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FOOD 525 > Principles of Food Toxicology > Flashcards

Principles of Food Toxicology Flashcards

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1
Q

Define: food toxicology.

A
  • The study of the adverse effects of substances present in foods on living organisms.
Fries (acrylamide - product of Maillard reaction); dairy products (aflatoxin M1 - secondary metabolite of moulds); SPAM (nitrosamines); tuna (heavy metals); corn (aflatoxins)
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2
Q

Food toxicology is a scientific discipline that studies: [5]

A
  • The nature, sources, and formation of toxic substances in foods
  • The deleterious effects on consumers (chemical, not physical)
  • The mechanisms and manifestations of these effects
  • The identification of limits of safety
  • Regulation of the use of these substances
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3
Q

What are the categories of toxicants? [6]

A
  • Foodborne and pathogenic microorganisms
  • Nutritional factors (looking at diet, not necessarily food; concerned with nutrient quality not the food matrix)
  • Naturally occurring toxicants
  • Reaction products (typically generated from heat - e.g., advanced pyrolysis)
  • Food additives
  • Environmental contaminants (pesticides; plasticizers with estrogenic-like activity that act like endocrine disrupters)
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4
Q

Food toxicology is a multidisciplinary field dealing with DOPER. Define this acronym: [5]

A
  • Detection - note that detection requires release of the compound from the food matrix where the toxicant may be bound to PRO/CHO/FAT
  • Occurrence
  • Properties
  • Effects - depends on biotransformation of the toxin (may cause a muted or enhanced effect); may accumulate
  • Regulations

DOPER

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5
Q

What is the exposure phase? [3]

A
  • Disintegration of dose form
  • Dissolution of active substance
  • Available for absorption
The dose & whether it is absorbed depends on the properties of the toxicant.
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6
Q

What is the toxicokinetic phase? [3]

A
  • Absorption & distribution
  • Metabolism & excretion
  • Toxicant available for action
Rate of change over time influences elimination from the body.
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7
Q

What is the toxodynamic phase? [3]

A
  • Toxicant-receptor
  • Interaction in target tissue
  • Biological effect

Relates to action mechanism.

e.g., caffeine interacting with adenosine receptor
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8
Q

To construct a decision tree, consider the following: [4]

A
  • The chemical agent capable of causing a deleterious response (e.g., defined as toxicant, poison)
  • A biological system with which the chemical agent interacts to produce a deleterious effect
  • A mechanism of interacting between chemical agent and biological system (e.g., receptor site)
  • A response that can be used to quantitate the deleterious effect on the biological system (e.g., measureable biomarker)
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9
Q

Define: toxicant.

A

A substance or chemical compound that has an [adverse] effect on organisms

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10
Q

Define: toxic

A

When the substance causes cellular or tissue injury by mechanisms other than physical trauma (i.e., chemical)

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11
Q

Define: toxicity.

A
  • The capacity of a substance to cause adverse health effects on a living organism.
  • The capacity to produce toxic injury to cells or tissues.
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12
Q

Define: hazard

A
  • The likelihood of a substance to cause harm.
  • The probability that harm or injury will result when the substance is used in a proposed manner and quantity.

Risk x probability = hazard

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13
Q

What are the effects of toxicants? [4]

A
  • Physiological damage
  • Carcinogenesis
  • Mutagenesis (may lead to induction of cancer)
  • Teratogenesis
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14
Q

Define: Physiological damage

A

Reversible/irreversible damage to the health of the organism

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15
Q

Define: carcinogenesis

A

Induction of cancer

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16
Q

Define: mutagenesis

A

Induction of genetic damage/mutation

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17
Q

Define: teratogenesis

A

Induction of birth defects

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18
Q
  • The study of the adverse effects of substances present in foods on living organisms.
A

Define: food toxicology.

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19
Q

A substance or chemical compound that has a negative effect on organisms

A

Define: toxicant.

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20
Q

When the substance causes cellular or tissue injury by mechanisms other than physical trauma.

A

Define: toxic

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21
Q
  • The capacity of a substance to cause adverse health effects on a living organism.
  • The capacity to produce toxic injury to cells or tissues.
A

Define: toxicity.

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22
Q
  • The likelihood of a substance to cause harm.
  • The probability that harm or injury will result when the substance is used in a proposed manner and quantity.
A

Define: hazard

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23
Q

Reversible/irreversible damage to the health of the organism

A

Define: Physiological damage

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24
Q

Induction of cancer

A

Define: carcinogenesis

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25
Q

Induction of genetic damage/mutation

A

Define: mutagenesis

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26
Q

Induction of birth defects

A

Define: teratogenesis

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27
Q

Describe the JECFA procedure for the evaluation of flavouring substances considered to be metabolised to innocuous products.

A
NOEL = no observable effect level; margin of safety associated with this
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28
Q

How is half life determined (single dose)?

A
  • After receiving a single dose of toxicant, blood is taken at different times thereafter to detect toxicant concentration (take 6 - 10 samples)
  • The toxicant concentration (log) versus time is plotted and a line can be obtained via first order kinetics
The significance of T1/2 is that it reflects rate of excretion, biotransformation and accumulation for the toxicant in the body. A long half-life corresponds to slow elimination and greater potential for accumulation and overall toxicity.
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29
Q

What is the significance of T1/2?

A
  • It reflects rate of excretion, biotransformation and accumulation for a toxicant in the body.
  • A long half-life corresponds to slow elimination and greater potential for accumulation and overall toxicity.
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30
Q
Given: rate constant; initial concentration; number of half-lives
A
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31
Q
A
After 10 half-lives - 99.9% elimination completion.
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32
Q

What is the dose-response relationship?

A
  • The dose makes the poison
  • All substances are poisons; there are none which are not a poison.
  • The amount of chemical (dose) a person is exposed to is important in determining the extent of toxicity that will occur.
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33
Q

What 4 important values are important when finding a compromise between a dose/exposure ratio that is safe, yet therapeutically effective?

A
  • Potency
  • Efficacy
  • Slope (rate)
  • Variability
A is more toxic than B | B has better efficacy | The rate of A is greater (steeper slope) | Must use the mean from testing in different animals
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34
Q

Describe how to determine potency and efficacy on a dose response curve.

A
  • Toxin X has greater biologic activity per dosing equivalent and is thus more potent than Toxin Y or Z.
  • Toxins X and Z have equal efficacy, indicated by their maximal attainable response (ceiling effect).
  • Toxin Y is more potent than Toxin Z, but the maximal efficacy is lower.
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35
Q

Define: ceiling effect.

A

Maximal attainable response

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36
Q

Maximal attainable response

A

Define: ceiling effect.

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37
Q

Describe the potency and efficacy of these toxins.

A
  • Toxin X has greater biologic activity per dosing equivalent and is thus more potent than Toxin Y or Z.
  • Toxins X and Z have equal efficacy, indicated by their maximal attainable response (ceiling effect).
  • Toxin Y is more potent than Toxin Z, but the maximal efficacy is lower.
38
Q
A

Substance A

39
Q

What does the dose-response curve determine?

A
  • The starting dose in an initial human trial designed to set guidelines for use.
Note the threshold (i.e., lag phase); represents there is no change in the slope until a certain dose. (e.g., aflatoxins in peanuts are allowed at a certain level (they are ubiquitous), because the amount present is below the threshold for toxicity).
40
Q

What is the LD50 value?

A
  • The median lethal dose or the amount of toxin necessary to kill 50% of experimental animals.
  • Value indicates the degree of toxicity of substances.
  • Values used to compare relative acute toxicity.
  • Values less than 500 mg/kg indicate high toxicity; 1g/kg moderate; 2g/kg low toxicity.
41
Q

What are the LD50 values for high, moderate, and low toxicity.

A
  • High < 500 mg/kg
  • Moderate < 1 g/kg
  • Low < 2 g/kg
42
Q

Give the estimate toxicity of common products.

A
43
Q

Describe types of exposure and levels of effects.

A
44
Q

Define acute level of effect.

A
  • Dose: high
  • Time of exposure: a few days
45
Q

Define subacute level of effect.

A
  • Dose: moderate
  • Time of exposure: a month
46
Q

Define subchronic level of effect.

A
  • Dose: low
  • Time of exposure: 1-3 months
47
Q

Define chronic level of effect.

A
  • Dose: very low
  • Time of exposure: >3 months
48
Q

Toxicokinetics is associated with exposure assessment.

True or False?

A

True.

Note that susceptibility factors apply to both sides.
49
Q

Toxicokinetics is associated with risk assessment.

True or False?

A

False.

Note that susceptibility factors apply to both sides.
50
Q

Toxicodynamics is associated with risk assessment.
True or False?

A

True.

Note that susceptibility factors apply to both sides.
51
Q

Toxicodynamics is associated with exposure assessment.
True or False?

A

False.

Note that susceptibility factors apply to both sides.

Susceptibility factors are very specific to individuals and why such a range of responses in a population from the same dose of a toxin exist.

52
Q

What is toxicokinetics?

A

Toxicokinetics is the application of kinetic modelling to determine the relationship between the systemic exposure of a compound in experimental animals and its toxicity.

a.k.a. the rate of change

53
Q

How is toxicokinetics used to establish relationships between exposures of toxins in toxicology experiments in animals and corresponding exposures in humans?

A
  • Toxicokinetics enables us to describe how the body handles toxicants as indicated by the plasma concentration of that xenobiotic over different times that describe the exposures.
  • The end result of defining the toxicokinetic processes that are specific to each toxin gives information on the biologically effective dose of that toxicant
  • Hence: The magnitude of the toxic effect will be a function of the concentration of altered molecular targets. This in turn is related to the concentration of the active form of the toxicant ( biologically effective dose) at the site where the molecular targets are located.
  • We refer to this as the Dose-Response Concept.

Based on steady-state kinetics.

54
Q

What is the dose-response concept?

A
  • The magnitude of the toxic effect will be a function of the concentration of altered molecular targets.
  • This in turn is related to the concentration of the active form of the toxicant ( biologically effective dose) at the site where the molecular targets are located.

Depends on the metabolic activity in the body.

55
Q

What are the 2 toxicokinetic phases?

A

1) Distribution phase
2) Biotransformation phase

Backbone of understanding how the toxin behaves in the body to elicit the toxic effect.

56
Q

What is the distribution phase?

A
  • Toxins are transported and then may bind to the protein carriers or tissue compounds
Note that the distribution & absorption phase is mostly studied in rodents; whereas, elimination can be studied safely in humans.

Measured through direct concentration in plasma.

57
Q

What is the biotransformation phase?

A
  • Cytochrome P-450 system:
    • phase 1 - activation (oxidation, reduction, hydrolysis)
    • phase 2 - conjugation reactions (-OH, -SH, -NH2, & COOH)
      • increased water solubility and ionization properties at physiological pH (enhanced secretion)

Measured by metabolite concentration in plasma.

58
Q

What is toxicodynamics?

A
  • Involves understanding how the molecular, biochemical, and physiological effects of a toxin, or their metabolite, interacts in a biological system.
If repair doesn't occur, the pathology will lead to cell death.
59
Q

How do we describe the interaction between the biologically active dose associated with active form of the toxin with a molecular, biochemical or physiological target?

Give examples of reactions [4], toxicological responses [3], and cellular/physiological outcomes [2].

A
PAH = polycyclic aromatic hydrocarbons produced by incomplete combustion.

Note that irreversible with repair is different from reversible - it depends on the situation. Think - teratogenicity for a fetus (= irreversible) compared to the same toxin exposure in an adult (= irreversible with repair).

60
Q

Regarding physiological activities, what do we require models for? [4]

A
  • (1) Absorption
  • (2) Accumulation
  • (3) Biotransformation/metabolism
  • (4) Excretion
    • (a) Gastrointestinal excretion (biliary; entero-hepatic circulation)
    • (b) Urinary excretion (glomerular filtration; trans-tubular secretion) - these are related to biotransformation because the parent compound is too small to be eliminated, but the biotransformed compound is large enough

Note that elimination of toxins is enhanced by soy proteins (compared to milk protein) because the peptides from soy digestion interfere with entero-hepatic reabsorption.

61
Q

What is absorption of toxicants and how are its characteristics assessed?

A
  • The process by which toxicants cross the epithelial cell barrier and enter into the blood circulation
  • The characteristics of this will be assessed using rate constants (e.g., ka = rate constant for absorption)
62
Q

Factors that will influence the kinetic distribution of a toxicant include [3]:

A
  • Route of exposure (e.g., oral usually takes longer than inhalation)
  • Mechanism of absorption
  • Chemical and physical properties of the toxicant
63
Q

List 4 routes of exposure.

A
  • Percutaneous (skin)
  • Respiratory
  • Gastrointestinal (through diet or air swallowing)
  • Parenteral (injections)
64
Q

Describe the GI tract as a route of exposure.

A

Absorption of food toxicants can take place anywhere, but much of the tissue structure in the digestion system is specially designed for absorption.

Usually not much absorption in the stomach, but this is where bound toxin is released from the acidic condition of the stomach. Free toxin may be absorbed in the small intestine. Entero-hepatic circulation appears at the end of the small intestine to the liver. There is also influence of the microbiome to transform/detoxify a toxin and enhance excretion.
64
Q

List 4 mechanisms of intestinal absorption.

A
  • Passive diffusion
  • Facilitated transport
  • Active transport
  • Pinocytosis

Most common in food toxicology are passive diffusion and facilitated transport.

65
Q

Describe the most important/relevant type of absorption of toxicants via the GI tract.

A
  • Passive diffusion
  • Lipid-soluble substances pass through membranes more easily
66
Q

Describe active transport in the GI tract.

A
  • Requires expenditure of cellular energy
  • Fundamental for excluding toxic compounds
  • This mechanism is important in the elimination of toxicants
Vitamin D for example, requires a binding protein to bring it across the cell membrane. This can be limiting and therefore affect the absorption efficiency.
67
Q

Which method of GI transport is fundamental for excluding toxic compounds?

A

Active transport

68
Q

Describe facilitated transport in the GI tract.

A
  • A form of passive transport facilitated by transport proteins
  • Polar and non-polar molecules
Diffusion down concentration gradients.
69
Q

Describe pinocytosis of the GI tract.

A
  • Cell membrane wrap toxicants and draw them inside the cell
  • High molecular weight and colloidal particles
70
Q

List factors that affect absorption in the GI tract. [4]

A
  • Blood flow
  • Lymph flow rate
  • Special biological inhibitors
  • Properties of the toxicant
71
Q

Describe how intestinal blood flow affects absorption in the GI tract.

A
  • Normal blood flow in the portal vein 1.2 L/hr/kg
  • This increases 30% after a meal!
  • Toxicants which increase blood flow, may also have enhanced absorption and toxicity.
Notice how as intestinal blood flow increases, the absorption of the compound increases.
72
Q

Describe how lymph flow rate affects absorption in the GI tract.

A
  • Lymph flow rate is 2 mL/hr/kg
  • Fats are absorbed and transported by lymph
  • Highly toxic substances (e.g., botulinum toxin) are transported via this route

Q: Does a high fat diet increase appearance rate of botulism symptoms?

A: Yes, because the spore is fat-soluble!

73
Q

Describe the blood-brain barrier with regard to toxicant exposure.

A
  • System with very low permeability to toxicants.
  • Newborns do not have a completely developed barrier.
  • Alcohol increases permeability of this barrier.

Some toxins can still cross the blood-brain barrier (e.g., saxitoxins).

Newborns and alcoholics are higher risk.

74
Q

Describe the placental barrier with regard to toxicant exposure.

A
  • Substrate flux (e.g., glucose)
  • Can inhibit (restrict) entrance of toxins to the fetus
  • Radiation; lipid-soluble toxicants; organophosphorus insecticides can cross the barrier
75
Q

What is able to cross the placental barrier? [3]

A
  • Radiation
  • Lipid-soluble toxicants
  • Organophosphorus insecticides
76
Q

Rate of absorption of a toxicant is higher in the GI tract when: [3]

A
  • Rate of absorption is higher if toxicant is:
    • more lipid-soluble
    • greatest concentration
    • smaller molecular weight
Effect of molecular weight of amides on the rate of absorption. In decreasing rates: acetamide>lactamide>malonamideamide>succuinamide. You can see as molecular weight increases, absorption decreases.
77
Q

Describe where the accumulation of food toxicants occurs in the body.

A
  • Organs (liver and kidneys)
  • Lipid rich tissues (e.g., DDT and PCBs pass into the blood by fatty tissues)
  • Bones (e.g., fluoride; lead; radium; tetracyclines [antibiotic])
  • Other tissues (e.g., arsenic in keratin-rich tissues; iodine in thyroid glands; carbon monoxide in hemoglobin)
78
Q

Where does biotransformation of toxicants occur?

A

Mainly in the liver, but also in the intestine, kidney, lung, brain, and skin.

79
Q

What does metabolism of toxicants achieve?

A
  • Decreases the biological activity
  • Increase polarity (increased toxicant polarity enhances excretion)

Phase 1 and 2 need to be balanced or that could lead to enhanced toxicity. An example of this is in alcohol metabolism, since the balance is in favour of phase 1 enzymes, which produces a highly toxic compound that is then not eliminated as quickly as it is produced.

80
Q

Describe biotransformation reactions of toxin versus nontoxic compounds.

A
81
Q

Describe phase 1 and phase 2 enzymatic biotransformation reactions.

A
  • Phase 1 reactions: decrease lipid solubility of the compound by introducing or exposing a functional group
  • Phase 2 reactions: produce water-soluble conjugated products by combining compounds with endogenous substrates
82
Q

List 3 examples of phase 1 enzymes responsible for biotransformation reactions.

A
  • Cytochrome P450 (a group of non-specific enzymes)
  • Monoamine oxidase
  • Flavin-containing monooxygenase

Phase 1 reactions decrease lipid solubility of the compound by introducing or exposing a functional group. This may lead to a more toxic compound, or a non-toxic compound. The key is to maintain balance between phase 1 and 2 so that toxicity can be eliminated and does not accumulate during biotransformation.

83
Q

List 2 examples of phase 2 enzymes responsible for biotransformation reactions.

A
  • Glutathione-S-transferase
  • Catechol-O-methyltransferase

Phase 2 reactions produce water-soluble conjugated products by combining compounds with endogenous substrates.

84
Q

Give an example of phase 1 and 2 enzymatic biotransformation reactions for shellfish toxin.

A
  • Phase 1: Cytochrome P450
  • Phase 2: Glutathione-S-transferase

Enzymes require cofactors to function - usually a micronutrient. (e.g., Cytochrome needs iron; glutathione needs selenium). Diet is important! This is one of the variabilities in terms of susceptibility.

85
Q

Give an example of phase 1 and 2 enzymatic biotransformation reactions for mycotoxins.

A
  • Phase 1: Cytochrome P450
  • Phase 2: Glutathione-S-transferase
Oxidation will continue (carcinogenic reaction) if a deficiency in phase 2 enzymes exists or if there is an imbalance in phase 1 and 2 enzymes.

Enzymes require cofactors to function - usually a micronutrient. (e.g., Cytochrome needs iron; glutathione needs selenium). Diet is important! This is one of the variabilities in terms of susceptibility.

86
Q

Describe the excretion of water-soluble biotransformed products.

A
  • Usually excreted in:
    • Urine (molecular weights < 400)
    • Bile (molecular weights >300)
87
Q

Describe the excretion of volatile compounds (with high vapour pressure).

A

Excreted via the lungs

88
Q

Describe the excretion of lipid-soluble compounds.

A
  • Can leave the body as:
    • Components of lactation fluid (e.g., aflatoxin M1)
    • Dead skin cells
    • Hair
    • Saliva
    • Reproductive tract secretions
89
Q

Define the biological half-life of a toxicant.

A

The time required for some measure of the amount of a toxicant in the body (e.g. body burden, tissue concentration) to decrease to 1/2 its concentration value observed at the initiation of evaluation interval.

Relates to the sum of all the activities: absorption; distribution; biotransformation; elimination

90
Q

Summarize the factors affecting distribution and excretion of toxicants & half-life. [10]

A

1) water compartments in the tissues of the body
2) lipid compartments in the tissues of the body
3) macromolecular binding
4) passage through the placenta
5) passage in the brain and cerebrospinal fluid
6) rate of pulmonary excretion
7) rate of renal excretion
8) rate of biliary excretion
9) rate of metabolism
10) lactation; perspiration; salivation; lachrymation (i.e., shedding tears); reproductive tract secretions

FOOD 525 (10 decks)

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