Truth: The review suffers from important omissions, fails to show GMOs are safe, and provides evidence of risk for some GMOs

Myth at a glance

A review by Nicolia and colleagues is widely cited to argue that over 1700 studies show GM foods and crops are safe. However, the studies cited in the Nicolia review and supplementary materials, taken as a whole, do not show that GMOs are safe.

The majority of the articles in the list of 1700 are irrelevant or tangential to assessing the safety of commercialized GM foods and crops for human and animal health and the environment.

The list includes some studies that are relevant to GMO safety and show actual or potential hazards of the GMO to health or the environment. The Nicolia review authors ignore or dismiss these findings without sound scientific justification. They also ignore evidence contradicting key assumptions upon which regulators have based their conclusions that GMOs are safe.

Nicolia and colleagues omit important studies that demonstrate hazards related to GMOs and ignore major controversies over the interpretation of scientific findings on GMOs.

The authors use unscientific justifications for ignoring or dismissing important papers, including their arbitrary decision to include only studies published in the ten years since 2002.

Assembling large but questionable lists of studies supposedly providing evidence of the safety of GMOs has become common practice by GMO proponents. In the long term it will have a corrosive effect on public trust in science.

A review by Nicolia and colleagues, “An overview of the last 10 years of genetically engineered crop safety research”,1 is widely cited2,3 to argue that over 1700 studies show genetically modified (GM) foods and crops are safe. The list, which the authors provide in supplementary materials to their main review paper, is a collection of publications on many different aspects of GMO (genetically modified organism) research and commercialization.

The following analysis of the Nicolia review and the 1700 publications listed in the supplementary materials is intended to investigate whether these claims are justified. This analysis is not exhaustive, but focuses on the most important aspects of the review. A full analysis would take months and would result in an impractically long report. However, even this level of investigation reveals many shortcomings in the Nicolia review and supports the conclusion that it fails to provide convincing evidence of the safety of GMO foods and crops. Details are presented below.

Overview of problems with the Nicolia review

1. Nicolia and colleagues include many studies that are largely irrelevant to assessing the safety for health and the environment of commercialised GMOs or GMOs in the commercialization pipeline.

Studies that could address the vital question of long-term impacts of GM foods on human and animal health would typically consist of long-term rodent feeding studies, similar to those performed to support regulatory authorization of pesticide active ingredients. In such a study, one group of animals would be fed a GM diet and the control group an equivalent non-GM diet, in which the GM ingredients are replaced with isogenic (with the same genetic background) non-GM ingredients. The experiment would last for 1-2 years.

Few such studies have been carried out on GMOs. Most of those that have been carried out were conducted by researchers independent of the GM industry, after the GMO in question was already in the food supply (post-commercialization): in other words, they were not required for regulatory approval and risk assessment. The rodent feeding studies routinely performed by industry to support regulatory authorization of their products generally last for a maximum of 90 days, a subchronic period that is too short to reveal long-term effects.

Long-term animal studies should be followed by systematic post-commercialization monitoring, in which products containing the GMO are labelled as such and the market monitored for human health impacts such as allergies, chronic toxicity, carcinogenicity, reproductive and developmental toxicity, and teratogenicity. These impacts cannot, by definition, be studied in short 90-day toxicity tests in rodents.

Yet no post-commercialization monitoring studies in humans have ever been performed for any GMO, despite mounting evidence of adverse effects on animal health (see below).

Studies that could help address the question of the safety of GMOs for the environment include those in which beneficial and non-target insects are exposed to GM insecticidal crops, investigations of the environmental toxicity of the herbicides used with GM crops, and studies of the effects of GM crop cultivation on soil microbial life, non-target insects, and other wildlife.

Only a relatively small proportion of the studies cited in the Nicolia review and supplementary list of 1700 papers attempt to address these questions.

The rest of the studies cited in the Nicolia review are simply irrelevant or tangential to investigation of the safety of GM foods and crops Irrelevant categories of studies include the following (examples of studies included in the review and supplementary materials are referenced):

i. Animal production studies, often performed by GM companies on their own products.4,5 These do not examine in detail the health impacts of GM feed but look at aspects of animal production of interest to the food and agriculture industry, such as weight gain and milk production.

While such studies provide the agriculture industry with useful information about whether an animal fed on the GMO will survive to slaughter age and deliver an acceptable meat or dairy product, they are usually short-term in comparison to the animal’s natural lifespan and provide no detailed information about the health of the animal.

Many of these studies are performed on animals such as cows, fish, and chickens. The digestive systems and metabolic functioning of these animals differ significantly from those of humans. Thus these studies are unlikely to provide useful information on human health risks.

ii. Opinion and advocacy pieces promoting the use of the concept of substantial equivalence in risk assessment.6,7,8

These papers do not provide any original data. Therefore these papers contribute nothing new to the safety debate. The concept of substantial equivalence concept was originated by the GM industry and inserted into GMO regulations worldwide, largely through the efforts of the industry-funded International Life Sciences Institute. It remains controversial and has been challenged by many independent scientists and experts. The Nicolia review omits this criticism and thus falsely claims “consensus” on the use of the concept (see below for a full discussion of this topic).

iii. Opinion pieces and reviews of safety assessment approaches and regulations relating to GMOs.

Many of these articles are written by GM proponents and promote the view that GMOs are safe and adequately regulated8,9 and/or promote industry-friendly approaches to safety assessment.10 While Nicolia and colleagues’ supplementary list includes articles that are critical of GMO regulation and assessment,11 the criticisms put forth by the authors of these articles do not make their way into the text of the Nicolia review paper. However, the scientific answer to both sides of this debate is that opinions are not data, and the papers in this category fail to provide any data.

iv. Studies on experimental GM crops that have never been commercialized.12,13 Some of these studies give important information about the imprecise and unpredictable nature of GM technology because they show unintended differences between the GM crop and the non-GM parent13 or toxic effects in animals exposed to the GM crop.12 However, because each GM transformation event is different, the findings of such studies are not useful in assessing the safety of the GMOs already in our food and feed supplies.

Considerations of relevance apart, Nicolia and colleagues fail to address the safety questions raised by such studies.

v. Studies on consumer perceptions of GM foods.14 Such studies are of special interest to those who wish to overcome public resistance to GMOs, but provide no new data and are therefore irrelevant to assessing GMO safety.

In conclusion, the above categories of studies cited by Nicolia and colleagues offer no hard data that can help answer the important question of whether commercialized or soon-to-be commercialized GMOs are safe.

2. Nicolia and colleagues omit from their list, or from their discussion, important studies that find risks and toxic effects from GMOs.

Nicolia and colleagues admit in their review that they “selected” studies for inclusion, though they do not disclose their selection criteria. Many relevant studies are simply omitted from their list of 1700 studies. Others are included in the list of 1700 studies and/or in the references to the main review paper, but the authors ignore their findings in the review. This is in spite of the fact that these findings are seminal to any discussion of GMO safety.15,16,17,18,19,20,21,22

In some cases, omissions are due to their arbitrary 10-year cut-off date. By choosing to focus on only the last 10 years of scientific research, the authors “select out” important early studies that found toxic effects in animals fed GM crops, including Ewen and Pusztai (1999)2,3 and Fares and El-Sayed (1998).2,4 There is no defensible scientific reason for excluding these studies.

Pro-GM lobbyists often claim in online forums that these studies have been “debunked”. But empirical findings of harm can only be challenged by replicating the study and getting a different result. No one has attempted to replicate any study that has found toxic effects from a GM food, so the findings reported in these studies stand.

Those who claim that the studies are “bad science” and not worthy of replicating must clarify their criteria for “good” and “bad” studies and apply the criteria equally to studies that find harm from GMOs and studies concluding GMOs are safe.

Since the publication of the early papers excluded from the Nicolia review, the GM industry and its allies have gained increasing control over scientific research and publication, making it increasingly difficult for independent researchers to conduct and publish research critical of GMOs.25,26 Therefore by restricting their review to research conducted later than 2002, Nicolia and colleagues bias their findings in favour of a false conclusion of GMO safety.

There is no valid scientific reason for excluding critical studies carried out in the late 1990s and early 2000s, especially as many focus on GMOs that are more widely grown today than when the studies were carried out. For example, the area of Bt insecticidal crops planted has increased since that time.

Even in a climate hostile to critical GMO research, independent researchers have managed to publish some papers that report toxic or allergenic effects from GMO diets after 2002. Nicolia and colleagues include some of these studies in their supplementary list of 1700, but then ignore the results reported in those papers in their main review paper. An example is a multigenerational study that found rats fed GM Bt maize over three generations suffered damage to liver and kidneys and alterations in blood biochemistry.21 A study that showed allergenic effects from GM peas27 is omitted even from the supplementary list.

An even more glaring omission in Nicolia and colleagues’ review (though included in the supplementary list) is the detailed research of Prof Manuela Malatesta, which found toxic effects, including more acute signs of ageing in the liver, in mice fed GM soy over a long-term period.16,17,18,19,20

Malatesta’s experiments represent some of the very few long-term animal feeding studies on commercialized GMOs. The seminal role of her research was made clear in a report issued by the French food safety agency ANSES28,29 on Prof Gilles-Eric Séralini’s long-term study, which found toxic effects in rats fed a GM maize and tiny amounts of Roundup herbicide.30

Like EFSA in Europe, ANSES is responsible in France for issuing opinions on the food safety of GMOs, including the maize Séralini found toxic. In its report, ANSES criticized Séralini’s study (thus validating its own prior verdict that the GM maize was safe), yet nevertheless called for more long-term studies on GMOs.

ANSES conducted its own literature search for long-term feeding studies on a glyphosate-tolerant GMO (which make up over 80% of all commercialized GMOs31) that were comparable with Séralini’s. It found just two studies: Malatesta’s 2008 report on her research, which found toxic effects,19 and a study that was only available in Japanese.32So out of three long-term studies on glyphosate-tolerant GM crops identified by ANSES, two showed that they are toxic and the findings of the third cannot be verified by the international scientific community. ANSES concluded that there was a “lack of studies on the potential effects of long-term exposure to various glyphosate-based formulations” and a “limited number of studies that have addressed the long-term effects of consuming GMOs”.29

The fact that even a regulatory body that was attempting to dismiss the Séralini study recognized the importance of Malatesta’s work underlines the lack of scientific justification for Nicolia and colleagues’ omission of this research from their discussion of GMO safety.

Nicolia and colleagues omit even from their supplementary list a study that directly contradicts a fundamental claim of safety for GM Bt insecticidal crops. Approvals of GM Bt crops worldwide are based on the assumption that Bt toxin is degraded in the mammalian digestive tract. However, this study by Canadian researchers found Bt toxins circulating in the blood of non-pregnant and pregnant women and in the blood supply to their foetuses.33,34,35,36 While this paper did not demonstrate that the Bt toxin came from GM crops, one key point is inescapable: Bt toxin is not degraded in the digestive tract. This places all approvals of GM Bt crops in question, because they have all been based on the assumption that Bt toxins are degraded in the digestive tract, an assumption that this paper clearly refutes.

3. Nicolia and colleagues dismiss empirical evidence of toxicity from GM foods by citing non-peer-reviewed opinion pieces.

Prof Gilles-Eric Séralini’s group at the University of Caen, France, reanalyzed data from industry studies. They found signs of toxicity in the liver and kidneys of rats fed GM Bt maize for only 90 days.37,38 A follow-up study tested these findings – and regulators’ claims that the maize was safe – by feeding the GM maize NK603 and tiny amounts of its associated herbicide, Roundup for the extended period of 2 years. This was the most detailed long-term animal feeding study ever performed on a GM food. The study (Séralini et al, 2012) found dramatically increased levels of severe liver and kidney damage and hormonal disturbances in the rats fed NK603 GM maize and/or Roundup. Additional unexpected observations were an increased incidence of tumours and premature death in most treatment groups.30

After a concerted campaign of attack by industry-linked lobbyists,39 the study was retracted over a year after publication by the journal that published it, Food and Chemical Toxicology, for unscientific reasons that were condemned by hundreds of scientists in public statements and published articles.40,41,42,43,44,45 In one case, a former member of the journal’s editorial board wrote a letter to the editor opposing the retraction.46

Nevertheless, at the time of the writing of the Nicolia review, the paper was part of the scientific literature. Unlike most of the studies that feature in the review, it offers rare empirical data on the long-term effects of GM food consumption. Even if an extremely conservative view were taken of the Séralini study and the data on tumours and mortality were dismissed due to the relatively low number of animals used (dedicated cancer studies normally require larger numbers of animals), this would not provide a reason to dismiss the toxicological data on organ damage and hormonal disturbances. These findings are solidly based and statistically significant.

The scientifically valid way for Nicolia and colleagues to challenge Séralini’s results would be to cite other toxicological studies in which the same GMO and associated pesticide were fed to animals over a long-term period and found not to cause the toxic effects observed by Séralini’s group. However, no such studies exist, since Séralini’s study was the first and only one of its kind on this particular GM maize.

In cavalier fashion, Nicolia and colleagues dismiss the findings of this pioneering study, as well as the findings of other studies on GMO toxicity by Séralini’s team,37,38 as being “of no significance” – without providing a scientifically defensible definition of “significance”.

Thus they base their conclusion not on empirical data, reasoned scientific argument, or even peer-reviewed papers. Instead, their only evidence is four non-peer-reviewed opinion pieces.

Of the four articles, two are opinions of the European Food Safety Authority,47,48 the agency that previously issued favorable verdicts regarding the safety of these same GMOs,49,50 leading to their approval for food and feed use in Europe. So in dismissing the Séralini group’s findings, EFSA was effectively defending its own position. As the former French environment minister Corinne Lepage said, for EFSA to admit that the study had any validity would be equivalent to “cutting the branch on which the agency has sat for years”.51

In addition, many EFSA staff and experts have conflicts of interest with the industries whose products the agency is supposed to regulate. This has been pointed out over many years by Members of the European Parliament52,53 and the European Court of Auditors,54 as well as civil society organisations.52,53 The European Parliament even withheld its approval of EFSA’s budget for the financial year ending 2010, largely out of concern over the industry-related conflicts of interest of its experts and staff.55

In an attempt to deal with this persistent criticism, EFSA instituted a new independence policy.56 But that did not appear to solve EFSA’s problems. A 2013 report by Corporate Europe Observatory found that over half of the agency’s experts who give opinions on the safety of GMOs, food contaminants, and additives had conflicts of interest with industry.57

Thus EFSA’s opinion pieces on the Séralini study can be discounted not only because they are not peer-reviewed and lack empirical evidence that contradicts Séralini’s data, but also because EFSA has conflicts of interest that prevent it from considering this matter impartially.

The third opinion piece cited by Nicolia and colleagues to dismiss the Séralini group’s findings is a self-published article on an agbiotech website written by two well-known GMO proponents, Wayne Parrott and Bruce Chassy.58 It contains factual inaccuracies and spurious arguments, including a claim that Prof Arpad Pusztai’s research on GM potatoes “bypassed” peer review, when in fact it passed an unusually stringent peer review process59 before being published in The Lancet.23

Parrott and Chassy also suggest that all studies finding harm from GM foods must be replicated by other researchers before they can be taken seriously. But they do not apply the same critical standard to studies that conclude GMO safety, even though most such studies are conducted by or for the same companies that hope to market the GMO concerned and are therefore subject to bias.60

Parrott and Chassy place the burden of proof of harm on publicly funded researchers to prove beyond doubt that the GMO is harmful – a level of proof that current scientific methods cannot provide. Science does not “prove”: it provides evidence that assists the evolution of scientific understanding of a topic. Parrott and Chassy’s partisan demand also flies in the face of internationally accepted biosafety rules and European laws on GMOs, which place the burden of proof of safety on the company that intends to market the GMO.6162 Even the US’s notoriously weak biotech policy states that the responsibility to ensure the safety of any GM food lies with the technology developer.63

The fourth opinion piece cited by Nicolia and colleagues is a comment article by François Houllier, president of the French research group INRA.64 Houllier offers no rigorous scientific analysis detailing why Séralini’s research should not be taken seriously. He briefly refers to common criticisms of the study, but fails to mention that they have been addressed by the study’s authors,65 as well as many others.53,66,67,68,69,70,71,42,72

Indeed, the focus of Houllier’s article is not the scientific methodology used by Séralini, but complaints about Séralini’s media campaign and the effect of anti-GMO activists’ actions on the public image of GMOs. These arguments have nothing to do with the science. Notably, however, Houllier’s article concludes with a call for more and better research on GM crop safety – a conclusion that is shared by Séralini’s team and many other scientists, espcially those who work independently from corporations.

Thus Nicolia and colleagues attempt to refute Séralini’s peer-reviewed original research without offering any empirical scientific evidence that challenges its findings. Instead they cite non-peer-reviewed opinion pieces containing inaccuracies and unsubstantiated personal views, but no empirical evidence. This tactic is not justified by normal scientific standards, though it is unfortunately commonly used in attempts to suppress critical research on GMOs.

4. As evidence of GMO safety, Nicolia and colleagues cite animal feeding studies that are too short to show long-term health effects.

The longest studies cited are 90-day studies on rodents, which are the longest toxicological tests that the industry generally carries out.73,74 In light of Séralini’s and Malatesta’s work, cited above, it is clear that 90-day studies are insufficient.

Short-term studies are useful for ruling out acute toxicity, but do not provide valid evidence regarding the long-term safety of GMOs. Effects that take a long time to show up, such as cancer, severe organ damage, compromised reproductive capacity, teratogenicity, and premature death, can be reliably detected only in long-term and multigenerational studies. Nicolia and colleagues seem unaware of this limitation of 90-day studies.

5. Nicolia and colleagues ignore the problem of non-substantial equivalence of GM crops and falsely claim a consensus on this hotly contested topic.

GM approvals worldwide are based on the assumption by industry and regulators that, if a GMO is substantially equivalent to its closest non-GM relative, based on measurements of the levels of a few basic components such as protein, carbohydrate, and fat, then that GMO does not need rigorous safety testing.

More detailed analyses often show that GM crops are not substantially equivalent to the non-GM comparator, revealing that the assumption of substantial equivalence is false. Yet Nicolia and colleagues completely overlook this issue.

Because of their chosen date range, Nicolia and colleagues omit a 1996 compositional analysis by Monsanto authors revealing that (contrary to these authors’ claim) the company’s GM glyphosate-tolerant soybean is not substantially equivalent to the non-GM isogenic comparator crop. The level of trypsin inhibitor, a major allergen, was significantly increased in the GM soybean.75

A study which is too recent to be included in the Nicolia review compared the nutritional composition of GM, industrially grown non-GM, and organic soybean lines. The study found that GM soybeans, claimed to be substantially equivalent to non-GM comparators by industry and regulators, could, with 100% accuracy, be differentiated from non-GM using only 5 of the parameters measured in the study. It was also reported that the GM soybeans contained high levels of glyphosate, whereas no such residues were present in the non-GM or organic soybeans. Also the nutritional profile of organic soybeans was superior,76 though no comparisons with organic crops are made in the regulatory process for GM crops.

While Nicolia and colleagues could not have included this study in their review, there is no excuse for ignoring the principle that any scientifically based assessment of equivalence would take into account the residues of the pesticide that the GM crop is engineered to be grown with.

Another revealing study that did fall within Nicolia and colleagues’ chosen date range is included in the supplementary list of 1700 studies but is not discussed in the review. The study found that a commercialized GM maize, MON810, had a markedly different profile of proteins compared with the isogenic non-GM counterpart when grown under the same conditions.77 Such differences can result in unexpected toxicity or allergenicity. Another compositional analysis showing that the GM crop tested was not substantially equivalent to the non-GM comparator crop78 was similarly ignored in the review, though included in the supplementary list of 1700 studies.

As well as ignoring evidence that specific GM crops are not substantially equivalent to their isogenic non-GM comparators, Nicolia and colleagues incorrectly claim that there is a “consensus” about the validity of the concept of substantial equivalence in risk assessment. To justify this claim, they cite two papers67 co-authored by Esther Kok,6 an affiliate of the GM industry-funded group, the International Life Sciences Institute, and Harry Kuiper, who during that time was head of EFSA’s GMO Panel. Kuiper was also was a long-time affiliate of ILSI, including after starting work at EFSA.79

This choice of authority is problematic and serves to illustrate the lack of consensus around the substantial equivalence concept. The independent research organization Testbiotech documented evidence showing that Kok collaborated, via the International Life Sciences Institute (ILSI), with GM companies and with EFSA’s Kuiper to promote the industry-friendly concept of substantial equivalence and insert it into EU regulations on GMOs.79 Testbiotech and the civil society organization Corporate Europe Observatory assert that this collaboration may have violated EU rules on EFSA’s independence. They filed a complaint with the EU Ombudsman against EFSA about the legacy of GM industry-crafted rules that Kuiper was allowed to build at the agency.80 A Member of the European Parliament, Bart Staes, also raised a Parliamentary question on the issue with the EU Commission.81

The Ombudsman ruled against Testbiotech’s complaint on a technicality, because it related to events before the current EFSA rules on conflicts of interest were put into place and thus at the time there were no rules for EFSA to violate.82 However, in this ruling the Ombudsman failed to address the fact that EU regulations in place since 2002 require EFSA experts to act independently.83

The concept of substantial equivalence has been heavily criticized and challenged from the beginning by independent scientists because it has never been scientifically or legally defined.3038798485868788 In practice, there can be substantial differences in the GMO compared with the non-GM comparator crop, but the GMO developer company still declares the GMO as “equivalent” and the regulators accept the designation.

Nicolia and colleagues admit that the literature on substantial equivalence is mostly composed of papers produced by GM companies, but fail to draw the obvious conclusion that only an appearance of consensus has been generated due to the dominance in the literature of this biased group of authors.

In 2013 the EU passed a regulation establishing criteria for the EU for equivalence in compositional analyses of GMOs,89 but these will not be applied to GMOs already approved or even to those in the approvals pipeline. According to the biologist Dr Frederic Jacquemart, president of the civil society group Inf’OGM and a member of France’s High Council for Biotechnology, no GMO that has been already approved in Europe or that is in the pipeline for approval would meet the criteria for equivalence.90

The criteria established by EU law are limited in applicability, since they do not define criteria for equivalence relevant to toxicology studies. Thus the current situation, in which significant differences are often found in GM-fed animals but are dismissed by the industry and/or regulators as not biologically meaningful,38,91 will continue.

Nicolia and colleagues’ claim of consensus on the concept of substantial equivalence is not consistent with the facts. It remains a contentious issue.

6. Nicolia and colleagues include animal feeding studies funded by the GM developer company, without acknowledging the problem of funding bias.

For example, included in Nicolia and colleagues’ supplementary list of 1700 papers are Monsanto’s rat feeding studies on its GM maize products, which concluded the maize varieties were safe.73,74,92 Nicolia and colleagues do not discuss the findings of these studies, but simply accept the Monsanto authors’ conclusions of safety, which have proved controversial. Statistical re-analyses of the data by industry-independent scientists revealed signs of toxicity to the liver and kidney of GM maize-fed rats.38,91,93

Nicolia and colleagues’ approach, with its indiscriminate treatment of a long list of studies, contrasts strikingly with the discriminating approach of two other peer-reviewed literature reviews. These focused on and evaluated those studies which specifically examine the food safety and nutritional value of GM foods on the basis of primary experimental evidence. These studies came to quite different conclusions from those of Nicolia and colleagues regarding the safety of GM foods.

The first of these reviews, by Domingo and colleagues (2011), focused on animal feeding studies on GMOs. The authors found that studies reporting that GMOs were safe were mostly carried out by researchers affiliated with the GMO developer company wishing to commercialize the GMO, whereas papers that raised “sometimes serious concerns” were authored by scientists independent of industry.15

While Nicolia and colleagues cite this paper, they omit to mention this important conclusion. Instead they only cite Domingo and colleagues’ incidental remark that industry has improved its record on “transparency” by publishing the results of its animal feeding studies in peer-reviewed journals – a point that is of secondary importance to the food safety of GMOs.

A second review examined studies on human and animal health risks of GMOs and looked more closely at the question of funding bias. The review confirmed Domingo and colleagues’ observation, finding that studies by authors with financial or professional conflicts of interest with the GM industry60 were strongly associated with conclusions that the GMO tested is as safe and/or nutritious as the non-GM comparator. This review was completely ignored by Nicolia and colleagues, being omitted even from their supplementary list of 1700 studies.

7. Nicolia and colleagues misrepresent the scientific evidence and the debate on microRNAs, with the result that risks and uncertainties are downplayed.

In recent years, an issue that has proven as controversial as substantial equivalence is regulators’ failure to assess the risks of microRNAs – small RNA messenger molecules that regulate gene expression and can silence genes – in GMOs.

A study (Zhang et al. 2011) found that plant microRNAs (small RNA molecules that regulate gene expression and can silence genes) survived cooking and degradation in the digestive tract, were found in the blood and tissues of mammals that had eaten them, and were biologically active in those mammals, affecting gene expression and the functioning of important processes in the body. While not on GM plants, the study showed that nucleic acids from plants could exercise a direct physiological effect on humans and animals that eat them, crossing not only the species barrier but the barrier separating the plant and animal kingdoms.94

Nicolia and colleagues discuss the paper by Zhang and colleagues and other papers on the same topic, but conclude reassuringly that “RNA in general” has a “history of safe use”, since it is a normal component of the diet. However, this argument fails to acknowledge that consumers are exposed to novel microRNAs when they eat certain GMOs.

GMOs are being engineered to make novel microRNA molecules that have never before been in the food supply, such as molecules that can kill insects or silence genes. These RNA molecules emphatically do not have a “history of safe use”.

The conclusion of Nicolia and colleagues only addresses the chemical nature of RNA. It is not just the chemical nature of RNA that poses risks or induces the intended effect, but the instructions or information that the RNA molecule contains – in other words, what it can do.

Professor Jack Heinemann, a molecular biologist with expertise regarding microRNA risks and an author of peer-reviewed studies on the topic,95,96 commented: “There is no basis for extrapolating the safety of novel dsRNA [double-stranded RNA, a type of microRNA] molecules from the history of safe use of dsRNA molecules in the cells of plants, animals, fungi and microorganisms that we eat.

“This is the key distinction: the adverse effects that might arise from dsRNA are determined by the actual sequence of nucleotides in the molecule (sequence-determined risks) and not the chemical nature of RNA. While there are also sequence-independent risks that should not be ignored, there is a difference between the sequence of novel dsRNA molecules in GM crops and those in nature, and that is why arguments about all dsRNAs being safe are dangerously flawed.”97

A 2011 study by Heinemann and colleagues refutes the “history of safe use” argument with the example of a Monsanto GM maize engineered to resist the corn rootworm pest. The corn rootworm has always eaten maize roots and maize roots contain RNA, including forms of dsRNA. However, when Monsanto introduces a novel dsRNA of a specific sequence into the cells of the plant, the corn rootworm eating that RNA dies. The rootworm’s long history of using conventional maize as a source of food does not protect it from the toxic effects of the novel dsRNA.95

Heinemann and colleagues emphasize that it is not valid to conclude that microRNA in a GM plant is as safe as microRNA molecules that might be present in non-GM crops that have long been in the human diet.

For example, rice has a long history of safe use in the human diet. If rice produced a microRNA that was toxic, it would have been screened out of our diets thousands of years ago. The authors comment that the safe use of a conventional plant with microRNAs does not extend to its GM counterpart any more than a scrapie-infected animal is as safe as a healthy animal.95 Chemically, there is no difference between the two animals, since both healthy and scrapie-infected animals contain the protein that prions, the infectious agent for scrapie, are made of (PrP). What makes one animal sick and the other healthy is the difference in the way the protein is folded. If it is misfolded, the animal will be scrapie-infected. The form of the protein determines its function – and the difference in function will determine whether the animal lives a healthy life or dies prematurely of a serious illness.

Nicolia and colleagues include Heinemann’s 2011 study containing the corn rootworm example95 in their list of 1700 studies, but ignore its findings in their review.

Even if Nicolia and colleagues failed to read the paper, they should be aware of the risks of GM crops engineered to contain dsRNA molecules, since a media controversy had blown up around the topic as early as September 2012. The debate followed the publication by Heinemann and colleagues of a report on the potential health risks of a GM wheat engineered to produce dsRNA molecules, which is being developed by the Australian research institute CSIRO.98

Such was the resulting public concern that the Science Media Centre felt it necessary to publish quotes from scientists dismissing Heinemann and colleagues’ report.99 Unlike Heinemann, however, the quote-providers had never published papers in scientific journals on the topic of microRNA risks. They also had major undeclared conflicts of interest with the GM industry, as reported by GMWatch.100

Nicolia and colleagues’ conclusion that microRNA molecules in GM plants have a “history of safe use” cannot be justified on the basis of current evidence, and their failure to address the scientific controversy around the topic is difficult to justify by any objective standards.

8. Nicolia and colleagues ignore important findings of adverse environmental and agronomic impacts from GMOs.

Impacts neglected in the Nicolia review include toxic effects of Bt crops on nontarget organisms, the spread of glyphosate-resistant superweeds, the GM contamination of native varieties of plants, and the effects on monarch butterflies of the spread of glyphosate-tolerant crops.

In line with their common practice in other areas of their paper, Nicolia and colleagues include in this section studies documenting adverse environmental and agronomic impacts of GM crops in their list of 1700 articles,31,101,102,103 but then ignore the findings in their review paper. This practice serves to inflate the number of studies that they claim document the safety of GMOs, catalogued in their list of 1700 articles, while failing to disclose the fact that these papers actually document adverse effects.

Examples include studies confirming GM contamination of native Mexican maize varieties,104,105 an issue of concern and debate even today, because Mexico is the genetic centre of origin for maize; and a study concluding that the spread of glyphosate-resistant crops and consequent over-use of glyphosate herbicides has caused intense selection pressure, resulting in the evolution of resistant weeds.31

Omitted even from their list of 1700 articles is a 2012 study that was highly critical of GM herbicide-tolerant crops. The study found that “Agricultural weed management has become entrenched in a single tactic – herbicide-resistant crops – and needs greater emphasis on integrated practices that are sustainable over the long term”. The study’s authors were not optimistic about the industry’s response to herbicide-resistant weeds – engineering crops to resist multiple herbicides, since “crops with stacked herbicide resistance are likely to increase the severity of resistant weeds… these crops will facilitate a significant increase in herbicide use, with potential negative consequences for environmental quality.” The researchers concluded that “The short-term fix provided by the new traits will encourage continued neglect of public research and extension in integrated weed management.”106

Nicolia and colleagues’ treatment of the toxic effects of Bt crops on non-target organisms is an extreme example of biased and misleading reporting. They claim, “The literature considering the effects on biodiversity of non-target species (birds, snakes, non-target arthropods, soil macro and microfauna) is large and shows little or no evidence of the negative effects of GE crops.”

But they only reach this conclusion by ignoring some important papers and misrepresenting the evidence in others. Assisted by their 10-year cut-off date, they misleadingly report a major scientific controversy around the effects of Bt toxins on non-target organisms.

The controversy began in the mid-1990s, when studies by a team led by Dr Angelika Hilbeck showed that Bt toxins of microbial and Bt plant origin caused lethal effects in the larvae of the green lacewing, a beneficial insect to farmers, when administered directly or via prey into their gut using a protocol that ensured ingestion.107,108,109A 2009 study by a different team of authors also led by Hilbeck (Schmidt et al, 2009) found that Bt toxins caused increased mortality in the larvae of another beneficial insect, the ladybird, even at the lowest concentration tested.101Ladybirds devour pests such as aphids and disease-causing fungi.

Based on this study and over 30 others, in 2009 Germany banned the cultivation of Monsanto’s Bt maize MON810,110 which contains one of the Bt toxins that Hilbeck’s team found to be harmful.101

Nicolia and colleagues included the Hilbeck ladybird study101 in their list of 1700 articles, but ignored it in their main review paper.

Rebuttal studies were carried out, apparently to disprove the findings of Hilbeck’s teams and undermine the scientific basis of the German ban. These studies affirmed the safety of Bt toxins for lacewings111,112,113 and ladybirds.11,4115,116 The authors of the rebuttal experimental study on ladybirds (Alvarez-Alfageme et al, 2011) found no ill effects on ladybird larvae fed on Bt toxins and said that the “apparent harmful effects” found by Schmidt and colleagues were due to “poor study design and procedures”.114

Nicolia and colleagues included several of these rebuttal studies in their list of 1700. However, they failed to cite followup studies by Hilbeck and colleagues that proved that the rebuttal studies were poorly designed and executed. Hilbeck and colleagues demonstrated that changes in the testing protocols were the underlying reasons for failing to find the same results in their rebuttal studies for both nontarget organisms, the green lacewing and the ladybirds.

In one followup study, Hilbeck and colleagues showed that the lacewings in the rebuttal study could not have ingested the Bt toxins in the form provided by the researchers, coated onto moth eggs, as their mouthparts are formed in such a way as to make ingestion impossible.110 This is equivalent to testing an orally administered drug for side-effects by applying it to the skin, ensuring that none of the human subjects actually swallows the drug.

For years, the US and EU regulatory agencies accepted these inadequate studies as valid evidence of safety to nontarget organisms until the US EPA admitted that the study protocol was unsuited to lacewings. In other words, this supposed biosafety test was incapable of detecting toxic effects even when they occurred. However, the EPA did not retrospectively give credit to studies that had ensured the proper ingestion of the Bt toxin or reconsider its verdict of safety for lacewings. Instead the EPA chose to continue to ignore these inconvenient findings and simply suggested that this inconveniently susceptible species be replaced in future testing programs with an insect that Hilbeck’s team had already found to be insensitive to Bt toxins. The EU’s EFSA, for its part, has not recognized the inadequacy of these biosafety tests in any of its opinions to date.110

Hilbeck and colleagues also did further experiments110,117 to test the claims of the authors of the rebuttal experimental study on ladybird larvae (Alvarez-Alfageme et al, 2011114). Again, the results of the rebuttal study were shown to be the consequence of their altered and inadequate protocols. Alvarez-Alfageme only dosed the ladybird larvae with Bt toxins in sugar solution once per 24-hour period in each of the four larval stages and then allowed them to recover by feeding them normal food. Schmidt, on the other hand, had exposed the larvae continuously over 9–10 days101– a different and arguably more realistic scenario.

Hilbeck and colleagues repeated Alvarez-Alfageme’s methodology – and found that the water in the sugar solution in which the Bt toxin had been fed completely evaporated after a few hours, making it unlikely that the larvae in Alvarez-Alfageme’s experiment had, as claimed, even ingested the Bt toxin. When Hilbeck and colleagues made the Bt toxins available continuously in a way that the ladybird larvae could access, a lethal effect on the larvae was found.117

In a commentary on the controversy, Hilbeck and colleagues criticized the confrontational tone, unscientific elements, and “concerted nature” of the three studies that attacked Schmidt’s initial findings. The authors noted that the “dogmatic ‘refutations’” and “deliberate counter studies” that routinely appear in response to peer-reviewed results on potential harm from GMOs were also a feature of the debate on risks of tobacco, asbestos, the controversial food packaging chemical bisphenol A, and mobile phones.110

Hilbeck and colleagues also criticized the “double standards” that led EFSA to apply excessive scrutiny to papers that draw attention to the risks of GM crops while overlooking obvious deficiencies in studies that assert the safety of GM crops.110

Unaccountably, Nicolia and colleagues omit the two confirmatory empirical studies by Hilbeck’s team110,117 even from their list of 1700 studies, though they fall within their chosen date range. They entirely ignore the scientific demolition by Hilbeck’s team of the flawed rebuttal studies.

Instead Nicolia and colleagues conclude the debate on Bt crops’ effects on non-target arthropods by citing two reviews with favorable conclusions on Bt crop safety. The first, by Gatehouse and colleagues, conceded that “some negative effects do occur in predatory arthropods and parasitoids following exposure to GM crops and/or the insecticidal proteins they express”. However, Gatehouse and colleaguesconvinced themselves of the desirability of GM insecticidal crops by assuming that they were replacing systems reliant on chemical insecticides: “The relatively few negative effects that have been recorded are invariably substantially less than would have occurred under traditional pesticide-reliant regime”.118

Gatehouse and colleagues failed to take into account such vital factors as the number of farmers who grow crops using no or minimal pesticides in agroecological or integrated pest management systems; the highly variable use of pesticides in years of light or heavy pest pressure; the increasing resistance of pests to Bt crops and the emergence of secondary pests, forcing farmers to return to chemical insecticides; and the routine use of insecticidal seed treatments even on Bt crop seeds, which are aimed at dealing with the pests not controlled by Bt toxins.

Crucially, Gatehouse and colleagues do not cite any data directly comparing the ecological impacts of planting GM Bt crops with the impacts of any alternative pest management regime. They simply choose as the comparator for Bt crops a “pesticide-reliant regime”. Gatehouse and colleagues do not define this worst-case regime or analyze how typical it is in the context of usual farming practices – a serious omission, given that in the mid-1990s, before the advent of Bt insecticidal maize, less than a third of all US maize had any insecticides applied to it.119 On the basis of the undefined “pesticide-reliant regime”, Gatehouse and colleagues conclude that GM Bt crops are the lesser of the two evils.118

One meta-analysis of studies on the effects of Bt crops on non-target invertebrates used fields with no insecticide applications as the comparator – and reached a conclusion on Bt crops diametrically opposed to that of Gatehouse and colleagues. The meta-analysis demonstrated a significant reduction of non-target invertebrates in Bt maize varieties expressing the Cry1Ab protein generally, and for MON810 maize (the sole GM maize currently being grown commercially in Europe) specifically, compared with fields with no insecticides applied. When non-GM fields were sprayed with insecticides, there was a higher invertebrate abundance in Cry1Ab maize generally, but not in MON810.120 This shows that for GM crops generally and for MON810 specifically, opposite conclusions can be reached from the same evidence base, depending on which comparator is used.

One lesson that can be drawn from this study is that deciding which questions to address in scientific research should not left to scientists alone, and certainly not to biotech and agrochemical multinationals. This role belongs to society as a whole, based on its environmental protection and food production goals.

The second review cited by Nicolia and colleagues to dismiss Bt crops’ effects on non-target arthropods is by Shelton and colleagues and was published in 2009.121

Unfortunately for the credibility of the Nicolia review, Shelton and colleagues relied heavily on the studies discussed above, which used methodologies that Hilbeck and colleagues subsequently exposed as inadequate.110 By giving the final word on this issue to Shelton and colleagues and failing to address the followup experiments by Hilbeck’s team, Nicolia and colleagues misrepresent the state of scientific knowledge and its surrounding controversy.

9. Nicolia and colleagues sidestep the debate about monarch butterflies

Monarch butterflies are viewed as an important indicator species against which to gauge the impacts of GM crops on the numerous non-target insect species that live in the agricultural environment where GM crops are used. Yet Nicolia and colleagues ignore the scientific debate about the effects of GM crops on monarch butterflies, which has concluded badly for GMO proponents.

An initial laboratory study by Losey and colleagues conducted in 1999, outside Nicolia and colleagues’ chosen date range, found that monarch butterfly larvae exposed to Bt maize (Event Bt11) pollen suffered higher mortality rates than larvae exposed to non-GM pollen.122 Losey’s study was criticized for using allegedly unrealistic doses of Bt pollen, but a followup study by Jesse and Obrycki (2000, also outside Nicolia and colleagues’ date range) using realistic doses also found lethal effects from Bt176 and Bt11 maize pollen.123

A different team of researchers (Hellmich et al, 2001) did further experiments and found significant growth inhibition and increased mortality in monarch larvae exposed to two out of four types of purified Bt toxin (Cry1Ab and Cry1Ac). However, the only Bt maize pollen that consistently negatively affected monarch larvae was from Bt176 maize, a variety that was withdrawn by the GM industry after it had already been cultivated for several years. The authors criticized the findings of Jesse and Obrycki on the grounds that the pollen on which the larvae were fed may have been contaminated with maize anthers, since maize anthers contain much higher concentrations of Bt toxin than does the pollen. The authors questioned whether monarch larvae in field conditions would be exposed to fractured anthers or could consume whole anthers.124

Jesse and Obrycki followed up with further experiments, published in 2004, within Nicolia and colleagues’ date range. Nevertheless, Nicolia and colleagues excluded these studies from their list. Jesse and Obrycki’s followup studies found a consistent trend of increased mortality when monarch larvae were exposed to Bt11 maize pollen and anthers naturally deposited on milkweed plants within a field. The researchers observed monarch larvae feeding on anthers that had become stuck to milkweed plants with moisture from rain and dew, confirming that monarch larvae are exposed to anthers. The researchers noted that “anthers do not represent experimental contamination as suggested by Hellmich and co-authors… but are a potential source of Bt toxin that needs to be considered”. They concluded that increases in mortality of monarch larvae in Bt maize fields due to the deposition of transgenic Bt anthers and pollen on milkweed “could harm monarch populations”.125

A review of the scientific literature on Bt crops and monarchs (also not included in Nicolia and colleagues’ list) concluded with regard to Jesse and Obrycki’s 2004 study that while the trend observed did not meet the confidence level of p<0.05 usually accepted in ecological studies, the results showed that “multiple year field studies are needed to quantify the potential effects of wide scale planting of Bt maize on monarch larvae, and that it is important to examine within-field mortality resulting from deposition of maize tissues that include pollen and anthers.”126

A study of chronic exposure by Dively and colleagues (2004), included in Nicolia and colleagues’ supplementary list but not addressed in their review paper, found that 23.7% fewer monarch larvae exposed to pollen of the Bt maize varieties Bt11 and MON810 survived to adult stage than larvae exposed to non-Bt maize pollen. However, Dively and colleagues minimized the importance of these findings, concluding that Bt maize would only cause 0.6% additional mortality in monarch populations.127

The debate over the effects of Bt maize pollen on monarchs should have at least led Nicolia and colleagues to conclude that there is no consensus on the safety of Bt crops to non-target organisms, instead of claiming, as they did, “little or no evidence” of “negative effects”.

The scientific debate on whether Bt crops do or do not harm monarchs took a different direction in 2012-13 after worrying new facts emerged. This time, it was not Bt crops that were named as the culprit, but the increased use of glyphosate herbicide due to the spread of GM glyphosate-tolerant crops.

First, the monarch census for the winter of 2012-13 found that the population of North American monarch butterflies over-wintering in Mexico was at the lowest level ever measured, with a 59% decline over the previous year. The cause of the sharp drop in population was named by insect ecologist and founder of the conservation program Monarch Watch Orley R. “Chip” Taylor as the spread of glyphosate-tolerant GM crops and the resulting over-use of glyphosate herbicides. The glyphosate spraying has killed the milkweed that is the prime food source for monarchs.128

Second, Taylor’s view was confirmed by a peer-reviewed study (Pleasants and Oberhauser, 2012) – absent from Nicolia and colleagues’ list of 1700. The study found a 58% decline in milkweeds in the US Midwest and an 81% decline in monarch production in the Midwest from 1999 to 2010. This loss occurred in parallel with the increased planting of GM glyphosate-tolerant maize and soybeans and consequent increased use of glyphosate herbicide to control weeds, including milkweed. Pleasants and Oberhauser conclude that a loss of agricultural milkweeds is a major contributor to the decline in the monarch population.129

An entirely unaddressed question to date remains what effect stacked trait Bt insecticidal and herbicide-tolerant crops will have on the few monarch larvae that remain in the Midwest. These crops, for instance Smartstax maize, contain unprecedented high levels of several Bt toxins.130

Nicolia and colleagues’ review does not even mention monarchs. However, their list of 1700 studies does contain a 2002 article on Bt crops and monarchs by Gatehouse and colleagues, which concludes that the commercial large-scale cultivation of Bt maize hybrids does not pose “a significant risk” to monarch populations.131

In summary, Nicolia and colleagues have selectively cited the literature on monarch impacts and failed to consider the recent compelling research findings on the impact of GM glyphosate-tolerant crops on monarchs.

10. Nicolia and colleagues fail to demonstrate consensus on GMO safety and themselves acknowledge that there is “intense debate” regarding the safety of GMOs.

Though their expressed aim is to “catch the scientific consensus” on GMO safety, Nicolia and colleagues, unlike those who cite the Nicolia review to promote GMOs, do not conclude that there is a consensus on the topic. Instead they accurately note that there is “intense debate”. Given this admission, it is inappropriate for GMO proponents to use the Nicolia review as evidence of scientific consensus regarding the safety of GMOs.

However, Nicolia and colleagues also claim, “The scientific research conducted so far has not detected any significant hazard directly connected with the use of GM crops.” In making this claim, they are ignoring or discounting a large and growing body of evidence of harm from peer-reviewed research papers, including papers cited in their list of 1700 articles.

In 2013 nearly 300 international scientists signed a joint statement saying that there is “No scientific consensus on GMO safety” and that some existing studies “give serious cause for concern”.132

 11. Nicolia and colleagues make unsubstantiated claims.

For example, Nicolia and colleagues claim that GM crops could be an “important tool” in producing healthy food with reduced environmental impacts and inputs, but offer no evidence in support of this claim.

They also claim that the EU Commission report, “A decade of EU-funded GMO research”, concluded that GM plants do not pose higher risks than conventionally bred plants. But the EU Commission report contains very little actual evidence evaluating whether GM foods are safer or more risky than non-GM foods. A few animal feeding studies were carried out and cited in the report, but none were on commercialized GM crops. In fact, these studies found unexpected problems with the GM food tested (see Chapter 3 for a detailed discussion).

Therefore claims that the report shows that GM plants are no riskier than non-GM foods are not evidence-based and are contrary to the small amount of toxicological data gathered by the studies performed under this research programme.

Historical background: The “big list of studies” tactic

The Nicolia review is the latest of several similar long lists of studies collated by GMO proponents and purporting to prove that GMOs are safe. Just like the Nicolia review, however, these lists of studies do not prove the safety of GMOs and in fact provide evidence of actual or potential hazards and omit findings of harm.

Another much-promoted list is on the Biofortified website.133 Yet another list of 600+ hundred studies collected by “GMO Pundit” David Tribe is claimed to “document the general safety and nutritional wholesomeness of GM foods and feeds.”134

Closer examination of Tribe’s list reveals:

  • Most of the studies cited are not safety studies on GM foods. In other words, they do not examine in detail the health effects in animals fed GM foods. Some are compositional studies that compare the levels of certain major nutrients, such as fat or protein, in a GM crop with levels in a non-GM crop. Others are feed conversion studies that measure how efficiently a livestock animal converts GM feed into a food product, such as meat or milk, over a short-term period.135
  • Some are short-term studies performed by industry, which are not long enough to reliably detect long-term health effects.73
  • Many of the studies, on examination of the actual data, turn out to show problems with GM foods. These include unintended differences in a GM food compared with the non-GM counterpart and harmful effects in animal feeding trials.38,23,24

The Biofortified list suffers from similar problems. As is clear from the analysis above, the Nicolia review falls into the same pattern of disingenuous use of scientific research to support misleading claims.

In the field of pro-GMO lobbying, the Nicolia review has taken the place of the Snell review of 24 suspposedly long-term animal feeding studies documenting the safety and nutritional wholesomeness of GM foods.136 The Snell review, however, suffers from serious shortcomings, which are discussed in detail in Chapter 3.

Conclusion

Nicolia and colleagues’ list of 1700 articles does not show that GM foods and crops are safe and in fact provides evidence that some GMOs are unsafe. The majority of the articles are irrelevant or tangential to assessing the safety of commercialized GM foods and crops for human and animal health or for the environment. They include opinion and advocacy pieces on GMO regulation and safety assessment, animal production studies of interest to the agriculture industry, and studies on consumer perception of GM foods. Many of the articles demonstrate that there is no scientific consensus on the safety, efficacy or desirability of GM technology in food production.

Claims that the list of studies compiled by Nicolia and colleagues shows GMO safety rely for their persuasiveness on the assumption that no one will have the time to read the studies cited or notice the omissions.

Given the economic incentives at work in the GM field, there is an understandable tendency among GM proponents to artificially inflate the evidence purporting to show that GMOs are safe. However, misrepresenting scientific studies to shore up a conclusion that is not justified by the data is unethical and will in the long term be corrosive to public trust in science.

Evidence-based debate is the lifeblood of science and is fulfilling for sincere scientists on both sides of a controversy, because it furthers the evolution of scientific knowledge. However, it should not be necessary to expend time and energy countering misleading claims made in the scientific literature that appear to be intended to further interests other than the evolution of scientific knowledge.

It takes few words and little effort to make a misleading claim, but many more words, time, and effort to counter such a claim. That much is demonstrated by this analysis, which, although long, is far from comprehensive and deals only with a few of the many misleading claims and serious omissions of Nicolia and colleagues’ review.

The presence in the scientific literature of papers such as the Nicolia review represent failures of the peer review process. Each time the authors cited a specific paper to support a claims or conclusions, the editors and peer reviewers should have asked them to identify the relevant supporting empirical data (derived from actual testing using appropriate methodologies), justifying the inclusion of the citation.

Traditionally, this is the standard of evidence upon which scientific debate is based. When editors and peer reviewers accept less, the result is that a publication enters the scientific literature that fails to meet minimum acceptable academic standards.

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