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Within-animal variation as an indication of the minimal magnitude of the critical effect size for continuous toxicological parameters applicable in the benchmark dose approach

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Author: Dekkers, S. · Telman, J. · Rennen, M.A.J. · Appel, M.J. · Heer,
Institution: TNO Industrie en Techniek TNO Kwaliteit van Leven
Source:Risk Analysis, 4, 26, 867-880
Identifier: 239402
doi: doi:10.1111/j.1539-6924.2006.00784.x
Keywords: Biology · Food and Chemical Risk Analysis · Adverse effect · Benchmark approach · Critical effect size · Within-animal variation · Benchmarking · Biodiversity · Data reduction · Error analysis · Parameter estimation · Risk assessment · Adverse effects · Benchmark approach · Critical effect size (CES) · Within-animal variation · Toxicity · Intraspecific variation · Rodent · Temporal variation · Toxicity · Variance analysis · Analysis of variance · Animal experiment · Circadian rhythm · Clinical chemistry · Controlled study · Effect size · Female · Hematology · Male · Nonhuman · Rat · Review · Sex difference · Toxicity testing · Toxicological parameters · Analysis of Variance · Animals · Data Interpretation, Statistical · Dogs · Dose-Response Relationship, Drug · Female · Male · Poisons · Rats · Rats, Wistar · Risk Assessment · Toxicology · Animalia


In this study, the within-animal variation in routinely studied continuous toxicological parameters was estimated from temporal fluctuations in individual healthy nonexposed animals. Assuming that these fluctuations are nonadverse, this within-animal variation may be indicative of the minimal magnitude of the critical effect size (CES). The CES is defined as the breaking point between adverse and nonadverse changes in a continuous toxicological parameter, at the level of the individual organism. The total variation in the data from individual nonexposed animals was divided in variation parts due to known factors (differences in sex, animal, and day) and a residual variation, by means of analysis of variance. Using the residual variation and the estimated analytical measurement error of a toxicological parameter, the within-animal variation can be estimated. The data showed within-animal variations ranging between 0.6% and 34% for different clinical chemistry and hematological parameters in 90-day rat studies. This indicates that different (minimal) CES values may be applicable for different parameters. © 2006 Society for Risk Analysis.