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Physiochemical analyses and molecular characterization of heavy metal-resistant bacteria from Ilesha gold mining sites in Nigeria

The contribution of the processes involved and waste generated during gold mining to the increment of heavy metals concentration in the environment has been well established. While certain heavy metals are req...

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Acetaminophen-traces bioremediation with novel phenotypically and genotypically characterized 2 Streptomyces strains using chemo-informatics, in vivo, and in vitro experiments for cytotoxicity and biological activity

We isolated two novel bacterial strains, active against the environmental pollutant acetaminophen/Paracetamol®. Streptomyces chrestomyceticus (symbol RS2) and Flavofuscus (symbol M33) collected from El-Natrun Val...

Biosoftening of banana pseudostem fiber using cellulase and pectinase enzyme isolated from Aspergillus niger for textile industry

Nowadays, farmers are facing a lot of problems for the disposal of banana pseudostem waste after the harvesting of banana. Banana pseudostem is a rich source of fiber, which is an alternative source of other n...

FolE gene expression for folic acid productivity from optimized and characterized probiotic Lactobacillus delbrueckii

Lactobacillus delbrueckii was one of the most common milk lactic acid bacterial strains (LAB) which characterized as probiotic with many health influencing properties.

Reverse transcription loop-mediated isothermal amplification (RT-LAMP) primer design based on Indonesia SARS-CoV-2 RNA sequence

The COVID-19 pandemic has highlighted the importance of tracking cases by using various methods such as the Reverse transcription loop-mediated isothermal amplification (RT-LAMP) which is a fast, simple, inexp...

In silico analysis of HLA-1 and HLA-2 recognition of a designed recombinant human papillomavirus vaccine based on L1 protein HPV subtype 45

Human leukocyte antigen (HLA) can bind and present the processed antigenic peptide derived from the vaccine to the T cell receptor, and this capability is crucial in determining the effectivity of the vaccine ...

In silico design of an epitope-based vaccine against PspC in Streptococcus pneumoniae using reverse vaccinology

Streptococcus pneumoniae is a major pathogen that poses a significant hazard to global health, causing a variety of infections including pneumonia, meningitis, and sepsis. The emergence of antibiotic-resistant st...

A scalable overexpression of a thermostable recombinant poly-histidine tag carboxyl esterase under lambda promoter: purification, characterization, and protein modelling

As a white biotechnological trend, esterases are thought to be among the most active enzymes’ classes in biocatalysis and synthesis of industrially importance organic compounds. Esterases are used in many appl...

Correction: Mycosynthesis of silver nanoparticles using marine fungi and their antimicrobial activity against pathogenic microorganisms

The original article was published in Journal of Genetic Engineering and Biotechnology 2023 21 :127

Whole genome sequence and comparative genomics analysis of multidrug-resistant Staphylococcus xylosus NM36 isolated from a cow with mastitis in Basrah city

Staphylococcus xylosus is a coagulase-negative, gram-positive coccus that is found in the environment and as a commensal organism on the skin and mucosal surfaces of animals. Despite the fact that S. xylosus is c...

Immunoinformatics-aided rational design of multiepitope-based peptide vaccine (MEBV) targeting human parainfluenza virus 3 (HPIV-3) stable proteins

Human parainfluenza viruses (HPIVs) are common RNA viruses responsible for respiratory tract infections. Human parainfluenza virus 3 (HPIV-3) is particularly pathogenic, causing severe illnesses with no effect...

Isolation of plant growth-promoting rhizobacteria from the agricultural fields of Tattiannaram, Telangana

Plant probiotics bacteria are live microbes that promote soil health and plant growth and build the stress-tolerant capacity to the plants. They benefit the plants by increasing nutrient absorption and release...

Exploring structural antigens of yellow fever virus to design multi-epitope subunit vaccine candidate by utilizing an immuno-informatics approach

Yellow fever is a mosquito-borne viral hemorrhagic disease transmitted by several species of virus-infected mosquitoes endemic to tropical regions of Central and South America and Africa. Earlier in the twenti...

Short tandem repeat (STR) variation from 6 cities in Iraq based on 15 loci

One thousand sixty-one individuals were sampled from the cities of Anbar, Baghdad, Basra, Diyala, Najaf, and Wasit in Iraq and typed for 15 forensic STRs to explore the genetic structure of Iraq and develop a ...

The hepato- and neuroprotective effect of gold Casuarina equisetifolia bark nano-extract against Chlorpyrifos-induced toxicity in rats

The bark of Casuarina equisetifolia contains several active phytoconstituents that are suitable for the biosynthesis of gold nanoparticles (Au-NPs). These nanoparticles were subsequently evaluated for their effec...

Cloning and characterization of an acidic lipase from a lipolytic bacterium in tempeh

Lipases have emerged as essential biocatalysts, having the ability to contribute to a wide range of industrial applications. Microbial lipases have garnered significant industrial attention due to their stabil...

Recent advances in genome annotation and synthetic biology for the development of microbial chassis

This article provides an overview of microbial host selection, synthetic biology, genome annotation, metabolic modeling, and computational methods for predicting gene essentiality for developing a microbial ch...

In-silico analysis of potent Mosquirix vaccine adjuvant leads

World Health Organization recommend the use of malaria vaccine, Mosquirix, as a malaria prevention strategy. However, Mosquirix has failed to reduce the global burden of malaria because of its inefficacy. The ...

Influenza vaccine: a review on current scenario and future prospects

Vaccination is a crucial tool in preventing influenza, but it requires annual updates in vaccine composition due to the ever-changing nature of the flu virus. While healthcare and economic burdens have reduced...

Endophytic bacteria Klebsiella spp. and Bacillus spp . from Alternanthera philoxeroides in Madiwala Lake exhibit additive plant growth-promoting and biocontrol activities

The worldwide increase in human population and environmental damage has put immense pressure on the overall global crop production making it inadequate to feed the entire population. Therefore, the need for su...

Immunoinformatics analysis of Brucella melitensis to approach a suitable vaccine against brucellosis

Brucellosis caused by B. melitensis is one of the most important common diseases between humans and livestock. Currently, live attenuated vaccines are used for this disease, which causes many problems, and unfort...

Enhancement effect of AgO nanoparticles on fermentative cellulase activity from thermophilic Bacillus subtilis Ag-PQ

Cellulase is an important bioprocessing enzyme used in various industries. This study was conducted with the aim of improving the biodegradation activity of cellulase obtained from the Bacillus subtilis AG-PQ str...

Studying the pathogenicity of 26 variants characterized in the first molecular analyses of Egyptian aplastic anemia patients

Aplastic anemia (AA) is a bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia which can lead to life-threatening complications. Our objective was to study the telomerase genes ( TER...

Optimizing the generation of mature bone marrow-derived dendritic cells in vitro: a factorial study design

Factorial design is a simple, yet elegant method to investigate the effect of multiple factors and their interaction on a specific response simultaneously. Hence, this type of study design reaches the best opt...

Biodiversity and biological applications of marine actinomycetes—Abu-Qir Bay, Mediterranean Sea, Egypt

The ability of actinomycetes to produce bioactive secondary metabolites makes them one of the most important prokaryotes. Marine actinomycetes are one of the most important secondary metabolites producers used...

A computational simulation appraisal of banana lectin as a potential anti-SARS-CoV-2 candidate by targeting the receptor-binding domain

The ongoing concern surrounding coronavirus disease 2019 (COVID-19) primarily stems from continuous mutations in the genome of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leading to the e...

Metagenomic analysis reveals diverse microbial community and potential functional roles in Baner rivulet, India

The health index of any population is directly correlated with the water quality, which in turn depends upon physicochemical characteristics and the microbiome of that aquatic source. For maintaining the water...

Mapping of conserved immunodominant epitope peptides in the outer membrane porin (Omp) L of prominent Enterobacteriaceae pathogens associated with gastrointestinal infections

Members of Enterobacteriaceae such as Escherichia coli O 157:H7, Salmonella sp., Shigella sp., Klebsiella sp., and Citrobacter freundii are responsible for the outbreak of serious foodborne illness and other muco...

Dual action of epigallocatechin-3-gallate in virus-induced cell Injury

Viral infections cause damage and long-term injury to infected human tissues, demanding therapy with antiviral and wound healing medications. Consequently, safe phytochemical molecules that may control viral i...

Designing a novel and combinatorial multi-antigenic epitope-based vaccine “MarVax” against Marburg virus—a reverse vaccinology and immunoinformatics approach

Marburg virus (MARV) is a member of the Filoviridae family and causes Marburg virus disease (MVD) among humans and primates. With fatality rates going up to 88%, there is currently no commercialized cure or va...

Bioinformatics study of phytase from Aspergillus niger for use as feed additive in livestock feed

Phytase supplementation in rations can reduce their phytic acid composition in order to enhance their nutritional value. Aspergillus niger is a fungus that can encode phytase. This study aims to determine the cha...

Improved production of Bacillus subtilis cholesterol oxidase by optimization of process parameters using response surface methodology

Cholesterol oxidase has numerous biomedical and industrial applications. In the current study, a new bacterial strain was isolated from sewage and was selected for its high potency for cholesterol degradation ...

Microsatellite diversity and complexity in the viral genomes of the family Caliciviridae

Microsatellites or simple sequence repeats (SSR) consist of 1–6 nucleotide motifs of DNA or RNA which are ubiquitously present in tandem repeated sequences across genome in viruses: prokaryotes and eukaryotes....

Prevalence of Extended Spectrum β-Lactamase Producers (ESBLs) with antibiotic resistance pattern of Gram negative pathogenic bacteria isolated from door handles in hospitals of Pokhara, Western Nepal

The presence of drug-resistant Gram-negative pathogenic bacteria and Extended Spectrum β-Lactamase Producers (ESBLs) in hospital associated fomites like door handles can serve as vehicles in transmission and m...

Application of statistical methodology for the optimization of l -glutaminase enzyme production from Streptomyces pseudogriseolus ZHG20 under solid-state fermentation

Actinomycetes are excellent microbial sources for various chemical structures like enzymes, most of which are used in pharmaceutical and industrial products. Actinomycetes are preferred sources of enzymes due ...

Investigating marine Bacillus as an effective growth promoter for chickpea

Microorganisms have characteristics that aid plant growth and raise the level of vital metabolites in plants for better growth including primary and secondary metabolites as well as several developmental enzym...

The pectinolytic activity of Burkholderia cepacia and its application in the bioscouring of cotton knit fabric

Enzymatic catalysis in different industrial applications is often preferred over chemical methods due to various advantages, such as higher specificity, greater efficiency, and less environmental footprint. Pe...

In silico analysis of a novel hypothetical protein (YP_498675.1) from Staphylococcus aureus unravels the protein of tryptophan synthase beta superfamily (Try-synth-beta_ II)

Staphylococcus aureus is a gram-positive spherical bacteria and the most common cause of nosocomial infections in the world. Given its clinical significance, the genome sequence of S. aureus has been elucidated t...

Nutrigenomics and microbiome shaping the future of personalized medicine: a review article

The relationship between nutrition and genes has long been hinted at and sometimes plainly associated with certain diseases. Now, after many years of research and coincidental findings, it is believed that thi...

Alpha-glucan: a novel bacterial polysaccharide and its application as a biosorbent for heavy metals

This study identified an extracellular bacterial polysaccharide produced by Bacillus velezensis strain 40B that contains more than 90% of the monosaccharide glucose as alpha-glucan. A prominent peak at 1074 cm −1 ,...

De novo assembly and comparative genome analysis for polyhydroxyalkanoates-producing Bacillus sp. BNPI-92 strain

Certain Bacillus species play a vital role in polyhydroxyalkanoate (PHA) production. However, most of these isolates did not properly identify to species level when scientifically had been reported.

Adverse effect of Tamarindus indica and tamoxifen combination on redox balance and genotoxicity of breast cancer cell

Breast cancer is the most significant threat to women worldwide. Most chemotherapeutic drugs cause cancer cell death and apoptosis by inducing oxidative stress and producing reactive oxygen species (ROS). Canc...

In silico molecular and functional characterization of a dual function antimicrobial peptide, hepcidin (GIFT-Hep), isolated from genetically improved farmed tilapia (GIFT, Oreochromis niloticus )

Antimicrobial peptides (AMPs), innate immune response molecules in organisms, are also known for their dual functionality, exemplified by hepcidin—an immunomodulator and iron regulator. Identifying and studyin...

Codon optimization of a gene encoding DNA polymerase from Pyrococcus furiosus and its expression in Escherichia coli

DNA polymerase is an essential component in PCR assay for DNA synthesis. Improving DNA polymerase with characteristics indispensable for a powerful assay is crucial because it can be used in wide-range applica...

Immunoinformatics study to explore dengue (DENV-1) proteome to design multi-epitope vaccine construct by using CD4+ epitopes

Immunoinformatics is an emerging interdisciplinary field which integrates immunology, bioinformatics, and computational biology to study the immune system. In this study, we apply immunoinformatics approaches ...

Mycosynthesis of silver nanoparticles using marine fungi and their antimicrobial activity against pathogenic microorganisms

At the present time, there is a persistent need to get rid of environmental contaminants by eco-friendly, sustainable, and economical technologies. Uncontrolled disposal practices of domestic and industrial so...

The Correction to this article has been published in Journal of Genetic Engineering and Biotechnology 2023 21 :164

Expression, purification, and characterization of self-assembly virus-like particles of capsid protein L1 HPV 52 in Pichia pastoris GS115

Cervical cancer caused by the human papillomavirus (HPV) is one of the most frequent malignances globally. HPV 52 is a high-risk cancer-causing genotype that has been identified as the most prevalent type in I...

Pangenome diversification and resistance gene characterization in Salmonella Typhi prioritized RfaJ as a significant therapeutic marker

Salmonella Typhi stands as the etiological agent responsible for the onset of human typhoid fever. The pressing demand for innovative therapeutic targets against S. Typhi is underscored by the escalating prevale...

Association between polymorphisms of immune response genes and early childhood caries — systematic review, gene-based, gene cluster, and meta-analysis

Early childhood caries is a significant public health concern affecting about 600 million children globally. The etiology of early childhood caries can be explained as an interplay between genetic and environm...

Experimental and hypothetical appraisal on inhibition of glucose-induced glycation of bovine serum albumin by quercetin

The specificity of protein functions depends on its folding ability into a functional structure. Protein folding is an essential systemic phenomenon that prevents incorrect folding which could result in harmfu...

• ISSN: 2090-5920 (electronic)

Genetic Engineering

• First Online: 28 March 2021

Cite this chapter

• David B. Resnik 13  

Part of the book series: The International Library of Bioethics ((ILB,volume 86))

223 Accesses

In this chapter I will apply the PP to ethical and policy issues related to genetic engineering of microbes, plants, animals, and human beings. I will argue that the PP can provide some useful insights into these issues, due to the scientific and morally uncertainty surrounding the consequences of genetic engineering for public health, the environment, society, and patients.

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By “genetic engineering” I mean technologies that involve direct modification or alteration of the genomes of cells or organisms. Changes brought about by genetic engineering might or might not be inheritable, depending on the type of change and the organism. Modification of the genomes of somatic cells in humans (discussed below) does not normally result in inheritable genetic changes, but modification of human germ cells, sperm, eggs, or embryos does (Resnik et al. 1999 ). Modification of bacterial genomes always results in inheritable genetic changes because bacteria are unicellular organisms. Ooplasm transfer, nuclear transfer, and reproductive cloning in human beings raise important ethical and social issues, but these procedures are not genetic engineering, according to my definition, because their purposes is not modify genomes, even though they involve the manipulation of genetic material. Synthetic biology uses genetic engineering methods to design cells, organisms, and biological system that do not already exist in the natural world (Biotechnology Innovation Organization 2020b ).

Some viruses encode their genetic information in RNA (ribonucleic acid).

A polymer is a large molecule.

James Watson (1928–) and Francis Crick (1916–2004) won the Nobel Prize in Physiology of Medicine in 1962 for discovering the structure of DNA. Their model was confirmed by Rosalind Franklin’s x-ray crystallography data, Watson and Crick did not name Franklin as an author on the paper that described their model of the structure of DNA. Franklin (1920–1958) was also not awarded the Nobel Prize for her contribution, because she died of ovarian cancer in 1958, and the Nobel Prize is not awarded posthumously (Maddox 2003 ).

Because mitochondria have their own DNA, scientists have speculated that mitochondria were at one time independent organisms that became incorporated into primordial, unicellular organisms (Alberts et al. 2015 ).

Prokaryotes are single-celled organisms with no distinct cell nucleus or organelles.

Mitochondria replicate independently of the cell.

Most higher life forms, including most plants, mammals, and human beings, are diploid (Alberts et al. 2015 ).

Many species of plants and animals that reproduce sexually can also propagate asexually. Growing a new plant from a cutting is a form of asexual propagation.

Plant stem cells can also generate different tissue types.

Berg, Gilbert, and Sanger won the Nobel Prize in chemistry in 1980 for their development of recombinant DNA techniques (Nobel Prize.org 2021 ).

Doudna and Charpentier won the Nobel Prize in Chemistry in 2000 for the discovery of CRISPR (Ledford and Callaway 2020 ).

Laboratory animals are used to produce monoclonal antibodies. An antigen is introduced into the animal, which produces antibodies in its lymphocyte cells. These cells are cultured and then antibodies are isolated. Since these antibodies would be rejected by the human immune system, the cells are genetically modified so that they produce antibodies with a human protein component, or humanized antibodies. The genetically modified cells are then cultured and humanized antibodies are isolated for production (GenScript 2020 ).

Somatic cells are cells other than the reproductive or germ cells, such as skin, nerve, muscle, liver or bone marrow cells.

Monsanto has developed GM crops (known as Bt crops) that produce Bacillus thuringiensis toxins, which are deadly to insects. Farmers were already using these toxins as pesticides were Bt crops were developed (Resnik 2012 ).

Monsanto has developed GM crops (known as “Roundup Ready” crops) that are immune to the effects of glyphosate, the active ingredient in the widely-used herbicide Roundup ™. Farmers can control weeds with damaging their crops by spraying their crops with Roundup (Resnik 2012 ).

Golden rice, for example, contains more beta carotene than normal rice (McDivitt 2019 ).

In 2018, 228 million people worldwide contracted malaria and 405,000 people died from the disease (World Health Organization 2020a ). About 390 million people contract the dengue virus each year and about 4000 die from the disease (World Health Organization 2020b ).

Oxitec has also genetically engineered diamondback moths (Plutella xylostella) to control these populations. Diamondback moths are a destructive pests that feed on cauliflower, cabbage, broccoli and canola (Campbell 2020a ).

E.g. Bt crops. See Footnote 12.

These are the sorts of problems encountered by the natural law approaches to morality, discussed in Chapter 3 .

Most defenders of the slippery slope argument in genetic only apply it to using genome editing in humans, but it could be applied to other applications of genetic engineering.

I am assuming that GM microbes will not be intentionally released into the environment, which would create risks not discussed here. Scientists have developed GM microbes to clean up oil spills but have not deployed them yet, mostly due to regulatory issues. In nature, microbes already play an important role in cleaning up oil spills (Ezezika and Singer 2010 ).

The reproduction rate is how many people infected persons infect. R 0  = 1 means that an infected person infects one more person on average; R 0  = 2 means an infected person infects two people on average.

It is worth noting, however, that a voluntary moratorium was a reasonable option when this technology was emerging in the 1970s.

As noted in Chapter 6 , a black market for alcohol emerged during Prohibition era in the US (1919–1933). The desire to avoid creating a black market for any product is an relevant to regulatory actions that involve prohibitions.

As a side note, members of Greenpeace broke into a research farm in Australia in 2011 and destroyed an entire crop of GM wheat. Members of another environmental damaged a crop of golden rice in the Philippines (Zhang et al. 2016 ).

To date, 156 Nobelists have signed the petition (Nobel Prize Winners 2016 ).

For a review of the GM food safety literature, also see Domingo ( 2016 ).

It is worth noting the long-term animal studies pose some scientific and technical challenges because most of the rodent species used in these types of experiments have a lifespan of about three years and normally develop tumors and other health problems as they age. So, it can be difficult to determine whether an adverse effect in a laboratory animal is due to an exposure to a GM food or the natural aging process. A two-year study published by Séralini et al. ( 2012 ) claiming that mice fed a diet of Roundup Ready GM corn had more tumors than mice fed the normal diet (the control group) was later retracted by the journal due to serious methodological flaws that undermined the validity of the data (Resnik 2015a ).

See Footnote 12.

Davidson ( 2001 ) defends a principle of charity for interpreting language. The basic idea here is that one should interpret a speaker’s statements as being rational, other things being equal. Interpreting disagreements about GM foods/crops as based on differing value priorities portrays these disagreements as rational, rather than based on irrational fear or ignorance.

It is also worth noting that bans on GM plants can create black markets because of the high demand for these products.

As of the writing of this book, Kenya is currently rethinking its ban on GM crops (Meeme 2019 ).

Most of the debate about chimeras so far has focused on inserting human cells into early animal embryos (or blastocysts), not on inserting human genes into animals.

It is also worth noting that a ban would probably create a black market because demand for GM animals and animal products it high.

There is a potential regulatory gap in the genetic engineering of animals for meat or animal products. Although regulations and ethical guidelines require IACUCs to review and oversee genetic engineering of animals for research conducted at academic institutions, there are no such requirements for genetic engineering of animals for non-research purposes, such as meat production. One could argue that companies that genetically engineer animals for non-research purposes should form ethics committees similar to IACUCs to oversee these activities.

Anderson led the research team that conducted the world’s first human gene therapy clinical trial. The experiment used an adenovirus vector to insert the adenosine deaminase gene into the T-cells of two young children with combined immunodeficiency. The trial showed that the procedure was safe and effective even if did not cure the patients (Blaese et al. 1995 ). In 2006, Anderson was convicted of molesting and sexually abusing a girl over a four-year period, beginning when she was 10 years old, and he served 12 years in prison. Anderson maintains that he is innocent and that his conviction was based on falsified evidence (Begley 2018 ).

See Footnote 29.

An example of somatic genetic enhancement would be a transferring a gene to an adult male to stimulate production of testosterone to enhance athletic and sexual performance.

It is worth noting that not everyone regards genetic enhancement immoral or morally questionable. The transhumanist movement embraces various forms of enhancement to benefit mankind and allow people to express creative freedom (Harris 2007 ; Bostrom 2008 , 2010 ; More and Vita-More 2013 ; Porter 2017 ; Rana and Samples 2019 ).

Some have attempted to define health in terms of a normal range of variation for an organism. In medicine, a normal physiological trait is a trait that falls within a range of variation for healthy functioning of the organism (Boorse 1977 ; Schaffner 1993 ). For example, normal fasting blood sugar levels range from 60 mg/dL to 100 mg/dL (WebMD 2020 ). Fasting blood sugar levels that are too high cause diabetes and levels that are too low cause hypoglycemia, both of which are unhealthy conditions. However, normality cannot be equated with the statistical norm for a population, since the statistical norm might be unhealthy. If most people in a population have a fasting blood sugar greater than 100 mg/dL, we would not say that a fasting blood sugar greater than 100 mg/dL is normal, even though it would be the statistical norm for that population. Thus, the concept of a normal range of variation cannot be defined statistically and depends on a broader concept of health, which may be influenced by moral, social, and cultural factors.

Some argue that “gene therapy” is a misleading term because it implies that the genetic interventions are likely to benefit the patient or human subject, when often they do not (Henderson et al. 2006 ).

See Resnik ( 2018a ) for discussion of additional safety protections for subjects enrolled in clinical research.

In 1996, the US Congress passed a ban, known as the Dickey-Wicker amendment, on the use of federal funds to create human embryos for research (Green 2001 ). Though the ban has been interpreted differently by different administrations, it is still in effect.

For further discussion of creating embryos for research, see Green ( 2001 ).

I will assume that parents who are willing to use medical technology to prevent the birth of children with genetic diseases view abortion as morally acceptable, at least for this purpose.

Prenatal genetic testing can also be used to avoid giving birth to children with chromosomal abnormalities, such as Trisomy 21 (Down Syndrome).

Embryos that are not implanted would be destroyed. I am assuming that parents would view this as morally acceptable.

See Resnik et al. ( 1999 ) and National Academies of Sciences, Engineering, and Medicine ( 2017 ) for additional examples of monogenic disorders that GGE might be used to prevent.

The concept of a parent can be confusing here, because people who related to the child genetically might not be related socially. The concept of a parent can be even more confusing when surrogate pregnancy is used to produce children, since woman who gestates and gives birth to the child might not be genetically related to the child, if she is carrying a fetus created by another couple in vitro.

This is one of the themes of the science fiction movie GATTACA.

This cost estimate is based on dividing the total cost of the Human Genome Project--$3 billion—by three. The Human Genome Project was a US-funded research project that took place from 1990 to 2003. Although sequencing the human genome was the primary goal of the project, it also included other activities, such as studies of human diseases, model organisms, genetic technologies, computational methods, and ethical issues (Human Genome Project 2020 ).

Interestingly, two of the scientists who called for the moratorium, David Baltimore and Paul Berg, participated in the Asilomar conference on recombinant DNA (discussed earlier).

These studies could include the creation of human embryos to study the safety and efficacy of GGE methods and techniques (Liang et al. 2015 ).

This is an example of the problem of incoherence discussed in Chapter 4 .

Alopecia areata is a condition that leads to hair loss. It is thought to have a genetic basis (McIntosh 2017 ).

The moratorium would not apply to GGE for research purposes.

The moratorium would not apply to research on embryos created by GGE, which would be necessary to obtain the knowledge needed to better understand the safety and efficacy of using GGE to produce children (Liang et al. 2015 ; Baltimore et al. 2015 ).

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Resnik, D.B. (2021). Genetic Engineering. In: Precautionary Reasoning in Environmental and Public Health Policy. The International Library of Bioethics, vol 86. Springer, Cham. https://doi.org/10.1007/978-3-030-70791-0_7

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12.4: Genetic Engineering - Risks, Benefits, and Perceptions

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Learning Objectives

• Summarize the mechanisms, risks, and potential benefits of gene therapy
• Identify ethical issues involving gene therapy and the regulatory agencies that provide oversight for clinical trials
• Compare somatic-cell and germ-line gene therapy

Many types of genetic engineering have yielded clear benefits with few apparent risks. Few would question, for example, the value of our now abundant supply of human insulin produced by genetically engineered bacteria. However, many emerging applications of genetic engineering are much more controversial, often because their potential benefits are pitted against significant risks, real or perceived. This is certainly the case for gene therapy, a clinical application of genetic engineering that may one day provide a cure for many diseases but is still largely an experimental approach to treatment.

Mechanisms and Risks of Gene Therapy

Human diseases that result from genetic mutations are often difficult to treat with drugs or other traditional forms of therapy because the signs and symptoms of disease result from abnormalities in a patient’s genome. For example, a patient may have a genetic mutation that prevents the expression of a specific protein required for the normal function of a particular cell type. This is the case in patients with Severe Combined Immunodeficiency (SCID), a genetic disease that impairs the function of certain white blood cells essential to the immune system.

Gene therapy attempts to correct genetic abnormalities by introducing a nonmutated, functional gene into the patient’s genome. The nonmutated gene encodes a functional protein that the patient would otherwise be unable to produce. Viral vectors such as adenovirus are sometimes used to introduce the functional gene; part of the viral genome is removed and replaced with the desired gene (Figure \(\PageIndex{1}\)). More advanced forms of gene therapy attempt to correct the mutation at the original site in the genome, such as is the case with treatment of SCID.

So far, gene therapies have proven relatively ineffective, with the possible exceptions of treatments for cystic fibrosisand adenosine deaminase deficiency, a type of SCID. Other trials have shown the clear hazards of attempting genetic manipulation in complex multicellular organisms like humans. In some patients, the use of an adenovirus vector can trigger an unanticipated inflammatory response from the immune system, which may lead to organ failure. Moreover, because viruses can often target multiple cell types, the virus vector may infect cells not targeted for the therapy, damaging these other cells and possibly leading to illnesses such as cancer. Another potential risk is that the modified virus could revert to being infectious and cause disease in the patient. Lastly, there is a risk that the inserted gene could unintentionally inactivate another important gene in the patient’s genome, disrupting normal cell cycling and possibly leading to tumor formation and cancer. Because gene therapy involves so many risks, candidates for gene therapy need to be fully informed of these risks before providing informed consent to undergo the therapy.

Gene Therapy Gone Wrong

The risks of gene therapy were realized in the 1999 case of Jesse Gelsinger, an 18-year-old patient who received gene therapy as part of a clinical trial at the University of Pennsylvania. Jesse received gene therapy for a condition called ornithine transcarbamylase (OTC) deficiency, which leads to ammonia accumulation in the blood due to deficient ammonia processing. Four days after the treatment, Jesse died after a massive immune response to the adenovirus vector. 1

Until that point, researchers had not really considered an immune response to the vector to be a legitimate risk, but on investigation, it appears that the researchers had some evidence suggesting that this was a possible outcome. Prior to Jesse’s treatment, several other human patients had suffered side effects of the treatment, and three monkeys used in a trial had died as a result of inflammation and clotting disorders. Despite this information, it appears that neither Jesse nor his family were made aware of these outcomes when they consented to the therapy. Jesse’s death was the first patient death due to a gene therapy treatment and resulted in the immediate halting of the clinical trial in which he was involved, the subsequent halting of all other gene therapy trials at the University of Pennsylvania, and the investigation of all other gene therapy trials in the United States. As a result, the regulation and oversight of gene therapy overall was reexamined, resulting in new regulatory protocols that are still in place today.

Exercise \(\PageIndex{1}\)

• Explain how gene therapy works in theory.
• Identify some risks of gene therapy.

Oversight of Gene Therapy

Presently, there is significant oversight of gene therapy clinical trials. At the federal level, three agencies regulate gene therapy in parallel: the Food and Drug Administration (FDA), the Office of Human Research Protection (OHRP), and the Recombinant DNA Advisory Committee (RAC) at the National Institutes of Health (NIH). Along with several local agencies, these federal agencies interact with the institutional review board to ensure that protocols are in place to protect patient safety during clinical trials. Compliance with these protocols is enforced mostly on the local level in cooperation with the federal agencies. Gene therapies are currently under the most extensive federal and local review compared to other types of therapies, which are more typically only under the review of the FDA. Some researchers believe that these extensive regulations actually inhibit progress in gene therapy research. In 2013, the Institute of Medicine (now the National Academy of Medicine) called upon the NIH to relax its review of gene therapy trials in most cases. 2 However, ensuring patient safety continues to be of utmost concern.

Ethical Concerns

Beyond the health risks of gene therapy, the ability to genetically modify humans poses a number of ethical issues related to the limits of such “therapy.” While current research is focused on gene therapy for genetic diseases, scientists might one day apply these methods to manipulate other genetic traits not perceived as desirable. This raises questions such as:

Exercise \(\PageIndex{2}\)

• Which genetic traits are worthy of being “corrected”?
• Should gene therapy be used for cosmetic reasons or to enhance human abilities?
• Should genetic manipulation be used to impart desirable traits to the unborn?
• Is everyone entitled to gene therapy, or could the cost of gene therapy create new forms of social inequality?
• Who should be responsible for regulating and policing inappropriate use of gene therapies?

The ability to alter reproductive cells using gene therapy could also generate new ethical dilemmas. To date, the various types of gene therapies have been targeted to somatic cells, the non-reproductive cells within the body. Because somatic cell traits are not inherited, any genetic changes accomplished by somatic-cell gene therapy would not be passed on to offspring. However, should scientists successfully introduce new genes to germ cells (eggs or sperm), the resulting traits could be passed on to offspring. This approach, called germ-line gene therapy, could potentially be used to combat heritable diseases, but it could also lead to unintended consequences for future generations. Moreover, there is the question of informed consent, because those impacted by germ-line gene therapy are unborn and therefore unable to choose whether they receive the therapy. For these reasons, the U.S. government does not currently fund research projects investigating germ-line gene therapies in humans.

Risky Gene Therapies

While there are currently no gene therapies on the market in the United States, many are in the pipeline and it is likely that some will eventually be approved. With recent advances in gene therapies targeting p53, a gene whose somatic cell mutations have been implicated in over 50% of human cancers, 3 cancer treatments through gene therapies could become much more widespread once they reach the commercial market.

Bringing any new therapy to market poses ethical questions that pit the expected benefits against the risks. How quickly should new therapies be brought to the market? How can we ensure that new therapies have been sufficiently tested for safety and effectiveness before they are marketed to the public? The process by which new therapies are developed and approved complicates such questions, as those involved in the approval process are often under significant pressure to get a new therapy approved even in the face of significant risks.

To receive FDA approval for a new therapy, researchers must collect significant laboratory data from animal trials and submit an Investigational New Drug (IND) application to the FDA’s Center for Drug Evaluation and Research (CDER). Following a 30-day waiting period during which the FDA reviews the IND, clinical trials involving human subjects may begin. If the FDA perceives a problem prior to or during the clinical trial, the FDA can order a “clinical hold” until any problems are addressed. During clinical trials, researchers collect and analyze data on the therapy’s effectiveness and safety, including any side effects observed. Once the therapy meets FDA standards for effectiveness and safety, the developers can submit a New Drug Application (NDA) that details how the therapy will be manufactured, packaged, monitored, and administered.

Because new gene therapies are frequently the result of many years (even decades) of laboratory and clinical research, they require a significant financial investment. By the time a therapy has reached the clinical trials stage, the financial stakes are high for pharmaceutical companies and their shareholders. This creates potential conflicts of interest that can sometimes affect the objective judgment of researchers, their funders, and even trial participants. The Jesse Gelsinger case (see Case in Point: Gene Therapy Gone Wrong ) is a classic example. Faced with a life-threatening disease and no reasonable treatments available, it is easy to see why a patient might be eager to participate in a clinical trial no matter the risks. It is also easy to see how a researcher might view the short-term risks for a small group of study participants as a small price to pay for the potential benefits of a game-changing new treatment.

Gelsinger’s death led to increased scrutiny of gene therapy, and subsequent negative outcomes of gene therapy have resulted in the temporary halting of clinical trials pending further investigation. For example, when children in France treated with gene therapy for SCID began to develop leukemia several years after treatment, the FDA temporarily stopped clinical trials of similar types of gene therapy occurring in the United States. 4 Cases like these highlight the need for researchers and health professionals not only to value human well-being and patients’ rights over profitability, but also to maintain scientific objectivity when evaluating the risks and benefits of new therapies.

Exercise \(\PageIndex{3}\)

• Why is gene therapy research so tightly regulated?
• What is the main ethical concern associated with germ-line gene therapy?

Key Concepts and Summary

• While gene therapy shows great promise for the treatment of genetic diseases, there are also significant risks involved.
• There is considerable federal and local regulation of the development of gene therapies by pharmaceutical companies for use in humans.
• Before gene therapy use can increase dramatically, there are many ethical issues that need to be addressed by the medical and research communities, politicians, and society at large.
• 1 Barbara Sibbald. “Death but One Unintended Consequence of Gene-Therapy Trial.” Canadian Medical Association Journal 164 no. 11 (2001): 1612–1612.
• 2 Kerry Grens. “Report: Ease Gene Therapy Reviews.” The Scientist , December 9, 2013. http://www.the-scientist.com/?articl...erapy-Reviews/ . Accessed May 27, 2016.
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Genetically Modified Organisms (GMOs): Transgenic Crops and Recombinant DNA Technology

People have been altering the genomes of plants and animals for many years using traditional breeding techniques. Artificial selection for specific, desired traits has resulted in a variety of different organisms, ranging from sweet corn to hairless cats. But this artificial selection , in which organisms that exhibit specific traits are chosen to breed subsequent generations, has been limited to naturally occurring variations. In recent decades, however, advances in the field of genetic engineering have allowed for precise control over the genetic changes introduced into an organism . Today, we can incorporate new genes from one species into a completely unrelated species through genetic engineering, optimizing agricultural performance or facilitating the production of valuable pharmaceutical substances. Crop plants, farm animals, and soil bacteria are some of the more prominent examples of organisms that have been subject to genetic engineering.

Current Use of Genetically Modified Organisms

Table 1: Examples of GMOs Resulting from Agricultural Biotechnology

The pharmaceutical industry is another frontier for the use of GMOs. In 1986, human growth hormone was the first protein pharmaceutical made in plants (Barta et al ., 1986), and in 1989, the first antibody was produced (Hiatt et al ., 1989). Both research groups used tobacco, which has since dominated the industry as the most intensively studied and utilized plant species for the expression of foreign genes (Ma et al ., 2003). As of 2003, several types of antibodies produced in plants had made it to clinical trials. The use of genetically modified animals has also been indispensible in medical research. Transgenic animals are routinely bred to carry human genes, or mutations in specific genes, thus allowing the study of the progression and genetic determinants of various diseases.

Potential GMO Applications

Many industries stand to benefit from additional GMO research. For instance, a number of microorganisms are being considered as future clean fuel producers and biodegraders. In addition, genetically modified plants may someday be used to produce recombinant vaccines. In fact, the concept of an oral vaccine expressed in plants (fruits and vegetables) for direct consumption by individuals is being examined as a possible solution to the spread of disease in underdeveloped countries, one that would greatly reduce the costs associated with conducting large-scale vaccination campaigns. Work is currently underway to develop plant-derived vaccine candidates in potatoes and lettuce for hepatitis B virus (HBV), enterotoxigenic Escherichia coli (ETEC), and Norwalk virus. Scientists are also looking into the production of other commercially valuable proteins in plants, such as spider silk protein and polymers that are used in surgery or tissue replacement (Ma et al ., 2003). Genetically modified animals have even been used to grow transplant tissues and human transplant organs, a concept called xenotransplantation. The rich variety of uses for GMOs provides a number of valuable benefits to humans, but many people also worry about potential risks.

Risks and Controversies Surrounding the Use of GMOs

Despite the fact that the genes being transferred occur naturally in other species, there are unknown consequences to altering the natural state of an organism through foreign gene expression . After all, such alterations can change the organism's metabolism , growth rate, and/or response to external environmental factors. These consequences influence not only the GMO itself, but also the natural environment in which that organism is allowed to proliferate. Potential health risks to humans include the possibility of exposure to new allergens in genetically modified foods, as well as the transfer of antibiotic-resistant genes to gut flora.

Horizontal gene transfer of pesticide, herbicide, or antibiotic resistance to other organisms would not only put humans at risk , but it would also cause ecological imbalances, allowing previously innocuous plants to grow uncontrolled, thus promoting the spread of disease among both plants and animals. Although the possibility of horizontal gene transfer between GMOs and other organisms cannot be denied, in reality, this risk is considered to be quite low. Horizontal gene transfer occurs naturally at a very low rate and, in most cases, cannot be simulated in an optimized laboratory environment without active modification of the target genome to increase susceptibility (Ma et al ., 2003).

In contrast, the alarming consequences of vertical gene transfer between GMOs and their wild-type counterparts have been highlighted by studying transgenic fish released into wild populations of the same species (Muir & Howard, 1999). The enhanced mating advantages of the genetically modified fish led to a reduction in the viability of their offspring . Thus, when a new transgene is introduced into a wild fish population, it propagates and may eventually threaten the viability of both the wild-type and the genetically modified organisms.

Unintended Impacts on Other Species: The Bt Corn Controversy

One example of public debate over the use of a genetically modified plant involves the case of Bt corn. Bt corn expresses a protein from the bacterium Bacillus thuringiensis . Prior to construction of the recombinant corn, the protein had long been known to be toxic to a number of pestiferous insects, including the monarch caterpillar, and it had been successfully used as an environmentally friendly insecticide for several years. The benefit of the expression of this protein by corn plants is a reduction in the amount of insecticide that farmers must apply to their crops. Unfortunately, seeds containing genes for recombinant proteins can cause unintentional spread of recombinant genes or exposure of non-target organisms to new toxic compounds in the environment.

The now-famous Bt corn controversy started with a laboratory study by Losey et al . (1999) in which the mortality of monarch larvae was reportedly higher when fed with milkweed (their natural food supply) covered in pollen from transgenic corn than when fed milkweed covered with pollen from regular corn. The report by Losey et al . was followed by another publication (Jesse & Obrycki, 2000) suggesting that natural levels of Bt corn pollen in the field were harmful to monarchs.

Debate ensued when scientists from other laboratories disputed the study, citing the extremely high concentration of pollen used in the laboratory study as unrealistic, and concluding that migratory patterns of monarchs do not place them in the vicinity of corn during the time it sheds pollen. For the next two years, six teams of researchers from government, academia, and industry investigated the issue and concluded that the risk of Bt corn to monarchs was "very low" (Sears et al ., 2001), providing the basis for the U.S. Environmental Protection Agency to approve Bt corn for an additional seven years.

Unintended Economic Consequences

Another concern associated with GMOs is that private companies will claim ownership of the organisms they create and not share them at a reasonable cost with the public. If these claims are correct, it is argued that use of genetically modified crops will hurt the economy and environment, because monoculture practices by large-scale farm production centers (who can afford the costly seeds) will dominate over the diversity contributed by small farmers who can't afford the technology. However, a recent meta-analysis of 15 studies reveals that, on average, two-thirds of the benefits of first-generation genetically modified crops are shared downstream, whereas only one-third accrues upstream (Demont et al ., 2007). These benefit shares are exhibited in both industrial and developing countries. Therefore, the argument that private companies will not share ownership of GMOs is not supported by evidence from first-generation genetically modified crops.

GMOs and the General Public: Philosophical and Religious Concerns

In a 2007 survey of 1,000 American adults conducted by the International Food Information Council (IFIC), 33% of respondents believed that biotech food products would benefit them or their families, but 23% of respondents did not know biotech foods had already reached the market. In addition, only 5% of those polled said they would take action by altering their purchasing habits as a result of concerns associated with using biotech products.

According to the Food and Agriculture Organization of the United Nations, public acceptance trends in Europe and Asia are mixed depending on the country and current mood at the time of the survey (Hoban, 2004). Attitudes toward cloning, biotechnology, and genetically modified products differ depending upon people's level of education and interpretations of what each of these terms mean. Support varies for different types of biotechnology; however, it is consistently lower when animals are mentioned.

Furthermore, even if the technologies are shared fairly, there are people who would still resist consumable GMOs, even with thorough testing for safety, because of personal or religious beliefs. The ethical issues surrounding GMOs include debate over our right to "play God," as well as the introduction of foreign material into foods that are abstained from for religious reasons. Some people believe that tampering with nature is intrinsically wrong, and others maintain that inserting plant genes in animals, or vice versa, is immoral. When it comes to genetically modified foods, those who feel strongly that the development of GMOs is against nature or religion have called for clear labeling rules so they can make informed selections when choosing which items to purchase. Respect for consumer choice and assumed risk is as important as having safeguards to prevent mixing of genetically modified products with non-genetically modified foods. In order to determine the requirements for such safeguards, there must be a definitive assessment of what constitutes a GMO and universal agreement on how products should be labeled.

These issues are increasingly important to consider as the number of GMOs continues to increase due to improved laboratory techniques and tools for sequencing whole genomes, better processes for cloning and transferring genes, and improved understanding of gene expression systems. Thus, legislative practices that regulate this research have to keep pace. Prior to permitting commercial use of GMOs, governments perform risk assessments to determine the possible consequences of their use, but difficulties in estimating the impact of commercial GMO use makes regulation of these organisms a challenge.

History of International Regulations for GMO Research and Development

In 1971, the first debate over the risks to humans of exposure to GMOs began when a common intestinal microorganism, E. coli , was infected with DNA from a tumor-inducing virus (Devos et al ., 2007). Initially, safety issues were a concern to individuals working in laboratories with GMOs, as well as nearby residents. However, later debate arose over concerns that recombinant organisms might be used as weapons. The growing debate, initially restricted to scientists, eventually spread to the public, and in 1974, the National Institutes of Health (NIH) established the Recombinant DNA Advisory Committee to begin to address some of these issues.

In the 1980s, when deliberate releases of GMOs to the environment were beginning to occur, the U.S. had very few regulations in place. Adherence to the guidelines provided by the NIH was voluntary for industry. Also during the 1980s, the use of transgenic plants was becoming a valuable endeavor for production of new pharmaceuticals, and individual companies, institutions, and whole countries were beginning to view biotechnology as a lucrative means of making money (Devos et al ., 2007). Worldwide commercialization of biotech products sparked new debate over the patentability of living organisms, the adverse effects of exposure to recombinant proteins, confidentiality issues, the morality and credibility of scientists, the role of government in regulating science, and other issues. In the U.S., the Congressional Office of Technology Assessment initiatives were developed, and they were eventually adopted worldwide as a top-down approach to advising policymakers by forecasting the societal impacts of GMOs.

Then, in 1986, a publication by the Organization for Economic Cooperation and Development (OECD), called "Recombinant DNA Safety Considerations," became the first intergovernmental document to address issues surrounding the use of GMOs. This document recommended that risk assessments be performed on a case-by-case basis. Since then, the case-by-case approach to risk assessment for genetically modified products has been widely accepted; however, the U.S. has generally taken a product-based approach to assessment, whereas the European approach is more process based (Devos et al ., 2007). Although in the past, thorough regulation was lacking in many countries, governments worldwide are now meeting the demands of the public and implementing stricter testing and labeling requirements for genetically modified crops.

Increased Research and Improved Safety Go Hand in Hand

Proponents of the use of GMOs believe that, with adequate research, these organisms can be safely commercialized. There are many experimental variations for expression and control of engineered genes that can be applied to minimize potential risks. Some of these practices are already necessary as a result of new legislation, such as avoiding superfluous DNA transfer (vector sequences) and replacing selectable marker genes commonly used in the lab (antibiotic resistance) with innocuous plant-derived markers (Ma et al ., 2003). Issues such as the risk of vaccine-expressing plants being mixed in with normal foodstuffs might be overcome by having built-in identification factors, such as pigmentation, that facilitate monitoring and separation of genetically modified products from non-GMOs. Other built-in control techniques include having inducible promoters (e.g., induced by stress, chemicals, etc.), geographic isolation, using male-sterile plants, and separate growing seasons.

GMOs benefit mankind when used for purposes such as increasing the availability and quality of food and medical care, and contributing to a cleaner environment. If used wisely, they could result in an improved economy without doing more harm than good, and they could also make the most of their potential to alleviate hunger and disease worldwide. However, the full potential of GMOs cannot be realized without due diligence and thorough attention to the risks associated with each new GMO on a case-by-case basis.

References and Recommended Reading

Barta, A., et al . The expression of a nopaline synthase-human growth hormone chimaeric gene in transformed tobacco and sunflower callus tissue. Plant Molecular Biology 6 , 347–357 (1986)

Beyer, P., et al . Golden rice: Introducing the β-carotene biosynthesis pathway into rice endosperm by genetic engineering to defeat vitamin A deficiency. Journal of Nutrition 132 , 506S–510S (2002)

Demont, M., et al . GM crops in Europe: How much value and for whom? EuroChoices 6 , 46–53 (2007)

Devlin, R., et al . Extraordinary salmon growth. Nature 371 , 209–210 (1994) ( link to article )

Devos, Y., et al . Ethics in the societal debate on genetically modified organisms: A (re)quest for sense and sensibility. Journal of Agricultural and Environmental Ethics 21 , 29–61 (2007) doi:10.1007/s10806-007-9057-6

Guerrero-Andrade, O., et al . Expression of the Newcastle disease virus fusion protein in transgenic maize and immunological studies. Transgenic Research 15 , 455–463(2006) doi:10.1007/s11248-006-0017-0

Hiatt, A., et al . Production of antibodies in transgenic plants. Nature 342 , 76–79 (1989) ( link to article )

Hoban, T. Public attitudes towards agricultural biotechnology. ESA working papers nos. 4-9. Agricultural and Development Economics Division, Food and Agricultural Organization of the United Nations (2004)

Jesse, H., & Obrycki, J. Field deposition of Bt transgenic corn pollen: Lethal effects on the monarch butterfly. Oecologia 125 , 241–248 (2000)

Losey, J., et al . Transgenic pollen harms monarch larvae. Nature 399 , 214 (1999) doi:10.1038/20338 ( link to article )

Ma, J., et al . The production of recombinant pharmaceutical proteins in plants. Nature Reviews Genetics 4 , 794–805 (2003) doi:10.1038/nrg1177 ( link to article )

Muir, W., & Howard, R. Possible ecological risks of transgenic organism release when transgenes affect mating success: Sexual selection and the Trojan gene hypothesis. Proceedings of the National Academy of Sciences 96 , 13853–13856 (1999)

Sears, M., et al . Impact of Bt corn on monarch butterfly populations: A risk assessment. Proceedings of the National Academy of Sciences 98 , 11937–11942 (2001)

Spurgeon, D. Call for tighter controls on transgenic foods. Nature 409 , 749 (2001) ( link to article )

Takeda, S., & Matsuoka, M. Genetic approaches to crop improvement: Responding to environmental and population changes. Nature Reviews Genetics 9 , 444–457 (2008) doi:10.1038/nrg2342 ( link to article )

United States Department of Energy, Office of Biological and Environmental Research, Human Genome Program. Human Genome Project information: Genetically modified foods and organisms, (2007)

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National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies; Board on Agriculture and Natural Resources; Committee on Genetically Engineered Crops: Past Experience and Future Prospects. Genetically Engineered Crops: Experiences and Prospects. Washington (DC): National Academies Press (US); 2016 May 17.

Genetically Engineered Crops: Experiences and Prospects.

• Hardcopy Version at National Academies Press

5 Human Health Effects of Genetically Engineered Crops

In this chapter, the committee examines the evidence that substantiates or negates specific hypotheses and claims about the health risks and benefits associated with foods derived from genetically engineered (GE) crops. There are many reviews and official statements about the safety of foods from GE crops (for example, see Box 5-1 ), but to conduct a fresh examination of the evidence, the committee read through a large number of articles with original data so that the rigor of the evidence could be assessed.

Sample of Statements About the Safety of Genetically Engineered Crops and Food Derived from Genetically Engineered Crops.

Some of the evidence available to the committee came from documents that were part of the U.S. regulatory process for GE crops conducted by the U.S. Environmental Protection Agency (EPA), the U.S. Department of Agriculture (USDA), and the U.S. Food and Drug Administration (FDA). Other evidence came from studies published by regulatory agencies in other countries or by companies, nongovernmental organizations (NGOs), and academic institutions. The committee also sought evidence from the public and from the speakers at its public meetings and webinars. 1

The committee thinks that it is important to make clear that there are limits to what can be known about the health effects of any food, whether non-GE or GE. If the question asked is “Is it likely that eating this food today will make me sick tomorrow?” researchers have methods of getting quantitative answers. However, if the question is “Is it likely that eating this food for many years will make me live one or a few years less than if I never eat it?” the answer will be much less definitive. Researchers can provide probabilistic predictions that are based on the available information about the chemical composition of the food, epidemiological data, genetic variability across populations, and studies conducted with animals, but absolute answers are rarely available. Furthermore, most current toxicity studies are based on testing individual chemicals rather than chemical mixtures or whole foods because testing of the diverse mixtures of chemicals experienced by humans is so challenging ( Feron and Groten, 2002 ; NRC, 2007 ; Boobis et al., 2008 ; Hernández et al., 2013 ).

With regard to the issue of uncertainty, it is useful to note that many of the favorable institutional statements about safety of foods from GE crops in Box 5-1 contain caveats, for example: “no overt consequences,” “no effects on human health have been shown,” “are not per se more risky,” and “are not likely to present risks for human health.” Scientific research can answer many questions, but absolute safety of eating specific foods and the safety of other human activities is uncertain.

The review in this chapter begins with an examination of what is known about the safety of foods from non-GE plants and how they are used as counterparts to those from GE crops in food-safety testing. U.S. food-safety regulatory testing for GE products and GE food-safety studies conducted outside the agency structure are then assessed. A variety of hypothesized health risks posed by and benefits of GE crops are examined, and the chapter concludes with a short discussion of the challenges that society will face in assessing the safety of GE foods that are likely to be developed with emerging genetic-engineering technologies.

• COMPARING GENETICALLY ENGINEERED CROPS WITH THEIR COUNTERPARTS

An oft-cited risk of GE crops is that the genetic-engineering process could cause “unnatural” changes in a plant's own naturally occurring proteins or metabolic pathways and result in the unexpected production of toxins or allergens in food ( Fagan et al., 2014 ). Because analysis of risks of the product of the introduced transgene itself is required during risk assessment, the argument for unpredicted toxic chemicals in GE foods is based on the assumption that a plant's endogenous metabolism is more likely to be disrupted through introduction of new genetic elements via genetic engineering than via conventional breeding or normal environmental stresses on the plant. The review below begins by discussing natural chemical constituents of plants in the context of food safety to provide a background on what the natural plant toxins are and how they vary in non-GE plants. The review then goes on to explain the premise used by regulatory agencies to compare GE crops with their non-GE counterparts.

Endogenous Toxins in Plants

Most chemicals of primary metabolism (for example, those involved in the formation of carbohydrates, proteins, fats, and nucleic acids) are shared between animals and plants and are therefore unlikely to be toxic. Perceived risks associated with alterations of plant compounds arise mainly from alterations of plant-specific molecules, popularly known as plant natural products and technically named secondary metabolites. Collectively, there are more than 200,000 secondary metabolites in the plant kingdom ( Springob and Kutchan, 2009 ). Crop species vary in the number of secondary metabolites that they produce. For example, potato ( Solanum tuberosum ) is known for its high diversity of secondary metabolites and can have more than 20 sesquiterpenes (a single group of related compounds), some of which are thought to confer resistance to diseases ( Kuc, 1982 ). The concentrations of these secondary metabolites within some tissues in a particular plant species may vary from high—for example, chlorogenic acids alone make up about 12 percent of the dry matter of green coffee beans ( Ferruzzi, 2010 )—to trace amounts (many minor saponins in legumes) and may be associated with particular stages of plant development (some found only in seeds) or may increase in response to external stimuli, such as pathogen or herbivore attack, drought, or altered mineral nutrition ( Small, 1996 ; Pecetti et al., 2006 ; Nakabayashi et al., 2014 ). Many secondary metabolites function as protective agents, for example, by absorbing damaging ultraviolet radiation ( Treutter, 2006 ), acting as antinutrients ( Small, 1996 ), or killing or halting insects and pathogens that damage crops ( Dixon, 2001 ). Plant secondary metabolites that protect against pathogen attack have been classified as either phytoanticipins (if they exist in a preformed state in a plant before exposure to a pathogen) or phytoalexins (if their synthesis and accumulation are triggered by pathogen attack) ( VanEtten et al., 1994 ; Ahuja et al., 2012 ). The toxic properties of some plant compounds are understood, but most of these compounds have not been studied. Some secondary metabolites and other products (such as proteins and peptides) in commonly consumed plant materials can be toxic to humans when consumed in large amounts, and examples are listed below:

• Steroidal glycoalkaloids in green potato skin, which can cause gastrointestinal discomfort or, more severely, vomiting and diarrhea.
• Oxalic acid in rhubarb, which can cause symptoms ranging from breathing difficulty to coma.
• Gossypol in cottonseed oil and cake, which can cause respiratory distress, anorexia, impairment of reproductive systems, and interference with immune function in monogastric animals.
• Nonprotein amino acid canavanine in alfalfa sprouts, which can be neurotoxic.
• Hemolytic triterpene saponins in many legume species, which can increase the permeability of red blood cell membranes.
• Cyanogenic glycosides in almonds and cassava, which can cause cyanide poisoning.
• Phototoxic psoralens in celery, which are activated by ultraviolet sunlight and can cause dermatitis and sunburn and increase the risk of skin cancer.

Friedman (2006) provided information that demonstrated that some glycoalkaloids in potato can have both harmful and beneficial effects. The Food and Agriculture Organization has recognized that foods often contain naturally occurring food toxins or antinutrients but that at naturally occurring concentrations in common diets they can be safely consumed by humans ( Novak and Haslberger, 2000 ; OECD, 2000 ). The health risks associated with some secondary metabolites in common foodstuffs are generally well understood, and the plants are either harvested at times when the concentrations of the compounds are low, the tissues with the highest concentrations of toxins are discarded, or, as in the case of cassava ( Manihot esculenta ), the food is prepared with special methods to remove the toxic compounds. In other cases, food preparation may be the cause of the presence of a toxic compound (for example, the formation of the probable carcinogen acrylamide when potatoes are fried at high temperatures or when bread is toasted). Plant breeders have generally screened for toxins that are typical of the plant group from which a crop was domesticated and have excluded plants that have high concentrations of the compounds.

Unintended changes in the concentrations of secondary metabolites can result from conventional breeding ( Sinden and Webb, 1972 ; Hellenas et al., 1995 ). In some cases, conventionally bred varieties have been taken off the market because of unusually high concentrations of a toxic compound, as in the case of a Swedish potato variety that was banned from sale in the 1980s because of high concentrations of glycoalkaloids ( Hellenas et al., 1995 ).

Rather than being a cause of worry, many secondary metabolites are perceived as having potential health benefits for humans and are consumed in increasingly large quantities ( Murthy et al., 2015 ). Examples include the isoflavone phytoestrogens found in a number of leguminous plants, such as soybean ( Glycine max ) and clover ( Trifolium spp.), which have been ascribed beneficial activities, including chemoprevention of breast and prostate cancers, cardiovascular disease, and post-menopausal ailments ( Dixon, 2004 ; Patisaul and Jefferson, 2010 ). Also, various perceived antioxidants, such as anthocyanins ( Martin et al., 2013 ), and some saponins may have anticancer activity ( Joshi et al., 2002 ). There is, however, disagreement as to whether many of the compounds are beneficial or toxic at the concentrations consumed in herbal medicines or dietary supplements (see, for example, Patisaul and Jefferson, 2010 ).

FINDING: Crop plants naturally produce an array of chemicals that protect against herbivores and pathogens. Some of these chemicals can be toxic to humans when consumed in large amounts.

Substantial Equivalence of Genetically Engineered and Non–Genetically Engineered Crops

A major question addressed in the regulation of GE crops is whether the concentrations of the toxic secondary metabolites are affected by genetic engineering. In addition to the plant toxins, nutrients, introduced genes, and proteins and their metabolic products in specific GE crops are assessed with a comparative approach that is generally encompassed by the concept of substantial equivalence.

The concept of substantial equivalence has a long history in safety testing of GE foods. The term and concept were “borrowed from the [U.S. FDA's] definition of a class of new medical devices that do not differ materially from their predecessors, and thus, do not raise new regulatory concerns” ( Miller, 1999:1042 ). No simple definition of substantial equivalence is found in the regulatory literature on GE foods. In 1993, the Organisation for Economic Co-operation and Development (OECD) explained that the “concept of substantial equivalence embodies the idea that existing organisms used as food, or as a source of food, can be used as the basis for comparison when assessing the safety of human consumption of a food or food component that has been modified or is new” ( OECD, 1993:14 ).

The Codex Alimentarius Commission's Guideline for the Conduct of Food Safety Assessment of Foods Derived from Recombinant-DNA Plants is careful to state that “the concept of substantial equivalence is a key step in the safety assessment process. However, it is not a safety assessment in itself; rather it represents the starting point which is used to structure the safety assessment of a new food relative to its conventional counterpart” ( CAC, 2003:2 ). The Codex guideline also makes clear that a safety assessment of a new food based on the concept of substantial equivalence “does not imply absolute safety of the new product; rather, it focuses on assessing the safety of any identified differences so that the safety of the new product can be considered relative to its conventional counterpart” ( CAC, 2003:2 ). The OECD (2006) came to a similar conclusion. Conflict among stakeholders often comes into play during the determination of what constitutes evidence of differences from substantial equivalence sufficient to justify a detailed food-safety assessment.

The Codex Alimentarius Commission concluded that the concept of substantial equivalence “aids in the identification of potential safety and nutritional issues and is considered the most appropriate strategy to date for safety assessment of foods derived from recombinant-DNA plants” ( CAC, 2003:2 ). Despite some criticism of the substantial-equivalence concept itself (for example, Millstone et al., 1999 ) and operational problems (for example, Novak and Haslberger, 2000 ), it remains the cornerstone for GE food-safety assessment by regulatory agencies. The present committee examined its use in practice and its empirical limitations.

The precautionary principle, which is described in more detail in Chapter 9 (see Box 9-2 ) is a deliberative principle related to the regulation of health, safety, and the environment and typically involves taking measures to avoid uncertain risks. The precautionary principle has been interpreted in a number of ways, but it is not necessarily incompatible with use of the concept of substantial equivalence. In the case of foods, including GE foods, it can be reasonably argued that even a small adverse chronic effect should be guarded against, given that billions of people could be consuming the foods. However, the degree of precaution taken in the face of uncertainty is a policy decision that varies among countries and according to the specific uncertainty being considered. For example, many European countries and the European Union (EU) as a whole generally take a more precautionary approach with GE foods and climate change whereas the United States has historically taken a more precautionary approach with tobacco products and ozone depletion ( Wiener et al., 2011 ). The reader is directed to Chapter 9 for further discussion of how different regulatory frameworks address uncertainty in the safety of GE foods.

Some differences between a GE food and its non-GE counterpart are intentional and identifiable (for example, the presence of a Bt toxin in maize kernels) or are due to practices directly associated with the use of the GE crops (for example, increased use of glyphosate). Some of the risks posed by the intended changes can be anticipated on the basis of the physiological and biochemical characteristics of the engineered change. There are often established protocols for assessing such risks, especially when a change involves exposure to a known toxin. However, other risks have been hypothesized for GE crops because previous uses of a trait (for example, Bt as an insecticidal spray) did not have consumption of the GE plant products as the route of exposure. New routes of exposure could result in unanticipated effects.

In contrast with such intended differences, some potential differences between GE crops and their non-GE counterparts are unintentional and can be difficult to anticipate and discern ( NRC, 2004 ). Two general sources of unintended differences could affect food safety:

• Unintended effects of the targeted genetic changes on other characteristics of the food (for example, the intended presence of or increase in one compound in plant cells could result in changes in plant metabolism that affect the abundance of other compounds).
• Unintended effects associated with the genetic-engineering process (for example, DNA changes resulting from plant tissue culture).

Much of the concern voiced by some citizens and scientists about the safety of GE foods is focused on potential risks posed by unintended differences. Some of the biochemical and animal testing done by or for government agencies is aimed at assessing the toxicity of such unintended differences, but what is adequate and appropriate testing for assessing specific toxicities is often difficult to determine. In some cases, the unintended effects are somewhat predictable or can be determined; in such cases, tests can be designed. In other cases, the change or risk could be something that has not even been considered, so the only effective testing is of the whole food itself. As discussed in Chapter 6 , there is a tradeoff between costs of such testing and societal benefits of reduction in risks.

The approach of comparing new varieties to existing varieties is just as applicable to crops developed by conventional plant breeding as it is to GE crops (see Chapter 9 ). The discussion above on endogenous toxins (see section “Endogenous Toxins in Plants”) shows that such crops pose some risks. The 2000 National Research Council report Genetically Modified Pest-Protected Plants found that “there appears to be no strict dichotomy between the risks to health and the environment that might be posed by conventional and transgenic pest-protected plants” ( NRC, 2000:4 ). Similarly, the 2004 National Research Council report Safety of Genetically Engineered Foods found that all forms of conventional breeding and genetic engineering may have unintended effects and that the probability of unintended effects of genetic engineering falls within the range of unintended effects of diverse conventional-breeding methods. The 2002 National Research Council report Environmental Effects of Transgenic Plants found that “the transgenic process presents no new categories of risk compared to conventional methods of crop improvement but that specific traits introduced by both approaches can pose unique risks” ( NRC, 2002:5 ). That finding remains valid with respect to food safety and supports the conclusion that novel varieties derived from conventional-breeding methods could be assessed with the substantial-equivalence concept.

FINDING: The concept of substantial equivalence can aid in the identification of potential safety and nutritional issues related to intended and unintended changes in GE crops and conventionally bred crops.

FINDING: Conventional breeding and genetic engineering can cause unintended changes in the presence and concentrations of secondary metabolites.

• OVERVIEW OF U.S. REGULATORY TESTING OF RISKS TO HUMAN HEALTH

Although the committee agrees that crops developed through conventional breeding could result in food-safety risks, its statement of task focuses on GE crops. Furthermore, there have been claims and counterclaims about the relative safety of GE crops and their associated technologies compared with conventionally bred crops and their associated technologies. Therefore, the remainder of this chapter examines possible risks and benefits associated with GE crops and assesses the methods used to test them in and beyond government regulatory systems.

Whether testing is done for regulatory purposes or beyond the regulatory realm, it typically involves three categories of testing: acute or chronic animal toxicity tests, chemical compositional analysis, and allergenicity testing or prediction. Although the precision, transparency, specific procedures, and interpretation of results vary among countries, criticisms about the adequacy of testing are not so much country-specific as they are method- and category-specific. For example, there may be arguments about whether a 90-day whole-food animal test is more appropriate than a 28-day test, but the bigger issue is about whether whole-food testing is appropriate. The committee uses a description of the U.S. testing methods as an example, but it mostly examines the criticism of food-safety testing more broadly.

The structure of the U.S. regulatory process for GE crops based on the Coordinated Framework for the Regulation of Biotechnology is briefly reviewed in Chapter 3 and is examined in more detail in Chapter 9 . The focus in this chapter is on the testing itself. The present section provides insight into U.S. procedures by describing the risk-testing methods used for two examples of traits in commercialized GE crops: Bt toxins and crop resistance to the herbicides glyphosate and 2,4-D.

Regulatory Testing of Crops Containing Bt Toxins

EPA considers plant-produced Bt toxins to be “plant-incorporated protectants,” a class of products generally defined as “a pesticidal substance that is intended to be produced and used in a living plant, or in the produce thereof, and the genetic material necessary for the production of that pesticidal substance” (40 CFR §174.3). EPA specifically exempts plant-incorporated protectants whose genetic material codes for a pesticidal substance that is derived from plants that are sexually compatible. Bt toxin genes are not exempted because they come from bacteria (see Chapter 9 for regulatory details).

For Bt toxins produced by GE crops, EPA took into consideration that there was already toxicity testing of Bt toxins in microbial pesticides and that the toxins were proteins that, if toxic, typically show almost immediate toxicity at low doses ( EPA, 2001a ; also see Box 5-2 ). The pesticidal safety tests mostly involved acute toxicity testing in mice and digestibility studies in simulated gastric fluids because one characteristic of food allergens is that they are not rapidly digested by such fluids.

Cry1F Testing by the U.S. Environmental Protection Agency.

Box 5-2 provides a verbatim example of the procedures used for testing as reported in EPA fact sheets for the Cry1F Bt toxin so that readers can see what is involved in the testing. The actual research is not typically done by EPA itself. The registrant is usually responsible for testing. Results of the tests of Cry1F show no clinical signs of any toxicity even when Cry1F protein was fed at 576 mg/kg body weight, which would be the equivalent of about ¼ cup of pure Cry1F for a 90.7-kilogram (200-pound) person. Another part of the testing described in Box 5-2 is allergenicity testing. Concerns about the EPA testing methods are discussed in sections below on each category of testing.

Regulatory Testing of Crops Resistant to Glyphosate and 2,4-D and of the New Uses of the Herbicides Themselves

The regulatory actions taken for herbicide-resistant (HR) crops are different from regulatory actions taken to assess Bt crops. With Bt crops, regulatory actions are related to the crop itself. With HR crops, there are regulatory processes for the plant itself and separate regulatory processes for the new kind of exposure that can accompany spraying of a herbicide on a crop or on a growth stage of a crop that has never been sprayed prior to availability of the GE variety.

EPA governs the registration of herbicides such as glyphosate and 2,4-D. Both glyphosate and 2,4-D were registered well before the commercialization of GE crops. However, EPA has authority to re-examine herbicides if their uses or exposure characteristics change.

A good example of such re-examination was the 2014 EPA registration of the Dow AgroSciences Enlist Duo® herbicide, which contains both glyphosate and 2,4-D for use on GE maize ( Zea mays ) and soybean. Because the glyphosate component of Enlist Duo had already been in use on GE maize and soybean, EPA did not conduct further testing of glyphosate alone. However, 2,4-D was registered previously only for applications to maize up to 20 centimeters tall and for preplant applications to soybean. The proposed use of 2,4-D on GE crops was expected to change use patterns and exposure and thereby triggered a safety assessment of the new use 2,4-D. Additionally, EPA compared the toxicity of the formulation that contained both herbicides to the toxicity of the individual herbicides and concluded the formulation did not show greater toxicity or risk compared to either herbicide alone.

In the human health risk assessment portion of the EPA Enlist Duo registration document, the following tests and results with 2,4-D were considered ( EPA, 2014a ):

• An acute dietary test in rats that found a lowest observed-adverse-effect level (LOAEL) of 225 mg/kg (about 1 ounce per 200-pound person).
• A chronic-dietary-endpoint, extended one-generation reproduction toxicity study in rats that found a LOAEL of 46.7 mg/kg-day in females and higher in males.
• Inhalation tests involving data from a 28-day inhalation toxicity study in rats that found a LOAEL of 0.05 mg/L-day.
• Dermal tests that showed no dermal or systemic toxicity after repeated applications to rabbits at the limit dose of 1000 mg/kg-day.
• Reviews of epidemiological and animal studies, which did not support a linkage between human cancer and 2,4-D exposure.

Analysis of the results of those tests and agronomic and environmental assessments resulted in the product's registration.

EPA received over 400,000 comments in response to the initial proposal to register the new use of 2,4-D. Some of the concerns submitted to EPA were similar to ones some members of the public expressed in public comments to the committee, including questions about whether EPA had considered toxicity of only the active ingredient or of the formulated herbicide and whether it had tested for synergistic effects of 2,4-D and glyphosate. EPA (2014b:7) responded that

acute oral, dermal, and inhalation data, skin and eye irritation data, and skin sensitization data are available for the 2,4-D choline salt and glyphosate formulation for comparison with the 2,4-D parent compound and glyphosate parent compound data, and these test results show similar profiles. The mixture does not show a greater toxicity compared to either parent compound alone. Although no longer duration toxicity studies are available, toxic effects would not be expected as the maximum allowed 2,4-D exposure is at least 100-fold below levels where toxicity to individual chemicals might occur, and exposure to people is far below even that level.

The committee did not have access to the actual data from the registrant. 2

EPA does not regulate the commercialization of the GE herbicide-resistant crops themselves. That is the role of USDA's Animal and Plant Health Inspection Service (APHIS) under the Plant Protection Act. Under its statutory authority, APHIS controls and prevents the spread of plant pests (see Box 3-5 ). On the basis of a plant-pest risk assessment (USDA–APHIS, 2014a), APHIS concluded that Enlist™ GE herbicide-resistant maize and soybean engineered to be treated with the Enlist Duo herbicide (containing glyphosate and 2,4-D) were unlikely to become plant pests and deregulated them on September 18, 2014 (USDA–APHIS, 2014b). In its document on the decision to deregulate Enlist GE herbicide-resistant maize and soybean (USDA–APHIS, 2014a:ii), APHIS states a general policy that “if APHIS concludes that the GE organism is unlikely to pose a plant pest risk, APHIS must then issue a regulatory determination of nonregulated status, since the agency does not have regulatory authority to regulate organisms that are not plant pests. When a determination of nonregulated status has been issued, the GE organism may be introduced into the environment without APHIS' regulatory oversight.”

FDA did not identify any safety or regulatory issues in its consultation with Dow AgroSciences on the Enlist maize and soybean varieties ( FDA, 2013 ). FDA also explained the basis of Dow's conclusion that Enlist soybean is not “materially different in composition” from other soybean varieties ( FDA, 2013 ):

Dow reports the results of compositional analysis for 62 components in soybean grain, including crude protein, crude fat, ash, moisture, carbohydrates, [acid detergent fiber] ADF, [neutral detergent fiber] NDF, total dietary fiber (TDF), lectin, phytic acid, raffinose, stachyose, trypsin inhibitor, soy isoflavones (i.e., total daidzein, total genistein, total glycitein), minerals, amino acids, fatty acids, and vitamins. No statistically significant differences in the overall treatment effect and the paired contrasts between each of the DAS-44406-6 soybean treatment groups and the control were observed for 29 of the components. A statistically significant difference in the overall treatment effect was observed for 16 components (crude protein, carbohydrates (by difference), NDF, calcium, potassium, cystine, palmitic acid, oleic acid, linoleic acid, linolenic acid, behenic acid, folic acid, γ-tocopherol, total tocopherol, lectin, and trypsin inhibitor). However, differences between the control and the DAS-44406-6 treatment groups were small in magnitude. Differences between DAS-44406-6 soybean and the control were considered not biologically relevant because the mean values were either within the ranges generated using the reference lines, consistent with the ranges of values in the published literature, or both.

FINDING: U.S. regulatory assessment of GE herbicide-resistant crops is conducted by USDA, and by FDA when the crop can be consumed, while the herbicides are assessed by EPA when there are new potential exposures.

FINDING: When mixtures of herbicides are used on a new GE crop, EPA assesses the interaction of the mixture as compared to the individual herbicidal compounds.

Technical Assessment of Human Health Risks Posed by Genetically Engineered Crops

As explained in Chapter 2 , the development and use of GE crops is governed by more than national and regional regulatory standards. In the cases of the GE crops commercially available in the United States and some other countries in 2015, inputs from many public and private institutions regarding their specific concerns have influenced the type and extent of GE crop food-safety tests conducted by companies, agencies, and other researchers. Many stakeholders have criticized the testing used by U.S. and other national regulatory agencies for lacking rigor (for example, Hilbeck et al., 2015 ). Researchers in companies, NGOs, and universities have sometimes conducted more extensive safety tests than are required by national agencies or have reanalyzed existing data, as described below. All testing as of 2015 fell into three categories: animal testing, compositional analysis, and allergenicity testing and prediction.

Animal Testing

Short-term and long-term rodent testing with compounds and whole foods.

One common criticism of the animal testing conducted by or for regulatory agencies in the United States and elsewhere is related to its short duration (for example, Séralini et al., 2014 ; Smith, 2014 ). Indeed, there is a range in the duration and doses within the test protocols used by regulatory agencies that depends in part on the product. Doses for subchronic and chronic toxicity studies are such that the lowest dose (exposure level), which is many times higher than expected for human exposure, is set to ensure that it does not elicit acute adverse effects that would interfere with examining the potential chronic-effect endpoints. As can be seen in the discussion above, EPA conducted an extended one-generation reproduction toxicity study in male and female rats in its assessment of 2,4-D, and it relied on previous long-term studies for the assessment of cancer risk associated with it. For assessment of the Bt toxin Cry1F and for the bacterially derived proteins in 2,4-D-resistant maize and soybean, company testing submitted to EPA, FDA, and USDA relied on acute toxicity testing. In all the cases above, the experiments were conducted by adding large amounts of a single test chemical to an animal's diet. Tests with high concentrations of a chemical are typical of EPA testing protocols for pesticides.

What is different between GE crop evaluation and that of general agricultural chemicals is the use of “whole food” tests. These tests are aimed at assessing potential hazards due to the combined intentional and unintentional changes that might have been caused by the genetic engineering of the crop. In such tests, it is not possible to use concentrations higher than what is in the crop itself because potential unintended effects are not typically known. Thus, it is impossible for a researcher to know what compounds should be increased in concentration in a fabricated diet, and the only way to assess such unintended effects is to feed the actual GE crop to test animals. For testing GE maize, soybean, and rice ( Oryza sativa ), 3 flour from kernels or seed is added to an animal's diet and constitutes between about 10–60 percent of the diet. The high percentages can be used because the crop products are nutritious for the animal. In the case of whole foods that are not typically part of a rodent's diet, whether GE or non-GE, it is impossible to achieve very high concentrations of the test food because it would cause nutritional imbalance. The whole-food tests done for regulatory agencies are generally conducted for 28 or 90 days with rats, but some researchers have run tests for multiple generations.

The utility of the whole-food tests has been questioned by a number of government agencies and by industry and academic researchers (for example, Ricroch et al., 2014 ), and they are not an automatic part of the regulatory requirements of most countries that have specific GE food-testing requirements ( CAC, 2008 ; Bartholomaeus et al., 2013 ). However, in its 2010 report A Decade of EU-Funded GMO Research (2001–2010) , the European Directorate-General for Research and Innovation concluded that “the data from a well-designed 90-day rodent feeding study, together with data covering the gene insert, the compositional analysis, and the toxicity of the novel gene product, form the optimal basis for a comparative assessment of the safety of [genetically engineered] food and its conventional counterpart in the pre-market situation” ( EC, 2010a:157 ). The European Food Safety Authority (EFSA) developed principles and guidance for establishing protocols for 90-day whole-food studies in rodents at the European Commission's request ( EFSA, 2011b ), and 90-day, whole-food studies were made mandatory by the European Commission ( EC, 2013 ). Most studies reported in the peer-reviewed literature have concluded that there was a lack of adverse effects of biological or toxicological significance (see, for example, Knudsen and Poulsen, 2007 ; MacKenzie et al., 2007 ; He et al., 2008 , 2009 ; Onose et al., 2008 ; Liu et al., 2012 ), even though some of the studies found statistically significant differences between the GE and non-GE comparator in toxicity.

The criticisms of whole-food tests come from two perspectives. One perspective is that whole-food studies cannot provide useful tests of food safety because they are not sensitive enough to detect differences (see, for example, Bartholomaeus et al., 2013 ; Kuiper et al., 2013 ; Ricroch et al., 2013a , 2014 ) and that animal testing is not needed because other types of required testing ensure safety ( Bartholomaeus et al., 2013 ; Ricroch et al., 2014 ). Ricroch et al. (2014) pointed to the costs of the 90-day tests, which they reported as being €250,000 (in 2013 money). The second perspective is that whole-food tests could be useful, but there is concern about their design and conduct or about the parties who conduct them (the companies commercializing the GE crops). That perspective is evident in Séralini et al. (2007) , Domingo and Bordonaba (2011) , Hilbeck et al. (2015) , and Krimsky (2015) . Boxes 5-3 and 5-4 describe some of the specific procedures and practices involved in doing these tests.

Common Procedures for Rodent Toxicity Studies for Safety Evaluation.

Laboratory Practices for Consistency among Studies.

The committee heard from invited speakers ( Entine, 2014 ; Jaffe, 2014 ) and members of the public who provided comments at meetings and it received a number of written public comments highlighting the work of one research group ( Séralini et al., 2012 , 2014 ) that has conducted a number of whole-food studies of GE herbicide-resistant and insect-resistant crops and of direct consumption of glyphosate. Some comments made to the committee pointed to the publications of that research group as evidence that GE crops and foods derived from GE crops were deleterious to human health; other comments questioned the robustness and accuracy of the research. The committee also heard from the lead researcher himself at one of its meetings ( Séralini, 2014 ). Because of the attention garnered by this specific research group, the committee examined the primary research paper from the group and many articles related to it ( Box 5-5 ).

Controversial Results of an Animal Feeding Study of Genetically Engineered Crops and Glyphosate.

A general question that remains for all whole-food studies using animals is, How many animals, tested for how long, are needed to assess food safety when a whole food is tested? That question is related to the question of how large an effect the tested food would have to have on the animal for it to be detected with the experiment. The statistical procedure called power analysis can answer the first question, but the committee did not find such analyses in articles related to GE crop whole-food studies. The EFSA scientific committee ( EFSA, 2011b ) provided general guidance on power analysis. Figure 5-2 , from the EFSA report, shows the relationship between the number of experimental units (cages with two animals) per treatment group and the power of an experiment in standard-deviation units. Standard deviations quantify how much the measurement of a trait or effect varies among animals that have been given the same diet. The report concluded that, if researchers follow OECD Test No. 408 of 10 males and 10 females per treatment ( OECD, 1998a ), a test should be able to detect a difference equal to about 1 standard deviation (with 90-percent confidence) unless the food has a different effect on males and females, in which case, the smallest difference that could be detected would be about 1.5 standard deviations from the experimental mean.

General statistical information on the number of experimental units needed per treatment group as a function of standardized effect size for 80-percent and 90-percent power and 5-percent significance level using a two-sided t test. SOURCE: EFSA (2011b). (more...)

Because the relationship is quite abstract for the nonstatistician, the committee examined the size of the standard deviations in a number of whole-food safety articles. It found that the sizes of the standard deviations compared with the mean value of a measured trait depended heavily on the trait being measured and on the specific research article. For example, in the Hammond et al. (2004) study, the average white blood cell count for the four treatments, each with 9 or 10 female Sprague-Dawley rats, is 6.84 10 3 /µl, and the average standard deviation is 1.89 10 3 /µl. On the basis of rough calculations, this test would have the power to discern statistically whether the GE food caused an increase in white blood cell count of about 35 percent with about 90-percent confidence. If the male white blood cell count effects and standard deviations were similar to those in females, the test could have found about a 25-percent increase.

OECD (1998a) made general recommendations, such as those used in Hammond et al. (2004) , for the number of units (cages with two animals) per treatment. Following these guidelines leads to the assumption that less than a 25-percent change in the white blood cell count was not biologically relevant. The EU Standing Committee on the Food Chain and Animal Health adopted the mandatory use of 90-day whole-food testing of GE crops, and its protocols generally follow OECD guidelines for the testing of chemicals ( EC, 2013 ).

EFSA also published a document ( EFSA, 2011c ) that focused specifically on the questions, What is statistical significance? and What is biological relevance? The accessibly written document makes clear that the two are very different and that it is important to decide how large a difference is biologically relevant before designing an experiment to test a null hypothesis of no difference. The problem in most whole-food animal studies is in determining how large a biological difference is relevant. Most of the statistically significant differences observed in the literature on the animal-testing data were around a 10- to 30-percent change, but the authors do not give detailed explanations of why they conclude that a statistically significant difference is not biologically relevant. A general statement is sometimes made that the difference is within the range for the species, but because the range of values for the species typically come from multiple laboratories, such a statement is not useful unless the laboratories, instrumentation, and health of the animals were known to be comparable.

Clearly, the European Commission relied on both expert judgment and citizen concerns in making its assessment of biological relevance of the effects of GE foods in requiring 90-day testing. It is reasonable to ask what balance of the two is the basis for this judgment. As pointed out by the 2002 National Research Council report, “risk analysis of transgenic plants must continue to fulfill two distinct roles: (1) technical support for regulatory decision making and (2) establishment and maintenance of regulatory legitimacy” ( NRC, 2002:6 ). Fulfilling the two roles can lead to different country-specific and region-specific decisions. This issue is discussed further in Chapter 9 .

One specific criticism of the 90-day whole-food studies revolves around an EU-funded project conducted by Poulsen et al. (2007) in which rice was genetically engineered to produce the kidney bean lectin, agglutinin E-form, which is known to have toxic properties. In a 90-day test, rats were fed diets of 60-percent rice with the lectin gene or 60-percent rice without the lectin gene. The researchers concluded that they did not find any meaningful differences between the two treatments. However, in a treatment in which the diets were spiked with 0.1-percent recombinant lectin (a high dose), biological effects including significant differences in weight of small intestines, stomach, and pancreas and in plasma biochemistry were found. Poulsen et al. included results from a preceding 28-day feeding study and compositional analyses of the rice diets. The criticism involves the question, If a whole-food study with a known toxin does not demonstrate effects, how can the test be considered useful? ( Bartholomaeus et al., 2013 ). If a whole-food study with an animal finds statistically significant effects, there is obviously a need for further safety testing, but when there is a negative result, there is uncertainty as to whether there is an adverse effect on health. In the specific case of lectin gene in rice, one could argue that the statistical power of the whole-food test was insufficient or that, when the toxin is in the structure of the food, it is no longer toxic so the food is safe.

Other Long-Term Studies with Rodents

In addition to the work of Séralini et al. (2012 , 2014 ), there have been other long-term rodent studies, some of which included multiple generations. Magana-Gomez and de la Barca (2009) , Domingo and Bordonaba (2011) , Snell et al. (2012) , and Ricroch et al. (2013b) reviewed the studies. Some found no statistically significant differences, but quite a few found statistically significant differences that the authors generally did not consider biologically relevant, typically without providing data on what was the normal range. In the multigeneration studies, the sire and dam are dosed via the diet before conception, and the parent generation and pups are dosed via the diet throughout the duration of the study to determine multiple generational outcomes, including growth, behavior, and phenotypic characteristics. Some studies have looked at three or four generations. For example, Kiliç and Akay (2008) conducted a three-generation rat study in which 20 percent of the diet was Bt maize or a non- Bt maize that otherwise was genetically similar. All generations of female and male rats were fed the assigned diets, and the third-generation offspring that were fed the diets were sacrificed after 3.5 months for analysis. The authors found statistical differences in kidney and liver weights and long kidney glomerular diameter between the GE and non-GE treatments but considered them not biologically relevant. Similarly, statistically significant differences were observed in amounts of globulin and total protein between the two groups. There was no presentation of standards used for judging what would be a biologically relevant difference or for what the normal range was in the measurements.

The standard deviations in measurements of the traits (that is, effects) of individual animals in a treatment in the long-term studies were similar to those of studies of shorter duration. Therefore, the power of the tests to detect statistically significant differences was in the range of 10–30 percent. The committee could not find justification for considering this statistical power sufficient. It can be argued that the number of replicates (number of units of two animals per treatment) in the studies should be substantially increased, but one argument against an increase in numbers is related to the ethics of subjecting more animals to testing ( EC, 2010b ). One could also argue that it is unethical to conduct an underpowered study. However, most if not all of the rodent studies are based on widely accepted safety evaluation protocols with fixed numbers of animals per treatment. Cultural values regarding precaution for human safety and those regarding the number of animals subjected to testing are in conflict in this case. As pointed out by Snell et al. (2012) , a close examination of the long-term and multigenerational studies reveals that some have problems with experimental design, the most common being that the GE and non-GE sources were not isogenic and were grown in different locations (or unknown locations). Those problems in design make it difficult to determine whether differences are due to the genetic-engineering process or GE trait or to other sources of variation in the nutritional quality of the crops.

In cases in which testing produces equivocal results or tests are found to lack rigor, follow-up experimentation with trusted research protocols, personnel, and publication outlets is needed to decrease uncertainty and increase the legitimacy of regulatory decisions. There is a precedent of such follow-up studies in the literature on GE crop environmental effects that could serve as a general model for follow-up food-safety testing (see Chapter 4 section “Genetically Engineered Crops, Milkweed, and Monarch Butterflies”). The USDA Biotechnology Risk Assessment Research Grants Program has enabled this approach in a few cases.

Beyond Rodent Studies

Mice and rats are typically used in toxicity studies because of their general physiological similarities to humans and their small size, but some farm animals are considered to be better models of human physiology than rodents. The best example is the pig, which is considered to be better than rodents as a model, especially with respect to nutritional evaluations ( Miller and Ullrey, 1987 ; Patterson et al., 2008 ; Litten-Brown et al., 2010 ). Porcine insulin has been used for decades to control blood sugar in patients who have childhood-onset diabetes mellitus (type I diabetes). Pig heart valves are used for human mitral valve replacement, and pig skin has been investigated as a possible donor tissue. The pig is monogastric as is the human, and its gastrointestinal tract absorbs and metabolizes nutrients (lipids and micronutrients) in the same manner as in humans.

Reviews of studies with animals fed GE foods have included studies using both rodents and farm animals ( Bartholomaeus et al., 2013 ; DeFrancesco, 2013 ; Ricroch et al., 2013a , b , 2014 ; Swiatkiewicz et al., 2014 ; Van Eenennaam and Young, 2014 ). Those animal studies have taken advantage of the fact that maize and soybean are major components of the diets of many farm animals. Some of the reported studies that used farm animals have designs similar to those of rodent studies and have variation in duration and replicates similar to that of the rodent experiments. Some of the tests were run for 28 days (for example, Brouk et al., 2011 ; Singhal et al., 2011 ), others for a long term ( Steinke et al., 2010 ) or in multiple generations ( Trabalza-Marinucci et al., 2008 ; Buzoianu et al., 2013b ).

The experiments with pigs are especially relevant. Most of them were conducted in one prolific laboratory ( Walsh et al., 2011 , 2012a , b , 2013 ; Buzoianu et al., 2012a , b , c , d , 2013a , b ). The studies range from examination of short-term growth of piglets to multigenerational studies of sows and piglets, with mixed designs having either generation or both exposed to Bt maize and non- Bt maize. Characteristics measured included food consumption and growth, assessment of organ size and health, immunological markers, and microbial communities. The authors of the studies generally concluded that Bt maize does not affect health of the pigs, but they reported a number of statistically significant differences between Bt maize treatment and control maize treatment. In one experiment ( Walsh et al., 2012a ), the weaned piglets that were fed Bt maize had lower feed-conversion efficiency during days 14–30 (P > 0.007) but no significant effect over the full span of the experiment. In another experiment ( Buzoianu et al., 2013b ), there was lower efficiency in the Bt treatment during days 71–100 (P > 0.01) but again no effect over the full span of the experiment.

In those experiments with pigs and experiments with other farm animals and rodents, there was apparently one source of the GE food and one source of the non-GE food per study, and it is generally not clear that the food sources were isogenic or grown in the same location. That makes it difficult to determine whether any statistical differences found were due to the engineered trait or to the batches of food used, which in at least some experiments varied in nutrient content and may have differed in bioactive compounds (produced in response to plant stressors), which may have a profound effect on outcomes of nutritional studies. Another issue is that many statistical tests were performed in most studies. That could result in accumulation of false-positive results ( Panchin and Tuzhikov, 2016 ). Although this is not a situation in which a stringent correction for doing multiple tests is called for ( Dunn, 1961 ), there is reason to be cautious in interpretation of statistical significance of individual results because multiple tests can lead to artifactual positive results. The issue of multiple test results is common in many fields, and one approach used in genetics is to use the initial tests for hypothesis generation with follow-up experiments that test an a priori hypothesis (for example, Belknap et al., 1996 ). If a straightforward application of Bonferonni correction is used, each animal study that measures multiple outcomes, whether for GE crops or any other potential toxicant, could require over 1,000 animals to obtain reasonable statistical power ( Dunn, 1961 ).

In addition to the literature on controlled experiments with livestock, Van Eenennaam and Young (2014) reviewed the history of livestock health and feed-conversion ratios as the U.S. livestock industry shifted from non-GE to GE feed. Producers of cattle, milk cows, pigs, chickens, and other livestock are concerned about the efficiency of conversion of animal feed into animal biomass because it affects profit margins. The data examined start as early as 1983 and run through 2011. Therefore, livestock diets shifted from all non-GE feed to mostly GE feed within the duration of the study. Van Eenennaam and Young found that, if anything, the health and feed-conversion efficiencies of livestock had increased since the introduction of GE crops but that the increase was a steady rise, most likely because of more efficient practices not associated with use of GE feed. In the studies that they reviewed, the number of animals examined was large (thousands). Of course, most livestock are slaughtered at a young age, so that data cannot address the issue of longevity directly. However, given the general relationship between general health and longevity, the data are useful.

FINDING: The current animal-testing protocols based on OECD guidelines for the testing of chemicals use small samples and have limited statistical power; therefore, they may not detect existing differences between GE and non-GE crops or may produce statistically significant results that are not biologically meaningful.

FINDING: In addition to experimental data, long-term data on the health and feed-conversion efficiency of livestock that span a period before and after introduction of GE crops show no adverse effects on these measures associated with introduction of GE feed. Such data test for correlations that are relevant to assessment of human health effects, but they do not examine cause and effect.

RECOMMENDATION: Before an animal test is conducted, it is important to justify the size of a difference between treatments in each measurement that will be considered biologically relevant.

RECOMMENDATION: A power analysis for each characteristic based on standard deviations in treatments in previous tests with the animal species should be done whenever possible to increase the probability of detecting differences that would be considered biologically relevant.

RECOMMENDATION: In cases in which early published studies produced equivocal results regarding health effects of a GE crop, followup experimentation using trusted research protocols, personnel, and publication outlets should be used to decrease uncertainty and increase the legitimacy of regulatory decisions.

RECOMMENDATION: Public funding in the United States should be provided for independent follow-up studies when equivocal results are found in reasonably designed initial or preliminary experimental tests.

Compositional Analysis

Compositional analysis of genetically engineered crops.

As part of the regulatory process of establishing substantial equivalence, GE crop developers submit data comparing the nutrient and chemical composition of their GE plant with a similar (isoline) variety of the crop. In the United States, submitting such data to FDA is voluntary, although as of 2015 this seems to always be done by developers. Developers and regulators compare key components of the GE variety with published reference guides that list the concentrations and variabilities of nutrients, antinutrients, and toxicants that occur in crops already in the food supply. 4 The section “Regulatory Testing of Crops with Resistance to Glyphosate and 2,4-D and the New Uses of the Herbicides Themselves” earlier in this chapter gives an example of the types of nutrients and chemicals that are generally measured. In the specific case of the soybean resistant to 2,4-D and glyphosate, measurements of 62 components in the soybean were submitted by Dow AgroSciences. There were statistically significant differences between the GE and comparison varieties in 16 of the 62. The differences were considered to be small and within the range of published values for other soybean varieties. They were therefore “considered not biologically relevant.” In compositional analysis, as in some of the whole-food animal testing, it is difficult to know how much of the variance and range in values for the components is due to the crop variety, the growing conditions, and the specific laboratory experimental equipment. In the United States, regulatory agencies require that the comparison be between the GE crop and its isogenic conventionally bred counterpart grown in side-by-side plots. In those cases, it is hard to attribute differences to anything but the genetic-engineering process.

FINDING: Statistically significant differences in nutrient and chemical composition have been found between GE and non-GE plants by using traditional methods of compositional analysis, but the differences have been considered to fall within the range of naturally occurring variation found in currently available non-GE crops.

Composition of Processed Genetically Engineered Foods

General compositional analysis and the specific content of the introduced proteins are typically conducted on raw products, such as maize kernels or soybean seed. However, much of the human consumption of these products occurs after substantial exposure to heat or other processing. If in processing of foods the amounts of GE proteins substantially increase, consumers are potentially exposed to a risk that is different from that anticipated from testing the raw material. In the production of oil, for example, the goal is to separate the oil from other compounds in the raw crop, such as proteins and carbohydrates. Crude oils can contain plant proteins ( Martín-Hernández et al., 2008 ), but in highly purified oils even sophisticated approaches have failed to find any nondegraded proteins ( Hidalgo and Zamora, 2006 ; Martín-Hernández et al., 2008 ). Those results are reflected in the fact that people who are allergic to soybean are not affected by purified oils ( Bush et al., 1985 ; Verhoeckx et al., 2015 ).

A few studies have searched for a means of finding DNA in plant-derived oils to identify the origin of the oil as GE or non-GE for labeling purposes ( Costa et al., 2010a , b ) or to identify the origin of olive oil ( Muzzalupo et al., 2015 ). It is possible to detect DNA, but the amounts are typically diminished in purified oils to 1 percent or less of the original content. Similarly, Oguchi et al. (2009) were not able to find any DNA in purified beet sugar. Some countries exempt products from labeling if GE protein or DNA is not detectable. For example, in Japan, where foods with GE ingredients typically require labeling, oil, soy sauce, and beet sugar are excluded because of degradation of GE proteins and DNA ( Oguchi et al., 2009 ). Australia and New Zealand have similar exemptions from labeling for such highly refined foods as sugars and oils ( FSANZ, 2013 ).

The detection of GE protein and DNA in other processed foods depends on the type of processing. For example, the amount of the Bt protein Cry1Ab detected by immunoassay in tortillas depends on cooking time ( de Luis et al., 2009 ). The detected amount of Cry9C protein remaining in samples of corn bread, muffins, and polenta was about 13, 5, and 3 percent of the amount in the whole-grain maize ( Diaz et al., 2002 ). For Cry1Ab in rice, Wang et al. (2015) found that baking was more effective in lowering the detection using polyclonal antibodies of the Cry1Ab protein than microwaving, but 20 minutes of baking at 180°C left almost 40 percent of the protein intact. Heat denaturation of proteins can lower antibody binding to epitopes and cause lower detection of GE proteins.

FINDING: The amount of GE protein and DNA in food ingredients can depend on the specific type of processing; some foods contain no detectable protein and little DNA. In a few countries that have manda tory labeling of GE foods, that is taken into account, and food without detectable GE DNA or GE protein is not labeled.

Newer Methods for Assessing Substantial Equivalence

As explained in Chapter 2 , governance of GE crops includes regulatory governance. Although not required to by governing bodies, companies and academic researchers have moved beyond the typical measurements of food composition to newer technologies that involve transcriptomics, proteomics, and metabolomics. The new methods provide a broad, nontargeted assessment of thousands of plant characteristics, including the concentrations of most of the messenger RNAs, proteins, and small molecules in a plant or food. These methods are more likely to detect changes in a GE crop than the current regulatory approaches. If a GE crop has been changed only as intended, any changes observed in these -omics measurements theoretically should be predictable in a given environment. The science behind the methods, including the current limitations of their interpretation, is discussed in Chapter 7 . The discussion here focuses on how the methods have already been applied in the assessment of risk of health effects of currently commercialized GE crops.

Ricroch et al. (2011) reviewed -omics data from 44 studies of crops and detailed studies of the model plant Arabidopsis thaliana . Of those studies, 17 used transcriptomics, 12 used proteomics, and 26 used metabolomic methods. Ricroch (2013) updated the number of studies to 60. The committee found that many more studies had been done since those reviews were published, and many of them have used multiple -omics approaches. The sophistication of the studies has increased ( Ibáñez et al., 2015 ) and is likely to increase further. As recommended in Chapter 7 , there is a need to develop further and share databases that contain detailed -omics data ( Fukushima et al., 2014 ; Simó et al., 2014 ).

In some studies of GE plants in which simple marker genes were added, there were almost no changes in the transcriptome ( El Ouakfaoui and Miki, 2005 ), but use of other -omics methods has revealed changes ( Ren et al., 2009 ). For example, in a comparison of glyphosate-resistant soybean and non-GE soybean, García-Villalba et al. (2008) found that three free amino acids, an amino acid precursor, and flavonoid-derived secondary metabolites (liquiritigenin, naringenin, and taxifolin) had greater amounts in the GE soybean and 4-hydroxy-l-threonine was present in the non-GE soybean, but not in the GE variety. They hypothesized that the change in the flavonoids may have been because the modified EPSPS enzyme (a key enzyme of the shikimate pathway leading to aromatic amino acids) introduced to achieve glyphosate resistance could have different enzymatic properties that influenced the amounts of aromatic amino acids. The committee was not aware of such a hypothesis before this metabolomic study. (A concern was expressed in a comment submitted to the committee that the EPSPS transgene would cause endocrine disruption. The committee found no evidence to suggest that the changes found by García-Villalba et al. would have such an effect.)

On the basis of previous experimentation, it is predicted that, when a gene for a nonenzymatic protein (such as a Bt toxin gene) is added to a plant, there will be very few changes in the plant's metabolism ( Herman and Price, 2013 ). However, when a gene has been added specifically to alter one metabolic pathway of a plant, a number of predicted and unpredicted changes have been found. For example, Shepherd et al. (2015) found that, when they downregulated enzymes (that is, decreased expression or activity) involved in the production of either of two toxic glycoalkaloids (alpha-chaconine and alpha-solanine) in a GE potato with RNA-interfering transgenes that regulated synthesis of one toxic glycoalkaloid, the other compound usually increased. When they downregulated production of both compounds, beta-sitosterol and fucosterol increased. Neither of these compounds has the degree of toxicity associated with alpha-chaconine and alpha-solanine. Other compounds also differed from controls in concentration, but some of the changes may have been due to products generated during the tissue-culture process used in these experiments and not to the transgenes.

Many of the studies have found differences between the GE plants and the isogenic conventionally bred counterparts, but for many components there is more variation among the diverse conventionally bred varieties than between the GE and non-GE lines ( Ricroch et al., 2011 , Ricroch, 2013 ). Furthermore, the environmental conditions and the stage of the fruit or seed affect the finding. Chapter 7 addresses the future utility of the -omics approaches in assessing the biological effects of genetic engineering.

FINDING: In most cases examined, the differences found in comparisons of transcriptomes, proteomes, and metabolomes in GE and non-GE plants have been small relative to the naturally occurring variation found in conventionally bred crop varieties due to genetics and environment.

FINDING: If an unexpected change in composition beyond the natural range of variation in conventionally bred crop varieties were present in a GE crop, -omics approaches would be more likely to find the difference than current methods.

FINDING: Differences in composition found by using -omics methods do not, on their own, indicate a safety problem.

Food Allergenicity Testing and Prediction

Allergenicity is a widespread adverse effect of foods, several plants, tree and grass pollens, industrial chemicals, cosmetics, and drugs. Self-reporting of lifetime allergic responses to each of the most common food allergens (milk, egg, wheat, soy, peanut, tree nuts, fish, and shellfish) ranges from 1 to 6 percent of the population ( Nwaru et al., 2014 ). Allergies are induced in a two-step process: sensitization from an initial exposure to a foreign protein or peptide followed by elicitation of the allergic response on a second exposure to the same or similar agent. Sensitization and elicitation are generally mediated by immunoglobulins, primarily IgE, and the responses may range from minor palatal or skin itching and rhinitis to severe bronchial spasms and wheezing, anaphylaxis, and death. In addition to IgE responses to food allergens, IgA has been identified as an inducible immune mediator primarily in the gastrointestinal mucosa in response to foods, foreign proteins, pathogenic microorganisms, and toxins. The role of IgA in classical allergy has been investigated ( Macpherson et al., 2008 ).

Assessment of the potential allergenicity of a food or food product from a GE crop is a special case of food-toxicity testing and is based on two scenarios: transfer of any protein from a plant known to have food-allergy properties and transfer of a protein that could be a de novo allergen. Predictive animal testing for allergens in foods (GE and non-GE) is not sufficient for allergy assessment ( Wal, 2015 ). Research efforts are ongoing to discover or develop an animal model that predicts sensitization to allergy ( Ladics and Selgrade, 2009 ), but so far none has proved predictive ( Goodman, 2015 ). Therefore, researchers have relied on multiple indirect methods for predicting whether an allergic response could be caused by a protein that is either added to a food by genetic engineering or appears in the food as an unintended effect of genetic engineering. Endogenous protein concentrations with known allergic properties also have to be monitored because it is possible that their concentration could increase due to genetic engineering.

A flow diagram of the interactive approach to allergen testing recommended by the Codex Alimentarius Commission ( CAC, 2009 ) and EFSA (2010 , 2011a ) is presented in Figure 5-3 ( Wal, 2015 ); Box 5-2 describes the EPA testing of the Bt toxin Cry1F that generally follows this approach. The logic behind the approach starts with the fact that any gene for a protein that comes from a plant that is known to cause food allergies has a higher likelihood of causing allergenicity than any gene from a plant that does not cause an allergic response. If the introduced protein is similar to a protein already known to be an allergen, it becomes suspect and should be tested in people who have an allergy to the related protein. Finally, if a protein fits none of the above characteristics but is not digested by simulated gastric fluid, it could be a novel food allergen. The latter factor comes from research demonstrating that some, but not all, proteins already known to be food allergens are resistant to digestion by gut fluid.

Flow chart summarizing the weight-of-evidence approach for assessment of allergenicity of a newly expressed protein in genetically engineered (GE) organisms. SOURCE: CAC (2009) and EFSA (2010, 2011a) in Wal (2015). NOTE: This approach starts with questions (more...)

There is one case in which that approach was used and a GE crop with allergenicity issues was detected early and prevented from being commercialized, and a second case in which a GE crop was withdrawn from the market based on the possibly that it included a food allergen. In the first case, research was conducted on a soybean line genetically engineered to produce a Brazil nut ( Bertholletia excelsa ) protein, which was a known allergen. Sera from patients allergic to Brazil nut protein were available and tested positive for activity against the GE soybean protein. Because the segregation from the human food supply of GE soybean with that protein could not be guaranteed, the project was halted ( Nordlee et al., 1996 ). The soybean variety was never commercialized.

In the second case, EPA allowed a Bt maize variety developed by Aventis CropScience with a potential for allergenicity (due to decreased digestion of the protein Cry9c in simulated gastric fluid) to be sold as cattle feed under the name StarLink™; because of the potential for allergenicity, the variety was not approved for direct human consumption. However, the Bt protein was found in human food, so the maize variety was removed from all markets. After that incident, EPA no longer distinguished between Bt proteins in human food versus in animal feed ( EPA, 2001b ). Bt crop varieties are approved in the United States for all markets or none.

The interactive approach for testing should work for GE crops when the testing is for a transgene that is expressed by the plant as a protein that does not affect its metabolism (for example, Bt toxins). The testing does not cover endogenous allergens whose concentrations have been increased by unintended effects of genetic engineering. In 2013, the European Commission set a requirement for assessing endogenous allergens in GE crops ( EC, 2013 ). A number of articles since then have supported the approach ( Fernandez et al., 2013 ) or have found it unnecessary and impractical ( Goodman et al., 2013 ; Graf et al., 2014 ). Soybean is an example of a crop that has endogenous allergens. A paper on endogenous soybean allergens concluded that there is enough knowledge of only some soybean allergens for proper testing ( Ladics et al., 2014 ). As emphasized by Wal (2015) , there is considerable variation among conventionally bred varieties in the concentrations of endogenous allergens, especially when they are grown under different conditions. Therefore, the existing variation must be taken into consideration in assessing a GE variety. Of course, the issue is not only the magnitude of variation but the potential change in the overall exposure of the global human population to the allergen.

One example of an existing potential allergen of concern is gamma-zein, one of the storage proteins produced in the maize kernel that is a comparably hard-to-digest protein ( Lee and Hamaker, 2006 ). Concern was expressed to the committee that GE maize may have higher amounts of gamma-zein, which could be allergenic ( Smith, 2014 ). Krishnan et al. (2010) found that young pigs consuming maize generate antibodies against gamma-zein. That observation and the fact that the protein withstands pepsin digestion suggest that gamma-zein could be an allergen. In a comparison of the Bt maize line MON810 with non- Bt maize, known maize allergens, including the 27-kDa and 50-kDa gamma-zein proteins, were not found to be in significantly different amounts ( Fonseca et al., 2012 ). On the other hand, conventionally bred Quality Protein Maize is reported to have a 2 to 3 fold higher concentration of the 27-kDa gamma-zein protein ( Wu et al., 2010 ). There is one patent for decreasing gamma-zein through genetic engineering. 5

There can be a connection between immune response and allergenicity. One well-cited study brought up in the public comment period was that by Finamore et al. (2008) , who assessed the effect of Bt maize ingestion on the mouse gut and peripheral immune system. They found that Bt maize produced small but statistically significant changes in percentage of T and B cells and of CD4+, CD8+, γδT, and αβT subpopulations at gut and peripheral sites and alterations of serum cytokines in weanlings fed for 30 days and in aged mice. However, there was no significant response in weaning mice that were fed for 90 days, which they related to further maturation of the immune system. They concluded that there was no evidence that the Bt toxin in maize caused substantial immune dysfunction. Similarly, Walsh et al. (2012a) did not find immune function changes in a long-term pig feeding study (80 or 110 days) on Bt MON810 maize compared with non-GE maize. Overall, no changes of concern regarding Bt maize feeding and altered immune response have been found.

At a public meeting that the committee held on health effects of GE foods, a question was raised about whether current testing for allergenicity is insufficient because some people do not have acidic conditions in their stomachs. Regarding that issue, digestibility of the proteins is assessed with simulated gastric fluid (0.32 percent pepsin, pH 1.2, 37°C), under the premise that an undigested protein may lead to the absorption of a novel allergenic fragment ( Astwood et al., 1996 ; Herman et al., 2006 ). Stomach fluid is typically acidic, with a pH of 1.5–3.5, which is the range at which pepsin (the digestive enzyme of the stomach) is active, and the volume of stomach fluid is 20–200 mL (about 1–3 ounces). Simulated gastric fluid was developed to represent human gastric conditions in the stomach and is used in bioavailability studies of drugs and foods ( U.S. Pharmacopeia, 2000 ).

In general, if the pH of the stomach is greater than 5, pepsin will not be active, and less breakdown of large proteins will take place. Hence, the usefulness of simulated gastric fluid in the case of a less acidic (higher pH) stomach is questionable, whether used for non-GE foods or GE foods. Untersmayr and Jensen-Jarolim (2008:1301) concluded that “alterations in the gastric milieu are frequently experienced during a lifetime either physiologically in the very young and the elderly or as a result of gastrointestinal pathologies. Additionally, acid-suppression medications are frequently used for treatment of dyspeptic disorders.” Trikha et al. (2013) used a group of 4,724 children (under 18 years old) who had received a diagnosis of gastroesophageal reflux disease (GERD) and who were treated with gastric acid-suppressive medication and matched with 4,724 children who had GERD but were not so treated. Those treated with acid-reducing medicine were more than 1.5 times as likely to have a diagnosis of food allergy as those who were not so treated. The difference between the two GERD groups was statistically significant (hazard ratio, 1.68; 95-percent confidence interval, 1.15–2.46).

The National Research Council report Safety of Genetically Engineered Foods pointed out that there were important limitations in allergenicity predictions that could be done before commercialization ( NRC, 2004 ). Since that report was published, there have been improvements in the allergen database, and research has been funded to improve precommercialization prediction. However, as the committee heard from an invited speaker, “no new methods have been demonstrated to predict sensitization and allergy in the absence of proven exposure” ( Goodman, 2015 ). Before commercialization, the general population will probably not have been exposed to an allergen similar enough to an allergen in a GE plant to cause cross-reactivity, so it would be useful to use the precommercialization tests only as a rough predictor. To ensure that allergens did not remain in the food system, the Safety of Genetically Engineered Foods report called for a two-step process of precommercialization testing and post-commercialization testing. Even though progress has been made on allergenicity prediction since that report was published in 2004, the committee found that post-commercialization testing would be useful in ensuring that no new allergens are introduced. There have been no steps toward post-commercialization testing since 2004. The committee recognized that such testing would be logistically challenging, as described in a scientific report to EFSA ( ADAS, 2015 ). Post-commercialization surveillance of such specific agents as drugs and medical devices is difficult, but there is generally a well-defined endpoint to look for in patients. In the case of food, the detection of an allergic response to a particular protein would be confounded by multiple exposures in the diet. However, several region-wide human populations have been exposed to GE foods for many years whereas others have not; this could enable an a priori hypothesis to be tested that populations that have been exposed to foods from specific GE crops will not show a higher rate of allergic response to such foods.

FINDING: For crops with endogenous allergens, knowing the range of allergen concentrations in a broad set of crop varieties grown in a variety of environments is helpful, but it is most important to know whether adding a GE crop to the food supply will change the general exposure of humans to the allergens.

FINDING: Because testing for allergenicity before commercialization could miss allergens to which the population had not previously been exposed, post-commercialization allergen testing would be useful in ensuring that consumers are not exposed to allergens, but such testing would be difficult to conduct.

FINDING: There is a substantial population of persons who have higher than usual stomach pH, so tests of digestibility of proteins in simulated acidic gastric fluid may not be relevant to this population.

• GENETICALLY ENGINEERED CROPS AND OCCURRENCE OF DISEASES AND CHRONIC CONDITIONS

The overall results of short-term and long-term animal studies with rodents and other animals and other data on GE-food nutrient and secondary compound composition convinces many (for example, Bartholomaeus et al., 2013 ; Ricroch et al., 2013a , b ; Van Eenennaam and Young, 2014 ) but not all involved researchers (for example, Dona and Arvanitoyannis, 2009 ; Domingo and Bordonaba, 2011 ; Hilbeck et al., 2015 ; also see DeFrancesco, 2013 ) that currently marketed GE foods are as safe as foods from conventionally bred crops. The committee received comments from an invited speaker ( Smith, 2014 ) and from the public regarding the possible relationship between increases in the incidence of specific chronic diseases and the introduction of GE foods into human diets. Appendix F includes a representative list of the comments about GE food safety that were sent to the committee through the study's website. The comments mentioned concerns about such chronic diseases as cancers, diabetes, and Parkinson's; possible organ-specific injuries (liver and kidney toxicity); and such disorders as autism and allergies. Smith (2003:39) made the claim that “diabetes rose by 33 percent from 1990 to 1998, lymphatic cancers are up, and many other illnesses are on the rise. Is there a connection to [genetically modified] foods? We have no way of knowing because no one has looked for one.”

As part of the committee's effort to respond to its task to “assess the evidence for purported negative effects of GE crops and their accompanying technologies,” it used available peer-reviewed data and government reports to assess whether any health problems may have increased in frequency in association with commercialization of GE crops or were expected to do so on the basis of the results of toxicity studies. The committee presents additional biochemical data from animal experiments but relies mostly on epidemiological studies that used time-series data. The epidemiological data for some specific health problems are generally robust over time (for example, cancers) but are less reliable for others. The committee presents the available data knowing that they include a number of sources of bias, including changes over time in survey methods and in the tools for detection of specific chronic diseases. As imperfect as the data may be, they are in some cases the only information available beyond animal experiments for formulating or testing hypotheses about possible connections between a GE food and a specific disease. The committee points out that the lack of rigorous data on incidence of disease is not only a problem for assessing effects of GE foods on health. More rigorous data on time, location, and sociocultural trends in disease would enable better assessment of potential health problems caused by environmental factors and other products from new technologies.

Cancer Incidence

A review of the American Cancer Society's database indicates that mortality from cancers in the United States and Canada has continued to decrease or stabilized in all categories except cancers of the lung and bronchus attributable to smoking. The decreases in mortality are due in part to early detection and improved treatment, so mortality data can mask the rate at which cancers occur. For that reason, the committee sought data on cancer incidence rather than cancer mortality. Figures 5-4 and 5-5 show changes in cancer incidence in U.S. women and men, respectively, from 1975 to 2011 ( NCI, 2014 ). If GE foods were causing a substantial number of specific cancers, the incidence of those cancers would be expected to show a change in slope in the time source after 1996, when GE traits were first available in commercial varieties of soybean and maize. The figures show that some cancers have increased and others decreased, but there is no obvious change in the patterns since GE crops were introduced into the U.S. food system. Figures 5-6 and 5-7 show cancer incidence in women and men in the United Kingdom, where GE foods are not generally being consumed. For the specific types of cancers that are reported in both the United States and the United Kingdom, there is no obvious difference in the patterns that could be attributed to the increase in consumption of GE foods in the United States. (The absolute numbers cannot be compared because of differences in methodology.)

Trends in cancer incidence in women in the United States, 1975–2011. SOURCE: NCI (2014). NOTE: Age-adjusted to the 2000 U.S. standard population and adjusted for delays in reporting. Dashed line at 1996 indicates year GE soybean and maize were (more...)

Trends in cancer incidence in men in the United States, 1975–2011. SOURCE: NCI (2014). NOTE: Age-adjusted to the 2000 U.S. standard population and adjusted for delays in reporting. Dashed line at 1996 indicates year GE soybean and maize were first (more...)

Cancer incidence in women in the United Kingdom, 1975–2011. DATA SOURCE: Cancer Research UK. Available at http://www.cancerresearchuk.org/health-professional/cancer-statistics. Accessed October 30, 2015. NOTE: Dashed line at 1996 indicates year (more...)

Cancer incidence in men in the United Kingdom, 1975–2011. DATA SOURCE: Cancer Research UK. Available at http://www.cancerresearchuk.org/health-professional/cancer-statistics. Accessed October 30, 2015. NOTE: Dashed line at 1996 indicates year (more...)

Forouzanfar et al. (2011) published data on breast and cervical cancer incidence worldwide from 1980 to 2010. As can be seen in Figure 5-8 , the global incidence of those two cancers has increased. An examination of the plots for North America (high income) (Canada and the United States), where GE foods are eaten, compared with the plots for western Europe, where GE foods generally are not eaten, shows similar increases in incidence of breast cancer and no increase in cervical cancer. The data do not support the hypothesis that GE-food consumption has substantially increased breast and cervical cancer. (The data for North America [high income] and western Europe are different from those in the studies above on the incidence of cancer in the United States and the United Kingdom.)

Global incidence of breast (A) and cervical (B) cancer. SOURCE: Forouzanfar et al. (2011). NOTE: North America (high income): Canada, United States; Western Europe: Andorra, Austria, Belgium, Cyprus, Denmark, Finland, France, Germany, Greece, Iceland, (more...)

Taken together, Figure 5 through Figure 8 do not support the hypothesis that GE foods have resulted in a substantial increase in the incidence of cancer. However, they do not establish that there is no relationship between cancer and GE foods because there can be a delay in the onset of cancer that would obscure a trend, and one could hypothesize that something else has occurred with GE foods in the United States that has lowered cancer incidence and thus obscured a relationship. The committee had limited evidence on which to make its judgments, but the evidence does not support claims that the incidence of cancers has increased because of consumption of GE foods.

There is ongoing debate about potential carcinogenicity of glyphosate in humans. Assessment of glyphosate is relevant to the committee's report because it is the principal herbicide used on HR crops (Livingston, et al. 2015), and it has been shown that there are higher residues of glyphosate in HR soybean treated with glyphosate than in non-GE soybean ( Duke et al., 2003 ; Bøhn et al., 2014 ). Box 5-5 provides details about a study by Séralini et al. (2012 , 2014 ) that concluded that glyphosate causes tumors in rats. The committee found that this study was not conclusive and used incorrect statistical analysis. The most detailed epidemiological study that tested for a relationship between cancer and glyphosate as well as other agricultural chemicals found “no consistent pattern of positive associations indicating a causal relationship between total cancer (in adults or children) or any site-specific cancer and exposure to glyphosate” ( Mink et al., 2012:440 ; also see section below “Health Effects of Farmer Exposure to Insecticides and Herbicides”).

In 1985, EPA classified glyphosate as Group C (possibly carcinogenic to humans) on the basis of tumor formation in mice. However, in 1991, after reassessment of the mouse data, EPA changed the classification to Group E (evidence of noncarcinogenicity in humans) and in 2013 reaffirmed that “based on the lack of evidence of carcinogenicity in two adequate rodent carcinogenicity studies, glyphosate is not expected to pose a cancer risk to humans” ( EPA, 2013:25399 ).

In 2015, the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) issued a monograph on glyphosate as part of its volume on some organophosphate insecticides and herbicides ( IARC, 2015 ). In the monograph, IARC classified glyphosate in Group 2A (probably carcinogenic to humans). A summary and reasons for the classification were published in Lancet Oncology ( Guyton et al., 2015 ).

The 2015 IARC Working Group found that, although there is “ limited evidence in humans for the carcinogenicity of glyphosate,” there is “ sufficient evidence in experimental animals for the carcinogenicity of glyphosate” ( IARC, 2015:78 ). Furthermore, IARC noted that there is mechanistic support in that glyphosate induces oxidative stress, which could cause DNA damage, and some epidemiological data that support the classification.

EFSA (2015) evaluated glyphosate after the IARC report was released and concluded that glyphosate is unlikely to pose a carcinogenic risk to humans. Canada's health agency concluded that “the level of human exposure, which determines the actual risk, was not taken into account by WHO (IARC)” ( Health Canada, 2015 ). The Canadian agency found that current food and dermal exposure to glyphosate even by those who work directly with glyphosate is not a health concern as long as it is used as directed on product labels ( Health Canada, 2015 ). EPA (2015) found that glyphosate does not interact with estrogen, androgen, or thyroid systems.

A comment to the committee expressed concern that glyphosate breaks down to formaldehyde, which was classified as a known human carcinogen by IARC (2006) . However, this hypothesis was not supported; Franz et al. (1997) used radiolabeled glyphosate and failed to show formation of formaldehyde in the normal environmental degradation of glyphosate.

FINDING: The incidence of a variety of cancer types in the United States has changed over time, but the changes do not appear to be associated with the switch to consumption of GE foods. Furthermore, patterns of change in cancer incidence in the United States are generally similar to those in the United Kingdom and Europe, where diets contain much lower amounts of food derived from GE crops. The data do not support the assertion that cancer rates have increased because of consumption of products of GE crops.

FINDING: There is significant disagreement among expert committees on the potential harm that could be caused by the use of glyphosate on GE crops and in other applications. In determining the risk from glyphosate and formulations that include glyphosate, analyses must take into account both marginal exposure and potential harm.

Kidney Disease

It has been hypothesized that kidney disease may have increased because GE proteins reached the kidney. The committee examined epidemiological data to determine whether there was a correlation between the consumption of GE foods and the prevalence of chronic kidney disease (CKD).

The total prevalence of all stages of CKD in the United States increased 2 percent from about 12 percent in 1988–1994 to 14 percent in 1999–2004, but the total prevalence has not increased significantly since then. Figure 5-9 presents prevalence data on the five progressively more serious, recognized stages of CKD ( USRDS, 2014 ). The greatest percent increase is seen in Stage 3, and based on the study ( USRDS, 2014 ), a large amount of the increase occurred in people with comorbidity of cardiovascular disease. Prevalence of CKD increases substantially with age ( Coresh et al., 2003 ), so the aging of the U.S. population may contribute to the overall increase ( U.S. Census Bureau, 2014 ), as does the increase in diabetes and hypertension ( Coresh et al., 2007 ).

Prevalence of chronic kidney disease by stage among National Health and Nutrition Examination Survey (NHANES) participants, 1988–2012. SOURCE: NHANES 1988–1994, 1999–2004, and 2005–2012; participants 20 years old and older; (more...)

FINDING: The available data on prevalence of chronic kidney disease in the United States show a 2 percent increase from 1988 to 2004, but the increase does not appear to be attributable to consumption of GE foods.

Obesity in humans is a complex condition associated with several genetic and environmental factors—including geography, ethnicity, socioeconomic status, lack of exercise, availability of fresh fruits and vegetables, and less nutritional meals ( Thayer et al., 2012 )—and an altered functioning microbiome ( Turnbaugh et al., 2009 ).

Studies of various species examined body-weight gain when animals were fed a GE crop, a non-GE isogenic comparator, or a non-GE, nonisogenic control. The authors concluded that there were no biologically relevant differences in body-weight gain regardless of the length of the studies ( Rhee et al. 2005 ; Hammond et al., 2006 ; Arjó et al., 2012 ; Buzoianu et al., 2012b ; Ricroch et al., 2013a , b ; Halle and Flachowsky, 2014 ; Nicolia et al. 2014) .

Human population studies have shown that obesity has become more prevalent in the United States (for example, Fryar et al., 2014 ). An (2015) provided a graphic of the change in U.S. adults (sorted by education level) from 1984 to 2013 ( Figure 5-10 ). As can be seen in the figure, the percentage of obese U.S. adults increased until about 2009, at which time it appears to level off. Because there is no increase in the slope after commercialization of GE crops, these data do not support the hypothesis that GE crops have increased obesity. These time-series data do not prove that there is no association, but if one is present, it is not strong.

FIGURE 5-10

Annual trend for adjusted prevalence of obesity in U.S. adults by education level, 1984–2013. SOURCE: An (2015). NOTE: Prevalence of obesity was adjusted to account for gender, age group, and race or ethnicity. Dashed line at 1996 indicates year (more...)

Those statistics on obesity coincide with those on the incidence of type II diabetes in the United States ( Abraham et al., 2015 ) and therefore do not support a relationship between GE crops and type II diabetes.

FINDING: The committee found no published evidence to support the hypothesis that the consumption of GE foods has caused higher U.S. rates of obesity or type II diabetes.

Gastrointestinal Tract Diseases

Although the gastrointestinal tract has evolved to digest dietary proteins in the stomach and small intestine effectively for absorption and use of amino acids, it is normal for some full proteins or their fragments to cross the gut barrier through a paracellular route (between cells) or damaged mucosa and for the immune system, which has a high presence at the interface of the gut wall and the internal circulation, to respond accordingly. It is also not unusual, given the high sensitivity of today's analytical equipment, for proteins or fragments to be detected in minute amounts in different body fluids. Detection methods are not specific to transgene-produced proteins but can find any dietary protein or fragment that is able to pass from the gastrointestinal tract into the bloodstream and tissues. The presence of a dietary protein or its fragment in the bloodstream or in tissues is not unusual or a cause for health concerns.

About 60–70 percent of the body's immune system is in the gastrointestinal tract's gut-associated lymphoid tissue, which has an interface with the gut luminal contents, including toxins, allergens, and the associated microbiota. For GE crops, a public concern has been that the immune system is compromised through ingested transgenic proteins. That possibility has been investigated in animal studies that examined immune system bio-markers and epithelial cell integrity (see section “Beyond Rodent Studies” above and Walsh et al., 2011 ).

It was suggested to the committee in presentations and public comments that fragments of transgenes may have some special properties that would result in human diseases if they were absorbed into the body through the digestive tract. The mechanism by which such genes or proteins would affect the body is not clear, although Smith (2013) hypothesized that consuming GE foods increased gut permeability.

FINDING: The committee could find no published evidence supporting the hypothesis that GE foods generate unique gene or protein fragments that would affect the body.

Celiac Disease

Celiac disease is an autoimmune disorder that affects about 1 percent of the population of western countries. It is triggered in susceptible people by consumption of gluten-containing cereal grains ( Fasano et al., 2003 ; Catassi et al., 2010 ). Symptoms of celiac disease are the result of an immune reaction that causes marked gastrointestinal inflammation in persons susceptible to gliadin, a component of gluten protein found in wheat, rye ( Secale cereale ), and barley ( Hordeum vulgare ) ( Green and Cellier, 2007 ). In addition to exposure to gluten, the etiology of celiac disease is multifactorial and includes genetic predisposition, microbial infection of the gastrointestinal tract, antibiotic exposure, and gastrointestinal erosion ( Riddle et al., 2012 ). Diagnosis is based on detection of serum concentrations (serotypes) of IgA tissue transglutaminase and endomysial antibody IgA, the relief of symptoms upon gluten avoidance, and tissue biopsy. The genetic changes related to the serotyped IgAs are found in about 30 percent of the Caucasian population, but susceptibility to celiac disease is found in only 1 percent of this population ( Riddle et al., 2012 ).

The committee was able to find data on the incidence of celiac disease in the United Kingdom ( West et al., 2014 ; Figure 5-11 ) and a detailed study conducted by the Mayo Clinic in one county in Minnesota ( Murray et al., 2003 ; Ludvigsson et al., 2013 ). In the Minnesota and UK studies, there is a clear pattern of increase in celiac-disease incidence (or at least its detection or the extent of self-reports) that started before 1996 ( Catassi et al., 2010 ), when U.S. citizens began to consume more GE foods and the use of glyphosate increased in the United States but not in the United Kingdom. The increases are similar in magnitude to that found in U.S. military personnel, in whom prevalence increased from 1.3 per 100,000 in 1999 to 6.5 per 100,000 in 2008 ( Riddle et al., 2012 ). The authors cautioned that most cases of celiac disease are undiagnosed. Some of the observed increase may be related to improvements in diagnostic criteria, greater awareness of the disease in physicians and patients, better blood tests, and increases in the number of biopsies. However, recent observations point to an increase in incidence beyond those factors (J. A. Murray, Mayo Clinic, personal communication, February 1, 2016).

FIGURE 5-11

Three-year rolling average incidence of celiac disease in 1990–2011, by age group, in the United Kingdom. SOURCE: West et al., 2014. NOTE: Dashed line at 1996 indicates year genetically engineered soybean and maize were first grown in the United (more...)

On the basis of data collected in the 2009–2010 National Health and Nutrition Examination Survey, Rubio-Tapia et al. (2012) reported a prevalence of celiac disease of 0.71 percent with 1.01 percent in non-Hispanic whites in a sample of 7,798 subjects. It should be noted that there has not been any commercial production of GE wheat, rye, or barley in the world. The committee found no evidence that the introduction of GE foods affected the incidence or prevalence of celiac disease worldwide.

FINDING: Celiac-disease detection began increasing in the United States before the introduction of GE crops and the increased use of glyphosate. It appears to have increased similarly in the United Kingdom, where GE foods are not typically consumed and glyphosate use did not increase. The data are not robust, but they do not show a major difference in the rate of increase in incidence of celiac disease between the two countries.

Food Allergies

Speakers and some members of the public suggested that the prevalence of food allergies has increased because of GE crops. The committee examined records on the prevalence of food allergies in the United States over time. As is clear from Figure 5-12 and Jackson et al. (2013) , the prevalence of food allergies in the United States is rising. For a rough comparator, the committee examined data on hospital admissions for food allergies in the United Kingdom over time ( Figure 5-13 ). UK citizens eat far less food derived from GE crops. The data ( Gupta et al., 2007 ) suggest that food allergies are increasing in the United Kingdom at about the same rate as in the United States (but the types of measurement are different).

FIGURE 5-12

Percentage of children 0–17 years old in the United States with a reported allergic condition in the preceding 12 months, 1997–2011. a Significantly increasing linear trend for food and skin allergy from 1997–1999 to 2009–2011. (more...)

FIGURE 5-13

Trends in hospital admission rates for anaphylaxis related to food allergy by age in the United Kingdom during 1990–2004. SOURCE: Gupta et al. (2007). NOTES: ICD = International Classification of Diseases. Green = ages 0–14 years; blue (more...)

FINDING: The committee did not find a relationship between consumption of GE foods and the increase in prevalence of food allergies.

Autism Spectrum Disorder

Autism is often described by such symptoms as difficulty in communicating, forming personal relationships, and using language and abstract concepts. According to the American Psychiatric Association (2013) , autism spectrum disorder (ASD) encompasses the previous diagnoses of autism, Asperger syndrome, pervasive developmental disorder not otherwise specified, and childhood disintegrative disorder. Accurate diagnosis of ASD can be difficult, but efforts to identify children with ASD have increased in the United States over the last three decades ( CDC, 2014 ).

In the 2010 Centers for Disease Control and Prevention (CDC) survey of ASD in 11 regions of the United States ( CDC, 2014 ), the overall prevalence in children 8 years old was about 1 in 68 (1.47 percent), but there was wide variation among regions and sociocultural groupings of children. The CDC report stated that “the extent to which this variation might be attributable to diagnostic practices, under-recognition of ASD symptoms in some racial/ethnic groups, socioeconomic disparities in access to services, and regional differences in clinical or school-based practices that might influence the findings in this report is unclear” ( CDC, 2014:1 ). The degree to which the increase in ASD prevalence since 1990 is due to improved diagnosis is also unclear.

Before 1990, few children in the United States or the United Kingdom had diagnoses of ASD ( Taylor et al., 2013 ), but the prevalence has increased dramatically in both countries. Researchers in the United States and United Kingdom wrote a report that examined prevalence of ASD in the United Kingdom over time and compared it with that in the United States ( Taylor et al., 2013 ). They concluded that “a continuous simultaneous extraordinary rise in the number of children diagnosed as autistic began in both countries in the early 1990s and lasted for a decade. The distribution of first time diagnosis according to age and gender was the same. These similarities between countries as well as within different locations in each country point to a common etiology for this extraordinary medical case” ( Taylor et al., 2013:5 ). There is a higher prevalence in the United States, but it is difficult to evaluate whether it is because of differences in efforts in and approaches to diagnosis and in sociocultural factors that seem to influence prevalence. The overall similarities in prevalence of ASD in the United Kingdom, where GE foods are rarely eaten, and in the United States, where GE foods are commonly eaten, suggest that the major rise in ASD is not associated with consumption of GE foods.

FINDING: The similarity in patterns of increase in autism spectrum disorder in children in the United States, where GE foods are commonly eaten, and the United Kingdom, where GE foods are rarely eaten, does not support the hypothesis of a link between eating GE foods and prevalence of autism spectrum disorder.

• OTHER HUMAN HEALTH CONCERNS RELATED TO GENETICALLY ENGINEERED CROPS

The committee heard from some members of the public and some invited speakers that ailments of gastrointestinal origin could be caused by GE crops or their associated technologies or by foods derived from GE crops. The committee investigated the evidence available for that hypothesis.

Gastrointestinal Tract Microbiota

The committee received comments from the public that foods derived from GE crops could change the gut microbiota in an adverse way. Three scenarios can be considered as related to the potential effects of GE crops on the gut microbiota: the effect of the transgene product (for example, Bt toxin), unintended alteration of profiles of GE plant secondary metabolites, and herbicide (and adjuvant) residue (for example, glyphosate) and its metabolites in HR crops.

Research on the human gut microbiota (the community of microorganisms that live in the digestive tract) is rapidly evolving with recent reports ( Dethlefsen and Relman, 2011 ; David et al., 2014 ) that suggest that microbiota perturbations occur fairly quickly owing to dietary components or antibiotic treatment. Microbiota composition and state are now well recognized to be linked to noncommunicable chronic diseases and other health problems, so factors that cause either beneficial or adverse changes in the microbiota are of interest to researchers and clinicians. However, the science has not reached the point of understanding how specific changes in microbiota composition affect health and what represents a “healthy” microbiota. The effect of different dietary patterns (for example, high-fat versus high-carbohydrate diets) on the gut microbiota has been linked to metabolic syndrome ( Ley, 2010 ; Zhang et al., 2015 ).

As discussed above, most proteins, including those in GE and conventionally bred crops, are at least partially digested in the stomach by the action of pepsin that is maintained by the acidic pH of the stomach in most people. Further digestion and absorption are a function of the small intestine, where amino acids and dipeptides and tripeptides are absorbed. Therefore, an effect of a dietary protein on the microbiota, whether from GE or non-GE foods, is unlikely. However, there is some evidence that Bt proteins can be toxic to microorganisms ( Yudina et al., 2007 ), and some nondegraded Bt protein is found within the lumen of the gut but not in the general circulation of pigs ( Walsh et al., 2011 ). Buzoianu et al. (2012c , 2013a ) studied the effect of Bt maize feeding on microbiota composition in pigs. In their 2012 study, 110-day feeding of Bt maize (variety MON810) and of isogenic non-GE maize diets led to no differences in cultured Enterobacteriaceae, Lactobacillus , and total anaerobes from the gut; 16S rRNA sequencing showed no differences in bacterial taxa, except the genus Holdemania with which no health effects are associated ( Buzoianu et al., 2012c ). In the follow-up study in which intestinal content of sows and their offspring were examined with 16S rRNA gene sequencing, the only observed difference for major bacterial phyla was that Proteobacteria were less abundant in sows fed Bt maize before farrowing and in offspring at weaning compared with the controls ( Buzoainu et al., 2013a ). Fecal Firmicutes were more abundant in offspring fed GE maize. There were other inconsistent differences in mostly low-abundance microorganisms. On the basis of the overall results from their studies, the authors concluded that none of the changes seen in the animals was expected to have biologically relevant health effects on the animals.

Relatively few studies have examined the influence of plant secondary metabolites from any crop on the gut microbiota. The review of Valdés et al. (2015) highlighted investigations on polyphenol-rich foods—such as red wine, tea, cocoa, and blueberries—on the microbiota. Effects were considered minor. As discussed above (see the section “Endogenous Toxins in Plants”), current commercialized GE crops do not have distinctly different secondary metabolite profiles that would lead one to think that they would affect the gut microbiota.

No studies have shown that there are perturbations of the gut microbiota of animals fed foods derived from GE crops that are of concern. However, the committee concluded that this topic has not been adequately explored. It will be important to conduct research that leads to an understanding of whether GE foods or GE foods coupled with other chemicals have biologically relevant effects on the gut microbiota.

FINDING: On the basis of available evidence, the committee determined that the small perturbations found in the gut microbiota of animals fed foods derived from GE crops are not expected to cause health problems. A better understanding of this subject is likely as the methods for identifying and quantifying gut microorganisms mature.

Horizontal Gene Transfer to Gut Microorganisms or Animal Somatic Cells

Horizontal (or lateral) gene transfer is “the stable transfer of genetic material from one organism to another without reproduction or human intervention” ( Keese, 2008:123 ). Since GE crops were commercialized, concern has been voiced by some scientists and some members of the public that foreign DNA introduced into plants through genetic-engineering technologies might, after ingestion, be transferred to the human gut microbiota and directly or indirectly (that is, from bacteria) into human somatic cells. Although most of the concern regarding horizontal gene transfer has been focused on antibiotic-resistance genes used as markers of the transgenic event, other transgenes, such as those with Bt toxins, have also been of concern.

A prerequisite for horizontal gene transfer is that the recombinant DNA must survive the adverse conditions of both food processing and passage through the gastrointestinal tract. Netherwood et al. (2004) showed in patients with a surgically implanted exiting tube placed at the end of the small intestine (an ileostomy) that a small amount of the GE soybean transgene EPSPS passed through the upper gastrointestinal tract to the point of the distal ileum; in subjects without an ileostomy, no transgene was recovered from their feces. In their review on stability and degradation of DNA from foods in the gastrointestinal tract, Rizzi et al. (2012) noted that recombinant plant DNA fragments were detected in the gastrointestinal tracts of nonruminant animals but not detected in blood or other tissues, although some nonrecombinant plant DNA could be found. The authors concluded that some natural plant DNA fragments persist in the lumen of the gastrointestinal tract and in the bloodstream of animals and humans.

For an event to be considered horizontal gene transfer, DNA must be in the form of a functional (rather than fragmented) gene, enter into bacterial or somatic cells, and be incorporated into the genome with an appropriate promoter, and it must not adversely affect the competitiveness of the cells; otherwise, the effect would be short-lived.

Plant DNA has not been demonstrated to be incorporated into animal cells; however, it has been shown to be transferred in prokaryotes (bacteria). Indeed, molecular geneticists had to find genetic-engineering approaches for getting DNA to be taken into eukaryote cells and incorporated into a genome. The report A Decade of EU-Funded GMO Research (2001–2010) ( EC, 2010a ) described a study that shows that rumen ciliates (a type of microorganism) exposed to Bt 176 maize for 2 or 3 years did not incorporate the Bt 176 transgene. There are no reproducible examples of horizontal gene transfer of recombinant plant DNA into the human gastrointestinal microbiota or into human somatic cells. Three independent reviews of the literature on the topic ( van den Eede et al., 2004 ; Keese, 2008 ; Brigulla and Wackernagel, 2010 ) concluded that new gene acquisition by the gut bacteria through horizontal gene transfer would be rare and does not pose a health risk.

FINDING: On the basis of its understanding of the process required for horizontal gene transfer from plants to animals and data on GE organisms, the committee concludes that horizontal gene transfer from GE crops or conventionally bred crops to humans does not pose a substantial health risk.

Transfer of Transgenic Material Across the Gut Barrier into Animal Organs

Conflicting reports exist regarding the question of intact transgenes and transgenic proteins from foods crossing the gut barrier. Spisák et al. (2013) published results that indicate that complete genes in foods can pass into human blood. That is plausible, but Lusk (2014) examined the approach used by Spisák et al. and found it more likely that the findings were due to contaminants. Lusk emphasized the need for negative controls in such studies. Placental transfer of foreign DNA into mice was found by Schubbert et al. (1998) by detection in the mouse fetus, but a later report from the same laboratory ( Hohlweg and Doerfler, 2001 ) did not find the transfer in an eight-generation study.

Studies with dairy cows and goats did not find transgenes or GE proteins in milk, although chloroplast DNA fragments were detected in milk ( Phipps et al., 2003 ; Nemeth et al., 2004 ; Calsamiglia, et al., 2007; Rizzi et al., 2008 ; Guertler et al., 2009 , Einspanier, 2013 ; Furgał-Dierżuk et al., 2015 ). That makes it clear that there is no apparent potential for trangenes or transgenic proteins to be present in dairy products. However, these animals are ruminants, and their digestive systems are different from that of humans.

Walsh et al. (2012a) studied the fate of a Bt gene and protein in pigs that have digestive systems that are more similar to that of humans. They found no evidence of the gene or protein in any organs or blood after 110 days of feeding on Bt maize, but they did find them in the digestive contents of the stomach, cecum, and colon. Fragments of Cry1Ab transgene (as well as other common maize gene fragments) but not the intact Bt gene were found in blood, liver, spleen, and kidney of pigs raised on Bt maize ( Mazza et al., 2005 ).

FINDING: Experiments have found that Cry1Ab fragments but not intact Bt genes can pass into organs and that these fragments present concerns no different than other genes that are in commonly consumed non-GE foods and that pass into organs as fragments.

FINDING: There is no evidence that Bt transgenes or proteins have been found in the milk of ruminants. Therefore, the committee finds that there should be no exposure to Bt transgenes or proteins from consuming dairy products.

OVERALL FINDING ON PURPORTED ADVERSE EFFECTS ON HUMAN HEALTH OF FOODS DERIVED FROM GE CROPS: On the basis of detailed examination of comparisons of currently commercialized GE and non-GE foods in compositional analysis, acute and chronic animal-toxicity tests, long-term data on health of livestock fed GE foods, and human epidemiological data, the committee found no differences that implicate a higher risk to human health from GE foods than from their non-GE counterparts.

• ASSESSMENT OF HUMAN HEALTH BENEFITS FROM GENETICALLY ENGINEERED CROPS

There are now a number of examples of crops, either commercialized or in the pipeline toward commercialization, that have GE traits that could improve human health. Improvement of human health can be the sole motivation for development of a specific crop trait, or it can be the secondary effect of a crop trait that is developed primarily for another reason. For example, the genetic engineering of rice to have higher beta-carotene has the specific goal of reducing vitamin A deficiency. GE maize that produces Bt toxins is engineered to decrease insect-pest damage, but a secondary effect could be a decrease in contamination of maize kernels by fungi that produce mycotoxins, such as fumonisins, that at high concentrations could impair human health. Beyond the direct effects of the crops on improvement of human health, there is also a potential indirect benefit associated with a decline in the exposure of insecticide applicators and their families to some insecticides because some GE plants decrease the need for insecticidal control.

Foods with Additional Nutrients or Other Healthful Qualities

Improved micronutrient content.

According to WHO, some 250 million preschool children are vitamin A–deficient. Each year, 250,000–500,000 vitamin A–deficient children become blind, and half of them die within 12 months of losing their sight. 6 Unlike children in wealthier societies, those children have diets that are restricted mostly to poor sources of nutrients, such as rice ( Hefferon, 2015 ). Overall improvement of the diets of the children and their parents is a goal that has not been reached; measures that improve the nutritional quality of their food sources are desirable although not optimal, as a diverse, healthy diet would be.

Crop breeders have used conventional breeding to improve the concentrations of beta-carotene in maize ( Gannon et al., 2014 ; Lividini and Fiedler, 2015 ), cassava, banana and plantain ( Musa spp.) ( Saltzman et al., 2013 ), and sweet potato ( Ipomoea batatas ) ( Hotz et al., 2012a , b ). There is some loss of beta-carotene during storage and cooking, but bioavailability is still good ( Sanahuja et al., 2013 ; De Moura et al., 2015 ). The most rigorous assessments of the effects of those high–beta-carotene varieties were conducted with orange-fleshed sweet potato (high in beta-carotene) in farming areas of Mozambique and Uganda. In both countries, there was increased beta-carotene intake. In Uganda, there was a positive relationship between consumption of high–beta-carotene sweet potato and positive vitamin A status ( Hotz et al., 2012a ). A more recent study in Mozambique found a decrease in diarrhea prevalence associated with consumption of the high–beta-carotene sweet potato ( Jones and DeBrauw, 2015 ).

No reported experiments have tested any crop with high–beta-carotene for unintended effects. There has been concern about the potential for too high a concentration of beta-carotene in crops because of the hypervitaminosis A syndrome that can be caused by direct intake of too much vitamin A, but that is not a problem when the source is beta-carotene ( Gannon et al., 2014 ).

Golden Rice, which was produced through genetic engineering to increase beta-carotene content, is one of the most recognized examples of the use of genetic-engineering technology to improve a crop's nutritional value. It is based on the understanding that rice possesses the entire machinery to synthesize beta-carotene in leaves but not in the grain. The breakthrough in the development of Golden Rice was the finding that only two genes are required to synthesize beta-carotene in the endosperm of the rice grain ( Ye et al., 2000 ). The first version of Golden Rice had a beta-carotene content of 6 µg/g. To raise the content to a point where it could alleviate vitamin A deficiency without consumption of very large amounts of rice, a second version of Golden Rice was produced by transforming the plant with the psy gene from maize. The carotene content was thereby raised above 30 µg/g ( Paine et al., 2005 ). Varieties that yield well, have good taste and cooking qualities, and cause no adverse health effects from unintended changes in the rice could have highly important health effects ( Demont and Stein, 2013 ; Birol et al., 2015 ). There have been claims that Golden Rice was ready for public release for well over a decade ( Hefferon, 2015 ), but this is not the case.

There is a publication on a field test of the first version of Golden Rice ( Datta et al., 2007 ), but the committee could not find information on the newer, higher–beta-carotene Golden Rice in the peer-reviewed literature. Therefore, it contacted the International Rice Research Institute (IRRI) Golden Rice project coordinator, Violeta Villegas, for an update on the status of the project. In discussions with Dr. Villegas (IRRI, personal communication, 2015), it was clear that the project is progressing with a new lead transgenic event, GR2-E, because of difficulties with the previous lead event, GR2-R. The GR2-E event has been backcrossed into varieties that have been requested by several countries including the Philippines, Bangladesh, and Indonesia. As of March 2016, Golden Rice GR2-E in PSBRc82 and BRRI dhan20 genetic backgrounds was being grown in confined field tests in the Philippines and Bangladesh, respectively. Both Golden Rice varieties underwent preliminary assessment inside the greenhouse prior to planting in confined field tests. If performance is good, the varieties will be moved to open field-testing on multiple locations. Once a food regulatory approval is received in one of the participating countries, IRRI will supply the rice with the GR2-E event to an independent third party to assess its efficacy at alleviating vitamin A deficiency.

Past issues with persons and organizations opposed to Golden Rice for a myriad of reasons may have affected IRRI's work on the rice, but the overall project status 7 points out that development of Golden Rice varieties that meet the needs of farmers and consumers and that are in full compliance with the regulatory systems of the partnering countries remains the primary objective. IRRI's summary statement on its Golden Rice project was that “Golden Rice will only be made available broadly to farmers and consumers if it is successfully developed into rice varieties suitable for Asia, approved by national regulators, and shown to improve vitamin A status in community conditions. If Golden Rice is found to be safe and efficacious, a sustainable delivery program will ensure that Golden Rice is acceptable and accessible to those most in need.” 8

Increasing concentrations of beta-carotene is only one goal of conventional crop breeding and genetic engineering. Projects for increasing iron and zinc in crops as different as wheat, pearl millet ( Pennisetum glaucum ), and lentil ( Lens culinaris ) are at varied stages of development ( Saltzman et al., 2013 ).

FINDING: Experimental results with non-GE crop varieties that have increased concentrations of micronutrients demonstrate that both GE and non-GE crops with these traits could have favorable effects on the health of millions of people, and projects aimed at providing these crops are at various stages of completion and testing.

Altering Oil Composition

Substantial efforts have been made to increase the oxidative stability of soybean oil, a major cooking oil all over the world, as a means of avoiding trans-fats generated through the hydrogenation process and enhancing omega-3 fatty acid content of the oil for use in both food and feed applications. Soybean oil is composed principally of five fatty acids: palmitic acid (16:0, carbon number:double bond number), stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2), and linolenic acid (18:3) in approximate percentages of 10, 4, 18, 55, and 13. High content of unsaturated fats creates a disadvantage in industrial processing because they are susceptible to oxidation and trans-fat generation during hydrogenation, whereas oils with a high percentage of oleic acid (about 80 percent) require less processing and offer another route to decrease concentrations of trans-fats in food products. High-oleic acid-containing soybean was produced by downregulating expression of the fatty acid desaturating enzymes FAD2-1A and -1B to decrease the concentration of trans-fats in soybean ( EFSA, 2013 ). In 2015, high-oleic acid soybean was commercially available in North America and was produced on a small area in the United States for specialty-product contracts (C. Hazel, DuPont Pioneer, personal communication, December 14, 2015).

Canola ( Brassica napus ), known in Europe as rapeseed, is the major oilseed crop in Canada. Canola was developed through conventional breeding at the University of Manitoba, Canada, by Downey and Stefansson in the early 1970s and had a good nutritional profile—58-percent oleic acid and 36-percent polyunsaturated fatty acids—in addition to low erucic acid and a moderate concentration of saturated fatty acid (6 percent). Because of demand for saturated functional oils for the trans - fat–free market, high-lauric acid GE canola was created in 1995 through an “ Agrobacterium mediated transformation in which the transfer-DNA (T-DNA) contained the gene encoding the enzyme 12:0 ACP thioesterase ( bay TE ) from the California Bay tree ( Umbellularia californica ). In addition, the T-DNA contained sequences that encoded the enzyme neomycin phosphotransferase II (NPTII). The expression of NPTII activity was used as a selectable trait to screen transformed plants for the presence of the bay TE gene. No other translatable DNA sequences were incorporated into the plant genome” ( Health Canada, 1999:1 ). The presence of lauric acid (12:0) in the oil allows it to be used as a replacement for other types of oils with lauric acid (for example, coconut and palm kernel oil) in such products as “confectionery coatings and fillings, margarines, spreads, shortenings, and commercial frying oils. It has also been used as a substitute for cocoa butter, lard, beef fats, palm oil, and partially or fully hydrogenated soybean, maize, cottonseed, peanut, safflower, and sunflower oils” ( Health Canada, 1999:2 ). However, low yield and comparably poor agronomic traits have removed high-lauric acid canola from the commercial market. The long-term use of crops with altered oil content is uncertain.

FINDING: Crops with altered oil composition might improve human health, but this will depend on the specific alterations, how the crops yield, and how the products of the crops are used.

Genetically Engineered Foods with Lower Concentrations of Toxins

Acrylamide is produced in starchy foods when they are cooked at high temperatures. Processing of potatoes for French fries and potato chips generates acrylamide. Toasting bread also produces acrylamide. That is viewed as a problem because the U.S. National Toxicology Program (2014) concluded that acrylamide “is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals” and causes neurological damage at high exposure. Acrylamide is produced from a chemical reaction between asparagine and a reducing sugar, so decreasing the concentration of either is expected to decrease acrylamide. A potato line was genetically engineered to have low amounts of free asparagine and in early tests had as little as 5 percent of the acrylamide compared with non-GE potatoes when cooked at high temperatures ( Rommens et al., 2008 ).

In 2014, USDA deregulated a low-acrylamide potato produced by Simplot Plant Sciences (USDA–APHIS, 2014c) on the basis of nonplant pest status. The company also provided information to FDA. No problems were found by FDA with respect to the company's assessment of composition or safety ( FDA, 2015 ). It should be noted that for many people reduced acrylamide in potatoes is expected to lower overall acrylamide intake substantially, but many foods contain acrylamide ( FDA, 2000b , revised 2006). An FDA survey of commonly consumed foods showed French fries at seven McDonald's locations had an average acrylamide concentration of 288 parts per billion (ppb), whereas Gerber Finger Foods Biter Biscuits had 130 ppb and Wheatena Toasted Wheat Cereal had 1,057 ppb, which is much more than from fast-food French fries ( FDA, 2002 , revised 2006). 9 Any toasted bread is expected to be high in acrylamide. Therefore, how much low-acrylamide potato decreases total exposure depends on individual diets. Furthermore, EPA has established limits for exposure to acrylamide, and current actual exposures are generally below the limits.

Although the low-acrylamide potato is the only GE crop with a lower food-toxin concentration that has been deregulated in the United States, other GE crops with lower natural toxin concentrations are in the pipeline. Potatoes and other crops in the “deadly nightshade” family (Solanaceae, which includes tomato and eggplant) produce glycoalkaloids, some of which have human toxicity, as described above (see the section “Endogenous Toxins in Plants” in this chapter). Langkilde et al. (2012) conducted a compositional and toxicological analysis of the potatoes with lower solanine and higher chaconine. The study used Syrian golden hamsters instead of rats because the hamsters are very sensitive to the glycoalkaloids. There were some statistically significant differences, but they were considered not of biological relevance. At this point, the evidence is not sufficient to conclude that a low-glycoalkaloid potato would be healthier for humans.

Highly toxic chemicals (aflatoxins and fumonisins) are produced by Fusarium and Aspergillis fungi on the kernels of maize ( Bowers et al., 2014 ). Aflatoxins are considered by the U.S. National Toxicology Program (2014) to be “human carcinogens based on sufficient evidence of carcinogenicity from studies in humans.” They are also associated with many other illnesses and considered a global health problem ( Wild and Gong, 2010 ). Fumonisins cause a number of physiological disorders and are considered possibly carcinogenic to humans ( IARC, 2002 ). Several investigators have reported a substantial decrease in fumonisins in Bt maize compared with conventionally bred varieties ( Munkvold and Desjardins, 1997 ; Bowers et al., 2014 ). However, there is no clear association between Bt maize and aflatoxin concentrations ( Wiatrak et al., 2005 ; Abbas et al., 2007 ; Bowen et al., 2014 ).

Research continues on how to use genetic engineering to develop varieties of maize and peanut ( Arachis hypogaea ) that inhibit aflatoxin production, but a GE solution has so far been elusive ( Bhatnagar-Mathur et al., 2015 ). A reduction in aflatoxin in both maize and peanut would have substantial health benefits in some developing countries ( Williams et al., 2004 ; Wild and Gong, 2010 ).

FINDING: It is possible that GE crops that would result in improved health by lowering exposure of humans to plant-produced toxins in foods could be developed, but there is insufficient information to assess the possibility. However, GE plants that indirectly or directly reduce fungal-toxin production and intake would offer substantial benefits to some of the world's poorest populations, which have the highest dietary intake of food-associated fungal toxins.

Health Effects of Farmer Exposure to Insecticides and Herbicides

Chapter 4 presents data that demonstrate substantially lower use of insecticides in some Bt crops than in conventionally bred crops. There is a logical expectation that a decrease in the number of insecticide applications would lead to lower farm-worker exposure and therefore lower health burden, especially in countries where acute poisonings due to applicator exposure are common. Racovita et al. (2015) reviewed five studies of Bt cotton in China, India, Pakistan, and South Africa that ranged from one to four growing seasons. All reported a decline in the number of insecticide applications to Bt versus non- Bt cotton. In a study in China by Huang et al. (2002) , Bt cotton was treated with insecticides 6.6 times and non- Bt cotton was treated 19.8 times during the growing season. The frequency of Bt and non- Bt cotton farmers reporting poisonings were 5 percent and 22 percent, respectively in 1999, 7 percent and 29 percent in 2000, 8 percent and 12 percent in 2001. Kouser and Qaim (2011) found fewer overall insecticide treatments in a study conducted in India: 1.5 treatments of Bt cotton and 2.2 treatments of non- Bt cotton. In this study, the farmers who used Bt cotton reported 0.19 poisonings per season while those with conventionally bred cotton reported 1.6 poisonings. Bennett et al. (2006) studied the same types of farmers in South Africa. Bt cotton was not yet widely available in the beginning of the experiment, but eventually some farmers adopted Bt cotton and decreased spraying. The study looked at overall poisonings according to hospital records over time; there were 20 poisonings in the year before common availability of Bt cotton and four in a later year, when there was 60 percent adoption of Bt cotton.

The findings of those and other studies (for example, Huang et al., 2005 ; Dev and Rao, 2007 ; Kouser and Qaim, 2013 ) are in line with an expectation of a decrease in poisonings when Bt cotton is grown instead of non- Bt cotton. However, Racovita et al. (2015:15) , who carefully assessed each of the studies, found many shortcomings that led them to conclude that “the link between [genetically modified] crop cultivation and a reduction in number of pesticide poisonings should be considered as still circumstantial.” The shortcomings include the fact that the number of poisonings is based on farmer recall of incidents sometimes more than a year after the field season or, in the Bennett et al. (2006) study, simply based on hospital cases. Another issue was that there may have been differences in risk–avoidance behavior between farmers who did and did not plant Bt cotton. Finally, the studies focused on farmers, not farm workers, who do not control farm operations. Racovita et al. (2015) called for more rigorous studies that would address the shortcomings of previous studies, given the politicized nature of the use of Bt crops.

Farm-worker exposure to insecticides and herbicides is lower in the United States and some other developed countries than is the case for farm workers on resource-poor farms. However, there is substantial exposure, and any effects seen in the United States would be of global concern. Prospective cohort studies of health are the high benchmark of epidemiology studies, and the Agricultural Health Study (AHS) funded by the U.S. National Institute of Environmental Health Sciences used this approach to evaluate private and commercial applicators in Iowa and North Carolina. The landmark study resulted in two peer-reviewed articles on glyphosate exposure and cancer incidence ( De Roos et al., 2005 ; Mink et al., 2012 ) and one on glyphosate exposure and non-cancer health outcomes ( Mink et al., 2011 ). De Roos et al. (2005:49) concluded that “glyphosate exposure was not associated with cancer incidence overall or with most cancer subtypes we studied.” The data suggested a weak association with multiple myeloma on the basis of a small number of cases, but that association was not found in a follow-up study ( DeRoos et al., 2005 ; Mink et al., 2012 ). Mink et al. (2012:440) reported on the continuation of the AHS cohort study and found “no consistent pattern of positive associations indicating a causal relationship between total cancer (in adults or children) or any site-specific cancer and exposure to glyphosate.” Mink et al. (2011) reviewed noncancer health outcomes that included respiratory conditions, diabetes, myocardial infarction, reproductive and developmental outcomes, rheumatoid arthritis, thyroid disease, and Parkinson's disease. They reviewed cohort, case–control, and cross-sectional studies within the AHS study and found “no evidence of a consistent pattern of positive associations indicating a causal relationship between any disease and exposure to glyphosate” ( Mink et al., 2011:172 ).

FINDING: There is evidence that use of Bt cotton in developing countries is associated with reduced insecticide poisonings. However, there is a need for more rigorous survey data addressing the shortcomings of existing studies.

FINDING: A major government-sponsored prospective study of farm-worker health in the United States does not show any significant increases in cancer or other health problems that are due to use of glyphosate.

• ASSESSMENT OF FOOD SAFETY OF CROPS TRANSFORMED THROUGH EMERGING GENETIC-ENGINEERING TECHNOLOGIES

Increased Precision and Complexity of Genetic-Engineering Alterations

At the time that the committee wrote its report, major commercialized GE crops had been engineered by using Agrobacterium tumefaciens mediated or gene gun-mediated transformation, both of which result in semirandom insertion of the transgene into the genome. Variation in expression of the transgene was routinely observed because of the specific genomic characteristics of the insertion sites. Because of that variation, there was a need to screen large numbers of transgenic plants to identify the optimal transgenic individual. Regulations in the United States require approval of each transformation event regardless of whether the transgene itself was previously approved for release in that crop. That is at least in part because of the potential for unintended effects of each insertion.

Precision genome-editing technologies now permit insertion of single or multiple genes into one targeted location in the genome and thereby eliminate variation that is due to position effects (see Chapter 7 ). Such precision is expected to decrease unintended effects of gene insertion, although it will not eliminate the effects of somaclonal variation (discussed in Chapter 7 ).

Consider, for example, the engineering of completely new metabolic pathways into a plant for nutritional enhancement. The simplest example would be a set of two genes, such as has been used to create Golden Rice to deliver precursors of vitamin A. A more complex example would be engineering of fish oils (very long-chain unsaturated fatty acids) to improve the health profile of plant oils; depending on the target species, this process has required introduction of at least of three and at most nine transgenes ( Abbadi et al., 2004 ; Wu et al., 2005 ; Ruiz-Lopez et al., 2014 ). If each of those transgenes is integrated into the genome on a different chromosome on the basis of separate insertion events, it will require a number of generations of crosses to put them all together in one plant. If, instead, all the transgenes could be targeted at the same site on a chromosome either simultaneously or one after another, they would not segregate from each other as they were moved into elite varieties. From a food-safety perspective, engineering transgenes into a single target locus also ensures that expression of the whole pathway is preserved so that the correct end product accumulates. Emerging genetic-engineering technologies currently enable insertion of a few genes in one construct, but in the future that number may increase dramatically.

In the future, the scale of genetic-engineering alterations may go much further than just manipulating oil profiles. The committee heard from speakers about projects aimed at changing the entire photosynthetic pathway of the rice plant ( Weber, 2014 ) to create an entirely novel crop ( Zhu et al., 2010 ; Ruan et al., 2012 ). The committee also heard from researchers interested in developing cereal crops with nitrogen fixation. Those projects are discussed further in Chapter 8 . Although the precision of future genetic-engineering alterations should decrease unintended effects of the process of engineering, the complexity of the changes in a plant may leave it not substantially equivalent to its non-GE counterpart.

It is also important to note that crops that use RNA interference (RNAi) were coming on the market when the committee was writing its report. EPA convened a science advisory panel to evaluate hazards that might arise from use of this genetic-engineering approach. The panel concluded that “dietary RNA is extensively degraded in the mammalian digestive system by a combination of ribonucleases (RNases) and acids that are likely to ensure that all structural forms of RNA are degraded throughout the digestive process. There is no convincing evidence that ingested [double-stranded] RNA is absorbed from the mammalian gut in a form that causes physiologically relevant adverse effects” ( EPA, 2014c:14 ). When the committee was writing its report, deployment of dietary RNAi was a new technology. EPA's panel made a number of recommendations, including investigating factors that may affect absorption and effects of dietary double-stranded RNAs and investigating the stability of double-stranded RNA in people who manifest diseases.

FINDING: The precision of emerging genetic-engineering technologies should decrease some sources of unintended changes in the plants, thus simplifying food-safety testing. However, engineering involving major changes in metabolic pathways or insertion of multiple resistance genes will complicate the determination of food safety because changes in metabolic pathways are known to have unexpected effects on plant metabolites.

Increased Diversity of Crops To Be Engineered

The most far-ranging effects of emerging genetic-engineering technologies may be the diversity of crops that will be engineered and commercialized. Commercial GE crops at the time the committee conducted its review were mainly high-production commodity crops (maize, soybean, and cotton) engineered with trans-kingdom genes, but the applications of emerging genetic-engineering technologies are much broader: these technologies can be easily applied to any plant species that can be regenerated from tissue culture. Furthermore, the emerging technologies described in Chapter 7 can focus on any gene in which an altered nucleotide sequence results in a desired trait.

As a consequence, the committee expects a sizable increase in the number of food-producing crop species that are genetically altered. Examples of new target crops include forages (grasses and legumes), beans, pulses, a wide array of vegetables, herbs, and spices, and plants grown for flavor compounds. New traits will probably include fiber content (either increased to add more fiber or decreased to improve digestibility), altered oil profiles, decreased concentrations of antinutrients, increased or more consistent concentrations of such phytochemicals as antioxidants (for example, flavonoids) and phytoestrogens (for example, isoflavones or lignans), and increased mineral concentrations. Some of these are considered further in Chapter 8 .

From a food-safety perspective, the increase in crops and traits presents a number of challenges. First is the need to develop better and more detailed baseline data on the general chemical composition and probably the transcriptomic profiles of currently marketed conventionally bred varieties of the crops (see Chapter 7 ). Perhaps more problematic will be designing whole-food animal-testing regimens if the food from the crop cannot be used as a major component of the test animals' diet. Maize, rice, soybean, and other grains can be added to diets at up to 30 percent without adverse effects on animal health. That is unlikely to be the case with new spices or some vegetables. It would be beneficial if new, publicly acceptable approaches for testing could be developed that do not require animal testing ( NRC, 2007 ; Liebsch et al., 2011 ; Marx-Stoelting et al., 2015 ). Chapter 9 addresses the potential need to move to an entirely product-based approach to regulation and testing based on the novelty of a new crop or food.

FINDING: Some future GE crops will be designed to be substantially different from current crops and may not be as amenable to animal testing as currently marketed GE crops.

RECOMMENDATION: There is an urgent need for publicly funded research on novel molecular approaches for testing future products of genetic engineering so that accurate testing methods will be available when the new products are ready for commercialization.

• CONCLUSIONS

The committee's objective in this chapter was to examine the evidence that supports or negates specific hypotheses and claims about the risks and benefits associated with foods derived from GE crops. As acknowledged at the beginning of the chapter, understanding the health effects of any food, whether non-GE or GE, can be difficult. The properties of most plant secondary metabolites are not understood, and isolating the effects of diet on animals, including humans, is challenging. Although there are well-developed methods for assessing potential allergenicity of novel foods, these methods could miss some allergens. However, the research that has been conducted in studies with animals and on chemical composition of GE foods reveals no differences that would implicate a higher risk to human health from eating GE foods than from eating their non-GE counterparts. Long-term epidemiological studies have not directly addressed GE food consumption, but available time-series epidemiological data do not show any disease or chronic conditions in populations that correlate with consumption of GE foods. The committee could not find persuasive evidence of adverse health effects directly attributable to consumption of GE foods.

New methods to measure food composition that involve transcriptomics, proteomics, and metabolomics provide a broad, nontargeted assessment of thousands of plant RNAs, proteins, and compounds. When the methods have been used, the differences found in comparisons of GE with non-GE plants have been small relative to the naturally occurring variation found in conventionally bred crop varieties. Differences that are detected by using -omics methods do not on their own indicate a safety problem.

There is some evidence that GE insect-resistant crops have had benefits to human health by reducing insecticide poisonings and decreasing exposure to fumonisins. Several crops had been developed or were in development with GE traits designed to benefit human health; however, when the committee was writing its report, commercialized crops with health benefits had been only recently introduced and were not widely grown, so the committee could not evaluate whether they had had their intended effects.

New crops developed with the use of emerging genetic-engineering technologies were in the process of being commercialized. The precision associated with the technologies should decrease some sources of unintended changes that occur when plants are genetically engineered and thus simplify food-safety testing. However, engineering involving major changes in metabolic pathways or insertion of multiple resistance genes will complicate the determination of food safety because changes in metabolic pathways are known to have unexpected effects on plant metabolites. Therefore, publicly funded research on novel approaches for testing future products of genetic engineering is needed so that accurate testing methods will be available when the new products are ready for commercialization.

The committee has compiled publicly available information on funding sources and first-author affiliation for the references cited in this chapter; the information is available at https://www ​.nationalacademies ​.org/ge-crops .

In November 2015, EPA took steps to withdraw the product's registration in light of new information that indicated there could be synergistic effects of the two herbicides, which could possibly result in greater toxicity to nontarget plants ( Taylor, 2015 ). A court ruling in January 2016 allowed the herbicide to remain on the market while EPA considered other administrative actions ( Callahan, 2016 ).

GE rice was not commercialized in 2015, but GE varieties in development have been tested.

OECD develops consensus documents that provide reference values for existing food crops ( OECD, 2015 ). These are publicly available online at http://www ​.oecd.org/science ​/biotrack/consensusdocumentsfortheworkonthesafetyofnovelfoodsandfeedsplants.htm (accessed May 9, 2016). The International Life Science Institute (ILSI) also maintains a crop composition database at www ​.cropcomposition.org (accessed May 9, 2016). ILSI reports that in 2013 the database contained more than 843,000 data points representing 3,150 compositional components.

Jung, R., W.-N. Hu, R.B. Meeley, V.J.H. Sewalt, and R. Nair. Grain quality through altered expression of seed proteins. U.S. Patent 8,546,646, filed September 14, 2012, and issued October 1, 2013.

Micronutrient deficiencies. Available at http://www ​.who.int/nutrition ​/topics/vad/en/ . Accessed October 30, 2015.

What is the status of the Golden Rice project coordinated by IRRI? Available at http://irri ​.org/golden-rice ​/faqs/what-is-the-status-of-the-golden-rice-project-coordinated-by-irri . Accessed October 30, 2015.

Acrylamide concentrations reported by FDA were for individual purchased food products and were not adjusted for unit-to-unit variation.

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Vet World   Vol.17     May-2024   Article - 18 

Research Article

Veterinary World, 17(5): 1098-1107

https://doi.org/10.14202/vetworld.2024.1098-1107

Effect of dietary Arthrospira platensis phycocyanin on broiler chicken growth performance, physiological status, fatty and amino acid profiles

Background and Aim: Natural antioxidants are crucial for preserving and enhancing the health, survival, reproduction, and reproductive function of poultry. Phycocyanin (PC) is a natural blue food colorant with various health benefits. The aim of this study was to extract Arthrospira platensis phycocyanin (ApPC) from A. platensis using simple and economical methods and investigate the impact of phytocyanin supplementation on the performance and fatty and amino acid profiles of broiler chicks.

Materials and Methods: PC was extracted from A. platensis by freezing and thawing, and optimization conditions such as pH and temperature were applied during storage periods. A total of 270 1-week-old Ross breed broiler chicks were randomly assigned to the following three treatment groups: basal diet supplemented with 0 mg of PC/kg diet (control), basal diet supplemented with 1 g PC/kg diet (T1), and basal diet supplemented with 2 g PC/kg (T2). In a completely randomized design, three cage replicates (30 birds each) were assigned to each of the three groups. The dietary effects of ApPC on growth performance (body weight gain [BWG], body weight [BW], feed intake, feed conversion ratio, serum constituents, and antioxidant indices) in broiler chickens, free amino acids, and fatty acids in muscles were evaluated. 

Results: Total BWG and BW increased without a significant effect on the total feed consumption. Serum levels of total proteins and albumin increased with increasing ApPC supplementation. In addition, globulin levels significantly increased. There was a significant decrease in serum total cholesterol levels among the treatments. The activity of antioxidant enzymes (superoxide dismutase, catalase, glutathione, and total antioxidant capacity) is significantly increased. In contrast, an increase in ApPC caused a significant decrease in malondialdehyde. The content and quantity of fatty acids and amino acids in the meat of broiler chicks supplemented with PC varies. 

Conclusion: The addition of PC to broiler chicken diets enhances antioxidant activities, BW, BWG, and meets quality requirements. 

Keywords: Antioxidant, fatty acid, Phycocyanin, poultry, protein, Spirulina.

How to cite this article: El-AbdNM, Hamouds RA, Saddiq AA, Al-Shaikh TM, Khusaifan TJ, and Abou-El-Souod G (2024) Effect of dietary Arthrospira platensis phycocyanin on broiler chicken growth performance, physiological status, and fatty and amino acid profiles, Veterinary World, 17(5): 1098-1107.

Received: 2024-02-04    Accepted: 2024-04-23    Published online: 2024-05-17

Corresponding author: Ragaa A. Hamouds    E-mail: [email protected]

DOI: 10.14202/vetworld.2024.1098-1107

Copyright: El-Abd, et al. This article is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/ by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Research Paper

Published on 2024-05-17.

Effects of feeding pomegranate seed pulp and coconut meal by-products on milk yield, milk quality, and metabolic responses of Awassi ewes and pre-weaning growth

Belal S. Obeidat, Manal H. Qadorah, and Milton G. Thomas

doi:10.14202/vetworld.2024.1149-1156

Volume-17 | Issue-5 | Article-24

Effects of herbal plant supplementation on rumen fermentation profiles and protozoan population in vitro

Antonius Antonius, Roni Pazla, Ezi Masdia Putri, Muhammad Ichsan Alma’i, Erika Budiarti Laconi, Didid Diapari, Anuraga Jayanegara, Laily Rinda Ardani, Leni Marlina, Riris Delima Purba, Ruslan Abdul Gopar, Windu Negara, Sharli Asmaraicen, and Putut Suryo Negoro

doi:10.14202/vetworld.2024.1139-1148

Volume-17 | Issue-5 | Article-23