Toxicology - deck I

Question 1

Xenobiotic

Answer 1

is a foreign, potentially harmful, substance, strange for life or for an organism
* that either is not normally naturally produced
* or not expected to be present within that organism,
but still found in this particular organism

Question 2

mutagenicity

Answer 2

is a term used to broadly describe the property of chemical agents or drug substances to induce genetic mutation

Question 3

teratogenicity

Answer 3

the ability to cause defects in a developing fetus

A teratogen is anything a person is exposed to or ingests during pregnancy that’s known to cause fetal abnormalities.

Question 4

define toxicant and toxin

Answer 4

The term “toxicant” denotes, above all, a synthetic substance causing adverse health effects.

A similar term “toxin” usually refers to any proteinous poison produced by a living organism.

Question 5

define zootoxin

Answer 5

also known as venom (from Latin venemus)

denotes a poisonous matter (toxin) normally secreted by snakes, scorpions, bees, and the like.

Question 6

what is ADME

Answer 6

is an abbreviation in pharmacokinetics and pharmacology for “absorption, distribution, metabolism, and excretion/elimination”, and describes the disposition of a pharmaceutical compound within an organism.

Question 7

what element contributes to DDT’s toxicity?

Answer 7

the 5 chlorine atoms in a DDT molecule = very bad

Question 8

Exposure to (contact with) the toxicant can be one of what 4 options

Answer 8

• acute: contact time with substance (toxicant) shorter than 24 hours, mostly once
• subacute: usually repeated contacts during 1 month
• subchronic: contact time 1-3 month, or
• chronic: contact time longer than 3 months. Usually everyday contact with food.

Question 9

Dose is usually expressed in

Answer 9

micrograms (µg) or milligrams (mg) per kg of body weight (bw)

Question 10

NOAEL

Answer 10

(no-observed-(adverse) effect-level) – the highest dose/concentration, not causing any adverse-toxic effect in any animal in a test group

NOAEL is the basis for the counting of acceptable daily intakes (ADI) and tolerable daily intakes (TDI)

Question 11

LOAEL

Answer 11

the lowest observed [adverse] effect level – the lowest dose causing an observable effect, at least in a portion of the animals.

Question 12

Absolute (LD100), minimal (LDmin) and median (LD50) LDs can be distinguished.

what are these

Answer 12

LD stands for lethal dose

In experimental toxicology, LD50, causes the death of 50% of animals of a test group at an acute contact with a toxicant.

LD100 belongs to the most durable animal and
LDmin to the weakest animal.

Question 13

what are LC50, LC100 and LCmin

Answer 13

LC stands for lethal concentration

Instead of doses, sometimes concentrations in blood plasma are used – the respective parameters will be LC50, LC100 and LCmin (mmol/l, μg/m3).

So LC100 meaning the concentration at which 100% of test group animals die.

Question 14

ED50

Answer 14

effective dose that evokes 50% of the possible alteration of the parameter

Question 15

IC50

Answer 15

IC stands for inhibitory concentration

The half maximal inhibitory concentration (IC50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function.

Question 16

ADI

Answer 16

Acceptable Daily Intakes (typically for food additives)

ADI is the quantity of a chemical compound that an individual can consume daily during all their lifetime without any harm to health.

Analogical number for food contaminants is tolerable daily intake (TDI)

Question 17

explain how Doses can be either external or internal

Answer 17

In toxicological studies, the net amount of a compound administered per kg of the test animal weight is regarded as the external dose.

Most substances will cause the toxic effect only after they have been absorbed into the general bloodstream.
The absorbed part of the external dose is called the absorbed or internal dose.

Question 18

define bioavailability

Answer 18

Bioavailability is the fraction of the administered external dose, that reaches the systemic circulation in unchanged form.

Question 19

transcytosis

Answer 19

is a type of transcellular transport in which various macromolecules are transported across the interior of a cell. Macromolecules are captured in vesicles on one side of the cell, drawn across the cell, and ejected on the other side.

Question 20

what types of compounds begin to absorb in the mouth already?

Answer 20

Ethanol, hydrocarbons and other neutral non-ionizable substances

Question 21

Weak acids diffuse across the membrane best of all in the

Answer 21

stomach

Question 22

Weak bases pass the membranes in the?

Answer 22

intestines, where pH ≈ 6.

basic compounds have positive charge

Question 23

A lipid-soluble non-ionizable substance absorbs where?

Answer 23

equally well in any part of the digestive tract, its absorbtivity increases by an increase in the Kow, that is, the lipophilicity of the substance.

This rule does not apply for very lipophilic (Kow > 3000) molecules that tend to form supramolecular colloidal solution in the stomach and intestines, the dispersed
particles of which, micelles, are too large to cross the membranes.

Question 24

Metals are absorbed mainly in the

Answer 24

first part of the small intestine – Cr, Mn, and Zn in the ileum; Fe, Cu, Hg, Th and Sb in the jejunum

Question 25

Metals may, during absorption, change their

Answer 25

valence form: for example, divalent (ferrous) iron can be oxidized into trivalent (ferric) iron,

Question 26

Once a substance is in the bloodstream, it or its metabolites may be (4)

Answer 26

* distributed between tissues, * excreted from the organism, * or contrarywise accumulated in a tissue, * biotransformed into different metabolites;

Question 27

Distribution of xenobiotics in the organism is a dynamic process, depending on

Answer 27

* the ratio of the rates of absorption, metabolism and elimination (excretion), * on the physical and chemical properties of the substance, * and on the particular environment in various body compartments.

Question 28

Knowing substance concentration in plasma, it is possible to calculate important pharmaco- or toxicokinetic parameters such as, (4)

Answer 28

* half-life, * area under the curve, * volume of distribution * body burden.

Question 29

Half-life (τ1⁄2) is

Answer 29

the time, during which one half of the initial dose of a substance becomes either degraded, metabolized, or eliminated from the organism. Is determined by metabolism and excretion rates.

Question 30

Area under the curve (AUC) is

Answer 30

the area in a plot of concentration of a xenobiotic in plasma (y-axis) against time (x-axis). AUC has the unit (mass/volume) × time and expresses the total amount of a xenobiotic absorbed by the body, irrespective of the rate of absorption.

Question 31

Volume of distribution VD (litres) is

Answer 31

the volume of body liquid in which a foreign compound is distributed. If a toxicant is distributed only in blood plasma, low VD will result, but if distributed in all body fluids, or concentrated (accumulated) in some solid tissue, such as adipose tissue, VD will be high.

Question 32

Body burden is the

Answer 32

total amount of the foreign compounds that are present in a body at a given point in time. Sometimes, it is also useful to consider the body burden of a specific single chemical, like lead, mercury, or dioxin.

Question 33

Toxic effect of a compound can be caused either by: (3)

Answer 33

* The parent compound * Metabolites, formed at the site of entry into the organism and/or in the liver that are sufficiently stable to reach target organs (systemic toxicity) * Metabolites, formed in the target organ

Question 34

Biotransformation of xenobiotics is mainly carried out in the

Answer 34

liver, but also in intestinal epithelium, kidneys, lungs, brain, and skin

Question 35

the Liver and kidneys together contain more than 90% of the

Answer 35

metabolic activity of an organism which determines the speed of elimination of the xenobiotic and its bioavailability.

Question 36

Xenobiotics are metabolized (biotransformed) in the organism in two consecutive phases (simplification) Phase I involves what?

Answer 36

activation of the substrate into a primary metabolite activation can happen via oxidation or reduction etc. (usually oxidation though)

Question 37

Xenobiotics are metabolized (biotransformed) in the organism in two consecutive phases (simplification) Phase II involves what?

Answer 37

conjugation of the primary metabolite into the secondary metabolite

Question 38

A majority (over 90%) of the Phase I reactions are catalyzed by

Answer 38

cytochrome P450 monooxygenase complex (CYP450 for mammalians/plants and P450 for bacterial species), (EC 1.14.) that: is a superfamily of mostly membraneous isoenzymes is a hemoprotein

Question 38

A majority (over 90%) of the Phase I reactions are catalyzed by

Answer 38

cytochrome P450 monooxygenase complex (CYP450 for mammalians/plants and P450 for bacterial species) that: is a superfamily of mostly membraneous isoenzymes is a hemoprotein

Question 39

Enzyme superfamily CYP450 is found mostly...?

Answer 39

in most of the tissues, but in particularly high concentrations in the liver. is located on the membrane of the smooth endoplasmic reticulum, but also in other organelles.

Question 40

how does CYP450 act on a substrate?

Answer 40

switches an oxygen atom into the substrate molecule, oxidizing the substance. In certain cases, CYP or P450 is capable of catalyzing also the opposite reaction – reduction of a substrate. requires a helper enzyme

Question 41

what is CYP450

Answer 41

an essential enzyme family found in mammals primarily found in liver cells

Question 42

what is the epoxidation of compounds

Answer 42

a conversion of a usually unsaturated compound into an epoxide. an epoxide is a cyclic ether with a three-atom ring, containing two atoms of carbon and one atom of oxygen Electrophilic epoxides formed are usually unstable and chemically reactive. They can interact with nucleophilic groups in crucial cellular macromolecules and thereby have a deleterious physiological effect.

Question 43

what is the largest group of the Phase II reactions.

Answer 43

Conjugation with glucuronic acid Respective enzyme is UDP-glucuronyltransferase (UGT) superfamily. UGT content is highest in liver

Question 44

how can the enterohepatic circulation increase exposure time to xenobiotics

Answer 44

glucuronides (so metabolites) of xenobiotics are transported to the intestines with the bile. after hydrolysis of the glucuronide by microbial β-glucuronidase in the intestines, enterohepatic circulation reciruclates the metabolites lengthening their half-life in plasma essentially enhancing exposure time of the target organs like liver. Toxicity increases.

Question 45

Hydrolysis of esters and amides is catalyzed by

Answer 45

esterases, a group of enzymes, characterized again by a broad substrate specificity. The conversion of both types of substrates is actually catalyzed by the same enzymes. The esterases accomplish numerous endogenous functions in the organism but they are also able to metabolize foreign compounds.

Question 46

esterases are historically divided

Answer 46

A, B and C-esterases. According to reactivity with toxic organophosphorus compounds, either as with substrate (A), as with inhibitor (B) and no reactivity(C).

Question 47

Toxicity of the well-known organophosphorus and carbamate insecticides is based on

Answer 47

the inhibition of acetylcholinesterase, belonging to the B-esterases.

Question 48

what are epoxides

Answer 48

Epoxides are mostly electrophilic molecules with a very reactive triangular oxirane cycle. The reaction between epoxy-group and other nucleophiles (like proteins) may also lead to other acute or subchronic damages (intoxications). Epoxides are generated from aflatoxins, PAHs, polyunsaturated fatty acids (PUFA)...

Question 49

Epoxide hydrolases are located primarily in the

Answer 49

endoplasmatic reticulum, but also in the cytosol of the hepatic cells.

Question 50

The activity of CYP450 in the small intestine is highly dependent on

Answer 50

dietary iron. A deficiency in this metal abruptly reduces the activity of several CYP-linked enzyme

Question 51

what are the two most important regulation mechanisms of an enzyme activity

Answer 51

Regulation of xenobiotic metabolism by induction and inhibition CYP450s are often the rate-limiting enzymes in the metabolic processes, and hence, have important role in the determination of in vivo kinetics and interactions.

Question 52

what does it mean to be a complementary molecule_

Answer 52

matching in dimensions and in charge distribution thus capable of binding

Question 53

Agonists are

Answer 53

exogenous substances that also bind to a receptor and activate it. They imitate the action of endogenous ligands like hormones or neurotransmitters, but usually weaker.

Question 54

Antagonists are

Answer 54

substances that, by binding very strongly and irreversibly to the receptor, inactivate it.

Question 55

what is CYP450

Answer 55

enzyme family that plays a huge role in metabolizing things that are foreign to the body like drugs etc. detoxification the original forms of drugs can't really be cleared so theyre first converted into a more familiar form via 2 phases for the purpose of excretion

Question 56

Most important cell receptor?

Answer 56

AhR aryl hydrocarbon or dioxin receptor functions to regulate a battery of genes of CYP AhR activates a whole gene battery involved in phase I and phase II metabolism.

Question 57

What is the most important route of elimination for xenobiotics?

Answer 57

the kidneysn, as 25% of the arterial blood passes through the kidneys, 20% of which is filtrated through glomeruli. Large molecules like proteins are not able to pass through intact glomeruli and fat-soluble molecules like bilirubin are reabsorbed from renal tubules.

Question 58

Substances are moved from the blood to the kidneys by one of the following 3 mechanisms:

Answer 58

* Filtration through glomerular pores – small molecules * Passive diffusion into renal tubules – fat-soluble molecules * Active transport into tubular liquid – separate systems for anions and cations

Question 59

What is para-aminohippuric acid

Answer 59

a metabolite of para-aminobenzoic acid that is used for study of transport of substances in kidneys transported from blood to renal tubules by a special anion-transporting system. PAH clearance is used to measure renal plasma flow

Question 60

What is Ficks law

Answer 60

Fick's laws of diffusion describe diffusion

Question 61

Elimination in the content of bile formed in the liver is especially important for

Answer 61

large polar molecules. Polar compounds with a molecular weight around 300 Da and higher, like glutathione conjugates, are eliminated from the organism by this route.

Question 62

liver has three specific transport systems, separate for (3)

Answer 62

the neutral molecules, anions, and cations. Saturation of these systems leads to the rise of the content of these substances in the liver; in the case of a toxic compound, it can cause liver damage.

Question 63

The biliary route of elimination can have these 4 adverse effects

Answer 63

* substantially increase the half-life of a compound * lead to the formation of toxic compounds in the intestines * increase the exposure of the liver to a toxicant * cause serious hepatic damage due to saturation of the excretion system

Question 64

What? has primary control over translocation, metabolism and toxic action because the total amount of herbicide available for these processes is determined by the amount of herbicide absorbed by the plant.

Answer 64

Absorption has primary control over translocation, metabolism and toxic action because the total amount of herbicide available for these processes is determined by the amount of herbicide absorbed by the plant.

Question 65

What is glutathione?

Answer 65

is a substance made from the amino acids glycine, cysteine, and glutamic acid. It is produced by the liver and involved in many body processes. is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, peroxides, lipid peroxides, and heavy metals.

Question 66

Metabolism PHASE III related to?

Answer 66

Phase III reactions are unique to plants because plants do not excrete xenobiotics or metabolites as animals do. Plants remove somehow the xenobiotic within their own system.

Question 67

what does PBTs stand for?

Answer 67

Persistent Bioaccumulative Toxic Chemicals

Question 68

Plants store many toxic metabolites also in their --?-- and these substances are released upon herbivore attack.

Answer 68

Plants store many toxic metabolites also in their vacuoles and these substances are released upon herbivore attack.

Question 69

The four main methods for removal of a toxicant from the GI tract are:

Answer 69

emetic preparations gastric lavage use of absorbents enema

Question 70

Activated C binds substances by --?--, however does not bind well to certain chemicals.

Answer 70

Activated C binds substances by van der Waals forces, does not bind well to certain chemicals, including alcohols, glycols, strong acids and bases, metals and most inorganics (lead, arsenic, fluorine, boric acid). Due to high degree of microporosity, 1 g of material has a surface area over 500 m2 (about 1/10 the size of a football field)

Question 71

Acceleration of elimination of a toxicant from an organism by 2 options.

Answer 71

by increasing urine volume or changing the urine pH. Method is efficient in case of either acidic or alkaline substances or their metabolites. Acidic compounds are better soluble at alkaline pH, basic compounds at acidic pH.

Question 72

Urine can be turned more alkaline, for example, by

Answer 72

feeding solid sodium carbonate or by injection of its solution into the vein. Successful in case of barbiturate or aspirin intoxications.

Question 73

Urine can be turned more acidic e.g. for amfetamine by administration of

Answer 73

ammonium chloride.

Question 74

sorbent definition

Answer 74

A material similar to molecular sieve material, which acts by adsorption (attracting molecules to its surface) are insoluble materials or mixtures of materials used to recover liquids through the mechanism of absorption, or adsorption, or both.

Question 75

Specific mechanisms of antidote action (3)

Answer 75

1. Antidote as an chelating agent. 2. Antidote as an accelerator of detoxication of a highly reactive metabolite. 3. Antidote as a decelerator of a toxicant's metabolism

Question 76

Explain mechanism: Antidote as an chelating agent.

Answer 76

Antidote reacts with a toxicant forming water-soluble chelate complexes, which are excreted faster than the parent compound.

Question 77

Explain mechanism: Antidote as an accelerator of detoxication of a highly reactive metabolite.

Answer 77

A good example is N-acetylcysteine, used as the antidote in case of paracetamol overdoses. It increases the synthesis of glutathione in hepatocytes; glutathione effectively binds para-benzoquinone-imine, a dangerous metabolite of paracetamol, removing it from the complex with a hepatic protein.

Question 78

Explain mechanism: Antidote as a decelerator of a toxicant's metabolism

Answer 78

is used when the metabolite is more toxic than the foreign substance. Hence, it is reasonable to reduce the metabolism of the toxicant. e.g. conversion (oxidation) of ethylene glycol, into toxic oxalic acid, is reduced by the administration of ethanol. Ethanol blocks the metabolism of ethylene glycol, enabling elimination of the glycol in the unaltered form.

Question 79

anoxemia and anoxia

Answer 79

anoxemia = a condition of subnormal oxygenation of the arterial blood. anoxia = an absence of oxygen.

Question 80

material cumulation

Answer 80

Chronic intoxication develops in the case of either material cumulation or functional cumulation. Material cumulation being accumulation of a toxic substance in the organism. In the case of toxic heavy metals (Pb, Hg, Cd, etc.), which have a long half-life in the organism, mainly material cumulation occurs, although functional also plays a definite role in the development of an intoxication.

Question 81

functional cumulation

Answer 81

Chronic intoxication develops in the case of either material cumulation or functional cumulation. Functional cumulation being accumulation of initially minute functional alterations in the organism. Long-term exposure to low doses of phosphororganic inhibitors depresses cholinesterases to such a low level that symptoms of intoxication start to appear.