Critical Examiner

Credit: Goetze’s Candy

A large source of fear stems from a lack of understanding, and a lot of people are afraid of genetically modified food.  Simply injecting the word “genetic” into anything conjures up images of any number of horrific scenarios created by modern pop culture that portray an apocalyptic world created by evil scientists who went too far “playing god.”  Look up any random poll online on the subject and you’ll see the majority of the public are against genetically modified food.  Personally, I feel that fear is unjustified.  However, I don’t have a background in this subject and I don’t exactly know the reasons people have behind the fear of genetically modified food besides the unreasonable “scientists shouldn’t be tampering with our food” argument.  So I decided to start my first blog post off looking further into this topic because I find the controversy compelling.  There’s a lot of ground to cover on the subject but I try to go over all the points that I feel are important, especially when it comes to dispelling all the misconceptions.

How we got here and a brief biology lesson

Imagine you’re a farmer 300 years ago who discovered wild strawberries and began planting them on your farm.  After growing several generations of strawberries you notice that some are bigger and sweeter than others.  You isolate these from the other strawberries and grow them on a separate piece of land; eventually you have a whole patch of strawberries that are bigger and sweeter than the typical wild strawberry.  That’s because some very small random mutation arose, probably from a simple error in DNA replication that was never corrected, and maybe it was due to a change in one or two nucleotide base pairs. And those strawberries that you decided to isolate originally produced generations of offspring that were also bigger and sweeter than the wild variety of strawberry because they contained the mutation that confers those traits.

Credit: Wilson’s Page Wikispaces

That’s a simplified and probably unrealistic example of selective breeding.  In the real world we can look at corn and how it has evolved to become the corn (or maize) that we have today.  Its inception probably represents one of humanity’s biggest agricultural feats.  As ubiquitous as corn is, it may be hard to believe that it cannot reproduce on its own without human intervention: in other words wild corn doesn’t exist.  The husk covers an ear of corn so tightly that if an ear falls to the ground, the kernels cannot escape the husk.  Even if the kernels were not covered in a husk, ultimately nothing would grow into maturity because the kernels are located too close together on the cob.  In order to grow, corn requires a certain amount of distance between seeds in the ground.  That’s why you see planted corn in neatly arranged rows and precise spacing in fields.  So it happened completely through human intervention that corn evolved from a type of grass native to Mexico and Central America called teosinte (pictured on the right).  Scientists think that it took over 10,000 years for teosinte to become modern corn, and they also believe that a change in as little as 5 genes is responsible.

In a very crude sense, that was an early form of genetic engineering.  Today, we can use science to take away the random element and turn on/off genes with desirable traits.  Instead of selective breeding, this process is called genetic engineering.  We can take that concept even further and in a literal sense, “cut and paste” genes from foreign organisms and put them into other plants and animals.

So, for example, we can take a gene from a strain of bacteria that confers resistance to cold, and put that gene in a plant like corn so that it can survive frosts that might otherwise devastate a supply of crops for an entire year.

That doesn’t mean that we would be introducing bacteria into the food supply, it’s the gene and the protein that gene produces.

All living organisms, be it plant, animal or bacteria, abide by the same basic fundamental rules: DNA functions as a code, clusters of DNA that code for something specific is called a gene and the purpose of genes is to produce a protein (actually it codes for a complementary sequence of RNA, which codes for protein but that’s beyond the scope of this discussion and I’ll keep it simple).  Proteins are basic molecular units that perform specific functions within a cell (ie formation of a structural component, communication within/outside of the cell, stress responders, etc).

Further, DNA is made of basic units called nucleotide bases.  There are only four of them and the same four exists in every living thing on earth: guanine, adenine, cytosine and thymine.  Proteins are composed of basic units called amino acids and there are 20 of them that are coded for by DNA.  Actually, not every organism can make all 20, some have to be obtained from the diet by consuming organisms that can make them…to complicate things a bit further, there are technically more than 20 amino acids due to modifications an amino acid can undergo.

So when you consume the corn we made using bacterial DNA in the previous example, your body doesn’t discriminate by saying “oh wait, we’re not supposed to be eating this, there’s bacterial DNA and protein in this.”  Instead, the message would be more like “here’s DNA and protein,” or more simply “FUEL!!!”  Your digestive tract is going to break down the DNA to its base nucleotides so that your body can use those nucleotide bases to renew the DNA in your ever-regenerating cells.  Similarly, the protein will be broken down to amino acids and used to make protein or be converted into glucose and fat.  Of course, there are proteins made in nature that are poisonous to humans, or hard to digest due to sequences of amino acids that are difficult for our enzymes to break down or contain a sequence that triggers an allergic or immunological response.  Obviously, we want to avoid using those in our genetically modified crops.  No biotechnology company would sign up to knowingly produce something like this…even if they were an unethical company, it would be a terrible business strategy.

How genetically modified crops are made

In a discussion like this I think it’s important to explain how we can make GM plants because the more we understand something, the less there is to fear.  One of the most common ways of introducing a gene from one organism to a plant is by using a vector (a vehicle for delivering the gene) called a plasmid.  A plasmid is a small circular piece of DNA found in bacteria that functions separately from the bacterial chromosome (main part of the bacterial DNA).  Bacteria use plasmids as way of transferring certain traits between other bacteria, especially traits that are favorable to survival such as antibiotic resistance.  Plasmids are ideal for genetic manipulation because they contain a small number of nucleotide base pairs and they can be inserted into non-bacterial cells and function independently of the host chromosomes.

The most commonly used plasmid for genetic engineering in plants is called a Ti plasmid, produced in a bacterium called Agrobacterium tumefaciens.  In the wild, Agrobacterium can infect plant cells with the Ti plasmid, which acts as a sort of retrovirus in plants.  A section of the plasmid DNA called T-DNA integrates into the plant DNA and produces a series of proteins that cause tumors in the plant.  For obvious reasons the part that causes disease in the plants is removed, rendering it safe for genetic manipulation.  Scientists can then use what’s called a restriction enzyme, usually isolated from E.coli or other bacteria, that cuts specific sequences of DNA and combine it with a suspension containing the Ti plasmid.  Meanwhile, separately repeating a similar process with the foreign DNA containing the gene that you want expressed in the plant.  Combine these two solutions with another enzyme called DNA ligase, which “stitches” the DNA back together, resulting in the Ti plasmid containing the foreign gene of interest within the T-DNA.  Then, the plasmids can be reintroduced into Agrobacterium that will be used to infect cultured plant cells with T-DNA.  This is now called a transgene, a gene transferred from one organism to another.  The Infected cultured cells can then be selected and used to generate a new plant containing the inserted gene.  I summarized this process in the figure on the right.

Enter GM crops

In 1996 the first commercialized GM crops were grown in 6 countries and 19 more joined that list by 2008.  According to a 2013 report by the International Service for the Acquisition of Agri-Biotech Applications (ISAAA) 94% of the cotton, 93% of the soybeans, 88% of the corn, 93% of the canola, and 97% of the sugar beets produced in the US are GM crops.[1, 2]  Other GM products we grow are alfafa, sugarcane, papaya and more recently squash.  Most of those crops only make their way into our diet by way of the oils produced from cotton, corn and canola.  Additionally, nearly all soy products now come from GM soybeans.  Because of all the oils, corn, and soy made from GM crops, estimates ranging from 40-70% of the processed food that you buy contain products of transgenes.  Sugar beets are refined into sugar and contain very little, if any, of the actual GM product and DNA.  Papaya is one of the few examples of a whole GM food that you’ll find on store shelves.  Produced in the United States, papaya is grown in Hawaii and has been genetically engineered to resist the papaya ringspot virus, which nearly wiped out the fruit in the 1980’s.  There are other government approved GM crops that exist with tomatoes, potatoes, and rice but they aren’t commercially available.  The vast majority of GM crops in the US are used as animal feed and do not actually make it into your food directly.

It would be really difficult to do a controlled human study with GM food due to many confounding factors.  You can potentially use prospective and retrospective studies but those are not very reliable because they are prone to bias and error.  It’s not always ideal to look at animal studies, but that’s the best we can do in this situation.  As it happens, there may be hundreds of such studies that have been undertaken in order to assess the safety of GM foods since the early 1990’s. I haven’t found anything to suggest that commercial GM food is unsafe for human consumption in any way.  In fact, GM foods have been assessed to be nutritionally equivalent to their non-GM counterpart.[3]  One of the more recently published reviews examined 12 long term rodent studies (from 90 days to 2 years) and 12 multigenerational studies (2 to 5 generations) involving GM maize, potato, soybean, and/or rice.[4]  All 24 of these studies found no negative impact on the health of these animals.  That review was funded by scientific and academic institutions, not biotechnology companies, and appears to have no obvious conflict of interest.

The Pusztai Affair

As I alluded to earlier, GM food does have the potential to be dangerous.  However, a GM food that creates adverse health effects in animals simply does not make it past the experimental phase and will not be available for human consumption.  Many drugs never make it past the experimental phase, and yet modern medicine has been a boon to humanity.  We just have to trust peer reviewed science to catch anything that might be dangerous.

In the GM food debate there is an unfortunate, textbook example where the peer review system was not used.  The result was a PR nightmare and solidified opinions of GM food that still linger in society. It comes from a study performed by Dr. Árpád Pusztai, a Hungarian-born biochemist who worked in Scotland.  In 1998 Pusztai made an announcement in an interview on a TV program that aired in the UK declaring that his experiments found that rats fed GM potatoes had abnormal growth in their stomach linings, stunted organ growth, and repressed immune systems.  Various media outlets ran with the story praising Pusztai while condemning GM food and calling for stricter regulations.

The first problem with this story stems from the fact that Pusztai made this announcement on public television before his research was complete.  The result were not even published at the time, meaning it was never peer reviewed and was not properly criticized by experts in the field; this is a big no no in science.  Scientists are expected to submit their results for publishing, where they will be peer reviewed anonymously by other scientists in the field to make sure the experiment uses sound science and comes to a reasonable conclusion based on the data.  After the interview aired, Pusztai’s work was reviewed by 6 anonymous, independent scientists who declared the work to be flawed.  They found that his data did not support the conclusions, that there were actually no significant differences between GM and non-GM fed rats, the diets were deficient in protein, and some groups of rats were fed raw potatoes which are known to be toxic to rats.  Additionally, the protein made by the GM-potatoes produced a type of lectin that is fatal to insects and triggers an immunological response in mammals.  The interest in lectins at the time was due to their potential to act as a pesticide.  The potatoes were made specifically for research to see how the animals responded to the lectin and they were never meant for commercialization.  Although, Pusztai contends the potatoes would have been approved to be eaten as food regardless of the conclusion of his research.  It’s hard for me to envision a scenario where a company would give the green light for those potatoes to be used commercially, as I talked about previously, it just does not make good business sense.

Keep in mind, this happened during a pivotal time, 2 years after GM seeds became available for sale.  So the public was still very wary of the change as they are with anything involving genetics.  When in vitro fertilization (IVF) first began to be utilized, people criticized it by saying it was unnatural and “test tube babies” would be stigmatized in society.  Opinions from the catholic church aside, it is now a widely accepted method of conception for couples who could not otherwise conceive and those test tube babies grow up like any other person.   But where would this technology be if scientists were publicly making unsubstantiated claims about the safety of IVF during those pivotal moments in time?

Pusztai represents an important case because the anti-GM people still use his original claims as part of their argument on the safety of GM food.  One of the things Pusztai wanted was to require longer feeding trials in testing GM crops before getting approval for human consumption, which is a valid concern since evaluation of GM food safety currently only requires 90 day feeding trials.  I also think there has to be some merit to cases like this that do highlight the potential of GM foods to do harm.  Then again, if you engineer a crop to produce a protein known to illicit a toxic response in humans what can you expect?

I’d like to end this section by saying that Pusztai was a well respected scientist with over 300 published papers, not a crack pot with an agenda.  It’s easy to get excited about the results of a study and he may have believed in his convictions at the time.  I think he just slipped up and was forced into a position of defending himself, then fortifying himself in that position.  Unfortunately, it cost him his job and reputation.

Dispelling the GM food misconceptions

The anti-GM people also rail against crops that produce Cry proteins. It’s a toxin, so it has to be dangerous, right?  The protein comes from a strain of bacteria called Bacillus thuringiensis (or BT), which produce these crystal proteins (Cry for short) called endotoxins that kill certain insects.  It causes the mid-gut of insects to rupture by changing the alkalinity, leaving them unable to eat and dying after a few days.  Our body chemistry is different, so it doesn’t have the same effect on us.  The bacteria have been used for almost 100 years as a natural insecticide and more recently have introduced Bt cry genes into corn, cotton and rice.  The organic and anti-GM groups argue that the endotoxins produced by these GM crops are dangerous to humans and other animals, despite all the evidence that says Cry proteins target only specific sets of insects and is safe in mammals.[5-9]  The studies I cited are just a few I found with a quick search in pubmed.  And the USDA found a reduction in synthetic pesticide use and environmental runoff over a 4 year period in Bt-cotton.  Doesn’t the organic movement strive to reduce pesticide use?

They will also say that food allergies have increased due to GM food, specifically citing that allergies to soy have more than doubled over the last decade.  So, how does it explain the rise in allergies to other food in recent years?  The fact is peanut and other tree nut allergies have tripled in the last decade, and gluten allergies have doubled.[10, 11]  The top 8 food allergens come from milk, eggs, fish, shellfish, tree nuts, peanuts, soybeans, and wheat.  Soy is the only GM product on that list.

It may be interesting to note that food allergies are only on the rise in developed countries, while the use of GM food is on the rise in third world countries.  There are other, more plausible theories about the cause of food allergies, but my favorites are vitamin D deficiencies, changes in friendly gut bacteria, and obesity…all first world problems.

New research suggests that vitamin D plays a role in food sensitization,[12] and we tend to get less sunlight in the developed world, so vitamin D deficiency has become more prevalent and is increasingly being associated with a number of health problems.  We also tend to medicate more often and with more exposure to antibiotics and microbial products we’re killing beneficial bacteria that reside in our gut.  These bacteria perform critical functions that aid in digestion and immunity.  More attention is being given to a possible link between our gut flora and allergies.  Obesity can also influence the amount of gut bacteria as well as increase sensitization to food.[10]

Monsanto

No discussion about GM crops would be complete if I didn’t talk about Monsanto.  Monsanto is a multi-billion dollar company that owns patents on 90% of the GM crops that are sold.  Yes, you can actually own a patent on a genetic modification.  The owner of such a patent is the only entity who can produce and sell the seeds.  Additionally, if you plant GM seeds you are obligated to pay royalties to the company who made the seeds.  Monsanto also owns the commercial herbicide (weed killer) called Roundup, and one of their trademark patents is on genetically modified “Roudup Ready” seeds that make the plants resistant to the herbicide.

One of the reasons Monsanto is criticized is because of their ruthless business tactics.  It’s said that Monsanto will sue farmers who are unknowingly growing their GM crops and not paying royalties to the company.   There’s an article on NPR that I found here stating that there’s only been one documented case of this, that there may have been misleading information regarding that particular farmer’s use of the seed, and that Monsanto will actually pay farmers to remove the GM crops if any are found to be growing on their land unknowingly.  Yet, there are plenty of people in the comments section of that article pointing out other cases where Monsanto has done this.  I would not know how to verify this, the legal system is beyond my scope and I’d prefer to focus on the science.  It wouldn’t change my opinion of GM crops.  Should we ban a technology because we don’t like how a company is using it?  I don’t think so.  My feeling is any multi-billion dollar company that basically holds a monopoly is going to be ruthless in their tactics and come under scrutiny from the public.  That’s how businesses like Walmart become so successful.  If anything, it highlights a greater need for tighter regulation over GM patents and how these companies operate.

So instead of looking at the company’s business tactics, I’d rather return focus on the science with Monsanto’s herbicide, Roundup.  Roundup’s active ingredient is a compound called glyphosate.  Glyphosate works to kill plants by inhibiting a plant specific enzyme called 5-enolpyruvyl shikimate-3-phosphate synthetase, which is a key enzyme used in plants to make aromatic amino acids.  Animals lack this particular enzyme and obtain aromatic amino acids from consuming plants.  So glyphosate should be relatively non-toxic to humans and animals.  Many of the studies out there regarding glyphosate have been funded by Monsanto, clearly a conflict of interest, making it difficult to parse through all the information out there.  I found a couple reviews that cover hundreds of studies that have been done, one of them unfortunately was funded by Monsanto, regardless, these studies assert that there’s been no link to cancer or genotoxicity in humans, even at exposures far above the EPA limit.[13, 14]

Yet there was a recent study that reported glyphosate acted on estrogen receptors in a particular breast cancer cell line and promoting cell proliferation.[15]  In direct contrast to this study, another study published around the same time period found that glyphosate actually inhibited cell growth in 8 cancer cell lines while having no effect in normal cell lines.[16]

What this actually means is that we don’t really know what’s going on, only that these scientists were able to generate the observed effects in cell lines that are already cancerous.  Still, people will still interpret this as “glyphosate causes cancer.”  I’ve already read articles that want to associate Roundup with the recent rise in breast cancer.  But anything observed in cell culture should be taken with a grain of salt, because cell culture alone can’t mimic the complex interactions associated with the body and especially the tumor microenvironment in cancer, which we’re only beginning to understand.  Oftentimes an effect is observed in cells and not reproducible in animal models or humans.  We’ve been able to cure cancer in cell culture for years, but then are continually unsuccessful when moving those experiments to mice or humans.  Basically, the information learned in those studies need to be adapted to animal experiments to see if we observe the same effects before we can say glyphosate causes or kills cancer.

Moving on, Roundup also contains a surfactant called MON 0818 that helps to penetrate the leaves of plants and has been found to be toxic to frogs[17], fish and other invertebrates.  Although in the study involving frogs, it seems the levels that produce a toxic effect would require direct application of Roundup to water, which is illegal, and it’s estimated that bioavailability of residual Roundup in the field and water run off would be quite low and well under the limits of toxicity to aquatic life.  This wasn’t the only study that realized the surfactants in Roundup could be problematic; others are suggesting that other adjuvants in the Roundup formulation could be toxic as well.

Organics dirty secret

The toxicity of Roundup should not overshadow the fact that conventional and organic farming already uses pesticides and herbicides aggressively. The organic farming methods only allow organic pesticides, meaning only chemicals that are “naturally” occurring but, just because a pesticide is labeled as organic doesn’t make it safe.  For example, rotenone, a commonly used organic pesticide, is a known mitochondrial inhibitor and may cause neurological and immune problems but only at high exposures.[18]  Fortunately, there doesn’t seem to be a real basis for organic food being safer than conventionally grown food, both contain what are generally regarded as safe levels of pesticide residues, although, organic food may contain slightly less pesticide residues.[19]  However, organic food may have a higher prevalence of bacteria because the food is not allowed to undergo irradiation like conventional food.  I’m not aware of any studies that prove or disprove this though.

Based on this information I wouldn’t necessarily say organic is a better alternative.  Conventional farming methods, Roundup, GM food, etc, are under much more scrutiny than organic.  As such, there are many more studies centered on those issues than there are in the organic industry.  If anything the lack of studies on organic food should make you feel safer buying non-organic.  Both sides are billion dollar industries and have a lot at stake, despite what organic products would have you believe.

Other concerns about GM food

There are other legitimate concerns over GM crops.  One of them is the possibility of herbicide resistant genes passing on to wild plant life creating resilient, difficult to tame “super weeds.”  It’s also inevitable that Bt-protein resistant insects will evolve.  There are farming methods in place, however, that should prevent this from happening.  Scientists are already working on other methods to deal with the eventual resistance.

Finally, there’s the issue of GM food labeling.  Currently half of the United States may be calling for mandatory laws requiring all food that has genetically modified material to be labeled as such.  I don’t feel the average consumer is educated enough to make an informed decision on the issue.  When you slap a special GM label on food, it implies that the food is different than other food and may pose some inherent risk.  It will also cost millions of dollars just to enforce the law and the costs will be passed on to consumers.  Ultimately, it’s going to cost farmers as well if consumers choose to purchase non-GM food and biotech companies decide to move business elsewhere.

The future of GM food and concluding thoughts

In the same 2013 ISAAA brief I cited earlier, on page 288, they note an overall global reduction in the use of pesticides, decreased use of fossil fuels and CO2 emissions due to farming methods that require little to no ploughing/tilling thanks to GM crops, and conservation of soil and water due to herbicide resistant crops.  In 2013 up to 18 million farmers benefited economically and reduced exposure to insecticides from GM crops, 90% of which were from developing countries and resource poor. [2]  There are currently 1.5 billion hectares of land worldwide suitable for growing crops.  GM crops allows us to increase yields on the land we currently have available.  This means less destruction of land and deforestation, while having the ability to feed more people worldwide.  It’s unlikely that neither conventional nor organic farming methods will have the ability to sustain the world’s population in the years to come and instead will require a combination of these methods with biotechnology to reduce pesticide/herbicide use, environmental impact and increase food yields.[20]

Currently the commercially available GM crops are mostly engineered for disease, weather, pest and herbicide resistance.  Rice has been developed to enhance the vitamin A content, called Golden Rice.[21]  Vitamin A deficient children develop blindness and other eye sight disorders and are 23% more likely to die of the measles, diarrhea, or malaria. Yet countries and movements such as Green Peace are seeking to ban golden rice because it’s a genetically modified food.  Much of the developing world depends on rice and are also suffering from micronutrient deficiencies because they don’t have access to a more diverse diet.  Iron deficiency, for example, affects 2 billion people and can cause mental retardation, decreased immune function and increased mortality of mother and child at birth.  Strategies to fortify the micronutrient value of rice and other grains are also being looked at.[22]

In addition to enhancing the nutritional value of food, scientists are looking at increasing the biomass of food which would further improve crop yields,[23] the creation of edible vaccines[24] and removal of allergens from food such as soybeans.[25]

GM food has a long way to go with all the resistance it has received.  Opponents of the new technology have good intentions but I believe they are misguided, and the amount of fear mongering and misinformation that is so prevalent in the media is certainly fueling their fire.   In my opinion, it is downright unethical to not pursue the biotechnology options that we have available to us to feed a starving population.

References
1.            James, C., A global overview of biotech (GM) crops. Landes Bioscience, Austin, America, GM Crops, 2010. 1: p. 1-8.
2.            James, C., Brief 46: Global status of commercialized biotech/GM crops: 2013. ISAAA Brief. Ithaca, NY: International Service for the Acquisition of Agri-biotech Applications, 2013: p. 290.
3.            Hollingworth, R.M., L.F. Bjeldanes, M. Bolger, I. Kimber, B.J. Meade, S.L. Taylor, and K.B. Wallace, The safety of genetically modified foods produced through biotechnology. Toxicol Sci, 2003. 71(1): p. 2-8.
4.            Snell, C., A. Bernheim, J.B. Berge, M. Kuntz, G. Pascal, A. Paris, and A.E. Ricroch, Assessment of the health impact of GM plant diets in long-term and multigenerational animal feeding trials: a literature review. Food Chem Toxicol, 2012. 50(3-4): p. 1134-48.
5.            Kumar, S., A. Chandra, and K.C. Pandey, Bacillus thuringiensis (Bt) transgenic crop: an environment friendly insect-pest management strategy. J Environ Biol, 2008. 29(5): p. 641-53.
6.            Wang, E.H., Z. Yu, J. Hu, and H.B. Xu, Effects of 90-day feeding of transgenic Bt rice TT51 on the reproductive system in male rats. Food Chem Toxicol, 2013. 62: p. 390-6.
7.            Devos, Y., A. De Schrijver, P. De Clercq, J. Kiss, and J. Romeis, Bt-maize event MON 88017 expressing Cry3Bb1 does not cause harm to non-target organisms. Transgenic Res, 2012. 21(6): p. 1191-214.
8.            Randhawa, G.J., M. Singh, and M. Grover, Bioinformatic analysis for allergenicity assessment of Bacillus thuringiensis Cry proteins expressed in insect-resistant food crops. Food Chem Toxicol, 2011. 49(2): p. 356-62.
9.            Glare, T.R., O’Callaghan, M., Bacillus thuringiensis: Biology, Ecology and Safety. ISBN 0-471-49630-8, 2000.
10.          Berin, M.C. and H.A. Sampson, Food allergy: an enigmatic epidemic. Trends Immunol, 2013. 34(8): p. 390-7.
11.          Lionetti, E. and C. Catassi, New clues in celiac disease epidemiology, pathogenesis, clinical manifestations, and treatment. Int Rev Immunol, 2011. 30(4): p. 219-31.
12.          Sharief, S., S. Jariwala, J. Kumar, P. Muntner, and M.L. Melamed, Vitamin D levels and food and environmental allergies in the United States: results from the National Health and Nutrition Examination Survey 2005-2006. J Allergy Clin Immunol, 2011. 127(5): p. 1195-202.
13.          Kier, L.D. and D.J. Kirkland, Review of genotoxicity studies of glyphosate and glyphosate-based formulations. Crit Rev Toxicol, 2013. 43(4): p. 283-315.
14.          Mink, P.J., J.S. Mandel, B.K. Sceurman, and J.I. Lundin, Epidemiologic studies of glyphosate and cancer: a review. Regul Toxicol Pharmacol, 2012. 63(3): p. 440-52.
15.          Thongprakaisang, S., A. Thiantanawat, N. Rangkadilok, T. Suriyo, and J. Satayavivad, Glyphosate induces human breast cancer cells growth via estrogen receptors. Food Chem Toxicol, 2013. 59: p. 129-36.
16.          Li, Q., M.J. Lambrechts, Q. Zhang, S. Liu, D. Ge, R. Yin, M. Xi, and Z. You, Glyphosate and AMPA inhibit cancer cell growth through inhibiting intracellular glycine synthesis. Drug Des Devel Ther, 2013. 7: p. 635-43.
17.          Moore, L.J., L. Fuentes, J.H. Rodgers, Jr., W.W. Bowerman, G.K. Yarrow, W.Y. Chao, and W.C. Bridges, Jr., Relative toxicity of the components of the original formulation of Roundup to five North American anurans. Ecotoxicol Environ Saf, 2012. 78: p. 128-33.
18.          Zhang, J., J. Tang, B. Cao, Z. Zhang, J. Li, A.D. Schimmer, S. He, and X. Mao, The natural pesticide dihydrorotenone induces human plasma cell apoptosis by triggering endoplasmic reticulum stress and activating p38 signaling pathway. PLoS One, 2013. 8(7): p. e69911.
19.          Smith-Spangler, C., M.L. Brandeau, G.E. Hunter, J.C. Bavinger, M. Pearson, P.J. Eschbach, V. Sundaram, H. Liu, P. Schirmer, C. Stave, I. Olkin, and D.M. Bravata, Are organic foods safer or healthier than conventional alternatives?: a systematic review. Ann Intern Med, 2012. 157(5): p. 348-66.
20.          Pretty, J., Agricultural sustainability: concepts, principles and evidence. Philos Trans R Soc Lond B Biol Sci, 2008. 363(1491): p. 447-65.
21.          Paine, J.A., C.A. Shipton, S. Chaggar, R.M. Howells, M.J. Kennedy, G. Vernon, S.Y. Wright, E. Hinchliffe, J.L. Adams, A.L. Silverstone, and R. Drake, Improving the nutritional value of Golden Rice through increased pro-vitamin A content. Nat Biotechnol, 2005. 23(4): p. 482-7.
22.          Bhullar, N.K. and W. Gruissem, Nutritional enhancement of rice for human health: the contribution of biotechnology. Biotechnol Adv, 2013. 31(1): p. 50-7.
23.          Rojas, C.A., A.S. Hemerly, and P.C. Ferreira, Genetically modified crops for biomass increase. Genes and strategies. GM Crops, 2010. 1(3): p. 137-42.
24.          Khandelwal, A., G.J. Renukaradhya, M. Rajasekhar, G.L. Sita, and M.S. Shaila, Systemic and oral immunogenicity of hemagglutinin protein of rinderpest virus expressed by transgenic peanut plants in a mouse model. Virology, 2004. 323(2): p. 284-91.
25.          Herman, E.M., R.M. Helm, R. Jung, and A.J. Kinney, Genetic modification removes an immunodominant allergen from soybean. Plant Physiol, 2003. 132(1): p. 36-43.