French research suggests that rats fed a diet which contained a Roundup-tolerant genetically modified maize died more frequently and earlier over the two year study than control groups. The study also suggests that females developed mammary tumours more often than and before controls.
Below are quotes from Australian, New Zealand and UK experts and a statistical analysis of the paper. Feel free to use these quotes in your stories. If you would like to speak to an expert, please don’t hesitate to contact us on (08) 7120 8666 or by email.
Dr Andrew Bartholomaeus is a toxicologist and Adjunct Professor at the University of Canberra and the University of Queensland. He is former General Manager Risk Assessment at Food Standards Australia and New Zealand.
“The study is poorly designed, reported in very limited detail, and is not in accordance with standard guidelines for chronic toxicity studies (e.g. OECD test guidelines). Only 10 animals per sex per group were included. For chronic studies larger numbers would be normal, and necessary, to ensure that the normal, random variations expected in such studies are not given undue weight and that normal mortality seen in aged rats does not skew the results. Expression of results as percentages with such small group sizes distorts the significance of the findings. A difference of 2 animals in any normal age-related finding, such as mammary tumours, could result in 40% incidence in one group and 60% in another for example without representing a treatment-related effect.
The claimed toxicity of Roundup is highly implausible and discordant with extensive data from well designed and conducted studies in multiple species. “Studies of glyphosate lasting up to 2 years, have been conducted with rats, dogs, mice, and rabbits, and with few exceptions no effects were observed. For example, in a chronic feeding study with rats, no toxic effects were observed in rats given doses as high as 400 mg/kg/day. Also, no toxic effects were observed in a chronic feeding study with dogs fed up to 500 mg/kg/day, the highest dose tested [see http://extoxnet.orst.edu/pips/glyphosa.htm].” Glyphosate is approximately 30-40% absorbed from the gastrointestinal tract, and whilst dosing with the formulation may affect absorption, doses used in more appropriately designed studies were considerably higher than those used by these authors.
Mammary gland tumors in aged Sprague dawley rats are a common and expected finding with a reported incidence of 67% in control animals carcinogenicity studies by the US National Toxicology Program of 67%.
The authors should be encouraged to make available the raw data to allow scrutiny by independent scientists at the same level of detail that is normal for company data.”
Disclaimer: I consult to Industry and Government in my area of expertise and provide de bono contributions to the research collaborations of ILSI IFBiC (International Food Biotechnology Committee of the International Life Sciences Institute).
Professor Brian Priestly is Director of the Australian Centre for Human Health Risk Assessment at Monash University, Melbourne
“The current paper is far from convincing from a toxicological perspective. The study was based on 10 rats of each sex per treated group, and there was no consistency to any dose-response relationship, and much variability between the outcomes in the various groups. It was difficult to determine whether any effects on health or survival (if really present) were attributable to the GM maize, to the Roundup herbicide (glyphosate) or to neither. While the results were analysed using an unusual statistical technique, I felt that the authors substantially over-interpreted the findings.”
Disclaimer: I currently sit on the Gene Technology Technical Advisory Committee, and my comments should in no way be considered to represent the views of the Gene Technology regulator. I am also a Science Fellow of Food Standards Australia New Zealand, and I assisted FSANZ by chairing a workshop on testing of GM foods in 2007. I am not a spokesperson for FSANZ on these issues.
Professor Rick Roush is the Dean of the Melbourne School of Land and Environment at the University of Melbourne
“Contrary to the claims in the media releases, this is NOT the first long term safety study into either Roundup or GM. There are more than a hundred feeding studies on GM. Further, the European Commission, based on their own research on a wide range of theoretical health and environmental risks, at a cost of more than 300 million euros, found in 2010 that “The main conclusion to be drawn from the efforts of more than 130 research projects, covering a period of more than 25 years of research, and involving more than 500 independent research groups, is that biotechnology, and in particular GMOs, are not per se more risky than e.g. conventional plant breeding technologies” (A Decade of EU-funded GMO Research 2010, p. 16).
Similar claims have been made by lead author Seralini in the past, and rejected by the European Food Safety Authority: http://www.efsa.europa.eu/en/press/news/gmo070628.htm. This paper itself has several errors, including gross statistical mistakes, as found in the previous EFSA review.
The World Health Organization (WHO) has stated: “GM foods currently available on the international market have passed risk assessments and are not likely to present risks for human health. In addition, no effects on human health have been shown as a result of the consumption of such foods by the general population” (http://www.who.int/foodsafety/publications/biotech/20questions/en/).”
Professor Mark Tester is Professor of Plant Physiology at the Australian Centre for Plant Functional Genomics, University of Adelaide and Director of the Australian Plant Phenomics Facility
“The first thing that leaps to my mind is why has nothing emerged from epidemiological studies in the countries where so much GM has been in the food chain for so long. If the effects are as big as purported, and if the work really is relevant to humans, why aren’t the North Americans dropping like flies?! GM has been in the food chain for over a decade over there – and longevity continues to increase inexorably!
And if the effects are as big as claimed, why have none of the previous 100+ plus studies by reputable scientists, in refereed journals, noticed anything at all?
Finally, this was a study of one event with one gene. To then extrapolate to all genetically modified crops is absurd. Even if it eventuates that there is an issue with this one event, or even this one gene, there is no reason at all for other genes introduced using GM to carry the same burden of risk. GM is an adaptation of a natural process that occurs all the time all over the planet – it is “only” a technology, a technique. It is how it is used that is more important. Generalisations about the risk of the technology per se are absurd.”
Below are comments collected by our colleagues at the New Zealand Science Media Centre.
Dr Mark Vickers, Senior Research Fellow, Liggins Institute, University of Auckland, comments:
“The data is not as robust as the authors have stated and experimental power is quite low. Key data as regarding fluid and fluid intakes and body growth all appear to be missing (although were measured). It is surprising that the paper was accepted for publication without such data.
“Rats are extremely sensitive to additives in water and as such it is essential to report fluid intake data (it is also important to detail the composition of the standard diet used as this is the reference point). Also, does an n=10 represent 10 biological replicates (i.e. 10 litter backgrounds) or littermates? Robust statistical analysis is also lacking. Further, this strain of rat is prone to develop tumours with advancing age (indeed 24 month survival in the SD rat is low in an ad-libitum feeding environment). A standard purified open source control diet (e.g. one of the AIN series diets used worldwide as a control diet) would have been a useful addition.”
Prof Thomas Lumley, Professor of Biostatistics, University of Auckland, comments:
“I do not think the herbicide risks look convincing, especially with respect to cancer. There is no consistent pattern in deaths with dose of either Roundup or GM corn: this is not just showing a threshold, as the authors suggest, since in all six of their comparisons the highest-dose group has lower mortality than lower-dose groups. The hypothesis of hormone-related cancer differences is not supported by the multivariate biochemical analysis, which found differences in salt excretion but not in testosterone or estradiol. The strongest conclusion that could be drawn from this study is that it would be worth studying a larger group of controls than just 10 and (since there is no sign of dose-response) just a single low dose of Roundup or GM corn.
“The researchers say “It is noteworthy that the first two male rats that died in both GM treated groups had to be euthanized due to kidney Wilm’s tumors”. This is noteworthy, but perhaps not in the way the researchers mean: increases in human Wilms’ tumor from GM corn or herbicide residues would already be obvious even at rates hundreds of times lower than reported in these rats.”
Assoc Prof Peter Dearden, Director of Genetics Otago, Biochemistry Department, University of Otago, comments:
“The paper by Seralini et at describes experiments that suggest that round-up resistant GMO plants, and Roundup itself, might be associated with toxic and carcinogenic effects in rats. The paper provides intriguing results, but they are vey preliminary. The numbers of individuals used are low, making the significance of the results hard to interpret. The controls for these experiments, vital to understand their significance, are not well reported. The relationship between treatment and effect is not clear. In my opinion this is interesting work, but with major flaws, with an outcome that needs to be followed up with robust, well described experiments.”
Below is an analysis by UK statisticians assessing the validity of the findings in the paper and comments from UK experts from our colleagues at the UK Science Media Centre.
Before The Headlines
Title, Date of Publication & Journal
‘Long term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize’, Food and Chemical Toxicology 19 September 2012
Claim supported by evidence?
The paper does not prove the claim that rats fed on a diet containing NK603 Roundup tolerant GM maize died earlier than rats fed on a standard diet.
Looking at the graphs of mortality for females (Fig 1), death might appear to be earlier with a GM diet than a standard diet; however this has not been proven statistically. Mortality is broadly similar for males with a GM diet and a standard diet. Similar comments apply to pathological findings.
It is evident that some treated groups have lower death rates / tumour rates than the comparable controls. This is not reported in the abstract.
There is no consistent dose-trend – if there were an effect, we would expect to see increases (e.g. in deaths) from 0 to 11 to 22 to 33. In contrast – in males, 33 (and C) have the lowest numbers of deaths.
“In females, all treated groups died 2–3 times more than controls, and more rapidly. This difference was visible in 3 male groups fed GMOs.” – this statement has not been subjected to standard methods of statistical analysis for survival time. The phrase “died 2–3 times more than controls” is based on exceptionally small numbers.
The authors suggest a threshold – this rarely occurs in practice. We would expect greatest mortality/ toxicity at the highest dose in a well-designed study. With small numbers as in this study we would expect to see a general trend of mortality increasing with dose.
It seems likely that the numbers in each group are too small for standard methods of statistical analysis to find significant effects on mortality or pathological findings.
There are virtually no p-values presented. The group sizes are small. This should be interpreted with extreme caution.
There are many treated groups, and a number of parameters. There is obvious potential for selected reporting, selection of methods etc. In such small groups, with so many parameters this is a big issue. This issue is amplified in the abstract and further in the press release. Strong statements are issued without sufficient backing / explanation.
Deaths are compared to the control mean (for males and females). Due to the distribution of deaths (most deaths occur in old age), this is almost bound to exclude the large majority of deaths in the control groups. The 2 or 3 deaths in the control group is determined by their methods, but is inappropriately presented as a true observation.
Prof Maurice Moloney, Institute Director and Chief Executive , Rothamsted Research, said:
“Although this paper has been published in a peer–reviewed journal with an IF of about 3, there are anomalies throughout the paper that normally should have been corrected or resolved through the peer-review process. For a paper with such potentially important findings, it would have been more satisfying to have seen something with a more conventional statistical analysis. A comparison of each measured parameter, which took into account the variance throughout the experiment, which would have been revealed using a multiple range test, would have provided better evidence for the concluding remarks and the abstract. Figure 1 does not provide any data from the controls and their variance is unreported here. Table 2 reports different numbers of individuals used for the controls than the treatments. In all cases the controls have used less individuals than used in the treatments. The data in Table 2 do not show confidence intervals or provide evidence of significant differences between all the treatments and the controls. The lack of a dose response effect is argued by the authors to be indicative of a “threshold” effect. This is an extrapolation of their findings and could only be determined by intermediate dosing. The photographs are very graphic, but do not include a control. Sprague-Dawley rats frequently develop mammary tumours in well-fed controls. Are we to conclude from this that no controls developed tumours? Numerically, we cannot tell, because they are absent also from Figure 2. We are performing a more detailed analysis of the statistics in relation to the conclusions, but for the present it is fair to point out that normally a referee would insist on showing the control data and its variance in such a study.”
Prof David Spiegelhalter, Winton Professor of the Public Understanding Of Risk, University of Cambridge, said:
“In my opinion, the methods, stats and reporting of results are all well below the standard I would expect in a rigorous study – to be honest I am surprised it was accepted for publication.
“All the comparisons are made with the ‘untreated’ control group, which only comprised 10 rats of each sex, the majority of which also developed tumours. Superficially they appear to have performed better than most of the treated groups (although the highest dose GMO and Roundup male groups also fared well), but there is no proper statistical analysis, and the numbers are so low they do not amount to substantial evidence. I would be unwilling to accept these results unless they were replicated properly.”
Dr Wendy Harwood, senior scientist, John Innes Centre, said:
“The full data set has not been made available, but the findings do not contradict previous findings that genetic modification itself is a neutral technology, with no inherent health or environmental risks.
“We have to ask whether a diet with this level of maize is normal for rats. Another control with an alternative diet should have been included.
“Ten rats per group is a small number. For example, is the death of three out of ten controls compared to five out of ten males in the treated group statistically significant?
“The data from the control group fed non-GM maize is not included in the main figures making it very difficult to interpret the results.
“Without access to the full data, we can only say that these results cannot be interpreted as showing that GM technology itself is dangerous. However they do indicate possible concerns over long-term exposure to Roundup that require further study.”
Further comments from other scientists:
“Other issues that have come up:
- ‘All data cannot be shown in one report and the most relevant are described here’ – this is a quote from the paper.
- Small sample size
- Maize was minimum 11% of the diet – not balanced
- No non-maize control?
- No results given for non-gm maize
- For nearly 20 years, billions of animals in the EU have been fed soy products produced from genetically modified soybean, mainly from Latin America. No problems have been reported by the hundreds of thousands of farmers, officials, vets and so on.
- The same journal publishes a paper showing no adverse health effects in rats of consuming gm maize (though this is a shorter 90-day study)
- Statistical significance vs relative frequencies.
- We also have to ask why the rats were kept alive for so long – for humane reasons this study would not have been given approval in the UK.
- In Fig.2, I assume the bars with a zero is for the non-maize control. Those bars don’t looks significantly different from the bars indicating 11, 22, and 33% of GM maize in the diet? Have the authors done stats on their data?
- Dawley (SD) rats are rarely kept over 6 month of age. mortality on this strain of rats is ~55% of mice still alive after 2yr. If indeed there is a known high incidence of tumours in ageing SD rats, it would seem hard – with such small numbers of rats as in this new study – to draw the conclusions that the authors do…
- Also to note, these type of studies with resulting tumours as those depicted in this paper would never have gotten HO approval to keep the animals alive this long. There are strict rules for how long animals can be kept with tumours and how large these are allowed to develop before an animal has to be humanely sacrificed.”
Prof Ottoline Leyser, Associate Director of the Sainsbury Laboratory, University of Cambridge, said:
“Like most of the GM debate, this work has very little to do with GM. The authors of the paper do not suggest that the effects are caused by genetic modification. They describe effects of the roundup herbicide itself and effects that they attribute to the activity of the enzyme introduced into the roundup resistant maize. There is good evidence that introducing genes in to crops using GM techniques results in fewer changes to the crops than introducing them using conventional breeding.
“This is unfortunately rather a subtle point and is somewhat tangential to the immediate issue.”
Prof Anthony Trewavas, Professor of Cell Biology, University of Edinburgh, said:
“The control group is inadequate to make any deduction. Only 10 rodents so far as I can see and some of these develop tumours. Until you know the degree of variation in 90 or 180 (divided into groups of ten) control rodents these results are of no value.
“These figures for normal appearance of tumours in these rodent lines are surely available and using a line which is very susceptible to tumours can easily bias any result. To be frank it looks like random variation to me in a rodent line likely to develop tumours anyway.”
Prof Tom Sanders, Head of the Nutritional Sciences Research Division, King’s College London, said:
“Most toxicology studies are terminated at normal lifespan i.e. 2 years immortality is not an alternative.
“No food intake data is provided or growth data. This strain of rat is very prone to mammary tumours particularly when food intake is not restricted.
“There is a lack of information on the composition of the diet. One concern is whether there were mycotoxins in the maize meal because of improper storage. Zearalanone is a well know phytoestrogen produced by filamentous fungi that grow on maize.
“The statistical methods are unconventional, there is no clearly defined data analysis plan and probabilities are not adjusted for multiple comparisons.”
Prof Alan Boobis, Professor of Biochemical Pharmacology, Imperial College London, said:
“Some of the effects are presented in a way that makes it difficult to evaluate their significance. For example, there does not appear to be a statistical analysis of the mammary tumours. These occur quite often in untreated animals. One would usually also take into account the historical controls in the testing lab, in reaching a conclusion. The pesticide itself has been subject to long term studies in rodents by others.”