Lash - Toxicology III

Question 1

What is a pesticide?

Answer 1

General classification that includes rodenticides, insecticides, herbicides, fungicides and fumigants; designed to kill various pests (plants and animals)
o Selective toxicity of pesticides exist, but all capable of some sort of toxicity in humans
o Exposures generally occur at home (oral) or at work (inhalation, dermal exposure)

Question 2

Chlorinated Hydrocarbon Insecticides: Properties (4)

Answer 2

Fat-soluble (low water-solubility; concentrates in adipose tissue)
- Capable of crossing placenta

Low-molecular weight

Stable

Poor biodegradability (half life= 10 years) resulting in BIOACCUMULATION
o	Persist in the environment

Question 3

Chlorinated Hydrocarbon Insecticides: mechanism of human toxicity

Answer 3

Interferes with inactivation of Na channel (alters transport of Na and K across axonal membranes)

Causes rapid, repetitive firing in most neurons after a single stimulus

Question 4

Chlorinated Hydrocarbon Insecticides:

Treatment
Example

Answer 4

Treatment:
o No specific regimen
o Provide support of physiologic function

Example: DDT (use now restricted)

Question 5

Clinical characteristics of organochlorine (chlorinated hydrocarbon) insecticides

Answer 5

Nausea, vomiting
Paresthesias of tongue, lips, and face
Restlessness
Apprehension, irritability
Tremor
Convulsions
Hypersusceptibility to stimuli
Coma
Respiratory failure
Death

Question 5

Organophosphorous Insecticides: Properties

Carcinogenic potential vs. toxicity

What pesticide is most frequently involved in fatal poisoning?

Absorbed by:

Excreted by:

Answer 5

Persist in the environment (negative environmental impact), but do not bioaccumulate

Extremely low carcinogenic potential but high acute toxicity

Parathion pesticide most common pesticide involved in fatal poisoning

All readily absorbed by the skin, GI tract and respiratory tract

Readily metabolized and hydrolyzed metabolites excreted in the urine

Question 5

Organophosphorous Insecticides mechanism of Toxicity:
Signs/symptoms
What may it also cause?

Answer 5

Inhibition of AChE by phosphorylation of esteratic site; some may also have direct cholinergic activity

Signs/symptoms therefore related to persistent ACh hyperstimulation
- Muscarinic, nicotinic and CNS effects

May also cause delayed neurotoxicity by phosphorylating another enzyme in neural tissue (neurotoxic esterase)

Question 5

Carbamate Insecticides: Mechanism of Toxicity: (3)

Answer 5

Inhibition of AChE by carbamoylation of esteratic site

Signs/symptoms similar to organophosphorous insecticides (due to ACh hyperstimulation)

Do not bioaccumulate (little negative environmental impact)

Question 6

Carbamate Insecticides differences from Organophosphorus Insecticides: (4)

Answer 6

Readily dissociate from AChE

Shorter duration of action

Less toxic

Non-persistent in the environment (little negative environmental impact

Question 7

Herbicide examples (3)

Answer 7

o 2,4-Dicholophenoxyacetic Acid (2,4-D)
o 2,4,5-Trichlorophenoxyacetic Acid (2,4,5-T)
o TCDD

Question 8

Herbicide properties (3)

Answer 8

Used to control many broad-leaf woody plants (act as growth hormones in plants)

Do no accumulate in animals

Slowly metabolized but readily excreted in the urine

Question 9

Herbicide: Mechanism of toxicity

Answer 9

Animals that have died due to massive ingestion of herbicides believed to be due to ventricular fibrillation

Question 10

Herbicide examples (3)

Answer 10

o 2,4-Dicholophenoxyacetic Acid (2,4-D)
o 2,4,5-Trichlorophenoxyacetic Acid (2,4,5-T)
o TCDD

Question 11

Polychlorinated Biphenyls (PCBs): Use and properties (4)

Answer 11

Use: Widely used, but use terminated in 1977. Still very persistent in the environment.

Properties:

• Very lipophilic
• Highly stable
• Poorly metabolized
• Resistant to environmental degradation (bioaccumulate in the food chain)

Question 12

Polychlorinated Biphenyls (PCBs): source and safety

Answer 12

Source: contaminated food

Safety: considered a major problem but have not been shown to be very hazardous to health unless food with extremely high levels is consumed

Question 13

Coumarin poisoning

Answer 13

Similar structure to vitamin K and functions as an anti-coagulant (OD leads to hemorrhage)

Also used as a rodenticide (D-con)

Treat by removing coumarin and administering vitamin K (competes for same substrates)

Question 15

Paraquat: mechanism of toxicity

Answer 15

Undergoes redox cycling in cells to generate large amount of reactive oxygen species (Superoxides and others)

Generation of oxidative stress causes changes in the regulation of cellular function and ultimately cell necrosis

Question 15

Effects of Two Chemicals Together: (4)

Answer 15

Additive: of individual responses (2+3=5)
o Most common: unless there is evidence otherwise, normally assumed that the effects of a mixture of chemicals is additive

Synergistic: together produce much more effect than would be expected based on mathematical sum of individual actions (2+2=20)

Potentiation: one may potentiate the other (ie. has no effect alone but may increase toxicity of another chemical; 2+0=14)

Antagonism: one may antagonize the other (10 + 0=2, 10 + (-4)=0); desirable and serve as basis for antidotes

Question 16

Polychlorinated Biphenyls (PCBs): source and safety

Answer 16

Source: contaminated food

Safety: considered a major problem but have not been shown to be very hazardous to health unless food with extremely high levels is consumed

Question 17

Physiological Antagonism

Answer 17

Drugs that stimulate antagonistic physiological mechanisms

May be of little clinical value and may even decrease survival
o Difficult to titrate the effect of one drug against another when 2 drugs act on opposing systems
o Duration of action of poison an antidote may differ, thereby producing poisoning by antidote

Question 18

Physiological Antagonism examples

Answer 18

CNS stimulants reverse respiratory depression
o May cause seizures/convulsions
o Mechanical support of respiration preferred

Question 19

Mechanisms of DDIs:(6)

Answer 19

• Physical interaction
• Plasma protein binding
• Competition at receptor sites
• Induction of drug metabolizing enzymes
• Inhibition of drug metabolizing enzymes
• Competition for renal tubular transport

Question 20

Overlooked DDIs

Answer 20

Alcohol, caffeine, tobacco

Question 21

Interactions due to alcohol:

Chronic use results in:
Competitive substrate for:
Potentiating:

Answer 21

o Chronic use results in INDUCTION of some liver cytochromes P450 enzymes (ie. CYP2E1) –> increasing metabolism of certain drugs and DECREASED effects
o Can be a competitive substrate for some P450s –> inhibiting metabolism of some drugs POTENTIATING their effects
o CNS effects of alcohol and many other drugs

Question 22

Interactions due to caffeine:

Answer 22

o	Inducer AND a substrate for microsomal drug metabolizing enzymes 
o	Potential harm via interaction with many common medications:
- Benzodiazepines
- Oral contraceptives
- Cimetidine
- MAO inhibitors
- Phenothiazines	
- Theophylline

Question 26

Interactions due to tobacco:

Answer 26

-	Interactions due to tobacco:
o	Inducer of some drug metabolizing enzymes
o	Decreases effects of commons drugs:
- Acetaminophen
- Antidepressants
- Benzodiazepines
- Cimetidine
- Oral contraceptives
- Estrogens
- Insulins
- Propanolol
- Theophylline

Question 27

Paraquat: Basics:

Answer 27

Non-selective herbicide used to destroy plant tissue on contact

Primary sites of damage in humans are lungs, liver and kidneys

Widespread proliferation of fibroblasts in the lung

Prompt removal of from digestive tract is important