Explanatory statement for the applicability of the Guidance of the EFSA Scientific Committee on conducting repeated-dose 90-day oral toxicity study in rodents on whole food/feed for GMO risk assessment

,

doi:10.2903/j.efsa.2014.3871

Cited by 71 publications

(60 citation statements)

References 17 publications

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“…G-TwYST study C is based on OECD guidance 408 on repeated dose 90-day oral toxicity studies in rodents (OECD 1998), EFSA guidance complementing the OECD guidance for whole food/feed studies (EFSA 2011b), and additional EFSA clarifications (EFSA 2013(EFSA , 2014. OECD guidance 408 (OECD 1998) requires numerical results to be evaluated by an appropriate and acceptable statistical method, but gives no further guidance on statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

G-TwYST study C a 90-day toxicity study in rats fed GM maize NK603 : statistical report

Goedhart

Voet

2018

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The purpose of oral toxicity study C in the EU project G-TwYST was to assess the effects of genetically modified (GM) maize NK 603, grown both with and without the use of RoundUp, when fed to rats for a period of 90 days at GM incorporation rates of 11%, 33% and 50% in the feed, if needed supplemented with near-isogenic non-GM maize to total maize inclusion rates of 33% or 50%. Differences between feeding groups were compared, using a recently developed method for equivalence testing, to differences between non-GM feeds obtained in previous studies performed in the EU project GRACE. Given tentative settings for regulatory parameters, for a set of 648 comparisons involving body and organ weights, haematology and clinical chemistry, equivalence was established in 99% of cases, higher than the minimal nominal confidence level of the test which was 95%. Equivalence was found to be more likely than lack of equivalence in 100% of cases. In addition to this primary analysis, the report also contains results for equivalence testing using external target effect sizes for a limited set of variables, results for classical statistical analysis of differences, graphs of standardised effect sizes such as performed in the GRACE study, results of factorial analysis, graphs showing correlations between variables associated with liver or kidney damage, and a post-hoc power analysis comparing trials with 33% and 50% maize inclusion rates.

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Section: Methodsmentioning

confidence: 99%

G-TwYST study C a 90-day toxicity study in rats fed GM maize NK603 : statistical report

Goedhart

Voet

2018

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“…4.5.1 Method G-TwYST study A is based on OECD guidance 453 on combined chronic toxicity and carcinogenicity studies (OECD 2009), EFSA guidance complementing the OECD guidance for whole food/feed studies (EFSA 2011b), and additional EFSA clarifications (EFSA 2013(EFSA , 2014. OECD guidance 453 (OECD 2009) requires numerical results to be evaluated by an appropriate and acceptable statistical method, but gives no further guidance on statistical analysis.…”

Section: Classical Statistical Analysismentioning

confidence: 99%

G-TwYST study A combined chronic toxicity and carcinogenicity study in rats fed GM maize NK603 : main statistical report

Goedhart

Voet

2018

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The purpose of oral toxicity study A in the EU project G-TwYST was to assess the effects of genetically modified (GM) maize NK 603, grown both with and without the use of RoundUp, when fed to rats for a period of up to two years at incorporation rates of 11% and 33% in the feed. The effects were assessed relative to the responses for male and female rats fed the near-isogenic non-GM maize, and the differences were compared, using classical and new statistical methods. The experimental design was a complete randomized block design with cage as the experimental unit. Five types of feed were administrated to cages with 2 rats in each cage. Experimental units, i.e. cages, were organized in blocks of 5 cages, and the feeding groups were randomized within blocks. Treatment identity was blinded for everyone involved in the experiments and for the statistical analysts until after decisions were made about outliers in the data. The four feeding groups with GM maize were each compared to the feeding group with non-GM maize for 36 variables at 3 months, 40 variables at 6 months, 44 variables at 12 months and 37 variables at 24 months, and for males and females separately. The variables were body weight, growth rate, feed intake, haematology, clinical chemistry and organ weights. Only data for animals that survived the experiment were statistically analysed. In total, 1256 comparisons on quantitative variables were made. In addition, the times of death were analysed using survival analysis, and an analysis of mortality at 24 months. Using classical statistical tests at the 5% false positive level (= 0.05), among the 1256 comparisons of GM groups to the non-GM group on quantitative variables, 80 (6.4%) significant differences were found using the parametric t-test, and 72 (5.7%) significant differences using the non-parametric Wilcoxon test. Using the tests at the 1% false positive level (= 0.01), there were 13 (1.0%) significant differences using the t-test (lowest P-value 0.002), and also 13 (1.0%) significant differences using the Wilcoxon test (lowest P=value 0.005). The number of significant test results is therefore equal or slightly higher than the expected false positive rate of the tests, and it was relatively high in the 12 months data (11% for the t-tests, and 9% for the Wilcoxon tests). The patterns of significant results are open for toxicological interpretation. Statistical tests were also performed based on the factorial structure of the feeding groups using analysis of variance. Using statistical tests at the 5% false positive level (= 0.05), 13 (4%) significant effects were found among 314 comparisons of the average of the four GM groups with the non-GM group, which therefore does not exceed the expected number of false positives given the nominal test level. More significant effects were found within the set of four GM groups. In 32 (10%) of the 314 cases there was a significant interaction effect, i.e. the differences between the GM groups with and without RoundUp were dependent on the GM inclusion rate 11%...

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“…In fact, as we shall see, a more appropriate analysis is one that focuses on the individual animals -each of which will respond differently to the treatment -but which takes account of the dependence within litters. The same misconception emerges in a different context -the housing of two or more rodents within a cage -generating a cage effect where it is mistakenly argued that if treatments are allocated to cages then the cage, and not the individual animal, should be the experimental unit [12].…”

Section: Introductionmentioning

confidence: 99%

Pesticides and transgenerational inheritance of pathologies: Designing, analysing and reporting rodent studies

Plewis

2020

Preprint

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The evidence for transgenerational transmission of pathologies in rodents exposed to pesticides is largely based on studies with weaknesses in design and analysis and a lack of transparency in reporting the results. This paper examines these methodological and statistical issues in detail. Its particular focus is on the estimation of 'litter effects': the tendency for rodents within a litter to be more alike than rodents in different litters. Appropriate statistical models were fitted to published data from a series of widely reported studies carried out at Washington State University. These studies were amalgamated into a single dataset in order to estimate these litter effects and the associated treatment effects. Litter effects varied by outcome and were often substantial. Consequently, the effective sample size was often substantially less than the number of observations with implications for the power of the studies. Moreover, the reported precision of the estimates of treatment effects was too low. These problems are exacerbated by unexplained missing data across generations. Researchers in the life sciences could be more cognisant of the guidelines established in medicine for reporting randomised controlled trials, particularly cluster randomised trials. More attention should be paid to the design and analysis of multi-generational rodent studies; their imperfections have important implications for assessments of the evidence relating to the risks of pesticides for public health.

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Explanatory statement for the applicability of the Guidance of the EFSA Scientific Committee on conducting repeated-dose 90-day oral toxicity study in rodents on whole food/feed for GMO risk assessment

Cited by 71 publications

References 17 publications

G-TwYST study C a 90-day toxicity study in rats fed GM maize NK603 : statistical report

G-TwYST study C a 90-day toxicity study in rats fed GM maize NK603 : statistical report

G-TwYST study A combined chronic toxicity and carcinogenicity study in rats fed GM maize NK603 : main statistical report

Pesticides and transgenerational inheritance of pathologies: Designing, analysing and reporting rodent studies

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