POTENTIAL ADVERSE HUMAN HEALTH EFFECTS OF GM FOODS By Dr. Stanley Ewen Independent Science Panel on GM - PowerPoint PPT Presentation

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POTENTIAL ADVERSE HUMAN HEALTH EFFECTS OF GM FOODS By Dr. Stanley Ewen Independent Science Panel on GM

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Co author in peer reviewed paper on ... Rodent stomach - upper third squamous ... The use of rodents has been grossly underused in food safety testing ... – PowerPoint PPT presentation

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Title: POTENTIAL ADVERSE HUMAN HEALTH EFFECTS OF GM FOODS By Dr. Stanley Ewen Independent Science Panel on GM


1
POTENTIAL ADVERSE HUMAN HEALTH EFFECTS OF
GM FOODSBy Dr. Stanley EwenIndependent
Science Panel on GM
2
Affiliation
  • Retired from Aberdeen University
  • Presently - National Health Service
    Histopathologist
  • No present or past involvement with commercial
    food production
  • Member of ISP
  • Co author in peer reviewed paper on carageenin
    and colonic ulceration

3
Assessment of potential adverse human health
effects.
  • Classical toxicological methods cannot be used to
    assess food safety due to compositional
    complexity thus substantial equivalence has
    prevailed
  • A physiological, nutritional or structural
    approach is more appropriate but acceptable
    animal studies, reported in quality journals, are
    few
  • Some of the relevant available evidence in the
    public domain will be outlined

4
Are the animal results helpful in assessing
potential health effects?
  • Do the transgenic products survive animal
    digestion?
  • Is there variability in survival of transgenic
    products in human GI tract?
  • Do the transgenic products bind to human
  • gut cells?

5
Binding of normal food and transgenic products to
animal gut
6
Binding of normal food components to mammalian
gut?
  • The usual food components that can bind are
    lectins, adhesins and toxins
  • Lectins will bind to specific sugars along the
    gut and many resist digestion and will reach
    colon some are mitogenic
  • Bacterial adhesins attach to sugars and may reach
    colon to bind to blood group substances in caecum
  • BT produces an AB toxin and the B subunit binds
    to cells surfaces

7
Wheat germ agglutinin fed to 100g rat for 10
days. IC with antibody to WGA
8
Rat jejunum crypt and villus length (µm) 10d
normal food
CRYPT VILLUS
PHA 246 (6) 548 (11)
SBL 180 (3) 512 (9)
SB meal 133 (3) 512 (9)
GNA 94 (2) 509 (22)
Egg albumen 118 (3) 579 (14)
Lactalbumin 103 (2) 607 (16)
9
Jejunal crypt of rat (100g) fed high dose
Galanthus nivalis agglutinin for 5 d. IC stained
with antibody to GNA
10
Jejunal crypt of rat (100g) fed PHA for 5d.
Freeze substitution plastic embedding
11
Animal GM feeding experiments need further
investigation
  • As a pathologist, I suggest that chronic
    toxicity, carcinogenesis and teratogenesis of GM
    products are seriously underinvestigated
  • Feeding a single GM food to an experimental
    animal is representative of diets in Africa
  • This is a neglected area and animals ought to be
    used to determine the safety of a GM product
  • Two historical experiments remain valid

12
PUBLISHED (1998 1999) RAW GM-POTATO MICRO
13
JEJUNUM Raw GM GNA potato fed 10d to rat
(starting weight 84g). HE
JEJUNUM (same distance from pylorus). Raw parent
potato
14
(No Transcript)
15
JEJUNAL CHANGES IN RATS FED GM POTATOES
(D Mello 2003)
16
IEL /100 epith. cells raw or boiled GM/parent
potatoes
jejunum raw boiled
parent 13.2(2.9) 7.6(0.3)
GNA-GM 21.4(3.9) 10.3(0.3)
Plt0.01 Plt0.0001
17
Intraepithelial lymphocytes in small bowel mucosa
  • Usually between villus cellsand believed to be
    suppressor/cytotoxic T lymphocytes
  • Surveillance function for damaged or virally
    infected cells
  • Greatly reduced in germ free animals
  • Greatly increased in cœliac disease

18
The effect of cookingon GM products
  • Experiments should test raw against cooked GM
    produce (DNA denatured at 95C for 5min)
  • Ewen Pusztai did demonstrate that raw GM
    potatoes produced unexpected hyperplasia
  • Boiling of GM potatoes almost completely reduced
    the hyperplastic effect on rat mucosa

19
Uncooked GM products
  • We assume that uncooked GM potatoes contain an
    unidentified growth factor
  • Fruit and vegetables may be consumed raw (up to
    40 of diet) and thus the availability of dietary
    transgenic DNA would be maximised
  • Pusztais 110 day cooked GM potato feeding
    displayed significant differences in organ
    weights (no histology taken)

20
Example from the past
  • The first commercial safety test was on GM
    tomato
  • Feeding trial of tomato fruit (protein and energy
    content cannot support growth)
  • 15 ml/kg of tomato homogenate to 5 female or male
    rats haematology and wt gain similar between
    groups
  • But starting weight of animals very wide (/-
    23) cf. Ewen Pusztai 84g /- 1g

21
Detailed results of safety test
  • 28 day histology study (gavage)
  • Urea and electrolytes not different
  • Treatment related erosions in gastric mucosa of
    4 female rats (increased to 7 by
    histopathological experts)
  • No lesions in male group or controls
  • Erosions can cause severe haemorrhage in human
    equivalent - these rat lesions deemed not
    related to GM ingestion 7 of 40 eating GM died
    at 2wk (cause of death not specified)

22
Murine liver and pancreatic changes after GM soya
  • Animals not pair fed and zone of EM hepatic
    sample not specified
  • Findings nuclei and nucleoli irregular in GM fed
    suggestive of increased metabolic rate
  • Reduced digestive enzyme synthesis in pancreas
    possibly due to reduced post transcriptional
    hnRNA processing
  • Liver has a vast reserve capacity but could
    hepatoma be accelerated in areas of hepatitis?

23
Pancreatic ultrastructural changes in mice fed GM
soyabean
  • 4 groups of 3 female mice fed for 1,2,5 or 8
    months on 14 GM soyabean
  • Significant reduction in amylase labelling over
    zymogen granules in all 4 groups of GM fed mice
    consistent with stimulation of secretion
  • Soya is associated with adenoma formation but not
    with ductal adenocarcinoma

24
MON 863 Maize
  • Contract rat study using 460 animals
  • Significant increases in WBC and lymphocyte
    counts in males and reduced retic. count in
    females were considered within normal range
  • But a government commissioned report by AJP
    indicates possible differences in interpretation
    of the findings
  • Histology was not taken from normal control rats
    for comparative quantitative measurements

25
Animal model - human diseasediscrepancies?
  • Rodent stomach - upper third squamous
  • The rat caecum is large and the colon produces
    faecal pellets
  • The use of rodents has been grossly underused in
    food safety testing
  • In vitro data cannot determine safety for human
    consumption unless tested in animals
  • Inter group differences revealed by sophisticated
    tests on comprehensive animal trials with
    substantially equivalent GM crops are meaningful

26
Simulated gastric juice digestion of DNA and
protein
  • Simplistic studies with artificial gastric juice
    and pepsin are inadequate in the human situation
  • Recombinant proteins are relatively easily
    destroyed by HCl pepsin use of toxin from GM
    plant should be obligatory
  • Babies and up to 2/5 of adults (PPI) have greatly
    reduced gastric acidity thus transgenic DNA
    survival in human gut could be facilitated
  • Especially as plant DNA is surrounded by lignin

27
Binding and survival of transgenic products in
humans
28
Historical GM deaths
  • Tryptophan (dietary supplement), produced by
    recombinant DNA, caused a completely new illness
    eosinophilia myalgia syndrome (EMS)
  • In or around 1989 there were 38 deaths recorded
    as a result of EMS
  • One or more toxic impurity caused the deaths but
    no animal model or in vitro test has been
    developed to identify the case-associated
    impurity in a relatively simple problem although
    deviant metabolism in some GM organisms is likely

29
PLANT DNA AND THE HUMAN GI TRACT (04)
  • First human study of GM soya ingestion
    (Netherwood et al.)
  • 3 of 7 ileostomy patients contained CaMV 35S
    promoter before study had started
  • All 7 passed excreta containing GM DNA after test
    meal (surprised that any could survive)
  • Faeces of 12 volunteer controls contained no CaMV
    (were they age and sex matched?)

30
Unanswered questions concerning Netherwood et al
  • We are not informed about the reason for
    resection of colon (not terminal ileum as stated)
    was the disease colonic malignancy or
    inflammatory bowel disease which could affect
    remaining small bowel function?
  • If unprocessed GM food was to be ingested
    possibly much more transgenic DNA would access,
    and be released into, the normal colon
  • Fate of stoma excreta septic tank to aquatic
    life?

31
DNA does persist in gut?
  • GM soya bean survived the whole length of remnant
    ileum when fed to humans with an ileostomy
  • Thus transgenic DNA could be taken up by small
    bowel bacteria
  • Transgenic DNA does survive to pass into human
    colon
  • In pigs,DNA is transferred to duodenal juice,
    lymphocytes and liver (Chowdury, J.anim.sci.
    2003)

32
Cell survival and vulnerability
  • Popular belief the cells of the gut have a
    rapid turnover thus the chances of adverse
    consequences are highly unlikely
  • This is true in the human small intestine but
    malignancy affects stomach and colorectum
  • Dysplastic cells are transformed or immortalised
    and have an extended lifespan

33
Unstable lesions in human GIT
  • Lesions of OGJ occur usually as a result of
    obesity induced reflux
  • Step 1 - metaplasia from squamous to columnar
    small bowel type mucosa
  • Step 2 - binding of lectin (Bt) to columnar
    epithelium with endocytosis
  • Step 3 growth factor effect

34
OESOPHAGUS DISEASED V. NORMAL
FEMALE 63Y
MALE 77Y
35
Unstable lesion (2)
  • Helicobacter pylori (HP) organisms infect 40-50
    of stomachs by 50 yr
  • HP produces intense inflammation with ensuing
    intestinal metaplasia
  • Binding of transgenic Bt toxin occurs with growth
    factor effect
  • Possible accelerated transition to dysplasia and
    neoplasia

36
STOMACH DISEASED V. NORMAL
MALE 52Y
FEMALE 63Y
37
Unstable lesion (3)
  • Colorectal cancer common in Scotland
  • Multi centre study (1985) revealed 60, 45 and
    13 autopsy incidence (all ages) in NE Scotland,
    Tromso and Kuopio resp.
  • Could the transgenic DNA growth effect speed up
    the interval between oncogene activation and
    invasive malignancy?

38
Other possible unexpected effects of GM products
in humans
39
Carcinogen Formation by GMOs
  • Genetic modification can cause deregulation of
    the synthesis of low MW toxins, mutagens and
    carcinogens and this has the potential to be the
    single greatest long term health risk
  • Plants will synthesize substances similar to
    cycasin from which azoxymethane is a short step
  • The metaplastic epithelium of Barretts or
    stomach are almost certainly absorptive

40
Beta glucuronidase
  • Steroids, toxins and drugs are detoxified by
    liver to glucuronide
  • Normal small intestine almost sterile thus
    bacterial deglucuronidation limited
  • But GUS gene-derived ß-glucuronidase could
    amplify deglucuronidation in the small intestine
    resulting in higher circulating levels of toxins,
    steroid and drugs (M.Hill personal commun.)

41
Allergy
  • Allergic reaction in larynx and pharynx is
    possible producing angioneurotic oedema before
    entering gastrointestinal tract
  • Many food allergens are stable to digestion
  • The longer an allergen is present in gut the more
    likely it is to lead to sensitisation
  • Present testing uses pepsin and acid with
    recombinant bacterial surrogates that may have
    lowered function and heat denaturation also
  • pH levels in human stomach may be much higher
    permitting longer allergen survival

42
GM crop herbicide safety
  • Formulations may cause synergistic, and dose
    dependent, delay of cells into M-phase
  • S. Richard June 2005 (Env.health perspect
    113,716) has shown that glyphosate is very toxic
    to cytotrophoblast (JEG3 cells from
    choriocarcinoma) at levels 100 times lower than
    agricultural levels. Those housed next to fields
    are at great danger from abortion (farmers should
    be obliged to identify pregnant women nearby).

43
Areas for expeditious investigation
  • Freese and Schubert believe that the plant GM we
    eat is virtually untested and argue very
    persuasively for 6 test screens viz.
  • 1. Carcinogenesis/mutagenesis with Ames test
  • 2. Metabolic profiling
  • 3. Teratogenesis over several generations
  • 4. DNA chip analysis
  • 5. Animal feeding acute and chronic
  • 6. Comprehensive allergenicity testing

44
Urgent human investigations
  • The in vitro binding ability of GM products to
    normal human gut mucosa is required. The tissues
    should be from healthy adults as well as children
    and those with known morbidity
  • Consideration should be given to in vivo
    ingestion with biopsy sampling

45
Considerations for Safety Assessment (1)
  • Parent and transformed lines must be grown and
    harvested under identical conditions
  • Analysis of protein, starch, lipid also
    proteomics and transcriptomics
  • Stability to degradation by acid, pepsin or other
    proteases of GM products has to be established in
    animal stomach and intestines
  • The morbid state of the human recipient should be
    fully considered (PPI, immunosuppression,
    co-morbidity)

46
Considerations for Safety Assessment (2)
  • Immunocytochemistry for presence or absence of
    GIT mucosal binding (lectins or BT toxin)
    including colon
  • Biological, immunological, hormonal properties
    and allergenicity should be establishes with GM
    crop product (not recombinants from E.Coli)
  • Young growing animals should be used to reveal
    unexpected effects on metabolism, organ
    development and immune system

47
Considerations for Safety Assessment (3)
  • Animal testing must use iso-proteic and
    iso-energetic diets most of the protein being
    derived from the GM crop
  • Obligatory - pair feeding daily weighing
  • Blood samples before, during and at end of period
    for immune, hormonal and haematological studies
  • At PM weights of organs (wet and dry) and samples
    at identical sites for quantitative histology

48
Conclusions
  • Possible effects on health must be answered
    before any long term benefits of GM products can
    be recommended without reservation
  • Additional sound science is essential to avoid
    unnecessary human health effects
  • Processing and cooking GM products reduces, but
    does not completely prevent, long term changes in
    rats
  • Raw GM products, such as fruit and vegetables,
    will make up to 40 of human diet in the future
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