Unit 2 Mechanisms

Question 1

Renal Tox: Cadmium

Answer 1

Cd binds to MT in the liver -> Cd blocks receptors in the kidney -> Cd increases -> **inhibits ETC ** -> mitochondrial dysfunction -> ROS -> apoptosis

Question 2

Renal Tox: Silica

Answer 2

Silica inhalation -> Silica accumulates in the Proximal Convulated Tubule -> Mitochondrial dysfunction
-> ROS -> inflammation -> fibrosis -> chronic kidney damage -> decreased eGFR

Question 3

Renal Tox: NSAIDS

Answer 3

• Glomerular toxicant
• **Cox-2 **inhibits PGE2 -> vasoconstriction -> decreased eGFR

Question 4

Liver Tox: Acetaminophen (APAP)

Answer 4

• APAP metabolized into NAPQI -> decreased GSH -> protein adducts -> ROS -> necrosis -> DAMPS -> innate immune response -> inflammation -> tissue repair

Question 5

Liver Tox: TCE

Answer 5

TCE is metabolized into TCE epoxide -> acyl chloride -> reactive aldehyde -> irreversibly binds to DNA and proteins -> genotoxicity

Question 6

Liver Tox: CCL4

Answer 6

Necrosis -> Fibrous -> Cirrohosis

Question 7

Liver Tox: Ethanol

Answer 7

Ethanol -> ADH -> Aldehyde -> Acetic Acid -> Excreted

Question 8

Liver Tox: Ethanol Overdose

Answer 8

Ethanol metabolized by CYP450 -> ROS -> mitochondrial dysfunction -> apoptosis

Question 9

Liver Tox: APAP and Ethanol

Answer 9

• Ethanol is metabolized by CYP450
• APAP metabolized into NAPQI -> protein adducts -> ROS -> mitochondrial dysfunction -> necrosis

NAC -> Increases depleted GSH

Question 10

Respiratory Tox: Silica

Answer 10

Silica inhalation -> immune response -> proteolytic enzyme release -> cytokine release -> chronic inflammation -> fibroblast proliferation -> fibrosis

Question 11

Respiratory Tox: Coal Dust

Answer 11

Coal dust inhaltion -> immune response -> chronic exposure -> alveolar wall injury -> emphysema (alveoli lung damage, shortness of breath)

Question 12

Respiratory Tox: Asbestos

Answer 12

Asbestos inhalation -> immune response -> chronic inflammation -> mitochondrial dysfunction -> ROS -> dna damage -> high cell turn over rate -> mutations -> cancer

Question 13

Respiratory Tox: PM 2.5

Answer 13

• Small, toxic particulate matter that damages the alveolar region of the lungs

Question 14

Respiratory Tox: ARDS - DAD

Answer 14

• Exudative (alveolar-capillary barrier damage -> edema)
• Proliferative (edema reabsorbed -> recovery of alveolar-capillary barrier)
• Fibrotic (recovery not possible, decreased lung compliance)

Question 15

Respiratory Tox: ARDS - DAD Mechanism

Answer 15

Hyperoxia damages ATI pneumocytes and alveolar macrophages -> ROS -> macrophages release neutrophil chemotactic compounds -> neutrophil recruitment -> lung tissue damage

Question 16

Respiratory Tox: High Pb

Answer 16

High Pb -> more blood soluble -> slower onset and offset time

Question 17

Respiratory Tox: Lower Pb

Answer 17

Lower Pb -> less blood soluble -> faster onset and offset

Question 18

Cardio Tox: Blood Flow

Answer 18

RA -> Tricuspid Valve -> RV -> Pulmonary Valve -> Lungs -> LA -> Mitral Valve -> LV -> Aorta -> Body

**Exception: Deoxygenated blood from the heart to the veins via the Pulmonary Artery **

Question 19

Cardio Tox: Doxorubicin

Answer 19

• Inflammatory response -> macrophages

Question 20

Cardio Tox: TCA

Answer 20

TCA -> HERG channel inhibitor -> QT prolongation -> heart arrythmia

Question 21

Cardio Tox: Glycosides

Answer 21

Glycosides -> Na/K ATPase inhibitor -> increase in Ca 2+
-> mitochondrial dysfunction -> ROS -> protein adducts

Question 22

Cardio Tox: Action Potentials

Answer 22

Na⁺ influx (Phase 0) → K⁺ efflux + Cl⁻ (Phase 1) → Ca²⁺ influx / K⁺ efflux (Phase 2) → K⁺ efflux (Phase 3) → Stable K⁺ balance (Phase 4).

Question 23

Dermal Tox: Irritant Dermatitis

Answer 23

• Low doses, multiple encounters
• RXNS at skin point of contact
• No immune response
• Chemical burn (Ammonia)

Question 24

Dermal Tox: Allergic Irritant

Answer 24

• Previous encounter needed
• Type IV Hypersensitivy (Langerhan Cells -> T cells -> Th1)
• Delayed RXN (48 hrs - 72 hrs)
• Poison Ivy

Question 25

Dermal Tox: Major Skin Components

Answer 25

* Epidermis (kertainocytes, langerhand cells, merkel cells, melanocytes) * Dermis (blood vessels, collagen, glands) * Hypodermis (adipose tissue)

Question 26

Dermal Tox: Absorption

Answer 26

* Straneum Corenum -> Epidermis -> Dermis * Hydrophobic, Lipophilic * Molecular weight, concentration, duration

Question 27

Dermal Tox: UV Radiation DNA Damage

Answer 27

* UV Radiation -> Thymine dimers -> DNA damage -> mutations -> Cox 1/2 activated -> PGE2 -> PGE2 binds EPI and EP4 receptors -> inflammation -> cell proliferation -> cancer

Question 28

Dermal Tox: Protoporphyria

Answer 28

Genetic defect inhibits heme production -> protoporphyria build up -> UV radiation interacts w/ protoporphyria and oxygen -> ROS -> protein adducts -> lipid peroxidase -> tissue damage

Question 29

Neuro Tox: Methyl Mercury

Answer 29

Sulfhydrl bindings -> ROS -> mitochondrial dysfunction -> inhibits glycolysis, protein and nucleic acid synthesis

Question 30

Neuro Tox: Domoic Acid

Answer 30

Increase in glutamate -> increase in Ca2+ -> mitochondrial dysfunction -> loss of ATP -> neuronal death

Question 31

Neuro Tox: Carbon disulfide/n-hexane

Answer 31

* crosslinking neurofilament proteins -> adducts -> protein modification -> distal axonopathy

Question 32

Neuro Tox: Triethylin

Answer 32

Metabolic inhibitor -> mitochondrial dysfunction -> loss of ATP in the oligodendrocytes

Question 33

Neuro Tox: Colchicine/Taxol

Answer 33

destabilizies microtubles/stabilizes microtubules

Question 34

Neuro Tox: Organophosphates

Answer 34

Organophosphates bind to Serine residue -> inhibits AchE from converting into Ach -> overstimulated nervous system

Question 35

Neuro Tox: Botox

Answer 35

Botox inhibits the release of Ach at the synapse by targeting and cleaving SNARE proteins -> muscle paralysis

Question 36

Neuro Tox: Cocaine and Amphetamine

Answer 36

blocks dopamine reuptake -> dopamine accumulates in the synpases -> ROS -> mitochondrial dysfunction -> neurodegeneration

Question 37

Immuno Tox: Innate

Answer 37

* Fast, non specific * No memory * Macrophages, Neutrophils * Phagocytosis

Question 38

Immuno Tox: Adapative

Answer 38

* Slow, specific * Memory * T cells -> B cells

Question 39

Immuno Tox: Hypersensitivity IV

Answer 39

* Fast * Langerhan cells -> T cells -> Th1

Question 40

Immuno Tox: Hypersensitivy I