be utilized for compounds with different characteristics. The resulting model satisfactorily simulated blood concentration and tissue dosimetry data from multiple published single chemical rat studies. The model was then utilized to predict tissue kinetics for the jet fuel hearing loss study (JTEH A, 25:1-14). The model was also used to predict rat kinetic comparisons between hypothetical exposures to JP-8 or a Virent Synthesized Aromatic Kerosene (SAK):JP-8 50:50 blend at the occupational exposure limit (200 mg/m3). The array model has proven useful for comparing potential tissue burdens resulting from complex mixture exposures. Full article
(This article belongs to the Special Issue Toxic Mixtures Evaluation and Management)
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17 pages, 2533 KiB  
Article
Dosing Methods to Enable Cell-Based In Vitro Testing of Complex Substances: A Case Study with a PAH Mixture
by Alexandra C. Cordova, Lucie C. Ford, Alan Valdiviezo, Alina T. Roman-Hubers, Thomas J. McDonald, Weihsueh A. Chiu and Ivan Rusyn
Toxics 2023, 11(1), 19; https://doi.org/10.3390/toxics11010019 - 26 Dec 2022
Cited by 1 | Viewed by 1876
Abstract
Cell-based testing of multi-constituent substances and mixtures for their potential adverse health effects is difficult due to their complex composition and physical–chemical characteristics. Various extraction methods are typically used to enable studies in vitro; however, a limited number of solvents are biocompatible with [...] Read more.
Cell-based testing of multi-constituent substances and mixtures for their potential adverse health effects is difficult due to their complex composition and physical–chemical characteristics. Various extraction methods are typically used to enable studies in vitro; however, a limited number of solvents are biocompatible with in vitro studies and the extracts may not fully represent the original test article’s composition. While the methods for dosing with “difficult-to-test” substances in aquatic toxicity studies are well defined and widely used, they are largely unsuited for small-volume (100 microliters or less) in vitro studies with mammalian cells. Therefore, we aimed to evaluate suitability of various scaled-down dosing methods for high-throughput in vitro testing by using a mixture of polycyclic aromatic hydrocarbons (PAH). Specifically, we compared passive dosing via silicone micro-O-rings, cell culture media-accommodated fraction, and traditional solvent (dimethyl sulfoxide) extraction procedures. Gas chromatography-tandem mass spectrometry (GC-MS/MS) was used to evaluate kinetics of PAH absorption to micro-O-rings, as well as recovery of PAH and the extent of protein binding in cell culture media with and without cells for each dosing method. Bioavailability of the mixture from different dosing methods was also evaluated by characterizing in vitro cytotoxicity of the PAH mixture using EA.hy926 and HepG2 human cell lines. Of the tested dosing methods, media accommodated fraction (MAF) was determined to be the most appropriate method for cell-based studies of PAH-containing complex substances and mixtures. This conclusion is based on the observation that the highest fraction of the starting materials can be delivered using media accommodated fraction approach into cell culture media and thus enable concentration-response in vitro testing. Full article
(This article belongs to the Special Issue Toxic Mixtures Evaluation and Management)
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23 pages, 2504 KiB  
Article
Leveraging Multiple Data Streams for Prioritization of Mixtures for Hazard Characterization
by Brianna N. Rivera, Christine C. Ghetu, Yvonne Chang, Lisa Truong, Robyn L. Tanguay, Kim A. Anderson and Susan C. Tilton
Toxics 2022, 10(11), 651; https://doi.org/10.3390/toxics10110651 - 29 Oct 2022
Cited by 2 | Viewed by 1572
Abstract
There is a growing need to establish alternative approaches for mixture safety assessment of polycyclic aromatic hydrocarbons (PAHs). Due to limitations with current component-based approaches, and the lack of established methods for using whole mixtures, a promising alternative is to use sufficiently similar [...] Read more.
There is a growing need to establish alternative approaches for mixture safety assessment of polycyclic aromatic hydrocarbons (PAHs). Due to limitations with current component-based approaches, and the lack of established methods for using whole mixtures, a promising alternative is to use sufficiently similar mixtures; although, an established framework is lacking. In this study, several approaches are explored to form sufficiently similar mixtures. Multiple data streams including environmental concentrations and empirically and predicted toxicity data for cancer and non-cancer endpoints were used to prioritize chemical components for mixture formations. Air samplers were analyzed for unsubstituted and alkylated PAHs. A synthetic mixture of identified PAHs was created (Creosote-Fire Mix). Existing toxicity values and chemical concentrations were incorporated to identify hazardous components in the Creosote-Fire Mix. Sufficiently similar mixtures of the Creosote-Fire Mix were formed based on (1) relative abundance; (2) toxicity values; and (3) a combination approach incorporating toxicity and abundance. Hazard characterization of these mixtures was performed using high-throughput screening in primary normal human bronchial epithelium (NHBE) and zebrafish. Differences in chemical composition and potency were observed between mixture formation approaches. The toxicity-based approach (Tox Mix) was the most potent mixture in both models. The combination approach (Weighted-Tox Mix) was determined to be the ideal approach due its ability to prioritize chemicals with high exposure and hazard potential. Full article
(This article belongs to the Special Issue Toxic Mixtures Evaluation and Management)
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14 pages, 1648 KiB  
Concept Paper
Integrating “One Health” Concepts in the Design of Sustainable Systems for Environmental Use
by Mark S. Johnson and Valerie H. Adams
Toxics 2023, 11(3), 280; https://doi.org/10.3390/toxics11030280 - 19 Mar 2023
Viewed by 926
Abstract
Ensuring for the national defense requires the use of substances such as energetics, propellants, pyrotechnics, and other materials in environmental applications. Systems that use these materials do so in testing and training environments and must be used in an environmentally sustained manner to [...] Read more.
Ensuring for the national defense requires the use of substances such as energetics, propellants, pyrotechnics, and other materials in environmental applications. Systems that use these materials do so in testing and training environments and must be used in an environmentally sustained manner to ensure success during actual kinetic defensive operations. Environmental and occupational health assessments require a weighted evaluation of toxicity, bioaccumulation, persistence, and environmental fate and transport considerations for each substance in the formulation to include potential combustion products. Data that support these criteria need to be collected in a phased and matrixed approach and considered iteratively as technology advances. Further, these criteria are often considered as disparate and separate; hence, comparing favorable aspects of one may or may not offset detrimental data from another. Here, we describe an approach to the phased collection of environmental, safety, and occupational health (ESOH) information for new systems and substances and provide recommendations for evaluating such data streams in making decisions for use and for evaluating alternatives. Full article
(This article belongs to the Special Issue Toxic Mixtures Evaluation and Management)
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