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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

Authors

  • Susan Dekkers,

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      Food and Chemical Risk Analysis, TNO Quality of Life, P.O. Box 360, Utrechtseweg 48, Zeist, 3700 AJ, The Netherlands.
  • Jan Telman,

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      Imaging Systems, TNO Science and Industry, P.O. Box 155, Stieltjesweg 1, Delft, 2600 AD, The Netherlands.
  • Monique A. J. Rennen,

    Corresponding author
      *Address correspondence to M. A. J. Rennen, Food and Chemical Risk Analysis, TNO Quality of Life, P.O. Box 360, Utrechtseweg 48, Zeist, 3700 AJ, The Netherlands; monique.rennen@tno.nl.
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      Food and Chemical Risk Analysis, TNO Quality of Life, P.O. Box 360, Utrechtseweg 48, Zeist, 3700 AJ, The Netherlands.
  • Marco J. Appel,

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      Toxicology & Applied Pharmacology, TNO Quality of Life, P.O. Box 360, Utrechtseweg 48, Zeist, 3700 AJ, The Netherlands.
  • Cees De Heer

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      Food and Chemical Risk Analysis, TNO Quality of Life, P.O. Box 360, Utrechtseweg 48, Zeist, 3700 AJ, The Netherlands.

*Address correspondence to M. A. J. Rennen, Food and Chemical Risk Analysis, TNO Quality of Life, P.O. Box 360, Utrechtseweg 48, Zeist, 3700 AJ, The Netherlands; monique.rennen@tno.nl.

Abstract

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.

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