Toxicology Ii Test 2

Front 1

How can damage occur in the cornea?

Back 1

-Scarring/vascularization
-Local effects can cause
inflammation (

Front 2

How can damage occur in the iris?

Back 2

-Local effects include
inflammation (

Front 3

How can ocular damage occur in the eaqueous outflow system?

Back 3

-Nourishes cornea and lens
-Drains via canal of Schlemm
-Blockage → increase i.o.p. → damage-may be associateed with damage to other parts of the eye

Front 4

How can ocular damage occur in the lens?

Back 4

Damage (cataract → loss of transparency
-Local effects include UV radiation
-Systemic effects include many drugs and chemicals

Front 5

How can ocular damage occur in the ciliary body?

Back 5

-muscle damage for focusing of lens
secretory damage for formation of aqueous humor (diuretics?)

Front 6

What ocular damage can occur in the retina/ choroid?

Back 6

-has Good blood supply
-Retinal damage can occur with visual disturbances or loss of vision
- destruction of photoreceptors!
-examples include:
-chloroquinine retinopathy
-cardiac glycosides
-sildenafil (Viagra

Front 7

What ocurlar damage can occur in the ganglion cells/optic nerve?

Back 7

-Damage is irreversible
-Classical agent = methanol!

Front 8

How cna you assess ocular damage?

Back 8

-Examination includes
-slit-lamp microscope
-tonogram
-Draize test- irritation
-Electrophysiology

Front 9

How are aminoglycosides ototoxic?

Back 9

1. highly charged- eliminated renally
2. ototoxicity possible following systemic and topical administration
3. effect may be delayed and unilateral
4. damage hair cells
5. site of action- cochleotoxic vs. vestibulotoxic
a. cochleotoxic dihydrostreptomycin, kanamycin, tobramycin
b. vestibulotoxic streptomycin, gentamicin
c. both- hydroxystreptomycin (potent)
d. less toxic- netilmicin
6. mechanism of toxicity- free radicals involved?

Front 10

How are loop diuretics ototoxic?

Back 10

1. ethacrynic acid, furosemide- cochleotoxic (usually reversible)
2. possible mechanism- alteration in ionic composition of endolymph?

Front 11

What are ototoxic drugs/ chemicals?

Back 11

-aminoglycosides
-loop diuretics
-NSAIDs
-antineplastic agents

Front 12

What are symptoms of ototoxicity?

Back 12

1. early vs. late
2. hearing loss may be subtle
a. damage proceeds from base of cochlea to apex
b. highest frequencies lost first

Front 13

What are techniques in assessing ototoxicity?

Back 13

1. audiometry
2. animal behavioral studies

Front 14

What are the general mechanisms of cardiotoxicity?

Back 14

-Altered coronary blood flow
-Vasoconstriction/blockages--> occlusion
-Ischemia-reperfusion Injury (IRI)
-Altered ion homeostasis
-Channel/transport proteins--> channelopathies
-Organelle dysfunction--> myopathy
-Apoptosis/oncosis

Front 15

How is vasoconstriction a mechanism of cardiotoxicity?

Back 15

Endothelial dysfunction:
-Clots at surface,
-LDL accumulation,
-Decreasse NO bioavailability
SMC dysfunction:
-Adrenergic responses
-Lipid loading-->foam cells
-Proliferation --> matrix
-Ca mishandling--> spasticity

Front 16

How are blockages a mechanism of cardiotoxicity?

Back 16

-Dec flow--> ischemia, hypoxia
-Inc turbulence--> inc cardiac work

Front 17

What does altered (reduced) coronary flow ultimately cause?

Back 17

-ATHEROSCLEROSIS
-Occlusion (acute/chronic)
-Myocardia Infarction

Front 18

What is the mechanism of action of ischemia-reperfusion injury having to do with xanthine oxidase and the formulation of reactive oxygen species?

Back 18

Ischemia:
-Less O2
-more glycolysis
-more lactic acid, less ATP
-Transmembrane gradients dissipate
-Cytosolic [Ca] increases
-Proteases activated
-XDH-> XO
Reperfusion:
+O2--> ROS --> +/- Fe--> CELL DEATH

Front 19

What is the mechanism of action of ischemia-reperfusion injury by deregulation of pH control from cardiotoxins?

Back 19

-Ischemia --> dec Na/K-ATPase + inc NHE-->inc Na, inc Ca--> inc alkaline proteases; held at bay …
-w/reperfusion, massive H+ efflux, alkaline proteases destroy cell

Front 20

What is the consequence of ischemia-reperfusion injury?

Back 20

-chronically, cardiomyopathy and/or congestive heart failure

Front 21

What is the impact of pre-conditioning on ishemia-reperfusion injury?

Back 21

Brief ( 2-5 min) ischemia bouts
Normal perfusion
Prolonged ischemia-- initiated w/in 1 h
->2h, lose protection
-2nd window 24-72h later
Protection against IRI
-Smaller infarcts, less enzyme release, fewer arrhythmias, maintained contractility
-Modest inc in ROS, PKC, AMP-act PK, stabile MPTP

Front 22

How are altered ion homeostasis or "channelopathies" a general mechanism of action of cardiotoxicity?

Back 22

-V.G. Na+ channels--> AP initiation
-V.G. K+ channels--> repolarization
a. long ARP for cardiac myocytes
b. No repolarization--> cardiac standstill
-V.G. Ca++ channels--> both excitation AND contraction
a. SA node/conduction: depolarization
b. Contractile myocytes: prolonged depolar, contraction
-Multi-subunit proteins, multi-gene determinants, onsite assembly, both extra-and intra-cellular modification = complex regulation

Front 23

How is long QT syndrome or arrythmias a general mechanism of action of cardiotoxicity?

Back 23

-Inherited or drug-induced
-Long QT interval on ECG reflects malfunction of ion channels=> impaired ventricular repolarization
- increased risk of torsade de pointes => ventricular arrhythmias, sudden cardiac death.
a. (twisting of the points) = ventricular tachycardia, with QRS complexes of changing amplitude that appear to “twist” around isolectric line
- INCIDENCE LQTS = LOW
- CONSEQUENCES LQTS and TdP = HIGH
a. Sudden cardiac death

Front 24

What are general risk factors for acquired long QT syndrome?

Back 24

-Bradycardia (e.g., complete AV block, other bradyarrhythmias, even transient)
-Hypokalemia, hypomagnesemia
-Structural/functional defects (myopathy, CHF, mitral valve prolapse
-Diuretic use, high dose anti-arrhythmic drug use, AIDS
-Female gender
-Starvation (Anorexia, liquid protein diets, gastroplasty, celiac disease)
- Nervous system injury (subarachnoid hemmorhage, pheochromocytoma)

Front 25

What are specific drugs that are risks for acquired long QT syndrome?

Back 25

-Antiarrhythmics (class 1A (quinidine, disopyramide, procainamide); class III (sotalol, amiodarone, ibutilide)
-Antibiotics (erythromyocin, clindamyocin, …)
-Histamine receptor antagonists (terfenadine, astemizole)
-Antidepressants (tetra/tricyclic)
-Antipsychotics (phenothiazines, haloperidol, sertindole)
-Cholinergic antagonists (cisapride, organophosphates)

Front 26

How is organelle dysfunction or myopathy a general mechanism of action of cardiotoxicity?

Back 26

-Ryanodine receptor irregularity
a. Calcium leak--> activation of Ca-dependent phospholipases, proteases-->degradation
-Mitochondrial dysfunction
a. Loss of ATP--> loss of membrane integrity
-Endoplasmic reticulum dysfunction
a. Protein misfolding, protein trafficking defects
-Sarcolemmal injury
a. Cytoplasmic calcium overload

Front 27

What is the mechanism of action of myocardial apoptosis?

Back 27

- microRNAs (miRNAs)--> mask binding sites in mRNA or relief of translational repression
-immune-mediated cytokines and/or hypoxia-mediated cytokines
-Adrenergic signalling

Front 28

What are the various forms of angiotoxicity?

Back 28

-Atherosclerosis
a. Tissue hypoxia
b. Hypertension
c. Altered immune reactivity (C-reactive protein)
-Vascular spasm
a.Altered cytokine production
b. Altered responsiveness to cytokines
c. Excess adrenergic input/response
-Altered hemodynamics
a. Clot formation--> occlusion, emboli
b. Turbulent, not laminar flow
c. Plaque rupture, destabilization

Front 29

How are angiotoxins selective?

Back 29

-Selected alterations in vascular reactivity (disruption of cellular membranes or contractile apparatus)
-Vessel-specific bioactivation of pro-toxicants
-Erratic or aberrant detoxification of parent chemical or its metabolites
-Preferential accumulation of active toxin in vascular cells

Front 30

How is allylamine an angiotoxin?

Back 30

-Primary alkylamine that serves as an intermediate in the synthesis of a variety of pharmaceuticals and other commercial products)
-converted via amine oxidase to acrolein and hydrogen peroxide=>cell injury via lipid peroxidation, protein adduct formation, glutathione conjugation

Front 31

How is benzo(a)pyrene an angiotoxin?

Back 31

• parent compound or metabolite-mediated “mutagenesis” --> genotoxicity via DNA adduct formation
• PKC inactivation --> altered smc proliferation
( deregulation of growth)
• AH (aryl hydrocarbon) receptor activation--> enhanced transcription of growth-related genes

Front 32

How is tobacco smoke an angiotoxin?

Back 32

-Endothelial injury
-Altered lipids
-Proliferation of smooth muscle cells
-Increased coagulation
-Vascular spasm

Front 33

How is homocysteine an angiotoxin?

Back 33

-HC = intermediate in methionine scavenger pathway
-HC emia/uria--> vascular toxicity, inc atherosclerosis
-Endothelial injury
-Altered lipid profiles
-Proliferation of smooth muscle cells

Front 34

What are the risk assessment tests of cardiovascular toxicity?

Back 34

-High throughput screening
a. Binding
b. Rb flux, voltage sensitive fluorescent dyes
-Patch clamp studies
a. Xenopus oocytes, stably transfected cells, isolated myocardial cells
-Small animal studies
a. Telemetry
b. Langendorff preps

Front 35

What is hematotoxicity?

Back 35

-blood toxicity
- BONE MARROW--> cells of blood
a. Stem cells--> blood cells (hematopoiesis)
b. Pluripotent--> myeloid precursor
- Cells, plasma (blood)
a. Transport, hemostasis, defense
b. Factors of import
1. High proliferation ( 1-3 X 106/sec)
2. High sensitivity (to intoxication)
3. Huge magnitude consequences

Front 36

What is the primary hematotoxic response?

Back 36

-One or more blood components affected
e.g., xenobiotics, drugs
-Alterations in rbc production, function, survival

Front 37

What is the secondary hematotoxic response?

Back 37

-Consequences of other tissue/ systemic injury
-May be reactive or compensatory
-Can be used to monitor toxic effects

Front 38

What is bone marrow toxicity?

Back 38

-Aplastic anemia: stem cell destruction
-=>Pancytopenia, reticulocytopenia, bone marrow hypoplasia
-High mortality
-e.g., chloramphenicol, benzene, ionizing radiation
-~50 % --> ~ 80% fat cells ( non-staining)

Front 39

How do you monitor bone marrow toxicity?

Back 39

-Bone marrow biopsy/smear
-Clonogenic assays:
a. Bone marrow or cord cells +/- specific growth factors
+/- different doses of toxins
b. What population(s) respond?

Front 40

What are chemical-mediated blood toxicity?

Back 40

ANEMIAS:
-Hemolytic--> inc reticulocytes in blood ( rbcs destroyed)
-Hypoproliferative
a. Fe deficiency--> dec MCV, hypochromasia
b. Sideroblastic (porphyrin synthesis def) --> inc Fe in erythroblast mito.
c. Megaloblastic( folate, vit B12 deficiency) --> macrocytosis, inc MCV
-Polycythemia (erythrocytosis): less common

Front 41

What are non-oxidative mechanisms of damage or RBC?

Back 41

-Inhibition of erythropoiesis
a. Lead
b. Other chemicals
-Inhibition of rbc metabolism
a. Copper

Front 42

What are oxidative mechanisms of damage or RBC?

Back 42

-High O2 levels--> lipid peroxidation

-hereditary G-6PDH deficiency

Front 43

What are immune-mediated mechanisms of damage to RBC?

Back 43

-Drug absorption (penicillins, cephalosporins)
-“innocent bystander” (quinidine, phenacetin)
-Protein carrier (cephalosporins)
a. Protein which binds to drug interacts with antibodies

Front 44

What are the mechanisms of hemoglobin damage?

Back 44

-Altered hemoglobin synthesis
a. HU--> a and b chains
b. Ethanol, zinc--> heme group
c. NSAIDs--> iron deficiency
-Methemoglobin (metHb) formation
a. Amyl nitrate, gas additives, etc--> Ferrous to ferric oxidation
b. Reversal mediated by NADH (cytochrome b5 reductase) or NADPH (methylene blue reductase)
-Sulfhemoglobin (e.g., phenacetin, napthalene)
a. irreversible sulfation--> denaturation
-Heinz bodies (e.g. phenols, polyethylene glycol)
a. inclusions ( aggregates?)--> hemolysis (species-dependent)
- Carboxyhemoglobin (CO poisoning– cherry red pigment)
a. Dec. O2 delivery, dec. O2 capacity-->hypoxia

Front 45

How do you assess erythrocyte damage?

Back 45

-Complete blood count and hematocrit
a. RBC: 4-6 M/mm3
b. MCV: 86-98 mm3 (fL)/cell
c. WBC: 4-10 K/mm3
-Hemoglobin levels: (12-18 g/dL)
a. Hematocrit: adult male (41-50%), adult female (36-44%)
-Cell morphology
a. Nucleation
b. Heinz bodies
c. Volume and chromaticity

Front 46

What are the mechanisms of damage to platelets and hemostasis?

Back 46

Pathologic conditions:
-Thrombocytopenia
a.Megakaryocytes
b. Platelets (<150,000/mm3)
c. Bruising, petechiae
-Thrombocytosis

Interference with clot formation:
-Alteration of platelet function (e.g. aspirin-->COX)
-Decreased synthesis of clotting factors

Front 47

How do you assess for platelet damage and hemostasis?

Back 47

-CBC/platelet count
a. RBC: 4-6 M/mm3
b. WBC: 4-10 K/mm3
1. Neutrophils (40-75%)
2. Lymphocytes (15-40%)
3. Monocytes (1-10%)
4. Eosinophils ( 1-6%), basophils (0-2%)
b. MCV: 86-98 mm3 (fL)/cell
c. Platelets: 150-450 K/mm3

-Cell morphology ( size, shape)

-Bleeding time (PT= prothrombin time; PTT= partial thromboplastin time; INR= international normalized ratio for adjustments)

Front 48

What cells are involved in innate immunotoxicity response? soluble mediators? specificity? Inc. response with challenge?

Back 48

-PMN, monocytes/Macrophages, Natural Killer cells
-Complement, lysosyme, acute phase proteins, TNF alpha/beta, other
-none
-no

Front 49

What cells are involved in acquired immunotoxicity response? soluble mediators? specificity? Inc. response with challenge?

Back 49

-T cells, B cells, Macrophages, Natural Killer cells
-Antibody, cytokines
-Yes (very)
-Yes

Front 50

What is the mechanism pathway of the humoral immunotoxicity response?

Back 50

-antigen + antigen presenting cell (APC) (B cells, Macrophages, dendritic cells)
-internalization, antigen processing, cell surface expression with MHC calls II peptides
-interaction with lymphocytes
-proliferation & differentiation
-specific Antibody (Plaque)-forming cells--> Ag-specific ANTIBODIES (Abs)

Front 51

What is the mechanism pathway of the cell-mediated immunotoxicity response?

Back 51

-Effector cell ( CTL, NK cells) recognition of target ( virally infected or tumor cell)
a. MHC-class I, Ab-specific
-Reorientation of effector, degranulation into target
-Disengagement of effector
-Death (apoptosis) of target

Front 52

What are the effects of immune suppression on phagocytes (neutrophils, macrophages)?

Back 52

-Neutropenia
a. Inhibition of granulopoiesis (antineoplastics, chloramphenicol, benzene)
b. Premature destruction (aminopyrene)
-Inhibition of chemotaxis ( e.g. colchicine)
-Inhibition of phagocytosis ( e.g. colchicine)

Front 53

What are the effects of immune suppression on lymphocytes?

Back 53

-B cells ( e.g. PCBs, dioxin)
-T cells (e.g., cyclosporin A, corticosteroids)
-Tumor resistance ( Natural Killer cells)

Front 54

What is autoimmunity as an immune enhancement?

Back 54

-Loss of tolerance for self antigens
-Chronic lymphocyte stiumation
-Inhibition of T suppressor activity

Front 55

What is hypersensitivity (allergy) as an immune enhancement? 4 types?

Back 55

-Type I ( e.g. penicillin): IgE-> mast cell degranulation--> swelling, redness, pain
Type II: IgG or IgM--> rbc destruction
Type III: IgG or IgM-complexes--> tissue destruction
Type IV (delayed): APC + T cells--> tissue damage

Front 56

How do you assess immunotoxicity?

Back 56

General:
-CBC/WBC, lymphoid organ weights, bone marrow
Contact hypersensitivity:
-Animal allergic dermatitis, human allergen testing
Popiteal lymph nodes:
-Cell # or proliferation; Ab response
Functional assays:
-Phagocytosis by neutrophils or macrophages
-Ab response to antigenic challenge
-Target cell destruction by CTL
-Host resistance to bacteria, viruses or tumor cells