Advancing In Vitro–In Vivo Extrapolations of Mechanism-Specific Toxicity Data Through Toxicokinetic Modeling

Brinkmann, Markus; Preuss, Thomas G.; Hollert, Henner

doi:10.1007/10_2015_5015

Cited by 15Environmental Toxicology and EcotoxicologyAnimal testing and alternativesCarcinogens and Genotoxicity Assessment

Advancing In Vitro–In Vivo Extrapolations of Mechanism-Specific Toxicity Data Through Toxicokinetic Modeling

Brinkmann, Markus, Preuss, Thomas G., Hollert, Henner·2016·Advances in Biochemical Engineering/Biotechnology

DOI 10.1007/10_2015_5015

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Abstract

International legislation, such as the European REACH regulation (registration, evaluation, authorization, and restriction of chemicals), mandates the assessment of potential risks of an ever-growing number of chemicals to the environment and human health. Although this legislation is considered one of the most important investments in consumer safety ever, the downside is that the current testing strategies within REACH rely on extensive animal testing. To address the ethical conflicts arising from these increased testing requirements, decision-makers, such as the European Chemicals Agency (ECHA), are committed to Russel and Burch's 3R principle (i.e., reduction, replacement, refinement) by demanding that animal experiments should be substituted with appropriate alternatives whenever possible. A potential solution of this dilemma might be the application of in vitro bioassays to estimate toxic effects using cells or cellular components instead of whole organisms. Although such assays are particularly useful to assess potential mechanisms of toxic action, scientists require appropriate methods to extrapolate results from the in vitro level to the situation in vivo. Toxicokinetic models are a straightforward means of bridging this gap. The present chapter describes different available options for in vitro-in vivo extrapolation (IVIVE) of mechanism-specific effects focused on fish species and also reviews the implications of confounding factors during the conduction of in vitro bioassays and their influence on the optimal choice of different dose metrics.

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A good example of this is the use of models to reduce, refine, or replace (the '3Rs') certain types of preclinical experiments.
“A good example of this is the use of models to reduce, refine, or replace (the “3Rs”)33 certain types of preclinical experiments.”
From Best Practices to Maximize the Use and Reuse of Quantitative and Systems Pharmacology Models: Recommendations From the United Kingdom Quantitative and Systems Pharmacology Network (2019) · cites this paper as [33]

Fish bioaccumulation and biomarkers in environmental risk assessment: a review
van der Oost, R., Beyer, J., & Vermeulen, N. P. E. (2002) · Environmental Toxicology and Pharmacology · doi:10.1016/s1382-6689(02)00126-6 · Cited by 4,905 · see citing works
The Challenge of Micropollutants in Aquatic Systems
Schwarzenbach, R. P., Escher, B. I., Fenner, K., Hofstetter, T. B., Johnson, C. A., von Gunten, U., & Wehrli, B. (2006) · Science · doi:10.1126/science.1127291 · Cited by 3,717 · see citing works
Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment
Ankley, G. T., Bennett, R. S., Erickson, R. J., Hoff, D. J., Hornung, M. W., Johnson, R. D., Mount, D. R., Nichols, J. W., Russom, C. L., Schmieder, P. K., et al. (2009) · Environmental Toxicology and Chemistry · doi:10.1002/etc.34 · Cited by 2,734 · see citing works
Enterocyte-like differentiation and polarization of the human colon carcinoma cell line Caco-2 in culture
Pinto, M. (1983) · HAL · Cited by 1,752 · see citing works
Bioaccumulation of persistent organic chemicals: mechanisms and models
Mackay, D., & Fraser, A. J. (2000) · Environmental Pollution · doi:10.1016/s0269-7491(00)00162-7 · Cited by 811 · see citing works
Enhancing ecotoxicological modeling and assessment. Body Residues and Modes Of Toxic Action
McCarty, L. S., & Mackay, D. (1993) · Environmental Science & Technology · doi:10.1021/es00046a001 · Cited by 549 · see citing works
A food web bioaccumulation model for organic chemicals in aquatic ecosystems
Arnot, J. A., & Gobas, F. A. P. C. (2004) · Environmental Toxicology and Chemistry · doi:10.1897/03-438 · Cited by 528 · see citing works
The fate of organic xenobiotics in aquatic ecosystems: quantitative and qualitative differences in biotransformation by invertebrates and fish
Livingstone, D. R. (1998) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/s1095-6433(98)10008-9 · Cited by 524 · see citing works
Modes of Action in Ecotoxicology: Their Role in Body Burdens, Species Sensitivity, QSARs, and Mixture Effects
Escher, B. I., & Hermens, J. L. M. (2002) · Environmental Science & Technology · doi:10.1021/es015848h · Cited by 522 · see citing works
Integration of Dosimetry, Exposure, and High-Throughput Screening Data in Chemical Toxicity Assessment
Wetmore, B. A., Wambaugh, J. F., Ferguson, S. S., Sochaski, M. A., Rotroff, D. M., Freeman, K., Clewell, H. J., Dix, D. J., Andersen, M. E., Houck, K. A., et al. (2012) · Toxicological Sciences · doi:10.1093/toxsci/kfr254 · Cited by 415 · see citing works
Revisiting Bioaccumulation Criteria for POPs and PBT Assessments
Gobas, F. A. P. C., de Wolf, W., Burkhard, L. P., Verbruggen, E. M. J., & Plotzke, K. P. (2009) · Integrated Environmental Assessment and Management · doi:10.1897/ieam_2008-089.1 · Cited by 411 · see citing works
Sandwich-cultured hepatocytes: an in vitro model to evaluate hepatobiliary transporter-based drug interactions and hepatotoxicity
Swift, B., Pfeifer, N. D., & Brouwer, K. L. R. (2010) · Drug Metabolism Reviews · doi:10.3109/03602530903491881 · Cited by 374 · see citing works
TOXICOKINETICS IN AQUATIC SYSTEMS: MODEL COMPARISONS AND USE IN HAZARD ASSESSMENT
Landrum, P. F., Lydy, M. J., & Lee, H. (1992) · Environmental Toxicology and Chemistry · doi:10.1002/etc.5620111205 · Cited by 365 · see citing works
A model for predicting the bioaccumulation of hydrophobic organic chemicals in aquatic food-webs: application to Lake Ontario
Gobas, F. A. P. C. (1993) · Ecological Modelling · doi:10.1016/0304-3800(93)90045-t · Cited by 353 · see citing works
Diversity of Mechanism-Based Pharmacodynamic Models
Mager, D. E., Wyska, E., & Jusko, W. J. (2003) · Drug Metabolism and Disposition · doi:10.1124/dmd.31.5.510 · Cited by 345 · see citing works
Physiologically-based pharmacokinetic (PBPK) model to predict IgG tissue kinetics in wild-type and FcRn-knockout mice
Garg, A., & Balthasar, J. P. (2007) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-007-9065-1 · Cited by 329 · see citing works
Drug-protein binding studies new trends in analytical and experimental methodology
Oravcová, J., Böhs, B., & Lindner, W. F. (1996) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/0378-4347(95)00425-4 · Cited by 317 · see citing works
Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH)
Lilienblum, W., Dekant, W., Foth, H., Gebel, T., Hengstler, J. G., Kahl, R., Kramer, P.-J., Schweinfurth, H., & Wollin, K. (2008) · Archives of Toxicology · doi:10.1007/s00204-008-0279-9 · Cited by 315 · see citing works
THE PRACTICE OF EXPOSURE ASSESSMENT: A STATE-OF-THE-ART REVIEW
Paustenbach, D. J. (2000) · Journal of Toxicology and Environmental Health Part B · doi:10.1080/10937400050045264 · Cited by 295 · see citing works
A Physiologically Based Pharmacokinetic and Pharmacodynamic (PBPK/PD) Model for the Organophosphate Insecticide Chlorpyrifos in Rats and Humans
Timchalk, C. A. (2002) · Toxicological Sciences · doi:10.1093/toxsci/66.1.34 · Cited by 285 · see citing works
Comparative study on the in vitro/in vivo estrogenic potencies of 17β-estradiol, estrone, 17α-ethynylestradiol and nonylphenol
den Belt, K. V., Berckmans, P., Vangenechten, C., Verheyen, R., & Witters, H. E. (2003) · Aquatic Toxicology · doi:10.1016/j.aquatox.2003.09.004 · Cited by 279 · see citing works
Peer Reviewed: Internal Exposure: Linking Bioavailability to Effects
Escher, B. I., & Hermens, J. L. M. (2004) · Environmental Science & Technology · doi:10.1021/es0406740 · Cited by 276 · see citing works
Model of PCB in the Lake Michigan lake trout food chain
Thomann, R. V., & Connolly, J. P. (1984) · Environmental Science & Technology · doi:10.1021/es00120a003 · Cited by 272 · see citing works
Dose metric considerations in in vitro assays to improve quantitative in vitro–in vivo dose extrapolations
Groothuis, F. A., Heringa, M. B., Nicol, B., Hermens, J. L. M., Blaauboer, B. J., & Kramer, N. I. (2013) · Toxicology · doi:10.1016/j.tox.2013.08.012 · Cited by 268 · see citing works
Chemical regulators have overreached
Härtung, T., & Rovida, C. (2009) · Nature · doi:10.1038/4601080a · Cited by 258 · see citing works
THE POWER OF SIZE. 1. RATE CONSTANTS AND EQUILIBRIUM RATIOS FOR ACCUMULATION OF ORGANIC SUBSTANCES RELATED TO OCTANOL–WATER PARTITION RATIO AND SPECIES WEIGHT
Hendriks, A. J., van der Linde, A., Cornelissen, G., & Sijm, D. T. H. M. (2001) · Environmental Toxicology and Chemistry · doi:10.1002/etc.5620200703 · Cited by 252 · see citing works
Adverse outcome pathways and ecological risk assessment: Bridging to population-level effects
Kramer, V. J., Etterson, M. A., Hecker, M., Murphy, C. A., Roesijadi, G., Spade, D. J., Spromberg, J. A., Wang, M., & Ankley, G. T. (2010) · Environmental Toxicology and Chemistry · doi:10.1002/etc.375 · Cited by 250 · see citing works
Methodology for demonstrating and measuring the photocytotoxicity of fluoranthene to fish cells in culture
Schirmer, K., Chan, A. G. J., Greenberg, B. M., Dixon, D. G., & Bols, N. C. (1997) · Toxicology in Vitro · doi:10.1016/s0887-2333(97)00002-7 · Cited by 243 · see citing works
Correlation of Biliary Excretion in Sandwich-Cultured Rat Hepatocytes and In Vivo in Rats
Liu, X., Chism, J. P., LeCluyse, E. L., Brouwer, K. R., & Brouwer, K. L. R. (1999) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(24)15299-3 · Cited by 228 · see citing works
Relevance of p‐glycoprotein for the enteral absorption of cyclosporin A: in vitro‐in vivo correlation
Fricker, G., Drewe, J., Huwyler, J., Gutmann, H., & Beglinger, C. (1996) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1996.tb15612.x · Cited by 223 · see citing works
Quantitativein vitrotoin vivoextrapolation of cell-based toxicity assay results
Yoon, M., Campbell, J. L., Andersen, M. E., & M.A., H. J. C. I. (2012) · Critical Reviews in Toxicology · doi:10.3109/10408444.2012.692115 · Cited by 217 · see citing works
Comparison of in Vivo and in Vitro Reporter Gene Assays for Short-Term Screening of Estrogenic Activity
Legler, J., Zeinstra, L. M., Schuitemaker, F., Lanser, P. H., Bogerd, J., Brouwer, A., Vethaak, A. D., de Voogt, P., Murk, A. J., & van der Burg, B. (2002) · Environmental Science & Technology · doi:10.1021/es010323a · Cited by 217 · see citing works
A physiologically based toxicokinetic model for the uptake and disposition of waterborne organic chemicals in fish
Nichols, J. W., McKim, J. M., Andersen, M. E., Gargas, M. L., M.A., H. J. C. I., & Erickson, R. J. (1990) · Toxicology and Applied Pharmacology · doi:10.1016/0041-008x(90)90338-u · Cited by 215 · see citing works
Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I. Challenges and research needs in ecotoxicology
Groh, K. J., Carvalho, R., Chipman, J. K., Denslow, N. D., Halder, M., Murphy, C. A., Roelofs, D., Rolaki, A., Schirmer, K., & Watanabe, K. H. (2014) · Chemosphere · doi:10.1016/j.chemosphere.2014.09.068 · Cited by 208 · see citing works
Measurement of free concentrations using negligible depletion-solid phase microextraction (nd-SPME)
Heringa, M. B., & Hermens, J. L. M. (2003) · TrAC Trends in Analytical Chemistry · doi:10.1016/s0165-9936(03)01006-9 · Cited by 208 · see citing works
Proposal to improve vertebrate cell cultures to establish them as substitutes for the regulatory testing of chemicals and effluents using fish
Schirmer, K. (2006) · Toxicology · doi:10.1016/j.tox.2006.04.042 · Cited by 201 · see citing works
Drug Binding in Plasma
Hervé, F., Urien, S., Albengres, E., Duché, J.-C., & Tillement, J. P. (1994) · Clinical Pharmacokinetics · doi:10.2165/00003088-199426010-00004 · Cited by 198 · see citing works
Use of a Dynamic in Vitro Lipolysis Model to Rationalize Oral Formulation Development for Poor Water Soluble Drugs: Correlation with in Vivo Data and the Relationship to Intra-Enterocyte Processes in Rats
Dahan, A., & Hoffman, A. (2006) · Pharmaceutical Research · doi:10.1007/s11095-006-9054-x · Cited by 195 · see citing works
PBPK modelling of inter-individual variability in the pharmacokinetics of environmental chemicals
Bois, F. Y., Jamei, M., & Clewell, H. J. (2010) · Toxicology · doi:10.1016/j.tox.2010.06.007 · Cited by 194 · see citing works
Using biological traits to predict species sensitivity to toxic substances
Baird, D. J., & den Brink, P. J. V. (2006) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2006.07.001 · Cited by 192 · see citing works
Physiologically Based Pharmacokinetic (PBPK) Modeling in Children
Barrett, J. S., Alberighi, O. D. C., Läer, S., & Meibohm, B. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2012.64 · Cited by 183 · see citing works
The use of Fish Cells in Ecotoxicology: The Report and Recommendations of ECVAM Workshop 47 ,
Castaño, A., Bols, N. C., Braunbeck, T. A., Dierickx, P. J., Halder, M., Isomaa, B., Kawahara, K., Lee, L. E. J., Mothersill, C. E., Pärt, P., et al. (2003) · Alternatives to Laboratory Animals · doi:10.1177/026119290303100314 · Cited by 181 · see citing works
Vision & strategy: Predictive ecotoxicology in the 21st century
Villeneuve, D. L., & García‐Reyero, N. (2010) · Environmental Toxicology and Chemistry · doi:10.1002/etc.396 · Cited by 171 · see citing works
Predicting Adult Fish Acute Lethality with the Zebrafish Embryo: Relevance of Test Duration, Endpoints, Compound Properties, and Exposure Concentration Analysis
Knöbel, M., Busser, F. J. M., Rico-Rico, Á., Kramer, N. I., Hermens, J. L. M., Hafner, C., Tanneberger, K., Schirmer, K., & Scholz, S. (2012) · Environmental Science & Technology · doi:10.1021/es301729q · Cited by 165 · see citing works
Life-cycle biomagnification study in fish
Sijm, D. T. H. M., Seinen, W., & Opperhuizen, A. (1992) · Environmental Science & Technology · doi:10.1021/es00035a014 · Cited by 165 · see citing works
Evaluation of physiologically based pharmacokinetic models for use in risk assessment
Chiu, W. A., Barton, H. A., DeWoskin, R. S., Schlosser, P. M., Thompson, C. M., Sonawane, B. R., Lipscomb, J. C., & Krishnan, K. (2007) · Journal of Applied Toxicology · doi:10.1002/jat.1225 · Cited by 157 · see citing works
Quantifying processes determining the free concentration of phenanthrene in basal cytotoxicity assays
Kramer, N. I., Krismartina, M., Rico-Rico, Á., Blaauboer, B. J., & Hermens, J. L. M. (2012) · Chemical Research in Toxicology · doi:10.1021/tx200479k · Cited by 156 · see citing works
In vitro–in vivo extrapolation of quantitative hepatic biotransformation data for fish
Nichols, J. W., Schultz, I. R., & Fitzsimmons, P. N. (2006) · Aquatic Toxicology · doi:10.1016/j.aquatox.2006.01.017 · Cited by 155 · see citing works
Toward More Useful In Vitro Toxicity Data with Measured Free Concentrations
Heringa, M. B., Schreurs, R. H. M. M., Busser, F. J. M., van der Saag, P. T., van der Burg, B., & Hermens, J. L. M. (2004) · Environmental Science & Technology · doi:10.1021/es049285w · Cited by 147 · see citing works
Predicting Concentrations of Organic Chemicals in Fish by Using Toxicokinetic Models
Stadnicka-Michalak, J., Schirmer, K., & Ashauer, R. (2012) · Environmental Science & Technology · doi:10.1021/es2043728 · Cited by 145 · see citing works
Potencies of estrogenic compounds in in vitro screening assays and in life cycle tests with zebrafish in vivo
Segner, H. E., Navas, J. M., Schäfers, C., & Wenzel, A. (2003) · Ecotoxicology and Environmental Safety · doi:10.1016/s0147-6513(02)00040-4 · Cited by 145 · see citing works
Passive Dosing for Producing Defined and Constant Exposure of Hydrophobic Organic Compounds during in Vitro Toxicity Tests
Smith, K. E. C., Oostingh, G. J., & Mayer, P. (2009) · Chemical Research in Toxicology · doi:10.1021/tx900274j · Cited by 142 · see citing works
The use of in vitro toxicity data and physiologically based kinetic modeling to predict dose-response curves for in vivo developmental toxicity of glycol ethers in rat and man.
Louisse, J., de Jong, E., van de Sandt, J. V. D., Blaauboer, B., Woutersen, R., Piersma, A., Rietjens, I., & Verwei, M. (2010) · Toxicological Sciences · doi:10.1093/toxsci/kfq270 · Cited by 136 · see citing works
Deriving quality criteria for water and sediment from the results of aquatic toxicity tests and product standards: Application of the equilibrium partitioning method
van der Kooij, L. A., van de Meent, D., van Leeuwen, K., & Bruggeman, W. A. (1991) · Water Research · doi:10.1016/0043-1354(91)90045-r · Cited by 131 · see citing works
Factors influencing nominal effective concentrations of chemical compounds in vitro: cell concentration
Gülden, M., Mörchel, S., & Seibert, H. (2001) · Toxicology in Vitro · doi:10.1016/s0887-2333(01)00008-x · Cited by 113 · see citing works
Prediction of in vivo embryotoxic effect levels with a combination of in vitro studies and PBPK modelling
Verwei, M., van Burgsteden, J. A., Krul, C. A. M., van de Sandt, J. J. M., & Freidig, A. P. (2006) · Toxicology Letters · doi:10.1016/j.toxlet.2006.01.017 · Cited by 109 · see citing works
In vitro–in vivo extrapolation: estimation of human serum concentrations of chemicals equivalent to cytotoxic concentrations in vitro
Gülden, M., & Seibert, H. (2003) · Toxicology · doi:10.1016/s0300-483x(03)00146-x · Cited by 108 · see citing works
Bioaccumulation in aquatic systems: methodological approaches, monitoring and assessment
Schäfer, S., Buchmeier, G., Claus, E., Duester, L., Heininger, P., Körner, A., Mayer, P., Paschke, A., Rauert, C., Reifferscheid, G., et al. (2015) · Environmental Sciences Europe · doi:10.1186/s12302-014-0036-z · Cited by 107 · see citing works
Overview of the Final MEIC Results: II. The In Vitro--In Vivo Evaluation, Including the Selection of a Practical Battery of Cell Tests for Prediction of Acute Lethal Blood Concentrations in Humans
Ekwall, B. (1999) · Toxicology in Vitro · doi:10.1016/s0887-2333(99)00061-2 · Cited by 105 · see citing works
Polybrominated dibenzo-p-dioxins and related compounds: Quantitative in vivo and in vitro structure-activity relationships
Mason, G., Zacharewski, T. R., Denommé, M. A., Safe, L. M., & Safe, S. H. (1987) · Toxicology · doi:10.1016/0300-483x(87)90027-8 · Cited by 104 · see citing works
Physicochemical substance properties as indicators for unreliable exposure in microplate-based bioassays
Riedl, J., & Altenburger, R. (2007) · Chemosphere · doi:10.1016/j.chemosphere.2006.12.022 · Cited by 103 · see citing works
Endocrine disruptor screening: regulatory perspectives and needs
Hecker, M., & Hollert, H. (2011) · Environmental Sciences Europe · doi:10.1186/2190-4715-23-15 · Cited by 103 · see citing works
Self-citation
Measured and Modeled Toxicokinetics in Cultured Fish Cells and Application to In Vitro - In Vivo Toxicity Extrapolation
Stadnicka-Michalak, J., Tanneberger, K., Schirmer, K., & Ashauer, R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0092303 · Cited by 98 · see citing works
Development and Verification of a Benthic/Pelagic Food Web Bioaccumulation Model for PCB Congeners in Western Lake Erie
Morrison, H. A., Gobas, F. A. P. C., LAZĂR, R. D., Whittle, D. M., & Haffner, G. D. (1997) · Environmental Science & Technology · doi:10.1021/es970265m · Cited by 94 · see citing works
Toxicokinetic variation in 15 freshwater arthropod species exposed to the insecticide chlorpyrifos
Rubach, M. N., Ashauer, R., Maund, S. J., Baird, D. J., & den Brink, P. J. V. (2009) · Environmental Toxicology and Chemistry · doi:10.1002/etc.273 · Cited by 93 · see citing works
Importance of Toxicokinetics for Interspecies Variation in Sensitivity to Chemicals
Nyman, A., Schirmer, K., & Ashauer, R. (2014) · Environmental Science & Technology · doi:10.1021/es5005126 · Cited by 90 · see citing works
Physiologically Based Modeling of the Toxicokinetic Interaction between Toluene and m-Xylene in the Rat
Tardif, R., Laparé, S., Krishnan, K., & Brodeur, J. (1993) · Toxicology and Applied Pharmacology · doi:10.1006/taap.1993.1111 · Cited by 89 · see citing works
Effects of structure on binding to the 2,3,7,8-TCDD receptor protein and AHH induction--halogenated biphenyls.
Safe, S. H., Bandiera, S. M., Sawyer, T. W., Zmudzka, B., Mason, G., Romkes, M., Denommé, M. A., Sparling, J., Okey, A. B., & Fujita, T. (1985) · Environmental Health Perspectives · doi:10.1289/ehp.856121 · Cited by 86 · see citing works
In vitro-in vivo extrapolation of quantitative hepatic biotransformation data for fish. II. Modeled effects on chemical bioaccumulation
Nichols, J. W., Fitzsimmons, P. N., & Burkhard, L. P. (2007) · Environmental Toxicology and Chemistry · doi:10.1897/06-259r.1 · Cited by 85 · see citing works
Impact of bioavailability on the correlation between in vitro cytotoxic and in vivo acute fish toxic concentrations of chemicals
Gülden, M., & Seibert, H. (2005) · Aquatic Toxicology · doi:10.1016/j.aquatox.2005.02.002 · Cited by 83 · see citing works
Heterocyclic Aromatic Hydrocarbons Show Estrogenic Activity upon Metabolization in a Recombinant Transactivation Assay
Brinkmann, M., Maletz, S., Krauss, M. K. V., Bluhm, K., Schiwy, S., Kuckelkorn, J., Tiehm, A., Brack, W., & Hollert, H. (2014) · Environmental Science & Technology · doi:10.1021/es405731j · Cited by 82 · see citing works
Self-citation
Modeling Kinetics of Subcellular Disposition of Chemicals
Baláž, Š. (2009) · Chemical Reviews · doi:10.1021/cr030440j · Cited by 82 · see citing works
Influence of Albumin on Sorption Kinetics in Solid-Phase Microextraction: Consequences for Chemical Analyses and Uptake Processes
Kramer, N. I., van Eijkeren, J. C. H., & Hermens, J. L. M. (2007) · Analytical Chemistry · doi:10.1021/ac070574n · Cited by 82 · see citing works
A Physiologically Based Toxicokinetic Model for the ZebrafishDanio rerio
Péry, A. R. R., Devillers, J., Brochot, C., Mombelli, E., Palluel, O., Piccini, B., Brion, F., & Beaudouin, R. (2013) · Environmental Science & Technology · doi:10.1021/es404301q · Cited by 82 · see citing works
A toxicokinetic model for the carry-over of dioxins and PCBs from feed and soil to eggs
van Eijkeren, J. C. H., Zeilmaker, M. J., Kan, C. A., Traag, W. A., & Hoogenboom, L. A. P. (2006) · Food Additives & Contaminants · doi:10.1080/02652030500512045 · Cited by 80 · see citing works
Overview of the Final MEIC Results: I. The In Vitro--In Vitro Evaluation
Clemedson, C., & Ekwall, B. (1999) · Toxicology in Vitro · doi:10.1016/s0887-2333(99)00060-0 · Cited by 80 · see citing works
Development of a Partition-Controlled Dosing System for Cell Assays
Kramer, N. I., Busser, F. J. M., Oosterwijk, M. T. T., Schirmer, K., Escher, B. I., & Hermens, J. L. M. (2010) · Chemical Research in Toxicology · doi:10.1021/tx1002595 · Cited by 80 · see citing works
Development and Verification of a Benthic/Pelagic Food Web Bioaccumulation Model for PCB Congeners in Western Lake Erie
Morrison, H. A., Gobas, F. A. P. C., LAZĂR, R. D., Whittel, A. D. M., & Haffner, G. D. (1998) · Environmental Science & Technology · doi:10.1021/es982000t · Cited by 78 · see citing works
Physiologically based toxicokinetic modeling of three waterborne chloroethanes in rainbow trout (Oncorhynchus mykiss)
Nichols, J. W., McKim, J. M., Lien, G. J., Hoffman, A. D., & Bertelsen, S. L. (1991) · Toxicology and Applied Pharmacology · doi:10.1016/0041-008x(91)90040-l · Cited by 77 · see citing works
Respiratory strategy is a major determinant of [3H]water and [14C]chlorpyrifos uptake in aquatic insects
Buchwalter, D. B., Jenkins, J. J., & Curtis, L. R. (2002) · Canadian Journal of Fisheries and Aquatic Sciences · doi:10.1139/f02-107 · Cited by 70 · see citing works
A Generic, Cross-Chemical Predictive PBTK Model with Multiple Entry Routes Running as Application in MS Excel; Design of the Model and Comparison of Predictions with Experimental Results
JONGENEELEN, F. J., & ten Berge, W. F. (2011) · The Annals of Occupational Hygiene · doi:10.1093/annhyg/mer075 · Cited by 70 · see citing works
A physiologically based pharmacokinetic model for oxytetracycline residues in sheep
Craigmill, A. L. (2003) · Journal of Veterinary Pharmacology and Therapeutics · doi:10.1046/j.1365-2885.2003.00451.x · Cited by 69 · see citing works
Cross-Species Extrapolation of Uptake and Disposition of Neutral Organic Chemicals in Fish Using a Multispecies Physiologically-Based Toxicokinetic Model Framework
Brinkmann, M., Schlechtriem, C., Reininghaus, M., Eichbaum, K., Buchinger, S., Reifferscheid, G., Hollert, H., & Preuß, T. G. (2016) · Environmental Science & Technology · doi:10.1021/acs.est.5b06158 · Cited by 68 · see citing works
Self-citation
An Integrated Approach to the Prediction of Systemic Toxicity using Computer-based Biokinetic Models and Biological In vitro Test Methods: Overview of a Prevalidation Study Based on the ECITTS Project
DeJongh, J., Forsby, A., Houston, J. B., Beckman, M., Combes, R. D., & Blaauboer, B. J. (1999) · Toxicology in Vitro · doi:10.1016/s0887-2333(99)00030-2 · Cited by 68 · see citing works
COMPARATIVE METABOLISM OF CARBON TETRACHLORIDE IN RATS, MICE, AND HAMSTERS USING GAS UPTAKE AND PBPK MODELING
Thrall, K. D. (2000) · Journal of Toxicology and Environmental Health · doi:10.1080/00984100050082085 · Cited by 63 · see citing works
A biologically based toxicokinetic model for pyrene in rainbow trout
Law, F. C. P., Abedini, S., & Kennedy, C. J. (1991) · Toxicology and Applied Pharmacology · doi:10.1016/0041-008x(91)90041-c · Cited by 59 · see citing works
Uptake and Elimination of Brevetoxin in Blood of Striped Mullet ( Mugil cephalus ) after Aqueous Exposure to Karenia brevis
Woofter, R. T., Brendtro, K. S., & Ramsdell, J. S. (2004) · Environmental Health Perspectives · doi:10.1289/ehp.7274 · Cited by 58 · see citing works
Some heterocyclic aromatic compounds are Ah receptor agonists in the DR-CALUX assay and the EROD assay with RTL-W1 cells
Hinger, G., Brinkmann, M., Bluhm, K., Sagner, A., Takner, H. O., Eisenträger, A., Braunbeck, T. A., Engwall, M., Tiehm, A., & Hollert, H. (2011) · Environmental Science and Pollution Research · doi:10.1007/s11356-011-0483-7 · Cited by 58 · see citing works
Self-citation
The tissue residue approach for toxicity assessment: Findings and critical reviews from a Society of Environmental Toxicology and Chemistry Pellston Workshop
Meador, J. P., Adams, W. J., Escher, B. I., McCarty, L. S., McElroy, A. E., & Sappington, K. G. (2010) · Integrated Environmental Assessment and Management · doi:10.1002/ieam.133 · Cited by 58 · see citing works
Physiologically based toxicokinetic model for maternal transfer of 2,3,7,8-tetrachlorodibenzo-p-dioxin in brook trout (Salvelinus fontinalis)
Nichols, J. W., Jensen, K. M., Tietge, J. E., & Johnson, R. D. (1998) · Environmental Toxicology and Chemistry · doi:10.1002/etc.5620171208 · Cited by 56 · see citing works
Comparative toxicokinetics of tributyltin in five marine species and its utility in predicting bioaccumulation and acute toxicity
Meador, J. P. (1997) · Aquatic Toxicology · doi:10.1016/s0166-445x(96)00827-2 · Cited by 56 · see citing works
Determination of lipid content in fish samples from bioaccumulation studies: contributions to the revision of guideline OECD 305
Schlechtriem, C., Fliedner, A., & Schäfers, C. (2012) · Environmental Sciences Europe · doi:10.1186/2190-4715-24-13 · Cited by 55 · see citing works
Cutting Edge PBPK Models and Analyses: Providing the Basis for Future Modeling Efforts and Bridges to Emerging Toxicology Paradigms
Caldwell, J. C., Evans, M. V., & Krishnan, K. (2012) · Journal of Toxicology · doi:10.1155/2012/852384 · Cited by 51 · see citing works
Development of a physiologic-based pharmacokinetic model for estimating sulfamethazine concentrations in swine and application to prediction of violative residues in edible tissues
Buur, J. L., Baynes, R. E., Craigmill, A. L., & Riviere, J. E. (2005) · American Journal of Veterinary Research · doi:10.2460/ajvr.2005.66.1686 · Cited by 51 · see citing works
New Science for Chemicals Policy
Schwarzman, M. R., & Wilson, M. P. (2009) · Science · doi:10.1126/science.1177537 · Cited by 51 · see citing works
Dynamical coupling of PBPK/PD and AUC-based toxicity models for arsenic in tilapia Oreochromis mossambicus from blackfoot disease area in Taiwan
Liao, C., Liang, H., Chen, B., Singh, S., Tsai, J., Chou, Y.-H., & Lin, W.-T. (2005) · Environmental Pollution · doi:10.1016/j.envpol.2004.11.005 · Cited by 50 · see citing works
Predicting branchial and cutaneous uptake of 2,2′,5,5′-tetrachlorobiphenyl in fathead minnows (Pimephales promelas) and Japanese medaka (Oryzias latipes): Rate limiting factors
Lien, G. J., & McKim, J. M. (1993) · Aquatic Toxicology · doi:10.1016/0166-445x(93)90044-2 · Cited by 48 · see citing works
Physiologically Based Toxicokinetic (PBTK) Modeling in Ecotoxicology
Krishnan, K., & Peyret, T. (2009) · Emerging topics in ecotoxicology · doi:10.1007/978-1-4419-0197-2_6 · Cited by 48 · see citing works
Physiologically-based toxicokinetic modeling of three waterborne chloroethanes in channel catfish, Ictalurus punctatus
Nichols, J. W., McKim, J. M., Lien, G. J., Hoffman, A. D., Bertelsen, S. L., & Gallinat, C. A. (1993) · Aquatic Toxicology · doi:10.1016/0166-445x(93)90049-7 · Cited by 47 · see citing works
Pharmacokinetic modeling of the dogfish shark (Squalus acanthias): Distribution and urinary and biliary excretion of phenol red and its glucuronide
Bungay, P. M., Dedrick, R. L., & Guarino, A. M. (1976) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1007/bf01062827 · Cited by 46 · see citing works
Nonpolar Narcosis: A Review of the Mechanism of Action for Baseline Aquatic Toxicity
Schultz, T. (1989) · doi:10.1520/stp16776s · Cited by 43 · see citing works
A physiologically based toxicokinetic model for lake trout (Salvelinus namaycush)
Lien, G. J., McKim, J. M., Hoffman, A. D., & Jenson, C. T. (2001) · Aquatic Toxicology · doi:10.1016/s0166-445x(00)00117-x · Cited by 43 · see citing works
How meaningful is the bioconcentration factor for risk assessment?
Franke, C. (1996) · Chemosphere · doi:10.1016/0045-6535(96)00104-x · Cited by 40 · see citing works
Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells II. Drug toxicity in the MIT-24 system compared with mouse and human lethal dosage of 52 drugs
Ekwall, B. (1980) · Toxicology Letters · doi:10.1016/0378-4274(80)90032-6 · Cited by 39 · see citing works
Physiologically-based toxicokinetic models help identifying the key factors affecting contaminant uptake during flood events
Brinkmann, M., Eichbaum, K., Kammann, U., Hudjetz, S., Brüll, C., Buchinger, S., Reifferscheid, G., Schüttrumpf, H., Preuß, T. G., & Hollert, H. (2014) · Aquatic Toxicology · doi:10.1016/j.aquatox.2014.03.021 · Cited by 33 · see citing works
Self-citation
Understanding Receptor-Mediated Effects in Rainbow Trout:In Vitro–in VivoExtrapolation Using Physiologically Based Toxicokinetic Models
Brinkmann, M., Eichbaum, K., Buchinger, S., Reifferscheid, G., Bui, T. T., Schäffer, A., Hollert, H., & Preuß, T. G. (2014) · Environmental Science & Technology · doi:10.1021/es4053208 · Cited by 33 · see citing works
Self-citation
Towardin vitrobiomarkers for developmental toxicity and their extrapolation to thein vivosituation
Louisse, J., Verwei, M., Woutersen, R. A., Blaauboer, B. J., & Rietjens, I. M. C. M. (2011) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2012.639762 · Cited by 32 · see citing works
A Critical Evaluation of the 2011 ECHA Reports on Compliance with the REACH and CLP Regulations and on the Use of Alternatives to Testing on Animals for Compliance with the REACH Regulation
Spielmann, H., Sauer, U. G., & Mekenyan, O. (2011) · Alternatives to Laboratory Animals · doi:10.1177/026119291103900509 · Cited by 29 · see citing works
Application of Bayesian Population Physiologically Based Pharmacokinetic (PBPK) Modeling and Markov Chain Monte Carlo Simulations to Pesticide Kinetics Studies in Protected Marine Mammals: DDT, DDE, and DDD in Harbor Porpoises
Weijs, L., Yang, R. S. H., Das, K., Covaci, A., & Blust, R. (2013) · Environmental Science & Technology · doi:10.1021/es400386a · Cited by 28 · see citing works
A physiologically based toxicokinetic model for methylmercury in female American kestrels
Nichols, J. W., Bennett, R. S., Rossmann, R., French, J. B., & Sappington, K. G. (2010) · Environmental Toxicology and Chemistry · doi:10.1002/etc.241 · Cited by 28 · see citing works
Data gaps threaten chemical safety law
Gilbert, N. (2011) · Nature · doi:10.1038/475150a · Cited by 24 · see citing works
Use of Measurement Data in Evaluating Exposure of Humans and Wildlife to POPs/PBTs
Swackhamer, D. L., Needham, L. L., Powell, D. E., & Muir, D. C. G. (2009) · Integrated Environmental Assessment and Management · doi:10.1897/ieam_2008-094.1 · Cited by 24 · see citing works
Evaluation of Critical Body Residue QSARS for Predicting Organic Chemical Toxicity to Aquatic Organisms
Barron, M. G., Anderson, M. J., Lipton, J., & Dixon, D. G. (1997) · SAR and QSAR in environmental research · doi:10.1080/10629369708031724 · Cited by 23 · see citing works
An oxytetracycline residue depletion study to assess the physiologically based pharmokinetic (PBPK) model in farmed Atlantic salmon.
Brocklebank, J. R., Namdari, R., & Law, F. C. P. (1997) · Europe PMC (PubMed Central) · Cited by 23 · see citing works
Priority Setting in the REACH System
Hansson, S. O., & Rudén, C. (2005) · Toxicological Sciences · doi:10.1093/toxsci/kfj071 · Cited by 19 · see citing works
Effect of combining in vitro estrogenicity data with kinetic characteristics of estrogenic compounds on the in vivo predictive value
Punt, A., Brand, W., Murk, A. J., van Wezel, A. P., Schriks, M., & Heringa, M. B. (2012) · Toxicology in Vitro · doi:10.1016/j.tiv.2012.09.014 · Cited by 17 · see citing works
PBT borderline chemicals under REACH
Zarfl, C., & Matthies, M. (2013) · Environmental Sciences Europe · doi:10.1186/2190-4715-25-11 · Cited by 11 · see citing works
Five years REACH – lessons learned and first experiences. I. an authorities' view
Schulte, C., Tietjen, L., Bambauer, A., & Fleischer, A. (2012) · Environmental Sciences Europe · doi:10.1186/2190-4715-24-31 · Cited by 7 · see citing works
Ancillary Approaches to Toxicokinetic Evaluations
Takacs, A. R. (1995) · Toxicologic Pathology · doi:10.1177/019262339502300212 · Cited by 6 · see citing works
Modeling the Uptake and Disposition of Hydrophobic Organic Chemicals in Fish Using a Physiologically Based Approach
Nichols, J. W. (2002) · Springer eBooks · doi:10.1007/978-94-017-3437-0_6 · Cited by 3 · see citing works
Model for estimating initial burden and daily absorption of lipophilic contaminants in cattle
Ji, F., van, E. J., & Ajam, S. (1999) · Cited by 3 · see citing works

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Authors: Brinkmann, M., Preuss, T. G., & Hollert, H.
Affiliations: RWTH Aachen University (DE)
Bayer (Germany) (DE)
Tongji University (CN)
Corresponding author: Brinkmann, Markus
Hollert, Henner
ORCID: Brinkmann, Markus
Preuss, Thomas G.
Hollert, Henner
Venue: Advances in Biochemical Engineering/Biotechnology
Publisher: Springer International Publishing
Published: 2016
Volume: 157
Pages: 293-317
ISSN: 0724-6145 (ISSN-L)
1616-8542
DOI: 10.1007/10_2015_5015
OpenAlex: W2520530891
Cited by: 15
References: 121
Citations by year: 2026: 3 · 2024: 1 · 2023: 1 · 2021: 2 · 2020: 3 · 2019: 3 · 2018: 1 · 2016: 1
FWCI: 5.12
Type: book chapter
Language: en
Open access: closed
Licence: www.springer.com/tdm (unspecified)
Locations: Advances in biochemical engineering, biotechnology (publishedVersion)
PubMed (publishedVersion)
RWTH Publications (RWTH Aachen) (submittedVersion)
Topics: Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Environmental Toxicology and Ecotoxicology
Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
Keywords: in vitro-in vivo extrapolation, toxicokinetic modeling, in vitro bioassay, alternatives to animal testing, 3Rs, REACH regulation, fish toxicity, dose metrics, confounding factors, aquatic ecotoxicology
MeSH terms: Animals, Biological Assay, Computer Simulation, Environmental Pollutants, Europe, Models, Biological, Guidelines as Topic, Patch-Clamp Techniques, Toxicity Tests, Models, Animal, Toxicokinetics

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Advancing In Vitro–In Vivo Extrapolations of Mechanism-Specific Toxicity Data Through Toxicokinetic Modeling

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