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Letter to the Editors regarding “10% Body weight (gain) change as criterion for the maximum tolerated dose: A critical analysis”
Citation:
Berry, C., S. Cohen, Jon Corton, J. Lauro Viana de Camargo, G. Eisenbrand, S. Fukushima, H. Greim, K. Weber, I. Reitjens, AND C. Strupp. Letter to the Editors regarding “10% Body weight (gain) change as criterion for the maximum tolerated dose: A critical analysis”. REGULATORY TOXICOLOGY AND PHARMACOLOGY. Elsevier Science Ltd, New York, NY, 139:105362, (2023). https://doi.org/10.1016/j.yrtph.2023.105362
Impact/Purpose:
This is a Letter to the Editors of the journal Regulatory Toxicology and Pharmacology regarding the article “10% Body weight (gain) change as criterion for the maximum tolerated dose: A critical analysis” by D. van Berlo, M. Woutersen, A. Muller, M. Pronk, J. Vriend, B. Hakkert (Regul. Toxicol. Pharmacol., 134 (2022), Article 105235)
Description:
This optional sub-product is a letter in response to a recently published paper in Reg Tox and Pharm: van Berlo D, Woutersen M, Muller A, Pronk M, Vriend J, Hakkert B. 2022. 10% Body weight (gain) change as criterion for the maximum tolerated dose: A critical analysis. Regul Toxicol Pharmacol. 134:105235. doi: 10.1016/j.yrtph.2022.105235. There is no abstract to this letter but below is the first part that is pasted: We find several reasons to disagree with the proposal by Van Berlo et al. (2022) who suggest that the predictive value of the rodent cancer bioassay might be improved by altering the way in which body weight is used in setting the highest dose in bioassays. The variables relating to body weight measured in toxicology studies include body weight, weight gain (relative to initial weight), and the efficiency of food utilization (EFU) expressed as body weight gain per 100 g food consumed (Hoffman et al., 2002). Depending on the progression of toxicity, a 10% reduction in body weight gain may or may not be a reliable indicator that the maximum tolerated dose (MTD) is achieved. Such a reduction in terminal body weight might be achieved by a continuous marginal effect on body weight development or by losses and gains from a number of causes over a study of considerable length (Everds et al., 2013; Kemi et al., 2000; Cadoni et al., 2017; Weber, 2017). Other observations (clinical signs, hematology, clinical chemistry, histopathology) must be factored into the decision to determine whether the MTD has been reached. High dosage increases the possibility of overdosing leading to saturation of metabolic and reparative pathways with no relevance to human exposure levels. Effects seen at dose levels from which humans are conservatively protected by regulation (i.e.: those inducing toxicity or exceeding the capacity of the metabolic system to deal with them) do not add to the protection goal, but have a price in animal suffering in the study itself and often trigger further unnecessary investigations. Mortality in control groups of rat standard cancer bioassays may reach 75% (Charles River, 2009; Weber et al., 2011); thus it is not surprising that regulatory bodies consider a study with high mortality at the top dose as unreliable and may ask for it to be repeated - a risk that increases substantially if doses higher than those that satisfy the criteria outlined above are used. Haseman from the National Toxicology Program has pointed out that, ‘ … (in) designing long-term rodent carcinogenicity studies, measures should be taken to minimize potential body weight differences between dosed and control groups … ’ (Haseman et al., 1997). Hazard-based testing assumes that results obtained at high doses are indicative of results that will occur at lower, environmentally relevant, doses. This assumption, underlying the publication of van Berlo et al., fails to acknowledge the general acceptance of the questionable relevance of findings in animal studies where homeostasis is disturbed by toxicity, and ignores the view, expressed in a number of publications, that the time has come to acknowledge that the standard 2-year rodent bioassay has limited predictive value in evaluating human risk (Cohen and Arnold 2011; Cohen 2017; Goodman 2018; Berry et al., 2019).
URLs/Downloads:
DOI: Letter to the Editors regarding “10% Body weight (gain) change as criterion for the maximum tolerated dose: A critical analysis”
1-S2.0-S0273230023000302-MAIN.PDF (PDF, NA pp, 343.818 KB, about PDF)
https://pubmed.ncbi.nlm.nih.gov/36828242/