A Population-Based Human In Vitro Approach to Quantify Inter-Individual Variability in Responses to Chemical Mixtures
Human cell-based population-wide in vitro models have been proposed as a strategy to derive chemical-specific estimates of inter-individual variability; however, the utility of this approach has not yet been tested for cumulative exposures in mixtures. This study aimed to test defined mixtures and t...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Series: | Toxics |
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| Online Access: | https://www.mdpi.com/2305-6304/10/8/441 |
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| author | Lucie C. Ford Suji Jang Zunwei Chen Yi-Hui Zhou Paul J. Gallins Fred A. Wright Weihsueh A. Chiu Ivan Rusyn |
| author_facet | Lucie C. Ford Suji Jang Zunwei Chen Yi-Hui Zhou Paul J. Gallins Fred A. Wright Weihsueh A. Chiu Ivan Rusyn |
| author_sort | Lucie C. Ford |
| collection | DOAJ |
| description | Human cell-based population-wide in vitro models have been proposed as a strategy to derive chemical-specific estimates of inter-individual variability; however, the utility of this approach has not yet been tested for cumulative exposures in mixtures. This study aimed to test defined mixtures and their individual components and determine whether adverse effects of the mixtures were likely to be more variable in a population than those of the individual chemicals. The in vitro model comprised 146 human lymphoblastoid cell lines from four diverse subpopulations of European and African descent. Cells were exposed, in concentration–response, to 42 chemicals from diverse classes of environmental pollutants; in addition, eight defined mixtures were prepared from these chemicals using several exposure- or hazard-based scenarios. Points of departure for cytotoxicity were derived using Bayesian concentration–response modeling and population variability was quantified in the form of a toxicodynamic variability factor (TDVF). We found that 28 chemicals and all mixtures exhibited concentration–response cytotoxicity, enabling calculation of the TDVF. The median TDVF across test substances, for both individual chemicals or defined mixtures, ranged from a default assumption (10<sup>1/2</sup>) of toxicodynamic variability in human population to >10. The data also provide a proof of principle for single-variant genome-wide association mapping for toxicity of the chemicals and mixtures, although replication would be necessary due to statistical power limitations with the current sample size. This study demonstrates the feasibility of using a set of human lymphoblastoid cell lines as an in vitro model to quantify the extent of inter-individual variability in hazardous properties of both individual chemicals and mixtures. The data show that population variability of the mixtures is unlikely to exceed that of the most variable component, and that similarity in genome-wide associations among components may be used to accrue additional evidence for grouping of constituents in a mixture for cumulative assessments. |
| first_indexed | 2024-03-09T03:45:54Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2305-6304 |
| language | English |
| last_indexed | 2024-03-09T03:45:54Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxics |
| spelling | doaj.art-d5bf0ff21625423d8a0343bd32d0849c2023-12-03T14:34:49ZengMDPI AGToxics2305-63042022-08-0110844110.3390/toxics10080441A Population-Based Human In Vitro Approach to Quantify Inter-Individual Variability in Responses to Chemical MixturesLucie C. Ford0Suji Jang1Zunwei Chen2Yi-Hui Zhou3Paul J. Gallins4Fred A. Wright5Weihsueh A. Chiu6Ivan Rusyn7Interdisciplinary Faculty of Toxicology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USAInterdisciplinary Faculty of Toxicology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USAInterdisciplinary Faculty of Toxicology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USADepartments of Biological Sciences and Statistics, North Carolina State University, Raleigh, NC 27695, USABioinformatics Research Center, North Carolina State University, Raleigh, NC 27695, USADepartments of Biological Sciences and Statistics, North Carolina State University, Raleigh, NC 27695, USAInterdisciplinary Faculty of Toxicology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USAInterdisciplinary Faculty of Toxicology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USAHuman cell-based population-wide in vitro models have been proposed as a strategy to derive chemical-specific estimates of inter-individual variability; however, the utility of this approach has not yet been tested for cumulative exposures in mixtures. This study aimed to test defined mixtures and their individual components and determine whether adverse effects of the mixtures were likely to be more variable in a population than those of the individual chemicals. The in vitro model comprised 146 human lymphoblastoid cell lines from four diverse subpopulations of European and African descent. Cells were exposed, in concentration–response, to 42 chemicals from diverse classes of environmental pollutants; in addition, eight defined mixtures were prepared from these chemicals using several exposure- or hazard-based scenarios. Points of departure for cytotoxicity were derived using Bayesian concentration–response modeling and population variability was quantified in the form of a toxicodynamic variability factor (TDVF). We found that 28 chemicals and all mixtures exhibited concentration–response cytotoxicity, enabling calculation of the TDVF. The median TDVF across test substances, for both individual chemicals or defined mixtures, ranged from a default assumption (10<sup>1/2</sup>) of toxicodynamic variability in human population to >10. The data also provide a proof of principle for single-variant genome-wide association mapping for toxicity of the chemicals and mixtures, although replication would be necessary due to statistical power limitations with the current sample size. This study demonstrates the feasibility of using a set of human lymphoblastoid cell lines as an in vitro model to quantify the extent of inter-individual variability in hazardous properties of both individual chemicals and mixtures. The data show that population variability of the mixtures is unlikely to exceed that of the most variable component, and that similarity in genome-wide associations among components may be used to accrue additional evidence for grouping of constituents in a mixture for cumulative assessments.https://www.mdpi.com/2305-6304/10/8/441population-wideinter-individual variabilitytoxicodynamicschemical mixturesdefined mixtureshuman health risk assessment |
| spellingShingle | Lucie C. Ford Suji Jang Zunwei Chen Yi-Hui Zhou Paul J. Gallins Fred A. Wright Weihsueh A. Chiu Ivan Rusyn A Population-Based Human In Vitro Approach to Quantify Inter-Individual Variability in Responses to Chemical Mixtures Toxics population-wide inter-individual variability toxicodynamics chemical mixtures defined mixtures human health risk assessment |
| title | A Population-Based Human In Vitro Approach to Quantify Inter-Individual Variability in Responses to Chemical Mixtures |
| title_full | A Population-Based Human In Vitro Approach to Quantify Inter-Individual Variability in Responses to Chemical Mixtures |
| title_fullStr | A Population-Based Human In Vitro Approach to Quantify Inter-Individual Variability in Responses to Chemical Mixtures |
| title_full_unstemmed | A Population-Based Human In Vitro Approach to Quantify Inter-Individual Variability in Responses to Chemical Mixtures |
| title_short | A Population-Based Human In Vitro Approach to Quantify Inter-Individual Variability in Responses to Chemical Mixtures |
| title_sort | population based human in vitro approach to quantify inter individual variability in responses to chemical mixtures |
| topic | population-wide inter-individual variability toxicodynamics chemical mixtures defined mixtures human health risk assessment |
| url | https://www.mdpi.com/2305-6304/10/8/441 |
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