Determination of whole mixture-based potency factors for cancer risk assessment of complex environmental mixtures by in vitro testing of standard reference materials
Whole mixture-based testing using in vitro new approach methodologies (NAMs) has been suggested to facilitate the hazard and risk assessment of complex environmental mixtures. Previous studies have shown that phosphorylation of DNA damage signaling proteins checkpoint kinase 1 (pChk1) and histone 2A...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | Environment International |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0160412022002720 |
| _version_ | 1818163820416204800 |
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| author | Marcos Felipe de Oliveira Galvão Ioannis Sadiktsis Tiago Marques Pedro Kristian Dreij |
| author_facet | Marcos Felipe de Oliveira Galvão Ioannis Sadiktsis Tiago Marques Pedro Kristian Dreij |
| author_sort | Marcos Felipe de Oliveira Galvão |
| collection | DOAJ |
| description | Whole mixture-based testing using in vitro new approach methodologies (NAMs) has been suggested to facilitate the hazard and risk assessment of complex environmental mixtures. Previous studies have shown that phosphorylation of DNA damage signaling proteins checkpoint kinase 1 (pChk1) and histone 2AX (γH2AX) are sensitive markers that can be used for estimating carcinogenicity potencies in vitro. Here, and with the aim to better validate the applicability, in vitro-based Mixture Potency Factors (MPFs) of Standard Reference Materials (SRMs) from environmental polycyclic aromatic hydrocarbon (PAH)-containing mixtures were determined and compared to published mutagenicity and tumorigenicity data. Also, genotoxicity was assessed by a flow cytometry-based micronucleus (MN) assay which showed that only benzo[a]pyrene (B[a]P) and coal tar SRM (SRM1597a) caused dose-dependent increases of MN formation, while extracts of diesel particulate matter (SRM1650b), diesel particulate extract (SRM1975), and urban dust (SRM1649b) did not. However, a dose-dependent activation of DNA damage signaling was observed for all PAHs and SRMs. The results demonstrated that all SRMs were more potent than B[a]P, at B[a]P-equivalent concentrations, to induce pChk1 and γH2AX, and that western blot was more sensitive than the In-Cell Western assay in detecting their activation in response to these complex mixtures. Relative MPFs, based on dose–response modelling of pChk1 and γH2AX, ranged 113 – 5270 for the SRMs, indicating several orders of magnitude higher genotoxic potential than B[a]P. Moreover, these MPFs were in good agreement with potency values based on published data from Salmonella mutagenicity and in vivo carcinogenicity studies. In conclusion, these comparisons further validate the feasibility of applying in vitro NAMs, such as whole-mixture based MPFs, in cancer risk assessment of complex mixtures. |
| first_indexed | 2024-12-11T16:55:38Z |
| format | Article |
| id | doaj.art-67e2d04faa8f4f7d8473df6675dd88d8 |
| institution | Directory Open Access Journal |
| issn | 0160-4120 |
| language | English |
| last_indexed | 2024-12-11T16:55:38Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Environment International |
| spelling | doaj.art-67e2d04faa8f4f7d8473df6675dd88d82022-12-22T00:57:57ZengElsevierEnvironment International0160-41202022-08-01166107345Determination of whole mixture-based potency factors for cancer risk assessment of complex environmental mixtures by in vitro testing of standard reference materialsMarcos Felipe de Oliveira Galvão0Ioannis Sadiktsis1Tiago Marques Pedro2Kristian Dreij3Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, SwedenDepartment of Materials and Environmental Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, SwedenInstitute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, SwedenInstitute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden; Corresponding author.Whole mixture-based testing using in vitro new approach methodologies (NAMs) has been suggested to facilitate the hazard and risk assessment of complex environmental mixtures. Previous studies have shown that phosphorylation of DNA damage signaling proteins checkpoint kinase 1 (pChk1) and histone 2AX (γH2AX) are sensitive markers that can be used for estimating carcinogenicity potencies in vitro. Here, and with the aim to better validate the applicability, in vitro-based Mixture Potency Factors (MPFs) of Standard Reference Materials (SRMs) from environmental polycyclic aromatic hydrocarbon (PAH)-containing mixtures were determined and compared to published mutagenicity and tumorigenicity data. Also, genotoxicity was assessed by a flow cytometry-based micronucleus (MN) assay which showed that only benzo[a]pyrene (B[a]P) and coal tar SRM (SRM1597a) caused dose-dependent increases of MN formation, while extracts of diesel particulate matter (SRM1650b), diesel particulate extract (SRM1975), and urban dust (SRM1649b) did not. However, a dose-dependent activation of DNA damage signaling was observed for all PAHs and SRMs. The results demonstrated that all SRMs were more potent than B[a]P, at B[a]P-equivalent concentrations, to induce pChk1 and γH2AX, and that western blot was more sensitive than the In-Cell Western assay in detecting their activation in response to these complex mixtures. Relative MPFs, based on dose–response modelling of pChk1 and γH2AX, ranged 113 – 5270 for the SRMs, indicating several orders of magnitude higher genotoxic potential than B[a]P. Moreover, these MPFs were in good agreement with potency values based on published data from Salmonella mutagenicity and in vivo carcinogenicity studies. In conclusion, these comparisons further validate the feasibility of applying in vitro NAMs, such as whole-mixture based MPFs, in cancer risk assessment of complex mixtures.http://www.sciencedirect.com/science/article/pii/S0160412022002720Standard reference materialPolycyclic aromatic hydrocarbonsMixture potency factorsDNA damage signalingCancer risk assessment |
| spellingShingle | Marcos Felipe de Oliveira Galvão Ioannis Sadiktsis Tiago Marques Pedro Kristian Dreij Determination of whole mixture-based potency factors for cancer risk assessment of complex environmental mixtures by in vitro testing of standard reference materials Environment International Standard reference material Polycyclic aromatic hydrocarbons Mixture potency factors DNA damage signaling Cancer risk assessment |
| title | Determination of whole mixture-based potency factors for cancer risk assessment of complex environmental mixtures by in vitro testing of standard reference materials |
| title_full | Determination of whole mixture-based potency factors for cancer risk assessment of complex environmental mixtures by in vitro testing of standard reference materials |
| title_fullStr | Determination of whole mixture-based potency factors for cancer risk assessment of complex environmental mixtures by in vitro testing of standard reference materials |
| title_full_unstemmed | Determination of whole mixture-based potency factors for cancer risk assessment of complex environmental mixtures by in vitro testing of standard reference materials |
| title_short | Determination of whole mixture-based potency factors for cancer risk assessment of complex environmental mixtures by in vitro testing of standard reference materials |
| title_sort | determination of whole mixture based potency factors for cancer risk assessment of complex environmental mixtures by in vitro testing of standard reference materials |
| topic | Standard reference material Polycyclic aromatic hydrocarbons Mixture potency factors DNA damage signaling Cancer risk assessment |
| url | http://www.sciencedirect.com/science/article/pii/S0160412022002720 |
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