Toxicokinetics

Question 1

Toxicity is the (intrinsic or extrinsic?) quality of a chemical to __________

Answer 1

Intrinsic

produce an adverse effect

Question 2

Toxicity is the Capacity to induce ______,_______, and ___________ effects

Answer 2

teratogenic, mutagenic and carcinogenic

Question 3

Anything can be a poison
T/F

Answer 3

T

Question 4

The _____ makes the poison

Answer 4

Dose

Question 5

Absorption
The process by which toxicants ————————

Answer 5

cross body membranes and enter the bloodstream

Question 6

Many environmental toxicants enter the food chain and are absorbed together with food.

T/F

Answer 6

T

Question 7

_________ is the most common route of unintentional exposure to a toxicant (especially for children)

While

intentional overdoses most frequently occur via the ______

Answer 7

accidental ingestion

oral route.

Question 8

Poisons in the GI tract usually produce systemic injury to an individual before they are absorbed

T/F

Answer 8

F
They usually do not

Question 9

Absorption of toxicants can take place along the entire GI tract: from the mouth to the rectum.

T/F

Answer 9

T

Question 10

Organic toxicant (acid or base) are usually absorbed by ________ in the part of the GI tract where it exists in its (ionized or non-ionized?) form

Answer 10

simple diffusion

non-ionized

Question 11

The ______________ can be used to determine the fraction of a toxicant that is in the non- ionized form and estimate the rate of absorption from the stomach or intestine

Answer 11

Henderson–Hasselbalch equations

Question 12

According to the HH equation, weak organic acids are mainly present in the non-ionized (lipid soluble) form in the ________ and ionised form in the ______

Answer 12

stomach

intestine

Question 13

Factors that affect the HH equation include __________ and _________

Answer 13

surface area and blood flow rate.

Question 14

Most toxicants are absorbed by __________ though

Answer 14

simple diffusion

Question 15

After oral ingestion, about ___% of lead,__% of manganese, ___% of cadmium, and __% of chromium salts are absorbed.

Answer 15

10

4

1.5

1

Question 16

Absorption: GIT

Particles and particulate matter can also be absorbed

T/F

Answer 16

T

Question 17

Absorption: GIT
Particles and particulate matter can also be absorbed
In this case, ______ determines absorption and is _______ related to absorption

Answer 17

particle size

inversely

Question 18

_______ arsenic significantly more toxic than its _______ form due to increased ________

Answer 18

powdered

coarse granular

surface area

Question 19

Absorption: GIT

In general, absorption through the GIT is influenced by:

Characteristics of the toxicant

○ Must have sufficient _______ partition

○ Be relatively (ionizer or non-ionized?) in most parts (lipid- soluble)

○ If a particle, must be of relatively ___ size

Answer 19

aqueous - lipid

non-ionized

low

Question 20

Absorption: GIT

Affected by Other xenobiotics/toxicants:

○Cd decreases the absorption of _______

Ca decreases ____ absorption

Mg decreases absorption of ______
—

Answer 20

Zn and Cu

Cd

Fluoride

Question 21

Absorption: GIT
ž
—
Affected by GI ________/______ within various segments of the GI tract

• could be as an effect of _____/______

Answer 21

Motility/residency time

Laxatives/Anti-diarrheas

Question 22

Absorption: GIT

Affected by Age

• Well water with a (low or high?) nitrate content produces _______ more frequently in (infants or adults ?) than in (infants or adults?)

*(Lower or Higher?) pH of the neonatal GI tract is permissive for the growth of bacteria

*Bacteria in the GI tract convert ____ to _____, increasing the risk of methemoglobinemia
ž
—
— —

Answer 22

High; methemoglobinemia

Infants
Adults

Higher

nitrate to nitrite

Question 23

Absorption: GIT

Snake venoms are much (more or less?) toxic by the oral route relative to intravenous exposure

Why?

Answer 23

Less

because they are broken down by digestive enzymes

Question 24

Absorption : GIT

nitroaromatic compounds are reduced by intestinal microflora to potentially ______ and ________ amines.

—
—

Answer 24

toxic and carcinogenic aromatic

Question 25

Absorption: Lungs Absorption or deposition of airborne poisons in the lungs can result in Death from poisoning— __________ Occupational disease— _________

Answer 25

carbon monoxide silicosis

Question 26

Absorption: Lungs Gases (e.g., _______,_______ ,_______ ) Vapors of volatile or volatilizable liquids (e.g., _______ and __________) Aerosols

Answer 26

carbon monoxide, nitrogen dioxide, and sulfur dioxide benzene and carbon tetrachloride

Question 27

Absorption: Lungs Depends on Gas molecules partition between two media: _______ and ______ during the absorptive phase ______ and ———- during the distributive phase

Answer 27

Air and blood blood and other tissues

Question 28

Absorption: Lungs Factors such as _______ and ______ of molecules are less important more important is the _________________

Answer 28

dissociation and lipid solubility blood-to-gas partition coefficient.

Question 29

Chloroform has a relatively (low or high?) blood to gas partition coefficient (approximately ___), whereas ethylene has a (low or high?) coefficient (____)

Answer 29

High 20 Low 0.14

Question 30

Absorption: Lungs The site of deposition of aerosols and particulates depends largely on the __________

Answer 30

size of the particles

Question 31

Absorption: Lungs The __________ the particle, the further into the respiratory tree the particle will deposit As particle size ____eases, the number of particles in a unit of space increases along with the total surface area of the particles

Answer 31

smaller (finer) decr

Question 32

Absorption: Skin Exposure is usually limited by its __________ nature.

Answer 32

relatively impermeable

Question 33

Absorption: Skin Fatal exposures to insecticides (and even gases e.g. sarin – nerve gas) have occurred in _______ after absorption through intact skin

Answer 33

agricultural workers

Question 34

Absorption: Skin Passage through the ________ is the rate-determining step.

Answer 34

stratum corneum

Question 35

Absorption: Skin All toxicants move across the stratum corneum by ________

Answer 35

passive diffusion

Question 36

____philic compounds are absorbed more readily across the stratum corneum , ____ proportional to their lipid solubility and _____ related to molecular weight

Answer 36

Lipo directly inversely

Question 37

Absorption: Skin Hydrophilic compounds are more likely to penetrate the skin through appendages such as _______

Answer 37

hair follicles

Question 38

The permeability of hydrophilic molecules doesn’t depend on diffusivity and thickness of the stratum corneum T/F

Answer 38

F also depends on it

Question 39

Absorption: SKIN Arrange in terms of decreasing absorption rate Forehead skin, scrotal skin, palm skin

Answer 39

Scrotal skin > forehead skin > palm

Question 40

Absorption: Skin Several factors influence the absorption of toxicants through the skin: *The ______ of the stratum corneum: caustic agents/Diseases *The _____ state of the stratum corneum e.g. occlusive application *_______: occupational exposure e.g. agricultural workers *______ as carriers - dimethyl sulfoxide (DMSO) *____________

Answer 40

integrity hydration Temperature Solvents Molecular size (again nanoparticles)

Question 41

Nanoparticles are relevant in absorption in which of the following routes Skin GIT lungs

Answer 41

All 3 bby!

Question 42

In studying effects of toxicants, other routes of administration may also be used. Intravenous – ____% absorption Intraperitoneal – _______ Subcutaneous – influenced by _____/____ Intramuscular - influenced by _____/_____

Answer 42

100 Hepatic first pass blood flow/formulation blood flow/formulation

Question 43

Distribution is a (slow or rapid ?) process.

Answer 43

Rapid

Question 44

The rate of distribution to organs or tissues is determined primarily by ________ and ________

Answer 44

blood flow rate of diffusion

Question 45

Distribution Some toxicants selectively accumulate in certain parts of the body as a result of _____ binding high solubility in ____ Lungs e.g. ______ accumulates in the lungs Bone e.g. ____

Answer 45

protein fat; paraquat Lead

Question 46

The target organ for toxicity may be the site of accumulation T/F

Answer 46

T

Question 47

The target organ for toxicity may be the site of accumulation and this is always the case T/F

Answer 47

F this is not always the case

Question 48

Distribution Binding to plasma proteins is the major site of protein binding Several different plasma proteins Albumin α1- ___ glycoprotein Transferrin-a ______- transports ___ Ceruloplasmin, which carries _____

Answer 48

Acid beta globulin; Fe copper

Question 49

Distribution Because of their high _______, plasma proteins and the toxicants bound to them (can or cannot?) cross capillary walls.

Answer 49

molecular weight Cannot

Question 50

Consequently, the fraction of a toxicant bound to plasma proteins is not immediately available for distribution into the extravascular space but available for filtration by the kidneys T/F

Answer 50

F Not available for both

Question 51

a toxicant in a storage depot (including fat deposits) is not in equilibrium with the free fraction of the toxicant in plasma T/F

Answer 51

F It is

Question 52

Distribution The binding of chemicals to plasma proteins is important for two reasons: 1) Toxicity is typically manifested by the amount that is (bound or unbound?) . 2) Risk of adverse effects resulting from ________________ – ______ displacement

Answer 52

unbound interactions with other highly bound compounds protein binding

Question 53

Distribution The potential for these compounds to produce carcinogenic, developmental, and endocrine effects is related to their ______________

Answer 53

accumulation/storage in body fat

Question 54

toxicants with a (low or high?) lipid/water partition coefficient may be stored in body fat concern is the possibility of increase in the concentration of toxicant in blood/target organ of toxicity may occur if ______________ occurs

Answer 54

High rapid mobilization from fat

Question 55

Distribution Compounds such as _____,_____, and _____ may be incorporated and stored in the bone matrix.

Answer 55

fluoride, lead, and strontium

Question 56

___%of the lead in the body is eventually found in the _______.

Answer 56

90 skeleton

Question 57

Toxicants can be released from the bone by ________ at the ____ surface and _____ of bone crystal through _______ activity.

Answer 57

ionic exchange crystal dissolution osteoclastic

Question 58

Toxicants are also distributed into the brain T/F

Answer 58

T

Question 59

Only the free fraction of a toxicant equilibrates rapidly with the brain. T/F

Answer 59

T

Question 60

Distribution Most toxic chemicals pass the placenta by _________ Exceptions → antimetabolites (_____ transport): structurally similar to ____________________

Answer 60

simple diffusion Active transport endogenous purines and pyrimidines

Question 61

Under steady-state conditions, the concentrations of a toxic compound in the plasma of the mother and fetus are usually different T/F

Answer 61

F They are usually the same

Question 62

Metabolism Rationale for metabolism: Eventual _______________. Unacceptably _____________ — —

Answer 62

accumulation to toxic levels long duration of action.

Question 63

Metabolism It can make the xenobiotic less toxic ( _______ ), but in some cases it can make it more toxic (________). E.g. the oxidation of ethanol (alcohol) to _______ ( _______ ), and the subsequent oxidation of that to _____ is an example of _________.

Answer 63

detoxication; activation Acetaldehyde; activation acetic acid; detoxication

Question 64

Metabolism So, the biotransformation of drugs can result in: a loss of activity e.g., acetaminophen to _______________; morphine to _____________) no change in activity e.g., the conversion of fluoxetine to its N-demethylated metabolite ___________ an increase in activity (e.g. codeine to _________; morphine to ________ —

Answer 64

acetaminophen glucuronide morphine 3-glucuronide norfluoxetine morphine morphine 6-glucuronide. ž

Question 65

Inhibitors/Inducers can not inhibit or induce their own metabolism T/F

Answer 65

F They can

Question 66

Inhibition/Induction are (reversible or irreversible?) , adaptive responses

Answer 66

reversible

Question 67

Metabolism Four discernable phenotypes: List them

Answer 67

Poor metabolizers (PMs) Intermediate metabolizers (IMs) Extensive metabolizers (EMs) Ultra-rapid metabolizers (UM)

Question 68

organophosphate toxicity is more in male or female???

Answer 68

Female

Question 69

( male or female?) rats sleep longer than (male or female?) on hexobarbital

Answer 69

Female sleep longer than male

Question 70

The _______ is perhaps the most important organ for the excretion of xenobiotics

Answer 70

kidney

Question 71

Toxicants with (low or high?) lipid/water partition coefficient are reabsorbed from the tubules of the nephron more efficiently ž ž ž

Answer 71

High

Question 72

Elimination In this case, urinary excretion (i.e., not reabsorbed) of the (ionized or non-ionized?) moiety is favored

Answer 72

ionized

Question 73

bases are excreted to a greater extent at (lower or higher?) pH whereas excretion of acids predominates at (lower or higher?) urinary pH

Answer 73

Lower Higher

Question 74

Elimination A practical application of this knowledge is illustrated by the treatment of phenobarbital poisoning with ___________ In a similar manner, urinary ______ can be used to increase the excretion of a weak _____ like phencyclidine (PCP) in drug abusers.

Answer 74

sodium bicarbonate. acidification base

Question 75

there is competition for renal secretion T/F With reason

Answer 75

T It’s by active transport

Question 76

Penicillin is actively secreted by the organic acid systems (OATs) of the kidney; competes with ______ and thus lengthen its half-life and duration of action

Answer 76

probenecid

Question 77

many functions of the kidney are incompletely developed at birth T/F

Answer 77

T

Question 78

some xenobiotics are eliminated more (slowly or rapidly?) in newborns than in adults, and therefore may be (more or less?) toxic to newborns.

Answer 78

Slowly More

Question 79

the clearance of penicillin by premature infants is only about ____% of that observed in older children. ž ž

Answer 79

20

Question 80

Elimination The non-absorbed portion contributes to the _________ of most chemicals to some extent. One other factor contributing to that is __________, which likely occurs by ______ out of enterocytes or via ______ of intestinal cells during the normal turnover of this epithelium.

Answer 80

fecal excretion intestinal secretion passive diffusion exfoliation

Question 81

First Pass Effect and direct excretion into the bile is also a source of elimination. T/F

Answer 81

T

Question 82

Protein bound compounds are not available for active biliary excretion T/F

Answer 82

F They are fully available

Question 83

_______ and ________ conjugates have a high predilection for excretion into bile

Answer 83

Glutathione and glucuronide

Question 84

_____ excretion of toxicants and/or their metabolites is most often the major source of fecal excretion

Answer 84

Biliary

Question 85

The secretion of toxic compounds into milk is extremely important T/F With reasons

Answer 85

T 1)a toxic material may be passed with milk from the mother to the nursing offspring 2)compounds can be passed along the food chain via dairy products

Question 86

Toxic agents are excreted into milk by _______

Answer 86

simple diffusion

Question 87

Compounds that can accumulate in fat such as pesticides, PCBs, PBBs and furans have been found in human breast milk, and milk can be a major route of their excretion T/F

Answer 87

T

Question 88

Metals chemically similar to Ca, such as Pb, and chelating agents that form complexes with calcium also are also excreted into milk to considerable extents ž ž T/F

Answer 88

T

Question 89

Quantitatively, the excretion of toxic agents in sweat and saliva is of major importance. T/F

Answer 89

F Minor

Question 90

Toxic compounds excreted into sweat may produce ________. Substances excreted in saliva enter the ____, where they are usually ____ to become available for ______

Answer 90

dermatitis mouth swallowed GI absorption.