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Food Toxicology: Genetically Modified Foods and Human Health Josef G. Thundiyil, MD, MPH, FACEP, FACMT Orlando Health ACMT Spring Course 2015
Objectives
Provide a scientific review of the health effects of GMO
Identify food sources of GMO
Discuss controversies
Examine recommendations regarding diet
Disclosures
Nothing to Disclose
Highly Politicized Topic Anxiety about unknown
vs. risk to human health
Concerns Environmental
Threat to biodiversity Ecological impact Animal rights Destruction of non target
organisms
Philosophical Playing God Integrity of the order of species Fear of unknown Few companies have large market
share and control
Human health Allergenicity
Toxicity Pesticide use Gene transfer Stability of gene Nutritional effects
Benefits
Food availability
Resistance to pesticide, viruses, diseases
Weed/drought/freeze resistance
Prolonged shelf life
Crop yield
Lower price
Decrease pesticide use
Improved nutritional value
Revolution in Biotechnology
Meet challenge of population growth
Consistent food supply
Counter world hunger
Political stability
What is GMO?
Genetically modified organism DNA has been altered (plants or animals)
Not “naturally” (mating or recombination)
Allows genes to be transferred between organisms
AKA gene technology, genetic engineering
Plant breeding Unconscious! deliberate saving of seeds
Domestication Selection of favorable traits
Mendelian genetics
Evolving science
Selective Breeding
Overlap and similarities but: Faster
Can introduce a gene that is not naturally occuring
Can occur between different species (eg. Human to bacteria)
Methods of DNA transfer DNA microinjection
Retrovirus mediated gene transfer
Stem Cell mediated gene transfer
Worldwide GMO use United States 42% acreage
88% of corn
93% of soy
94% of cotton
75% of papaya
90% canola
54% sugar
Worldwide 12% Brazil 17%
Argentina 16%
India 6%
Canada 6%
Europe <1%
Crops also used for animal feed
Traits
1st generation Resistance to herbicides, pests, diseases, viruses
2nd generation Increased protein, healthier fats, improved
flavor
3rd generation Drought and freeze resistance
Other Drugs, biofuels, bioluminescence
Most Common Traits Resistance toward herbicides- HT (80%)
Glyphosate resistant (Roundup Ready) Inhibitor of 5-enolpyruvylshikimate-3phosphate synthase (EPSPS)
Amino acid pathway
Replaced with gene of EPSPS from bacteria CP4 EPSPS
Resistance toward insect damage Bacillus thuringiensis (Bt)
Natural toxin: Cry endotoxin, VIP
Used in organic farming
Short lived
Inserts into insect gut and damages
GMO Health Effects >4000 studies
Overwhelming support for safety of GMO
Environment
Many animal species
Many types of GMO
Drawbacks Short term studies: 30-90 days
Gross measures Mortality
Weight gain
Macroscopic evaluation
Paucity of human studies
National/International Organizations Endorse GMO
Safe for human consumption
WHO
FDA
USDA
EPA
National Academy of Sciences
CDC
European Food Safety Authority
New food
These are for population or areas of food insecurity
Standard is “substantial equivalence”
Is lack of evidence confirming danger confirmation of safety?
Many conventional crops have toxicities
Potential Health Effects
Allergenicity
Toxicity
Gene Transfer
Herbicide use
Allergenicity
Nordlee, Taylor et al. NEJM, 1996 2s albumin from Brazil nut transgenically added to soybean. 3 subjects with Brazil nut allergy exposed with skin prick from
soybean extracts and conventional soy All 3 had reactions to brazil nut, GM soy and negative for soy
Immune blotting 8/9 subjects IgE bound to Brazil nut and GM soybeans
Transfer of allergenic property can occur through genetic modification
Allergenicity 2001 StarLink corn- Bt meant for animal feed made its way
into human food supply with Cry9c- potential allergen Found in taco shells Extensive media coverage
CDC investigated Case definition and used questionnaires to ID 28 subjects in
15 states through AERS Secured serum samples and tested for IgE reactivity to Cry9c
and compared to banked 1996 pre StarLink blood All were non-reactive
No allergic reactions to GM foods on the market Most common food allergens are not GMO
milk, eggs, peanuts, tree nuts, fish, shellfish, soy, and wheat Still on shelves
Toxicity on Intestines
Research Letter Lancet, Pustzai et al. 1999 Rats fed GM potatoes vs conventional
Evaluated rat intestines
Groups of 6 rats fed for 10 days Raw/boiled: GM potatoes, conventional potatoes,
conventional potatoes with GM protein supplemented
Rats fed GM potatoes Raw: increase proliferation of jejunum
Boiled: Hyperplasia of stomach
Decreased proliferation of cecum
Toxicity 168 pigs 1:1 randomization GM soy/corn or non GM diet
22.7 weeks slaughtered and eval by blinded vet
No difference on feeding, weight gain, organ weights, mortality, blood markers
GM pigs Uteri 25% heavier
Higher rate of severe stomach inflammation 32% v 12% p=0.004
Carman et al, Journal of Organic Systems 2013
Abnormal hearts: GM pigs 6%; control group 15%
GM Conventional
Toxicity- Long Term
10 rats randomized to diet to GM maize vs. conventional maize for 2 years Females developed large mammary tumors
94 days before controls
Liver abnormalities 2.5-5.5 times more common than controls
Pituitary tumors more common in GM group
Mortality 25% in controls; 60% in GM
Unlimited access to food/ food intake not reported
Seralini et al 2014
Study was eventually retracted by the journal
Long Term Toxicity Review of 12 long term and 12 multigenerational studies 90 days to
2 years No signs of toxicity overall Sheep: changes in liver nuclei Mice
B cell compartment expanded lymphoid tissue in GM wheat Different expression of liver proteins in HT Soy Microscopic pancreas changes in HT Soy
Hisological differences in liver in HT Soy Rats
Bt maize minor histological changes in liver and kidney Salmon: mid intestine smaller in HT Soybean
Relevance of differences in unknown Natural variation Non GM (control groups) no isogenic lines used Indicate need for further study
Snell et al, 2012
Gene Transfer
Transfer a novel trait to a new organism that may be harmful
Silence genes
Change gene expression
Develop toxic compound
Mutagenesis
Absorption into systemic circulation or milk
Humans consume 0.1-1 g/day of DNA
Antibiotic Resistance
Transfer of new gene to plant is inefficient 5 in 1000 cells
To determine which cells have taken up gene a marker is used Antibiotic resistance is one such marker Cells are treated with antibiotic Only cells with transferred gene survive
Factors are considered Antibiotic importance Resistance patterns in soil and gut flora
Kanamycin resistance Not used: ampicillin resistance, amikacin resistance
Gene transfer
Phipps et al. 2005
GM corn fed to 60 lactating dairy cows for 12 weeks
Weekly samples obtained No transgenic DNA detected in milk
No difference in milk yield or composition
Study in chickens showed no DNA made it to small intestines
Oral Gene Transfer
Schubbert 1997 DS DNA given orally to 6 m/6 f mice
Fragments of DNA were recovered, small intestine, large intestine, feces and blood of mice in decreasing amounts
0.05% DNA in circulation
Likely transferred through intestinal wall Unknown mechanism
Intestinal tract is not an absolute barrier for absorption of DNA
Human study
7 ileostomy patients and 12 control fasted Baseline stool sample then fed GM soy burgers and GM
soy milk shake and marker
Stool samples for 72 hours collected
3 ileostomy subjects showed evidence of prexisting gene in stool
No transgene in controls
0.1 to 3.7% of transgene
recovered in case
Netherwood et al, Nature Biotech 2004
Gene transfer Very low likelihood event
Horizontal gene transfer is orders of magnitude lower than vertical gene transfer: 1 in 1012
Even transfer to bacteria occurs spread is small
10% of gut bacteria has some antibiotic resistance
We eat antibiotic resistance from soil (e.g. kanamycin)
No evidence that gene transfer to flora or into mammalian DNA occurs
No laboratory evidence of gene transfer from eukaryote to bacteria
Occurs in traditional breeding More consistency in transgenic crops
Herbicide Use 80% of GM crops are HT
Decreased herbicide use…initially
Increase in glyphosate use Based on ecological studies
Fewer alternative herbicides
Bonny S, 2001 Sustainability
Is increasing glyphosate use a concern?
Glyphosate toxicity
Inhibits EPSPS enzyme in plants Low oral, dermal, inhalation acute toxicity
Chronic toxicity NOEL 362 mg/kg Minimal dermal/inhalation absorption in occupationally
exposed Rapidly excreted from human body Uptake by plant leaves: half life 9 days Does not bioaccumulate in animals, eggs, milk: half life 3
hours Not lipid soluble
Glyphosate and Cancer
EPA Not carcinogenic
IARC 2015: 2A: probable carcinogen Most studies show no genotoxicity
In vitro lymphocytes: sister chromatid exchange and chromosomal aberrations (Lioi et al, 1998)
Agricultural Health Study (AHS) (DeRoos et al, 2005)
57311 pesticide applicators followed for approx 7 years Self reported exposure
No link with 13 different cancers
4 case control studies found a link between glyphosate and NHL
Glyphosate Toxicity
Not absorbed by plant roots But by leaves and stems
Increased concentrations with late harvest applications Human exposure >500 fold less than Oral reference
dose set by EPA
Generally considered safer than other herbicides
Likely does not impact human health
What now?
Paucity of Human data Over 20 years of human use
Most animal studies suggest safety What about the microscopic changes?
Future Research Factor GMO
Set to begin worlds largest study on GMO
Secret location
Transparent funding
25 million dollars
Thousands of rats over 2-3 years
Multigenerational
Safety of GMO and associated pesticides Long term toxicity
Carcinogenicity
Fertility or birth defects
Human data
>7400 patients over 5 years randomized to specific diets
Prevention Eat a variety of foods
FDA recommends
Corn, papaya, squash
Avoid processed foods
Cooked foods are safer 95 degrees degrades DNA
GMO foods are not labeled Eat organic
100% or USDA certified
Buy Non GMO certified
Areas of Concern Use of antibiotic resistance markers
Appropriate use of glyphosate by farmers
Compositional changes to GMO should undergo evaluation Develop improved techniques for toxicologic evaluation Microarrays, proteomics, metabolomics
Monitor allergenicity Identify and track those at risk Standardize methods for reporting food allergies
Post-marketing surveillance for unanticipated adverse events Continuing Survey of Food Intakes by Individuals and the National
Health and Nutrition Examination Survey (NHANES)
Indirect health concerns from environmental effects
Conclusion
GMO are ubiquitous revolutionary technology with potential
Overall meets standard of substantial equivalence
No reason to suspect adverse health events
No health adverse health effects documented from GMO
As toxicologists, we should monitor and be aware of the ongoing studies pertaining to this
Questions