Integration of Dosimetry, Exposure, and High-Throughput Screening Data in Chemical Toxicity Assessment
Abstract
High-throughput in vitro toxicity screening can provide an efficient way to identify potential biological targets for chemicals. However, relying on nominal assay concentrations may misrepresent potential in vivo effects of these chemicals due to differences in bioavailability, clearance, and exposure. Hepatic metabolic clearance and plasma protein binding were experimentally measured for 239 ToxCast Phase I chemicals. The experimental data were used in a population-based in vitro-to-in vivo extrapolation model to estimate the daily human oral dose, called the oral equivalent dose, necessary to produce steady-state in vivo blood concentrations equivalent to in vitro AC(50) (concentration at 50% of maximum activity) or lowest effective concentration values across more than 500 in vitro assays. The estimated steady-state oral equivalent doses associated with the in vitro assays were compared with chronic aggregate human oral exposure estimates to assess whether in vitro bioactivity would be expected at the dose-equivalent level of human exposure. A total of 18 (9.9%) chemicals for which human oral exposure estimates were available had oral equivalent doses at levels equal to or less than the highest estimated U.S. population exposures. Ranking the chemicals by nominal assay concentrations would have resulted in different chemicals being prioritized. The in vitro assay endpoints with oral equivalent doses lower than the human exposure estimates included cell growth kinetics, cytokine and cytochrome P450 expression, and cytochrome P450 inhibition. The incorporation of dosimetry and exposure provide necessary context for interpretation of in vitro toxicity screening data and are important considerations in determining chemical testing priorities.
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In vitro assays in ToxCast were not predictive of complex in vivo endpoint.
“Since in vitro assays in ToxCast were not predictive of such complex endpoint,95”
From QSAR without borders (2020) · cites this paper as [95]
Cites
David, F. N., & Tukey, J. W. (1977) · Biometrics · doi:10.2307/2529486 · Cited by 12,707 · see citing works
A physiological approach to hepatic drug clearance
Wilkinson, G. R., & Shand, D. G. (1975) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt1975184377 · Cited by 1,887 · see citing works
Toxicity Testing in the 21st Century: A Vision and a Strategy
Krewski, D. R., Acosta, D., Andersen, M. E., Anderson, H. A., Bailar, J. C., Boekelheide, K., Brent, R., Charnley, G., Cheung, V. G., Green, S., et al. (2010) · Journal of Toxicology and Environmental Health Part B · doi:10.1080/10937404.2010.483176 · Cited by 1,696 · see citing works
Self-citationPhysiological Parameter Values for Physiologically Based Pharmacokinetic Models
Brown, R. P., Delp, M. D., Lindstedt, S. L., Rhomberg, L. R., & Beliles, R. P. (1997) · Toxicology and Industrial Health · doi:10.1177/074823379701300401 · Cited by 1,408 · see citing works
Toxicity testing in the 21st century: A vision and a strategy
Gibb, S. (2007) · Reproductive Toxicology · doi:10.1016/j.reprotox.2007.10.013 · Cited by 1,266 · see citing works
Obach, R. S. (1999) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(24)14938-0 · Cited by 1,232 · see citing works
The ToxCast Program for Prioritizing Toxicity Testing of Environmental Chemicals
Dix, D. J., Houck, K. A., Martin, M. T., Richard, A. M., Setzer, R. W., & Kavlock, R. J. (2006) · Toxicological Sciences · doi:10.1093/toxsci/kfl103 · Cited by 1,013 · see citing works
Self-citationMetabolism and Kinetics of Bisphenol A in Humans at Low Doses Following Oral Administration
Völkel, W., Colnot, T., Csanády, G. A., Filser, J. G., & Dekant, W. (2002) · Chemical Research in Toxicology · doi:10.1021/tx025548t · Cited by 1,006 · see citing works
Judson, R., Houck, K. A., Kavlock, R. J., Knudsen, T. B., Martin, M. T., Mortensen, H. M., Reif, D. M., Rotroff, D. M., Shah, I., Richard, A. M., et al. (2009) · Environmental Health Perspectives · doi:10.1289/ehp.0901392 · Cited by 610 · see citing works
Self-citationBuchet, J. P., Lauwerys, R., & Roels, H. A. (1981) · International Archives of Occupational and Environmental Health · doi:10.1007/bf00405933 · Cited by 536 · see citing works
The Simcyp <sup>®</sup> Population-based ADME Simulator
Jamei, M., Marciniak, S., Feng, K., Barnett, A., Tucker, G., & Rostami-Hodjegan, A. (2009) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425250802691074 · Cited by 533 · see citing works
Simulation and prediction of in vivo drug metabolism in human populations from in vitro data
Rostami‐Hodjegan, A., & Tucker, G. T. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2173 · Cited by 533 · see citing works
The Toxicity Data Landscape for Environmental Chemicals
Judson, R., Richard, A., Dix, D. J., Houck, K. A., Martin, M. T., Kavlock, R. J., Dellarco, V. L., Henry, T. R., Holderman, T. S., Sayre, P. G., et al. (2008) · Environmental Health Perspectives · doi:10.1289/ehp.0800168 · Cited by 510 · see citing works
Self-citationCalculation of Benchmark Doses from Continuous Data
Crump, K. S. (1995) · Risk Analysis · doi:10.1111/j.1539-6924.1995.tb00095.x · Cited by 410 · see citing works
Endocrine Profiling and Prioritization of Environmental Chemicals Using ToxCast Data
Reif, D. M., Martin, M. T., Tan, S. W., Houck, K. A., Judson, R., Richard, A. M., Knudsen, T. B., Dix, D. J., & Kavlock, R. J. (2010) · Environmental Health Perspectives · doi:10.1289/ehp.1002180 · Cited by 405 · see citing works
Self-citationMeasured and estimated GFR in healthy potential kidney donors
Rule, A. D., Gussak, H. M., Pond, G. R., Bergstralh, E. J., Stegall, M. D., Cosio, F. G., & Larson, T. S. (2004) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2003.09.026 · Cited by 382 · see citing works
Pharmacokinetics of Triclosan Following Oral Ingestion in Humans
Sandborgh‐Englund, G., Adolfsson‐Erici, M., Odham, G., et al. (2006) · Journal of Toxicology and Environmental Health · doi:10.1080/15287390600631706 · Cited by 348 · see citing works
Validation of a rapid equilibrium dialysis approach for the measurement of plasma protein binding.
Waters, N., Jones, R., Williams, G., & Sohal, B. (2008) · Journal of Pharmacy and Science · doi:10.1002/jps.21317 · Cited by 322 · see citing works
Toxicity Testing in the 21st Century: Bringing the Vision to Life
Andersen, M. E., & Krewski, D. R. (2008) · Toxicological Sciences · doi:10.1093/toxsci/kfn255 · Cited by 320 · see citing works
Self-citation(2001) · PubMed · Cited by 316 · see citing works
McGinnity, D. F., Soars, M. G., Urbanowicz, R. A., & Riley, R. J. (2004) · Drug Metabolism and Disposition · doi:10.1124/dmd.104.000026 · Cited by 272 · see citing works
Incorporating Human Dosimetry and Exposure into High-ThroughputIn VitroToxicity Screening
Rotroff, D. M., Wetmore, B. A., Dix, D. J., Ferguson, S., M.A., H. J. C. I., Houck, K. A., LeCluyse, E. L., Andersen, M. E., Judson, R., Smith, C. M., et al. (2010) · Toxicological Sciences · doi:10.1093/toxsci/kfq220 · Cited by 251 · see citing works
Self-citationToxicity Testing in the 21st Century: Implications for Human Health Risk Assessment
Kavlock, R. J., Austin, C. P., & Tice, R. R. (2008) · Risk Analysis · doi:10.1111/j.1539-6924.2008.01168.x · Cited by 239 · see citing works
Self-citationWilson, M. P., & Schwarzman, M. R. (2009) · Environmental Health Perspectives · doi:10.1289/ehp.0800404 · Cited by 218 · see citing works
Martin, M. T., Dix, D. J., Judson, R., Kavlock, R. J., Reif, D. M., Richard, A. M., Rotroff, D. M., Romanov, S., Medvedev, A. V., Poltoratskaya, N., et al. (2010) · Chemical Research in Toxicology · doi:10.1021/tx900325g · Cited by 217 · see citing works
Self-citationBhattacharya, S., Zhang, Q., Carmichael, P. L., Boekelheide, K., & Andersen, M. E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020887 · Cited by 208 · see citing works
Self-citationAndersen, M. E., M.A., H. J. C. I., Tan, Y., Butenhoff, J. L., & Olsen, G. W. (2006) · Toxicology · doi:10.1016/j.tox.2006.08.004 · Cited by 206 · see citing works
Self-citationJudson, R., Kavlock, R. J., Setzer, R. W., Hubal, E. A. C., Martin, M. T., Knudsen, T. B., Houck, K. A., Thomas, R. S., Wetmore, B. A., & Dix, D. J. (2011) · Chemical Research in Toxicology · doi:10.1021/tx100428e · Cited by 204 · see citing works
Self-citationLaKind, J. S., & Naiman, D. Q. (2008) · Journal of Exposure Science & Environmental Epidemiology · doi:10.1038/jes.2008.20 · Cited by 203 · see citing works
Chemical Genomics Profiling of Environmental Chemical Modulation of Human Nuclear Receptors
Huang, R., Xia, M., Cho, M.-H., Sakamuru, S., Shinn, P., Houck, K. A., Dix, D. J., Judson, R., Witt, K. L., Kavlock, R. J., et al. (2011) · Environmental Health Perspectives · doi:10.1289/ehp.1002952 · Cited by 196 · see citing works
Self-citationThe fate of 2,4-dichlorophenoxyacetic acid (2,4-D) following oral administration to man
Sauerhoff, M. W., Braun, W. H., BLAU, G. E., et al. (1977) · Toxicology · doi:10.1016/0300-483x(77)90018-x · Cited by 179 · see citing works
Hays, S. M., Aylward, L. L., LaKind, J. S., et al. (2008) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2008.05.004 · Cited by 177 · see citing works
LaKind, J. S., Aylward, L. L., Brunk, C., et al. (2008) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2008.05.007 · Cited by 168 · see citing works
Biokinetic Modeling and in Vitro – in Vivo Extrapolations
Blaauboer, B. J. (2010) · Journal of Toxicology and Environmental Health Part B · doi:10.1080/10937404.2010.483940 · Cited by 168 · see citing works
Predictive Model of Rat Reproductive Toxicity from ToxCast High Throughput Screening1
Martin, M. T., Knudsen, T. B., Reif, D. M., Houck, K. A., Judson, R., Kavlock, R. J., & Dix, D. J. (2011) · Biology of Reproduction · doi:10.1095/biolreprod.111.090977 · Cited by 164 · see citing works
Self-citationLoccisano, A. E., Campbell, J. L., Andersen, M. E., & M.A., H. J. C. I. (2010) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2010.12.004 · Cited by 141 · see citing works
Self-citationActivity profiles of 309 ToxCast™ chemicals evaluated across 292 biochemical targets
Knudsen, T. B., Houck, K. A., Sipes, N. S., Singh, A. V., Judson, R., Martin, M. T., Weissman, A. D., Kleinstreuer, N., Mortensen, H. M., Reif, D. M., et al. (2011) · Toxicology · doi:10.1016/j.tox.2010.12.010 · Cited by 135 · see citing works
Self-citationEnvironmental Impact on Vascular Development Predicted by High-Throughput Screening
Kleinstreuer, N., Judson, R., Reif, D. M., Sipes, N. S., Singh, A. V., Chandler, K. J., DeWoskin, R. S., Dix, D. J., Kavlock, R. J., & Knudsen, T. B. (2011) · Environmental Health Perspectives · doi:10.1289/ehp.1103412 · Cited by 132 · see citing works
Self-citationEvaluation of high-throughput genotoxicity assays used in profiling the US EPA ToxCast™ chemicals
Knight, A. W., Little, S. B., Houck, K. A., Dix, D. J., Judson, R., Richard, A., McCarroll, N., Akerman, G. S., Yang, C., Birrell, L., et al. (2009) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2009.07.004 · Cited by 120 · see citing works
Self-citationBjörklund, H. V., & Bylund, G. (1991) · Xenobiotica · doi:10.3109/00498259109044401 · Cited by 117 · see citing works
Nielsen, P., & Gyrd-Hansen, Ν. (1996) · Journal of Veterinary Pharmacology and Therapeutics · doi:10.1111/j.1365-2885.1996.tb00054.x · Cited by 104 · see citing works
Advancing Exposure Characterization for Chemical Evaluation and Risk Assessment
Hubal, E. A. C., Richard, A., Aylward, L. L., Edwards, S., Gallagher, J. E., Goldsmith, M., Isukapalli, S., Tornero‐Velez, R., Weber, E., & Kavlock, R. J. (2010) · Journal of Toxicology and Environmental Health Part B · doi:10.1080/10937404.2010.483947 · Cited by 103 · see citing works
Self-citationAbsorption and Excretion of 2,4-Dichlorophenoxyacetic Acid in Man
Kohli, J. D., Khanna, R. N., Gupta, B. N., Dhar, M. M., Tandon, J. S., & Sircar, K. P. (1974) · Xenobiotica · doi:10.3109/00498257409049349 · Cited by 103 · see citing works
Profiling Bioactivity of the ToxCast Chemical Library Using BioMAP Primary Human Cell Systems
Houck, K., Dix, D., Judson, R., Kavlock, R., Yang, J., & Berg, E. (2009) · Journal of biomolecular screening · doi:10.1177/1087057109345525 · Cited by 101 · see citing works
Self-citationHays, S. M., & Aylward, L. L. (2008) · Journal of Applied Toxicology · doi:10.1002/jat.1410 · Cited by 92 · see citing works
ADME Optimization and Toxicity Assessment in Early- and Late-Phase Drug Discovery
Caldwell, G. W., Yan, Z., Tang, W., et al. (2009) · Current Topics in Medicinal Chemistry · doi:10.2174/156802609789630929 · Cited by 87 · see citing works
El-Masri, H. A., & Kenyon, E. M. (2007) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-007-9075-z · Cited by 85 · see citing works
Buck, S. S. D., & Mackie, C. E. (2007) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.3.6.865 · Cited by 58 · see citing works
Rotroff, D. M., Beam, A. L., Dix, D. J., Farmer, A. A., Freeman, K., Houck, K. A., Judson, R., LeCluyse, E. L., Martin, M. T., Reif, D. M., et al. (2010) · Journal of Toxicology and Environmental Health Part B · doi:10.1080/10937404.2010.483949 · Cited by 58 · see citing works
Self-citationOrganophosphate poisonings with parathion and dimethoate
Hoffmann, U., & Papendorf, T. (2006) · Intensive Care Medicine · doi:10.1007/s00134-005-0051-z · Cited by 57 · see citing works
An analogue of piperonyl butoxide facilitates the characterisation of metabolic resistance
Moores, G. D., Philippou, D., Borzatta, V., et al. (2008) · Pest Management Science · doi:10.1002/ps.1661 · Cited by 56 · see citing works
A mechanistic redefinition of adverse effects – a key step in the toxicity testing paradigm shift
Boekelheide, K. (2010) · ALTEX · doi:10.14573/altex.2010.4.243 · Cited by 56 · see citing works
Gentry, P. R. (2002) · Toxicological Sciences · doi:10.1093/toxsci/70.1.120 · Cited by 54 · see citing works
The percutaneous absorption and skin distribution of lindane in man
Dick, I., Blain, P. G., & Williams, F. M. (1997) · Human & Experimental Toxicology · doi:10.1177/096032719701601104 · Cited by 53 · see citing works
Non-animal methodologies within biomedical research and toxicity testing
Knight, A. (2008) · ALTEX · doi:10.14573/altex.2008.3.213 · Cited by 51 · see citing works
Bapiro, T. E., Sayi, J., Hasler, J. A., Jande, M. B., Rimoy, G., Masselle, A., & Masimirembwa, C. M. (2005) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-005-0037-3 · Cited by 47 · see citing works
Fenitrothion: toxicokinetics and toxicologic evaluation in human volunteers.
Meaklim, J., Yang, J., Drummer, O. H., et al. (2002) · Environmental Health Perspectives · doi:10.1289/ehp.5726 · Cited by 43 · see citing works
Nephrotoxicity induced by dimethoate in adult rats and their suckling pups
Mahjoubi-Samet, A., Fetoui, H., & Zeghal, N. (2008) · Pesticide Biochemistry and Physiology · doi:10.1016/j.pestbp.2008.01.009 · Cited by 39 · see citing works
National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population 1999‐2002
Pfeiffer, C. M., Schleicher, R. L., Osterloh, J., et al. (2009) · The FASEB Journal · doi:10.1096/fasebj.23.1_supplement.551.26 · Cited by 35 · see citing works
Public Availability of Data on EU High Production Volume Chemicals. Part 1.
Remi, A., gaarn, H. B., & Yvonne, V. D. B. (2003) · Joint Research Centre (European Commission) · Cited by 34 · see citing works
The percutaneous absorption and skin distribution of lindane in man
Dick, I. P., Blain, P. G., & Williams, F. M. (1997) · Human & Experimental Toxicology · doi:10.1177/096032719701601103 · Cited by 31 · see citing works
Pharmacokinetics of picloram in male volunteers
Nolan, R. J., Freshour, N. L., Kastl, P. E., et al. (1984) · Toxicology and Applied Pharmacology · doi:10.1016/0041-008x(84)90007-3 · Cited by 24 · see citing works
Distribution of dimethoate in the body after a fatal organphosphateintoxication
Tarbah, F., Shaheen, A. M., Benomran, F. A., et al. (2007) · Forensic Science International · doi:10.1016/j.forsciint.2007.04.232 · Cited by 23 · see citing works
Cimetidine-carbaryl interaction in humans: evidence for an active metabolite of carbaryl.
May, D. G., Naukam, R. J., Kambam, J. R., et al. (1992) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)10899-9 · Cited by 21 · see citing works
The disposition of four tetracyclines in normal subjects
Green, R. G., Brown, J., & Calvert, R. T. (1976) · European Journal of Clinical Pharmacology · doi:10.1007/bf00558336 · Cited by 10 · see citing works
Toxicity testing gets a makeover
Abbott, A. (2009) · Nature · doi:10.1038/461158a · Cited by 10 · see citing works
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- Authors
- 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., Allen, B., Judson, R. S., Singh, R., Kavlock, R. J., Richard, A. M., & Thomas, R. S.
- Affiliations
- The Hamner Institutes for Health Sciences (US)
- Environmental Protection Agency (US)
- University of North Carolina at Chapel Hill (US)
- ORCID
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-09-26
- Volume
- 125
- Issue
- 1
- Pages
- 157-174
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- OpenAlex
- W2147334256
- Cited by
- 415
- References
- 66
- Citations by year
- 2026: 22 · 2025: 25 · 2024: 24 · 2023: 25 · 2022: 26 · 2021: 29 · 2020: 30 · 2019: 38 · 2018: 31 · 2017: 35 · 2016: 26 · 2015: 28 · 2014: 30 · 2013: 22 · 2012: 23
- FWCI
- 33.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Environmental Toxicology and Ecotoxicology
- Keywords
- in vitro-in vivo extrapolation, dosimetry, chemical toxicity assessment, ToxCast, plasma protein binding, chemical prioritization, cytochrome P450 inhibition, cell growth kinetics
- MeSH terms
- Animals, Biological Availability, Blood Proteins, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Erythrocytes, Humans, Metabolic Clearance Rate, Models, Biological, Permeability, Protein Binding, Mass Spectrometry, Toxicity Tests, Caco-2 Cells, Computational Biology, Hepatocytes, Small Molecule Libraries, High-Throughput Screening Assays
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