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SDose–Response and Thresholds in Mutagenicity Studies: A Statistical Testing Approach

Ludwig A. Hothorn and Frank Bretz

The analysis of dose–response relationships is an important objective in toxicology, and one in which both modelling and testing approaches are used. One particular question is whether a threshold exists at low doses. The concept of a pragmatic threshold is used, i.e. low doses with biologically unimportant effects are assumed to be threshold doses. “Biologically unimportant” means, in statistical terms, a lower effect than the effect of the negative control, or at least a just-tolerable margin δ higher than the effect of the negative control. Therefore, threshold doses can be tested in terms of a one-sided hypothesis of equivalence. A new approach is proposed, assuming, at the least, that the low dose is a threshold dose, and the highest dose is superior to the negative control. By analogy to the k-fold rule commonly used in mutagenicity studies, tests on ratio-to-control are used. The a priori definition of the threshold margin is inherently needed. A further approach proposes the analysis of dose–response relationships by means of order-restricted inference (the so-called trend test). A modification of a multiple-contrast test is used, in which only those contrasts are included that are sensitive for no effects at low doses. A further modification treats the complicated, but real, problem of simultaneous existence of a threshold, a monotonic increase, and a downturn effect at high dose(s). A parametric procedure is considered, together with an extension for proportions. The important problem of a priori sample size definition is discussed. The approaches are demonstrated by means of examples based on real data.
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Is Phenylbutazone a Genotoxic Carcinogen? A Weight-of-Evidence Assessment

Robert D. Combes

Published in silico, in vitro, in vivo laboratory animal and human data, together with information on biotransformation and data from structure–activity analyses with two decision-tree systems (ACToR and Toxtree), have been used in a weight-of-evidence (WoE) assessment to determine whether phenylbutazone (PBZ) is a genotoxic or a non-genotoxic carcinogen. This was undertaken to facilitate the risk assessment of human exposure to this veterinary drug via the consumption of horsemeat from treated animals. Despite problems with data interpretation at all tiers of the database, it was concluded that PBZ behaves like a genotoxic carcinogen with a threshold dose. This conclusion is based mainly on the results of a definitive rodent bioassay, and on the following observations: a) that PBZ has weak in vitro activity only at high concentrations in some genotoxicity assays, accompanied by high levels of cytotoxicity; b) that it (and a major metabolite) is able to cause sister chromatid exchanges in vivo in rodents; and c) that it can induce cytogenetic effects in vivo in humans. It also takes into account the known and predicted activities of the parent drug, some of its metabolites and two structural analogues, and, importantly, several of the drug’s other biochemical effects that are unrelated to toxicity. However, this conclusion is not fully supported by all the evidence, and much of the information is based on old papers. Therefore, more studies are required to establish whether the concentration thresholds seen in vitro would translate to dose thresholds for carcinogenicity, such that a safe dose-level could be defined for the purposes of assessing risk. It was disappointing that a WoE approach to evaluating all of the available hazard data, as is increasingly being advocated to improve the hazard identification paradigm, was unable to provide definitive answers in this case, particularly in view of the large numbers of animals that had been used to provide much of the information.

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