NOTE: Below is an initial response by scientists to some criticisms of the newly published study showing that a commercialised GM maize, Monsanto’s NK603, caused massive tumours, organ damage, and premature death in rats. Roundup, the herbicide used with NK603 maize, was also found to cause similar effects at levels below those considered safe by regulators.
http://www.gmwatch.org/latest-listing/51-2012/14208

One main criticism has been that Seralini used “the wrong rat” in his study. Seralini’s critics said that the Sprague-Dawley (SD) rat is “prone” to tumours and so no conclusion can be drawn from the increase in tumours from treatment with GM maize and Roundup. The suggestion is that the rats would have got the tumours anyway, even without GM maize or Roundup.

Of course, the big problem with this argument is that the GM maize-fed and Roundup-exposed groups got significantly more tumours than the controls, as the scientists’ response below explains.

We only add to this that data on cancer incidence in SD rats and humans gathered by the Ramazzini Institute in Italy show that the Sprague-Dawley (SD) rat is an excellent human-equivalent model for long-term carcinogenicity studies. The cancer pattern of SD rats was found to accurately mirror that of humans (see slides 13–16 of this presentation): http://bit.ly/QsDRno

In other words, the SD rat has high predictive power for identifying carcinogenic effects in humans. 

It’s true that as SD rats age, they get more “spontaneous” tumours. But so do humans. And SD rats, like humans, also develop cancers from environmental exposures to carcinogens, and these will be added onto the background “spontaneous” level of cancers, just as we see in Seralini’s study. 

Plus, hundreds of carcinogenicity and chronic toxicity studies done on pesticides, chemicals, and GM foods by industry for regulatory purposes use the S-D rat. So if Seralini’s critics want to argue that the S-D rat is “the wrong rat”, they will have to chuck out all the pesticides, chemicals, and GM foods that were approved on the basis of S-D rat tests. That means, goodbye, glyphosate, as well as to many GM foods.
—
—
Response to criticism on the science
Sustainable Food Trust
21 Sept 2012
http://research.sustainablefoodtrust.org/wp-content/uploads/2012/09/Response-to-criticisms.pdf

The publication of GM animal feeds trials study yesterday morning has stimulated a very large volume of responses, in the form of media reporting, tweets and email feedback. Many of these raise a number of vitally important questions about aspects of the research and its methodology.

In response to the issues raised, and in line with the Sustainable Food Trust’s organisational mission of serving the public interest by ensuring that peer-reviewed results on the outcome of different farming systems are subjected to public scrutiny, we have assimilated some responses, supplied by scientists with expertise in this field.

The Sustainable Food Trust feels it is important to note that we are not an organization of scientists. We are an organization that is committed to communication; collaboration and public debate around the type of food systems that will sustainably feed a growing world population. Our role in this project has been to act as communicators of research findings that we feel are significantly important to the debate about the future of our food systems.

As an organization we are committed to publishing independent, peer-reviewed research findings from a range of sources.

We hope that the statements below will address the questions, and stimulate further debate about this vitally important issue.

Further questions concerning the science and methodology of this research will have to be answered directly by Professor Seralini and the CRIIGEN team.
—

CRITICISM: Strain of rats used Sprague-Dawley (SD) is prone to tumours

RESPONSE: SD rats have been used in most animal feeding trials to evaluate the safety of GM foods, and their results have been used by the biotech industry to secure approval to market GM products. They were used in the 90-day feeding trial that was conducted by industry to evaluate the toxicity of NK603 GM maize as part of the application for approval within the EU. They were also used in the original glyphosate two-year toxicity studies conducted in 2002 for regulatory approval within the EU.

The industry standard for toxicity tests performed by industry for regulatory purposes is the international protocol set out by the OECD (Organisation for International Cooperation and Development). This says that long-term carcinogenicity studies should be performed with the same strain of rat as used in shorter mid-term experiments, because this allows effects seen in the shorter experiment to be tracked to see how they develop in the long-term experiment, without the confounding factor that would occur if a different strain of rat was employed. Therefore, based on the past use of SD rats in trials of GM food and glyphosate it was scientifically correct and consistent to use this strain in Prof Seralini’s long-term study.

The rats that consumed NK603 GM maize and/or Roundup in Prof Seralini’s trial had an incidence of tumours, which was not just significantly greater than the control rats but also also significantly greater than observed in previous studies of SD rats. The tumour incidence in the test groups in his study was overall around three times higher than that the normal rate observed in the Harlan Sprague Dawley rat strain he used, as reported in the literature (Brix et al., 2005) including in the largest study with 1329 Sprague Dawley female rats (Chandra et al., 1992).

Furthermore, the key is that there were both quantitative and qualitative differences in the tumours arising in control and test groups. In the control rats they appeared much later and at most there was one tumour per animal if at all. In the treated rats the tumours began to be detected much earlier (four months in males; seven months in females), grew much faster and many animals had two or even three tumours. Many animals in the test groups had to be euthanised under animal welfare rules due to the massive size of the tumours; none of the control animals had to be euthanised but died in their own time. One should not ignore these biological facts.

Just to illustrate the point by analogy. We know that a small proportion of people who never smoke get lung cancer. If you smoke, the rate/risk of getting lung cancer is about 12 times higher than if you don’t smoke. The measurement is called a “relative risk”. So, imagine that there is an ethnic group of people with a higher rate of naturally occurring lung cancer. We know that if people in that group smoke, their rate of lung cancer will still increase like everybody else.


CRITICISM: The control groups were far too small. Looks like “random variation” in rats liable to develop tumours.

RESPONSE: This two year life-long experiment was conducted in a GLP environment according to international OECD guidelines in terms of animals used.

Standard practice is for the control group to be matched in size to the experimental groups. The experimental groups were 20 animals [10 male + 10 female] and therefore the control group should be 20 animals.

Prof [Anthony] Trewavas is not correct to say: “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.” The 20 animal control group is big enough to get a measure of tumour frequency. You don’t need to look at hundreds of animals. If he believes this, then he should also agree that the studies done by others including industry are also invalid.

The key thing is that there are big differences between the tumour frequencies in the control and the experimental groups (see previous answer). Claims that the results are just the result of random variation in a rat line that has a high frequency of tumours are not valid. The evidence for this is that the differences between the groups are much larger than the standard deviations of the two groups. In Seralini’s study, the differences are so large that it is not necessary to use a statistical test. This study used more rats in test groups, for a far longer duration, than any previous investigation employed by industry to obtain approval for NK603 GM maize and other GM crop products.


CRITICISM: The statistical analysis was flawed. Didn’t use standard methods. A “statistical fishing trip”.

RESPONSE: The statistical analysis was one of a number of valid methods that could have been used to evaluate a diverse set of data sets. An expert statistician was part of the research team and this was certainly not a “fishing trip”. Significance in many liver and kidney parameters are shown and highlighted in the Tables 1 and 2.


CRITICISM: No data was given about the rats’ food intake or possible contamination of the maize with fungus, which could have influenced results.

RESPONSE: The rats had unrestricted access to food and water and there were no differences in consumption or drinking levels between controls and test groups except for the group exposed to the highest Roundup concentration, which drank less water, perhaps due to the presence of high amounts of this herbicide making the water taste different.

All feeds were biochemically analysed to make sure they were nutritionally equivalent and no other toxins were present.


CRITICISM: Why were some test groups healthier than controls? How does one address the 30% premature death rate of males within the control group?

RESPONSE: From the mortality and tumour incidence rates in Figures 1 and 2 some test groups were not significantly better or worse than the controls. Yes, there were some premature deaths not only in the male but also female control groups. However, the levels are still lower than that observed in most test groups.


CRITICISM: Another red flag was that tumour rates didn’t increase in line with the dose of GMOs fed to animals, as scientists would expect to see if the genetically engineered corn were to blame, said Kevin Folta, a plant molecular biologist at the University of Florida in Gainesville. Instead, “you are likely seeing variation of normal tumour incidence in a small population of rats,” he said.

RESPONSE: We are not dealing here with a regular poison effect where increasing the dose will increase toxic effects. What is observed is due to hormonal system disturbances, which are known to display nonlinear effects (“U” or “G” shape responses to exposure). That is, for example, a low dose can have a disturbing effect and a higher dose can have no effect and then an even higher dose can elicit a response (U-shape response). Indeed, non-linear responses were to be expected in the rats treated with Roundup, as glyphosate, its active ingredient, is known to disrupt the endocrine system. In addition, in this case a threshold effect was also observed where a low dose appeared to saturate the system and so a higher dose had no additional effect.

(For an authoritative review on non-linear dose responses in hormonal systems, which the data implies is taking place in Prof Seralini’s study, see Hormones and Endocrine Disrupting Chemicals: Low Dose Effects and Nonmonotonic Dose Responses, Vandenberg et al 2012).


CRITICISM: The mechanism is unclear. Why should GM maize cause tumours? Why should Roundup have the same effect?

RESPONSE: These are very good questions that only future research will provide clear answers. However, Prof Seralini’s team hypothesises that the reason why the GM maize alone [without Roundup added] is affecting the liver and mammary gland systems is due to the EPSPS GM gene. The function of this GM gene may be the reason why the authors found that the GM maize had significantly lower amounts (up to 50%) of substances (caffeic and ferulic acids), which have protective effects against cancer formation and even mammalian tumours. Moreover, these phenolic acids and in particular ferulic acid may modulate estrogen hormone function as does glyphosate in the Roundup.

Future research will ascertain whether these hypotheses are significant contributory factors or whether the cause lies elsewhere, such as disturbances arising from the mutagenic effects of the GM transformation process.


CRITICISM: The results are out of line with other long-term studies that have investigated the safety of GMOs fed to a range of animals including chickens, rats, mice, quail, monkeys and fish, said Agnes Ricroch, a geneticist at the University of Paris XI and Pennsylvania State University, who co-wrote a review of 24 such studies that was published this year.

RESPONSE: It is scientifically incorrect to compare this long-term study with this particular variety of GM maize to other investigations using different GM feeds and different animals. Different animals have different anatomies and biochemistry; different GM feeds will have different compositions. One needs to compare like with like.

The study by Prof Seralini is the first long term feeding trial with this particular variety of Roundup tolerant GM maize, fed at three different doses. The only previous investigation with NK603 GM maize is a 90 day feeding study conducted by industry as part of its application for approval within the EU. This involved only two doses and a much narrower range of analyses. However, upon close independent scrutiny even this short term feeding trial showed signs of liver and kidney toxicity. The paper referred to [Ricroch] is a review of 24 GM feeding studies that are mostly short to medium term (90 days) and also measure a small range of organ and biochemical functions compared with Prof Seralini’s work.

Some of the studies referred to in this [Ricroch] review do in fact show statistically significant signs of toxicity to liver, kidney and immune systems arising from the consumption of GM soy and maize. Nevertheless, the authors dismissed these as not biologically relevant, without further empirical investigation. Despite these early signs of toxicity, the authors of this review did not recommend extending these mostly short and medium-term studies to see what would happen. Prof Seralini’s work has now filled in this gap with a two-year lifetime trial and has provided hard data which raises serious concerns.


CRITICISM: GM has been in the food chain for years in the US. Why isn’t there evidence of people and animals suffering more tumours or dying earlier? Why aren’t Americans “dropping like flies?”

RESPONSE: Most GM crops are fed to farm animals, which have relatively short lives either for meat or dairy production and so there is probably not enough time for tumours to develop.

Americans have been eating GM food (soya, maize) for only a relatively short time in significant quantities in processed foods. So it may be too short a period for long-term effects such as tumour formation to be noticeable. However, we should also note that there is no labelling of GM foods in the USA and no monitoring of the population for ill-effects, so if GM food were causing ill health this would be going undetected.