Relation between statistics and treatment-related changes obtained from toxicity studies in rats: if detected a significant difference in low or middle dose for quantitative values, this change is considered as incidental change?

Kobayashi, Kazuo; Sakuratani, Yuki; Abe, Takemaru; Nishikawa, Satoshi; Yamada, Jun; Hirose, Akihiko; Kamata, Eiichi; Hayashi, Makoto

doi:10.2131/jts.35.79

Cited by 6 publications

(3 citation statements)

References 57 publications

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“…The one-sided Williams test 30 fulfills these criteria. Moreover, in its generalized version as multiple contrast test 3 it provides simultaneous confidence intervals (to claim biological relevance as an alternative to p-values) and is available for several relevant data conditions, namely variance heterogeneity, 31 unbalanced designs, 32 ratioto-NC comparisons, 33 proportions, 34,35 poly-3 estimates, 36 survival functions, 37 a nonparametric version, 38 and multiple endpoints. 39 Therefore, the Williams trend test can be seen as the standard test in toxicology, accordingly recommended.…”

Section: Trend Testsmentioning

confidence: 99%

Statistical evaluation of toxicological bioassays – a review

Hothorn

2014

Toxicol. Res.

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The basic conclusions in almost all reports on new drug applications and in all publications in toxicology are based on statistical methods. However, serious contradictions exist in practice: designs with small samples sizes but use of asymptotic methods (i.e. constructed for larger sample sizes), statistically significant findings without biological relevance (and vice versa), proof of hazard vs. proof of safety, testing (e.g. no observed effect level) vs. estimation (e.g. benchmark dose), available statistical theory vs. related userfriendly software. In this review the biostatistical developments since about the year 2000 onwards are discussed, mainly structured for repeated-dose studies, mutagenicity, carcinogenicity, reproductive and ecotoxicological assays. A critical discussion is included on the unnecessarily conservative evaluation proposed in guidelines, the inadequate but almost always used proof of hazard approach, and the limitation of data-dependent decision-tree approaches.

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Section: Trend Testsmentioning

confidence: 99%

Statistical evaluation of toxicological bioassays – a review

Hothorn

2014

Toxicol. Res.

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“…Lack of consistency at similar doses in the same species and strain and lack of dose–response relationships can be observed for malignant lymphomas in mice (Tables 5, 6) and adenomas in rat (Table 6). Kobayashi et al (2010) reviewed the grounds for considering statistically significant changes as incidental, observing similar trends for unpublished and peer-reviewed scientific publications. Lack of dose–response is reported as the main justification for disregarding the results as incidental, followed by lack of physiological/toxicological significance of the effects and the comparison with historical controls.…”

Section: Discussionmentioning

confidence: 92%

Glyphosate toxicity and carcinogenicity: a review of the scientific basis of the European Union assessment and its differences with IARC

et al. 2017

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Glyphosate is the most widely used herbicide worldwide. It is a broad spectrum herbicide and its agricultural uses increased considerably after the development of glyphosate-resistant genetically modified (GM) varieties. Since glyphosate was introduced in 1974, all regulatory assessments have established that glyphosate has low hazard potential to mammals, however, the International Agency for Research on Cancer (IARC) concluded in March 2015 that it is probably carcinogenic. The IARC conclusion was not confirmed by the EU assessment or the recent joint WHO/FAO evaluation, both using additional evidence. Glyphosate is not the first topic of disagreement between IARC and regulatory evaluations, but has received greater attention. This review presents the scientific basis of the glyphosate health assessment conducted within the European Union (EU) renewal process, and explains the differences in the carcinogenicity assessment with IARC. Use of different data sets, particularly on long-term toxicity/carcinogenicity in rodents, could partially explain the divergent views; but methodological differences in the evaluation of the available evidence have been identified. The EU assessment did not identify a carcinogenicity hazard, revised the toxicological profile proposing new toxicological reference values, and conducted a risk assessment for some representatives uses. Two complementary exposure assessments, human-biomonitoring and food-residues-monitoring, suggests that actual exposure levels are below these reference values and do not represent a public concern.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-017-1962-5) contains supplementary material, which is available to authorized users.

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“…In addition, the incidence of outliers in clinical chemistry or hematology and unusual histopathologic findings in controls is surveyed in larger databases. Laboratory-specific and inter-laboratory data collections aid in the interpretation of findings seen in dosed animals (Deschl et al, 2002;Elmore and Peddada, 2009;Hall and Everds, 2003;Kobayashi et al, 2010). For example, in normally distributed data and a large sample size, roughly 1 in 22 observations will differ by twice the standard deviation or more from the mean.…”

Section: Discussionmentioning

confidence: 99%