Download Begrippenlijst TOX30306 Food Supplements

Begrippenlijst TOX30306
Food Supplements
- Upper intake level (UL):
Maximum level of intake that is physically tolerable in such a way that no adverse
effects occur in humans.
- Difference UL and ADI:
UL is the maximum level of intake that is physically tolerable in such a way that no
adverse effects occur in humans. ADIs are derived from NOAELs, ULs cannot be
derived from NOAELs since then intake levels might be lower than the reference
daily intake.
- Annex I:
List of compounds which may be used in vitamin and mineral supplements and the
tolerable upper intake levels of each compound.
- Annex II:
List of substance that may be used to manufacture vitamin and minerals.
- List of safety evaluation points for vitamins and minerals:
- Nutrients are essential for human well-being within a certain range of intakes
- There is a long history of safe consumption
- Some nutrients may be consumed chronically at levels of significantly above those
obtained from endogenous nutrients in foods without reported adverse effects.
- Data on adverse effects in humans may help reduce uncertainty factors
- Protection is present against nutrients through homeostatic regulation, such as
excretion or absorption.
- A tolerable upper intake level is present. This is the maximum level of total chronic
daily intake of a nutrient which is judged to be unlikely to produce a risk of adverse
health effects.
- Concerns of Food plants supplements:
- Overconsumption
- Natural is equal to safe for consumers
- Availability of harmful plant food supplements
- Often no requirement of proven safety of PFS
- Toxicity of PFS caused by:
- Naturally present toxic ingredients
- Harmless ingredients may be replaced with a toxic alternative
- Adulteration (deliberately adding illegal compounds)
- Contamination of harmful compounds
Naturally present compounds:
- Pyrolizidine alkaloids (PA):
Cause obstruction of small veins in liver (hepatoxicity) and cancer In animals
- Alkenylbenzenes:
Present in PFS containing oil of basil, fennel, nutmeg and more. Cause liver tumours
(genotoxocity) in rodents at high levels.
Replacement of harmless ingredients with toxic alternative:
- Anisatin in Japanese star anise is not present in Chinese star anise:
Inhibits GABA causing epileptic abnormalities
- Aristolochic acids:
- Causing cardiovascular damage, kidney damage and cancer in kidneys and urinary
tract.
Adulteration
- Sibutramine:
- Increased risk of adverse cardiovascular events
- Sildenafil
- Increased risk on skincancer
Contaminants
Polycyclic aromatic hydrocarbons (PAH) Benzo [a] pyrene:
- Genotoxic carcinogenic
- EFSA Tiers:
Used to assess PFS on risk for adverse effects.
- EFSA Tier 1:
Nature of preparation
Its tended uses and levels of use
Whether the preparation has long history of no adverse effects.
- EFSA Tier 2:
For botanical compounds lacking a history of food use, or levels of use exceed
historical intake levels. This compound needs an ADI, TDI or TTC or MOE.
- Labels of PFS:
- Indication of nature of ingredients
- Recommended daily intake and warning of risks to health if this is exceeded
- Is not a substitute for varied diet
- Not a medicinal product
- Should be out of reach of young children
- Most not contain a statement that it can cure, prevent or treat diseases
- Any statement that a varied diet cannot provide the appropriate quantities
- Any misleading claims -> elimination from the market.
Natural toxins
Glycosides
Are bioactive compounds that have a sugar attached to the part which is responsible
for the toxic action. Aglycon is such a toxic compound in a glycoside.
Aglycon has potential to decrease bone loss in post-menopausal woman. (Also called
genistein).
Improper preparation
Anti-Nutritional factors (ANF)
Trypsin inhibitors:
Inhibit with protein digesting enzymes
Lectins
Interfere with absorption nutrients in intestine
Solanine
Inhibits acetylcholinesterase, preventing breakdown of neurotransmitter
acetylcholine. Leading to irritation and injury of GI tract, abdominal cramps, vomiting,
diarrhae, weakness and unconsciousness
Famine foods
Cyanogenic glycosides
May release hydrogen cyanide (HCN). HCN inhibits cytochrome c (Complex IV of
OXPHOS) ultimately causing the paralytic disease Konzo. HCN detoxification creates
thiocyanate, which inhibits iodide uptake in the thyroid and leads to swelling of the
neck.
Toxic amino acid: Lathyrogens
Grass pea (lathyrus sativus):
Oxalyldiaminopropionic acid (ODAP) is the active
compound which causes muscle weakness, stiffness
and paralysis of leg muscles (neurotoxicity). Due to
overstimulation of the glutamate receptor.
ODAP -> Neurolathyrism
Sweet pea (lathyrus odoratus): Beta-aminopropionitrile (BAPN) is the active
compound that causes weak connective tissue due to
inhibition of formation of cross connections between
collagen and elastin
BAPN -> Osteolathyrism
Supplements
Glucosinolates:
Isothiocyanates: claimed to have anti-cancer properties through induction of
protective enzymes. But might be genotxic themselves
Alkenylbenzenes: Genotoxic and carcinogenic.
Sensitive individuals
Fava glycosides:
Vicine and convicine: Initiate low levels of G6PD, leading to low levels of gluthathione
(GSH), leading to lack of protection against oxidative stress which affects red blood
cells.
Herbal teas
Pyrrolizidine alkaloids
Liver necrosis, liver cancer, liver damage
Phytoestrogens
Genistein
Disrupt the reproductive performance due to properties similar to 17B-estradiol.
Natural toxins in animals
Bacterial toxins
Clostridium botulinum
Inhibits rlease of acetylcholine in presynaptic membrane of motor endplates.
Leading to weakness of muscles, due to botulinum toxin which can be fatal.
Fycotoxins (marine algae)
Dinoflagellates
Group of flagellate eukaryotic organisms which accumulate in the food chain.
Saxitoxic: Paralytic shellfish posion
Blocks Na-Influx, resulting in nausea, vomiting, diarrhoea, numbness, tingling lips,
coordination probelsm, confusion, paralysis, respiratory distress and death.
Brevetoxin: Neurotoxic shellfish posion
Activates sodium channel by enchancement of Na-permeability. Leading to nausea,
vomiting, diarrhoea, numbness, tingling lips, coordination problems, confusion
But NO paralysis, respiratory distress or death.
Ciguatoxin: Ciagatura fish posion
Enhances Na permeability to activate sodium channels. Leading to nausea, vomiting,
diarrhoea, numbness, tingling lips, coordination problems, confusion
But NO paralysis, respiratory distress or death.
Domoic acid: Amnesic shellfish poison
Overstimulates glutamate neurons, leading to neurotoxicity.
High intracellular calcium levels cause neuronal cell death, lesions in areas of the
brain.
Okadaic acids: Diarrhetic shellfish poison
Inhibits ser/thr protein phosphatases leading to hyperphosphorylation of proteins.
Including ion channels in intestinal epithelia, resulting in impaired water balance and
loss of fluids.
Fish toxins
Tetrodotoxin
Neurotoxin by blocking sodium channels causing paralysis and death
Scombrotoxins
Fish rich in histidine, which leads to an allergic reaction. Scombroid fish.
Food additives
Reasons additives are added
- To maintain product consistency
- To improve or maintain nutritional value
- To maintain pleasure experience & wholesomeness
- To regulate pH
- To enhance flavour or change colour
Direct additive
- For specific purpose added
Indirect additive
- Unintentionally though predictably becomes part of food (packaging).
Evidence needed to become European recognised additive:
- performs as intented
- will not cause adverse health effects
- Usage does not mislead consumer
Nitrosamine
Nitrate is added to food as additive to kill Clostridium and prevent product of
botulinum. But nitrate with amines can form nitrosamine and cause stomach cancer.
Classification of additives based on carcinogenicity
Group 1: carcinogenic to man -> forbidden
Group 2A: Probably carcinogenic -> forbidden
Group 2B: Possibly carcinogenic -> more research
Group 3: Compound cannot be classified because of insufficient data -> more
research
Group 4: Proven to be non-carcinogenic for humans
Southhampton study conclusions EFSA:
- Limited consistency with respect to age and gender of children and the different
mixtures.
- Unknown relevance of the effect observed.
- Lack of information on dose-reponse
- Lack of a biologically plausible mechanism
- Use of mixture of compounds, instead of single compounds
- Observer bias of teachers, parents and classroom observers
Food allergy types
Type 1 = hypersensitivity -> release of histamine and cytokines by mast cells when
allergen is encountered.
Type 4 = Delayed hyper sensitivity -> macrophages present allergens to T-cells, cells
release interleukins, which stimulates the immune system and cause inflammation.
Acetyl saliculic acid sensitivity
Interference with prostaglandin synthesis. Leading to urticarial (netelroos), angioneurotic oedema, rhinitis, asthma and hyperkinesis.
AZO-dyes
Are frequently associated with hypersensitivity.
Tartrazine
Is an AZO dye suspected of causing hypersensitivity.
Sulfite
suspected of causing asthmatic like allergic reactions.
Biotransformation
Bioavailability depends on 5 steps
Liberation from GI tract
Transport across intestinal membrane
Blood circulation and distribution
Metabolism or biotransformation
Excretion
Metabolism of xenobiotics
Phase 1:
Modification:
Reaction: Oxidation, reduction and hydrolysis
Product: Polar metabolite with functional OH, NH2, SH, COOH group
Cofactor: NADPH
Phase2:
Conjugation:
Enzyme: Epoxide hydrolase, glutathione S-transferase,
glucuronosyntransferase and sulfotransferase.
Product: Hydrophilic metabolites
Conjugation with: Water, glutathione, glucuronic acid and sulfate
Measurement of biotransformation
Mix of compound, cofactor, S9/microsomes(for biotransformation) is incubated and
measured.
Abundance of P450 CYP1A2 isoenzymes differ with
Age
Gender
Lifestyle; smoking, grapefruit juice or barbecue meat consumption
Genetics
Chemicals
Acrylamide
Formed during heating, through sugars and asparagine. Is carcinogenic, neurotoxic,
reduces fertility.
Anethole
Flavoring substance
Aspartame
Only dangerous for PKU patients because of phenylalanine, which they cannot
breakdown and can cause brain damage in high concentrations.
Dioxin
Accumulates in fat, toxic in low doses. Slow metabolism and elimination. Is thought
to decrease sperm count and cause liver tumours at higher dose levels.
TCDD
Is a dioxin, which is thought to decrease sperm count and cause liver tumours at
higher dose levels.
PCB
Is a dioxin, which is thought to decrease sperm count and cause liver tumours at
higher dose levels.
BDE-47
BDE-47 accumulates in fat because it is hardly broken down and bioaccumulates. Is
potential health treat.
Bisphenol A
Present in a lot of stuff. In high numbers may cause infertility and harm the hormone
system.
Butyl benzyl phthalate (BBP)
Present in a lot of stuff. In high numbers may cause infertility and harm the hormone
system.
Chloramphenicol
Antibiotic which is not used. Adverse effects: anemia, leukemia, bone marrow
suppression, nausea and diarrhea.
Coumarin
Compound present in plants. Chronic exposure leads to liver damage, reduced blood
clotting and carcinogenic.
Curcumin
Colouring compound. It thought to have positive effect on cancer, diabetes. Anticarcinogenic
Metals
Methylmercury
Converted to MeHg by microorganisms. Ccumulated by fish. Can cause
neuro(developemental) adverse effects, through increased intracellular calcium, cell
death and ROS.
Lead
Inhibits heme synthesis leading to anemia. Initiates demyeliation, leading to neuro
toxicity, through disturbance of calcium homeostasis and ROS. Can accumulate in
bones in which the half life increases drastically.
Cadmium
Nephrotoxicity and osteoporosis. When metallothionein (chelator) binding saturates
severe kidney damage occurs, through ROS, calcium loss and bone loss. Subgroups
such as children, smokers, vegetarians and people living in areas rich in cadmium are
more vulnerable.
Arsenic
Genomic instability due to decrease of global methylation leading to cancer risk.
Especially skin cancer.
Chelators
Methallothionein
Ethylene-diamino-tetra-cetic-acid
Dimercaptopropanol
Veterinary drugs
MRL
Maximum residue level of pesticides.
Forazolidone
Widely used in pigs and chickens. Mutagenic and carcinogenic so no NOAEL. Its
quickly broken down, metabolites aswell. But mouse studies proven opposite so not
risk taken and banned.
B-agonist
More meat, less fat. But affects human heart so its prohibited.
Combination toxicology
Complex vs. Simple mixtures
Complex mixture > 10 compounds
Simple mixture < 10 compounds
Simple similar action
No interaction, similar mode of action
Simple dissimilar action
No interaction, different mode of action
Interaction
Potentiation or antagonism
Response addition
Summation of effect A and B
Dose addition
Summation of doses A and B
Oxidants
Reactive oxygen species:
- Superoxide anion radical
- Hydroxyl radical
- Hydrogen peroxide
- Singlet oxygen
Sources of ROS
- Decoupling one-electron transport chains
- Enzymatic reaction
- Redox cycling (paraquat)
- Inflammation neutrophils/macrophages
- From other ROS (Haber-Weiss reaction)
Damage produced by ROS
- Oxidation proteins/enzymes -> loss of function
- Oxidation of DNA -> mutagenicity and carcinogenicity
- Oxidation unsaturated fatty acids -> lipid peroxidation (disturbs membrane
structure)
Antioxidants
- Vitamin C
- Vitamin E
- Carotenoids
- GSH (glutathione)
- Ubiquinone coenzyme Q10
- Polyphenols
Antioxidant enzymes
- Superoxide dismutase (SOD)
- Catalase
- Glutathione peroxidase
Natural anti-oxidants
- Carotenoids
- Vitamin E
- Vitamin C
- Polyphenols like flavonoids
- Peptides (glutathione)
- Conjugated linoleic acid
- Coenzyme Q (ubiquinine)
These can donate e- or H+ or form a stable AOX radical.
Antioxidants
Plasma level which adverse effect
4-5 times
Reasons beta-carotene supplementation may increase risk on long cancer
- Reactive beta carotene metabolites
- Disturbing retinal signalling, thereby activating oncogenes and down regulating
tumour suppressor genes
Sint janskruid
decreased P450 efficiency, leading to decreased medicines efficiency.
Polyphenols (quercetin)
health claims; inhibition of cancer, ageing, cardiovascular disease and
photosensitivity diease. At high levels more indicdence of tumors.
Flavourings
Three types of flavourings
- Flavour substance which are chemically identified
- Flavour preparation from plant or animal origen (natural flavour complexes)
- Thermal process flavour or smoke flavours
Ames test
Salmonella Thyphimurium cannot form colonies due to absence of external
amino acid source, unless reversion of the mutation restores biosynthesis of the
amino acid.
TK test
Mammalian gene mutation test (TK). TK+/- (non mutated) die, whilst TK-/- survive. So
mutation is needed to survive
Chromosome aberration test (CAT)
Chinese hamster ovary cells or human lymphocytes. Arrest cells in metaphase, then
after exposure to compound examine structural changes in chromosomes.
Flavours are grouped in 3 classes:
Class 1: flavours have simple chemical structure, suggesting low oral toxicity
Class 2: flavours have less innocent structures, but are not suggestive of toxicity
Class 3: may suggest toxicity, or have structural features that permit no strong initial
presumption of safety.
The Threshold of toxicological concern (TTC) is used.
Class 1 – 1800ug/day
Class 2 – 540 ug/day
Class 3 – 90 ug/day
Diacetyl
flavour giving buttery flavour. Inhalation is dangerous, however the safety evaluaton
is only for oral exposure.
Couramin
is not genotixic, but is carcinogenic. So a thresholded mode of action.
Alkenylbezenes is genotixic, restricted in the EU.
Nanotoxicology
Uptake in intestine
- Transcellular through normal intestinal enterocytes.
- Paracellular (between enterocytes through tight junctions).
- Peyers patches lymphatic tissue containing M cells. These M cells take up, process
and present the nano-particles to the immune system.
Uptake depends on:
- Particle size
- Surface charge (positively charged become trapped in negatively mucus) (negatively
pass right through).
- Attachment of ligands
- Coating with surfactants
Possible health hazard:
- ROS production (which can affect membranes typically)
- Frustrated phagocytosis
- Fibrosis and risk on GI carcinomas
- Systematic effect: particles can be transported via nerves. Interleukines may be
important for systematic effect (inflammation effect and fibrosis of GI tract).
Safety assessment:
- Precautionary principle: nothing can changes, if they imply risks for humans or
environment. Even if this risk is not proven yet.
- Proportionality principle: measures taken should be based on risk-benefit
evaluation.
Pesticides
Exceedance can result from
- Unauthorised pesticides
- Pesticides not authorised for a specific crop
- Higher application rate or shorter pre-harvest intervals
- Insufficient washing out
Organophates
- Inhibit acetylcholinesterase
- Leads to overstimulation of postsynaptic receptors.