topic 23

Question 1

Why is the liver vulnerable to damage by toxins? What does toxin injury in the liver present like?

Answer 1

 Biotransformation of xenobiotics &
endogenous substances

 Subject to action of parent toxins and/or
their metabolites
 Dose-related & idiosyncratic

 Toxic injury not unique histologically or clinically
 Same pathology as other hepatic diseases;
such as steatosis, necrosis, inflammation, fibrosis, cholestasis

Question 2

What usually happens in CYP phase I reactions? What else can happen? What is one possible toxic results?

Answer 2

 Phase I usually “deactivates” the substance

 However, some metabolites retain the activity of the parent or are even more active in reacting with cellular molecules

 “Reactive metabolites” = unstable; including
free radicals, electrophiles or nucleophiles
 Responsible for much toxin-induced hepatic
damage

Question 3

What should happen with reactive electrophillic metabolites? What happens if that doesnt work? What are two examples of drugs that form reactive metabolites?

Answer 3

 Electron-loving metabolite immediately attracted
to a molecule able to donate or share electrons.
 eg, glutathione, the detoxifying conjugate,
having its nucleophilic sulfur atom

 Otherwise, S, N, O atoms in cellular macro-
molecules of proteins, DNA, RNA are targeted.
…..forming “adducts”

 Cyt P450 generates such reactive metabolites
 examples: acetaminophen & carbon tetrachloride

Question 4

What can happen with reactive metabolites at membranes?

Answer 4

 Reactive metabolites may also add to double bonds or abstract H+ atoms from fatty acids in lipid bilayer membrane

 Creates 2º lipid radicals that react with oxygen, leave a peroxyl residue on the fatty acid, and regenerate a lipid radical

 Chain reactions/ repetitive cycles of membrane-
damaging interaction occur in the membrane

Question 5

What is the classice hepatic lobule arrangement? Where is the portal triad located? Where are most CYP450 enzymes located? Where are most nutrients located? Where does acetaminophen do its damage?

Answer 5

Landmarks: Put central vein in the center & draw 3

rings around it

centri-lobular zone (CL)
 Midzonal (MZ)
 Periportal area (PP)

The portal triad surrounds the outside of the periportal area. This is where most nutrients are located. The CL zone is where most enzymes are and where acetaminophen causes injury.

Question 6

How common is toxin caused hepatocellular carcinoma? What are 2 agents that can cause it? What is the most common promoter? What can cause angiosarcoma of the liver?

Answer 6

 Hepatocellular carcinoma is rarely linked to toxins

 Ethanol, aflatoxin (Aspergillus on moldy legumes

and grains)

 Most common promoter:

Viral infection (HBV)

 Angiosarcoma of liver
Vinyl Chloride

Question 7

What are some suspected synthetic human hepatocarcinogens? Naturally occuring?

Answer 7

Synthetic

 Dimethyl nitrosamine

 Diethyl nitrosamine

 DDT

 CCl4

 Chloroform (CHCl3)

 PCBs

Naturally occurring

 Pyrrolizidine alkaloids
 Comfrey tea

 Safrole
 Sassafras

 Arsenic

Question 8

Why is the kidney vulnerable to toxin damage? What are the results?

Answer 8

 Renal tissues exposed to all exogenous

substances excreted in urine

 Toxin-induced injury can mimic many

types of renal conditions

 In a patient with kidney damage, consider

all the other possibilities, too

 Don’t be hasty in blaming a toxin

Question 9

What are some therapeutic agents that lead to renal toxicity?

Answer 9

 Antimicrobials
 Aminoglycosides , e.g. gentamycin
 Antifungal amphotericin

 Antineoplastics
 e.g. Cisplatin

 Iodinated radiocontrast agents

Analgesics
 e.g. Phenacetin, acetaminophen, NSAIDs

Question 10

What are some occ. and env. toxins that lead to renal toxicity?

Answer 10

Occ & Env chemicals
 Metals
 eg, Inorganic mercury, cadmium, lead

 Hydrocarbon solvents
 CCl4,toluene

 Aniline dyes (precursor to indigo)
 Aniline derivatives used to make APAP

 Diquat (herbicide)

 Ethylene glycol

Question 11

What part of the kidney is most commonly damaged? Where do toluene, analgesics, and gold each cause damage?

Answer 11

 Proximal tubule most commonly injured
 Most Cytochrome P450
 So, most subject to reactive metabolites

 Toluene: distal renal tubule

 Analgesics: interstitium

 Gold: glomerulus

Question 12

What is the most common presentation of kidney damage due to toxins? How serious is it?

Answer 12

 Most common presentation of toxic injury: acute renal failure
 Relatively abrupt decline in plasma
filtering and tubular processing

 Grades of severity from minor impairment to total failure of both kidneys
 Substantial degree of recovery from acute
injury often possible

Question 13

What is the most common cause of acute renal impairment? How does it work? What are 4 toxins that can cause it?

Answer 13

Acute tubular necrosis  ATN most common cause
of acute renal impairment

 Tubule cells damaged, swell, die & collapse into
the lumen

• CCl4
• Gentamycin
• Mercury
• Acetaminophen overdose

Question 14

Where is orellanine found? What renal condition does it cause? What is the pathology? How does it happeN?

Answer 14

Direct toxin-induced acute renal injury:
Tubulo-interstitial nephritis

 Orellanine in Cortinarius mushrooms

 Interrupts ATP production

 Pathology: Unremarkable glomeruli; interstitial
inflammation

Question 15

What are 3 things that can cause tubule lumen obstruction?

Answer 15

 Obstruction of tubule lumen

 Oxalate crystals
• Ethylene glycol metabolism

 Myoglobin from muscle breakdown

• 2,4-D; neuroleptic malignant syndrome; any
toxin causing prolonged seizures

 Hemoglobin from intravascular hemolysis
• Arsine gas, chlorates

Question 16

What are 3 agents that can cause chronic renal impairment through chronic exposure?

Answer 16

 Slowly progressing decline in renal function
 Tends to be permanent

 Associated with chronic exposure, eg,

 Phenacetin (cumulative 2-kg exposure)

 Cadmium

 Toluene (eg, glue sniffing) causing distal
renal tubular acidosis

Question 17

What are some agents that are risk factors for urinary tract cancer?

Answer 17

• Cigarette smoking
• Poly Aromatic Hydrocarbons (PAH)
• Asbestos
• Phenacetin
• Cadmium

• Aristolochia fangchi (herb used for weight loss)
BOARD EXAM ALERT

Question 18

What does reproductive toxicology include?

Answer 18

 Study of disturbances induced by chemicals throughout the entire reproductive cycle

1. Impairment of reproductive functions in parents
2. Effects on the progeny:
   • “Developmental” toxicology specifically studies effects prior to adulthood, only some of which are “birth defects”

Question 19

What are structural developmental defects known as? How are they caused? What percent of live births have them? What percent of those are due to drugs or toxins?

Answer 19

“Terata”

Regarded as the classic ‘birth defect’
• Malformation evident at birth
• Short period of embryonic vulnerability

Causative agents are “teratogens” and produce specific abnormalities at specific times during gestation

Dose-related incidence

 Only ~ 2% of live births show terata; most
of which are minor

 ~ 5% of these (1 in 1000) are due to drug or toxin exposure

Question 20

What is the number one principle of reproductive toxicology?

Answer 20

 Expression of toxic effect depends on when
in fetal development exposure occurs

 Critical period for terata is organogenesis (wks 2 thru 8)

 To cause structural damage, exposure to a

potential teratogen must occur DURING - not before or after - the critical period in organogenesis when
that particular body part is arising

Question 21

How does generalized toxic effect manifest? What happens if mother is sick?

Answer 21

If mother is sick for any reason, or is affected by toxin, it may also affect the embryo or fetus
 “Indirect effect” of mother’s illness on baby

 Generalized toxic effect manifests as general growth retardation
 “Low birth-weight baby”
 eg, smoking, ethanol

Question 22

How and when might medicine that a mother is taking affect the fetus?

Answer 22

 In 3rd trimester … pharmacologic or toxic activity in fetus
 Sufficiently matured … many target organs
respond to the agent

 May be serious, often reversible: eg
 Hypotension /ACE inhibitor Hypoglycemia/ sulfonylurea

 Withdrawal from maternal use of abusable
drugs – narcotics, benzodiazepines, cocaine, amphetamines, etc

Question 23

What are some agents that affect fertility in men?

Answer 23

 Many suspects but few proven guilty, eg
alcohol …testicular toxin

 Agents associated with low semen quality

• Lead, mercury
• 2,4-D (dichloro phenoxy acetic acid)
• Ethylene glycol ethers
• Estrogens (environmental estrogens?)
• Di Bromo Chloro Propane (DBCP)*****

BOARD EXAM ALERT

Question 24

What are some agents associated with difficulty in conceiving for women?

Answer 24

 Difficulty conceiving associated with

• Volatile organic solvents
• PCBs
• Pesticides / agricultural work
• Formaldehyde

Question 25

What is the risk equation? What is a definition of risk? what is a definition of hazard? What is a definition of hazard?

Answer 25

RISK =HAZARD x EXPOSURE

Key concept: Risk is a function of both the hazard of the material and the extent of exposure to the material

Risk: the chance that a given adverse effect will occur due to a given exposure. Risk is scenario-specific

Hazard: the total spectrum of harmful potential inherent to the chemical, and the conditions under
which the adverse effects occur

 Exposure: description of the conditions of contact of the individual with the substance
• How much (quantity, dose, concentration)
• How long (duration)
• How often (frequency)
 To change risk, change the exposure

Question 26

What are dose response curves used to determine in toxicology? What are two landmarks to find on a dose response curve? Why look for those landmarks?

Answer 26

Note: To determine the dose that does NOT ‘make the poison’

NOEL (No-Observable-Effect Level)  An actual test dose that did not produce the observable effect in the test

population LOEL (Lowest-observable-effect level)
 The lowest actual test dose that *did* produce the observable effect

 Just as larger doses affect more of the population, lower doses affect fewer of the population
 Once the dose is low enough, it will fail to adversely affect ANY individual
 It is clinically important to have some idea of the dose that is insufficient to cause a harmful effect

Question 27

What is the threshhold dose? How is it estimated?

Answer 27

 Extrapolated dose below which the effect cannot be detected in the tested population & above which the effect first becomes apparent

 Between the highest NOEL & the lowest LOEL value

 Closest approximation is just a smidgen above the
NOEL.

Question 28

What happens once a LOEL and NOEL are found in animals?

Answer 28

 NOEL and/or LOEL obtained from animal
experiments

 “Safety factors” aka “uncertainty factors” are applied to account for inter-species and inter-individual differences

 “Safe” exposure level is determined

 Forms the basis for regulation of an allowable
chemical residue in food, water, air, or soil.

 LOWER by orders of magnitude than the dose
that did not affect test animals

Question 29

Why is LD50 useful?

Answer 29

VERY IMPORTANT: Basis for comparison
of potency of chemicals

 Allow relative ranking with respect to ability to kill the test animal species

 Don’t necessarily need to compare the dose response curves

 Just compare the midpoints (LD50)