Using in vitro data to derive acceptable exposure levels: A case study on PBDE developmental neurotoxicity
Background: Current acceptable chemical exposure levels (e.g., tolerable daily intake) are mainly based on animal experiments, which are costly, time-consuming, considered non-ethical by many, and may poorly predict adverse outcomes in humans. Objective: To evaluate a method using human in vitro dat...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Environment International |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0160412023006840 |
| _version_ | 1797349423162851328 |
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| author | Sherri Bloch Laura Lévêque Irva Hertz-Picciotto Birgit Puschner Ellen Fritsche Jördis Klose Nynke I. Kramer Maryse F. Bouchard P. Charukeshi Chandrasekera Marc-André Verner |
| author_facet | Sherri Bloch Laura Lévêque Irva Hertz-Picciotto Birgit Puschner Ellen Fritsche Jördis Klose Nynke I. Kramer Maryse F. Bouchard P. Charukeshi Chandrasekera Marc-André Verner |
| author_sort | Sherri Bloch |
| collection | DOAJ |
| description | Background: Current acceptable chemical exposure levels (e.g., tolerable daily intake) are mainly based on animal experiments, which are costly, time-consuming, considered non-ethical by many, and may poorly predict adverse outcomes in humans. Objective: To evaluate a method using human in vitro data and biological modeling to calculate an acceptable exposure level through a case study on 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) developmental neurotoxicity (DNT). Methods: We reviewed the literature on in vitro assays studying BDE-47-induced DNT. Using the most sensitive endpoint, we derived a point of departure using a mass-balance in vitro disposition model and benchmark dose modeling for a 5% response (BMC05) in cells. We subsequently used a pharmacokinetic model of gestation and lactation to estimate administered equivalent doses leading to four different metrics of child brain concentration (i.e., average prenatal, average postnatal, average overall, and maximum concentration) equal to the point of departure. The administered equivalent doses were translated into tolerable daily intakes using uncertainty factors. Finally, we calculated biomonitoring equivalents for maternal serum and compared them to published epidemiological studies of DNT. Results: We calculated a BMC05 of 164 μg/kg of cells for BDE-47 induced alteration of differentiation in neural progenitor cells. We estimated administered equivalent doses of 0.925–3.767 μg/kg/day in mothers, and tolerable daily intakes of 0.009–0.038 μg/kg/day (composite uncertainty factor: 100). The lowest derived biomonitoring equivalent was 19.75 ng/g lipids, which was consistent with reported median (0.9–23 ng/g lipids) and geometric mean (7.02–26.9 ng/g lipids) maternal serum concentrations from epidemiological studies. Conclusion: This case study supports using in vitro data and biological modeling as a viable alternative to animal testing to derive acceptable exposure levels. |
| first_indexed | 2024-03-08T12:30:02Z |
| format | Article |
| id | doaj.art-3c281d7386a04c87b32276cbe2a80b81 |
| institution | Directory Open Access Journal |
| issn | 0160-4120 |
| language | English |
| last_indexed | 2024-03-08T12:30:02Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Environment International |
| spelling | doaj.art-3c281d7386a04c87b32276cbe2a80b812024-01-22T04:15:34ZengElsevierEnvironment International0160-41202024-01-01183108411Using in vitro data to derive acceptable exposure levels: A case study on PBDE developmental neurotoxicitySherri Bloch0Laura Lévêque1Irva Hertz-Picciotto2Birgit Puschner3Ellen Fritsche4Jördis Klose5Nynke I. Kramer6Maryse F. Bouchard7P. Charukeshi Chandrasekera8Marc-André Verner9Department of Occupational and Environmental Health, School of Public Health, Université de Montréal, Montreal, QC, Canada; Centre de recherche en santé publique, Université de Montréal and CIUSSS du Centre-Sud-de-l'Île-de-Montréal, Montreal, QC, CanadaDepartment of Occupational and Environmental Health, School of Public Health, Université de Montréal, Montreal, QC, Canada; Centre de recherche en santé publique, Université de Montréal and CIUSSS du Centre-Sud-de-l'Île-de-Montréal, Montreal, QC, CanadaDepartment of Public Health Sciences, University of California, Davis, CA, USAMichigan State University Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Michigan State University, Lansing, MI, USA; Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USAIUF-Leibniz-Research Institute for Environmental Medicine, Duesseldorf, Germany; DNTOX GmbH, Düsseldorf, Germany; Medical Faculty, Heinrich-Heine-University, Düsseldorf, GermanyIUF-Leibniz-Research Institute for Environmental Medicine, Duesseldorf, GermanyDivision of Toxicology, Wageningen University, Wageningen, the NetherlandsDepartment of Occupational and Environmental Health, School of Public Health, Université de Montréal, Montreal, QC, Canada; Institut national de la recherche scientifique, Université du Québec, Quebec City, QC, CanadaCanadian Centre for Alternatives to Animal Methods, University of Windsor, Windsor, ON, CanadaDepartment of Occupational and Environmental Health, School of Public Health, Université de Montréal, Montreal, QC, Canada; Centre de recherche en santé publique, Université de Montréal and CIUSSS du Centre-Sud-de-l'Île-de-Montréal, Montreal, QC, Canada; Corresponding author at: Department of Occupational and Environmental Health, School of Public Health, Université de Montréal, 2375 chemin de la Côte-Sainte-Catherine, office 4105, Montreal, QC H3T 1A8, Canada.Background: Current acceptable chemical exposure levels (e.g., tolerable daily intake) are mainly based on animal experiments, which are costly, time-consuming, considered non-ethical by many, and may poorly predict adverse outcomes in humans. Objective: To evaluate a method using human in vitro data and biological modeling to calculate an acceptable exposure level through a case study on 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) developmental neurotoxicity (DNT). Methods: We reviewed the literature on in vitro assays studying BDE-47-induced DNT. Using the most sensitive endpoint, we derived a point of departure using a mass-balance in vitro disposition model and benchmark dose modeling for a 5% response (BMC05) in cells. We subsequently used a pharmacokinetic model of gestation and lactation to estimate administered equivalent doses leading to four different metrics of child brain concentration (i.e., average prenatal, average postnatal, average overall, and maximum concentration) equal to the point of departure. The administered equivalent doses were translated into tolerable daily intakes using uncertainty factors. Finally, we calculated biomonitoring equivalents for maternal serum and compared them to published epidemiological studies of DNT. Results: We calculated a BMC05 of 164 μg/kg of cells for BDE-47 induced alteration of differentiation in neural progenitor cells. We estimated administered equivalent doses of 0.925–3.767 μg/kg/day in mothers, and tolerable daily intakes of 0.009–0.038 μg/kg/day (composite uncertainty factor: 100). The lowest derived biomonitoring equivalent was 19.75 ng/g lipids, which was consistent with reported median (0.9–23 ng/g lipids) and geometric mean (7.02–26.9 ng/g lipids) maternal serum concentrations from epidemiological studies. Conclusion: This case study supports using in vitro data and biological modeling as a viable alternative to animal testing to derive acceptable exposure levels.http://www.sciencedirect.com/science/article/pii/S0160412023006840Risk assessmentIn vitro toxicology testingMass-balance modelingPharmacokinetic modelingTolerable daily intakeBiomonitoring equivalent |
| spellingShingle | Sherri Bloch Laura Lévêque Irva Hertz-Picciotto Birgit Puschner Ellen Fritsche Jördis Klose Nynke I. Kramer Maryse F. Bouchard P. Charukeshi Chandrasekera Marc-André Verner Using in vitro data to derive acceptable exposure levels: A case study on PBDE developmental neurotoxicity Environment International Risk assessment In vitro toxicology testing Mass-balance modeling Pharmacokinetic modeling Tolerable daily intake Biomonitoring equivalent |
| title | Using in vitro data to derive acceptable exposure levels: A case study on PBDE developmental neurotoxicity |
| title_full | Using in vitro data to derive acceptable exposure levels: A case study on PBDE developmental neurotoxicity |
| title_fullStr | Using in vitro data to derive acceptable exposure levels: A case study on PBDE developmental neurotoxicity |
| title_full_unstemmed | Using in vitro data to derive acceptable exposure levels: A case study on PBDE developmental neurotoxicity |
| title_short | Using in vitro data to derive acceptable exposure levels: A case study on PBDE developmental neurotoxicity |
| title_sort | using in vitro data to derive acceptable exposure levels a case study on pbde developmental neurotoxicity |
| topic | Risk assessment In vitro toxicology testing Mass-balance modeling Pharmacokinetic modeling Tolerable daily intake Biomonitoring equivalent |
| url | http://www.sciencedirect.com/science/article/pii/S0160412023006840 |
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