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DABT 2025 > Heart and Vascular Toxicity > Flashcards

Heart and Vascular Toxicity Flashcards

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1
Q

What are common toxic agents for heart/vascular toxicity?

A

Doxorubicin, cocaine, alcohol, carbon monoxide, cadmium, TKIs (imatinib), fluoroquinolones, particulate matter, catecholamines, arsenic.

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2
Q

What is the mechanism of doxorubicin-induced heart toxicity?

A

Induces myocyte apoptosis via ROS and MAPK activation, causing cardiomyopathy.

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3
Q

What is the mechanism of cocaine-induced heart toxicity?

A

Inhibits norepinephrine reuptake, causing vasoconstriction and arrhythmias.

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4
Q

What is the mechanism of carbon monoxide heart toxicity?

A

Reduces oxygen delivery, causing myocardial ischemia and arrhythmias.

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5
Q

What are biomarkers for heart/vascular toxicity?

A

Elevated cardiac troponins, BNP, creatine kinase, ECG changes (QT prolongation).

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6
Q

What are testing methods for heart/vascular toxicity?

A

ECG, echocardiography, biomarker assays, histopathological examination.

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7
Q

What are endpoints for heart/vascular toxicity?

A

Cardiomyopathy, arrhythmias (e.g., Torsades de Pointes), atherosclerosis, hypertension.

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8
Q

How do fluoroquinolones cause heart toxicity?

A

Prolong QT interval via hERG channel inhibition, risking arrhythmias.

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9
Q

What is the role of alcohol in heart toxicity?

A

Causes alcoholic cardiomyopathy via ROS and acetaldehyde toxicity.

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10
Q

How does cadmium contribute to vascular toxicity?

A

Promotes atherosclerosis via endothelial damage and oxidative stress.

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11
Q

What factors are critical when designing a study to assess cardiotoxicity? (Domain I.A)

A

Study design includes dose, exposure duration, and endpoints like ECG changes or troponin levels, per ICH S7B guidelines, using GLP-compliant models (e.g., telemetry in dogs) (ABT Handbook, Domain I.A; Web: ICH, 2024).

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12
Q

How does doxorubicin cause cardiotoxicity mechanistically? (Domain II)

A

Doxorubicin generates ROS via redox cycling, disrupting mitochondrial function in cardiomyocytes, leading to apoptosis and heart failure (ABT Handbook, Domain II.A; Document: Neuro Tox; Web: NIH, 2025).

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13
Q

What endpoints identify cardiac hazards in acute toxicity studies? (Domain III.A)

A

Endpoints include arrhythmias, QT prolongation, and cardiac necrosis, assessed via ECG and biomarkers (e.g., cTnI), per OECD Test No. 417 (ABT Handbook, Domain III.A; Web: OECD, 2024).

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14
Q

How is occupational exposure to carbon disulfide assessed for vascular toxicity? (Domain III.B)

A

Exposure is measured via air sampling (ppm) and urinary metabolites (e.g., TTCA), correlating with atherosclerosis risk (ABT Handbook, Domain III.B; Document: Neuro Tox; Web: ATSDR, 2024).

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15
Q

How does cocaine induce cardiovascular toxicity? (Domain II)

A

Cocaine inhibits norepinephrine reuptake, causing vasoconstriction and hypertension via adrenergic alpha-1 receptor activation, leading to ischemia (ABT Handbook, Domain II.D; Document: Principles & Mechanisms; Web: PubMed, 2024).

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16
Q

How are in vitro models used to study cardiotoxicity? (Domain I.B)

A

Human iPSC-derived cardiomyocytes assess contractility and ion channel effects (e.g., hERG) per CiPA guidelines, reducing animal use (ABT Handbook, Domain I.B; Web: FDA, 2024).

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17
Q

What susceptibility factors influence lead-induced hypertension? (Domain II)

A

Genetic polymorphisms (e.g., ALAD) and age increase susceptibility to lead’s vascular effects, elevating blood pressure via ROS (ABT Handbook, Domain II.C; Document: Principles & Mechanisms; Web: NIH, 2025).

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18
Q

How is dose-response assessment applied to anthracycline cardiotoxicity? (Domain III.C)

A

BMD models quantify heart failure risk from doxorubicin, establishing NOAEL for safe cumulative doses (ABT Handbook, Domain III.C; Web: EPA, 2023).

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19
Q

How are vascular risks from benzene characterized in risk assessment? (Domain III.D)

A

Risks (e.g., endothelial dysfunction) are characterized using MOE and hazard quotients, integrating animal and human data (ABT Handbook, Domain III.D; Web: ECHA, 2024).

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20
Q

How does applied toxicology address public health concerns from cardiotoxic drugs? (Domain IV)

A

Biomonitoring (e.g., troponin) and epidemiology guide drug safety labeling and withdrawal (e.g., cisapride), protecting public health (ABT Handbook, Domain IV.A; Web: FDA, 2024).

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21
Q

How is the hERG assay designed to comply with regulations? (Domain I.A)

A

The hERG assay (ICH S7B) tests QT prolongation risk in vitro, using patch-clamp techniques in HEK293 cells, ensuring GLP compliance (ABT Handbook, Domain I.A; Web: ICH, 2024).

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22
Q

What mechanistic role does oxidative stress play in arsenic-induced vascular toxicity? (Domain II)

A

Arsenic induces ROS, impairing endothelial nitric oxide synthase (eNOS), causing vasoconstriction and atherosclerosis (ABT Handbook, Domain II.A; Document: Chemical Carcinogenesis; Web: ATSDR, 2024).

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23
Q

How are cardiac endpoints interpreted in repeat-dose studies? (Domain I.C)

A

Endpoints like hypertrophy or fibrosis are analyzed via histopathology and ECG, integrating with systemic effects (ABT Handbook, Domain I.C; Web: NIH, 2025).

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24
Q

What biomarkers assess cardiac exposure to cadmium? (Domain III.B)

A

Cadmium levels in blood and urine correlate with myocardial damage, measured via ICP-MS (ABT Handbook, Domain III.B; Document: Principles & Mechanisms; Web: EPA, 2023).

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25
How does amphetamine cause cardiovascular toxicity, and what is its AOP? (Domain II)
Amphetamine stimulates catecholamine release, activating beta-1 receptors, causing tachycardia and hypertension via cAMP pathways (ABT Handbook, Domain II.D; Document: Principles & Mechanisms; Web: PubMed, 2024).
26
How are in silico models used to predict cardiotoxicity? (Domain I.B)
QSAR models predict hERG inhibition, guiding drug development and reducing animal testing (ABT Handbook, Domain I.B; Web: ECHA, 2024).
27
What genetic factors influence susceptibility to cisplatin cardiotoxicity? (Domain II)
Polymorphisms in SLC22A2 increase cisplatin uptake in cardiomyocytes, enhancing toxicity risk (ABT Handbook, Domain II.C; Web: NIH, 2025).
28
How is the benchmark dose applied to nicotine’s cardiovascular effects? (Domain III.C)
BMD models hypertension from nicotine exposure, establishing a POD for safe levels (ABT Handbook, Domain III.C; Document: Neuro Tox; Web: EPA, 2023).
29
How does weight of evidence integrate data for cardiac risk characterization? (Domain III.D)
WoE uses in vitro (hERG), in vivo (telemetry), and human data, applying Bradford Hill criteria to assess causation (ABT Handbook, Domain III.D; Web: ECHA, 2024).
30
How does applied toxicology evaluate vascular risks from air pollutants? (Domain IV)
Epidemiological studies (e.g., NHANES) assess PM2.5’s role in atherosclerosis, developing AQG levels for public health (ABT Handbook, Domain IV.A; Web: WHO, 2024).
31
What statistical methods analyze cardiotoxicity study results? (Domain I.C)
ANOVA compares ECG parameters, and logistic regression models dose-response for arrhythmias (ABT Handbook, Domain I.C; Web: PubMed, 2024).
32
How does digitalis cause cardiotoxicity? (Domain II)
Digitalis inhibits Na+/K+-ATPase, increasing intracellular calcium, causing arrhythmias via altered membrane potential (ABT Handbook, Domain II.A; Document: Principles & Mechanisms; Web: NIH, 2025).
33
How are vascular hazards from solvents identified in regulatory studies? (Domain III.A)
Hazards (e.g., toluene-induced vasculitis) are identified via OECD Test No. 408, focusing on histopathology (ABT Handbook, Domain III.A; Web: OECD, 2024).
34
What exposure metrics assess PM2.5’s cardiovascular effects? (Domain III.B)
PM2.5 exposure (μg/m³) is measured via air monitors, correlating with hypertension risk (ABT Handbook, Domain III.B; Web: EPA, 2023).
35
How does ethanol’s toxicity affect cardiac function mechanistically? (Domain II)
Ethanol disrupts mitochondrial oxidative phosphorylation, reducing ATP and causing cardiomyopathy (ABT Handbook, Domain II.E; Document: Neuro Tox; Web: PubMed, 2024).
36
How are alternative testing methods validated for cardiotoxicity? (Domain I.A)
CiPA assays validate iPSC-cardiomyocyte models against in vivo telemetry data, ensuring reliable QT risk prediction (ABT Handbook, Domain I.A; Web: FDA, 2024).
37
What role do species differences play in anthracycline cardiotoxicity? (Domain II)
Mice show higher mitochondrial sensitivity to doxorubicin than humans due to differences in GSH metabolism (ABT Handbook, Domain II.B; Web: NIH, 2025).
38
How is the margin of safety calculated for NSAID-induced cardiotoxicity? (Domain III.D)
MOS is NOAEL (from animal studies) divided by human exposure, ensuring safe ibuprofen use (ABT Handbook, Domain III.D; Web: FDA, 2024).
39
How does applied toxicology address cardiac risks in occupational settings? (Domain IV)
OSHA PELs and PPE (e.g., respirators) mitigate carbon disulfide exposure, reducing coronary risk (ABT Handbook, Domain IV.C; Web: CDC, 2024).
40
What is the role of calcium dysregulation in cardiotoxicity? (Domain II)
Sustained calcium elevation (e.g., from digitalis) depletes ATP, causing arrhythmias and necrosis (ABT Handbook, Domain II.A; Document: Principles & Mechanisms; Web: PubMed, 2024).
41
How are cardiac study results communicated to regulatory bodies? (Domain I.C)
Results are reported in ICH S7B-compliant formats, with ECG data and histopathology for FDA submissions (ABT Handbook, Domain I.C; Web: FDA, 2024).
42
How does TCDD’s mechanism cause vascular toxicity? (Domain II)
TCDD activates AhR, upregulating CYP1A1, causing endothelial dysfunction and atherosclerosis (ABT Handbook, Domain II.E; Document: Chemical Carcinogenesis; Web: ATSDR, 2024).
43
What ecotoxicological endpoints are relevant for cardiovascular toxicity? (Domain III.A)
Fish cardiac edema from PAHs is assessed via OECD Test No. 236, indicating environmental hazards (ABT Handbook, Domain III.A; Web: OECD, 2024).
44
How is internal cardiac exposure to mercury measured? (Domain III.B)
Mercury levels in cardiac tissue are measured via AAS, correlating with arrhythmias (ABT Handbook, Domain III.B; Document: Principles & Mechanisms; Web: EPA, 2023).
45
How does chloroquine’s toxicity affect cardiac function? (Domain II)
Chloroquine causes lysosomal phospholipidosis in cardiomyocytes, impairing contractility (ABT Handbook, Domain II.A; Document: ADE; Web: PubMed, 2024).
46
How is the therapeutic index used for antiarrhythmic drug effects? (Domain III.C)
TI compares therapeutic doses to those causing QT prolongation, ensuring safe use (ABT Handbook, Domain III.C; Web: FDA, 2024).
47
How does applied toxicology mitigate cardiac risks from consumer products? (Domain IV)
BPA’s cardiotoxic potential leads to product restrictions, reducing exposure via safer plastics (ABT Handbook, Domain IV.C; Web: ECHA, 2024).
48
What are the limitations of in vitro cardiotoxicity assays? (Domain I.B)
In vitro assays lack systemic metabolism, limiting prediction of in vivo drug interactions (ABT Handbook, Domain I.B; Web: FDA, 2024).
49
How does vinyl chloride’s vascular toxicity inform risk assessment? (Domain III.D)
Vinyl chloride’s angiogenic potential is assessed via dose-response models, setting safe exposure limits (ABT Handbook, Domain III.D; Document: Chemical Carcinogenesis; Web: EPA, 2023).
50
What is the role of omics in studying cardiotoxicity mechanisms? (Domain II)
Transcriptomics identifies pathways (e.g., MAPK) in NSAID-induced cardiac injury (ABT Handbook, Domain II.F; Web: PubMed, 2024).
51
How are cardiovascular effects of air pollutants assessed in epidemiology? (Domain IV)
Studies correlate PM10 exposure with myocardial infarction, guiding AQG levels (ABT Handbook, Domain IV.E; Web: WHO, 2024).
52
What analytical methods characterize test agents for cardiac studies? (Domain I.A)
LC-MS analyzes drug stability (e.g., ICH Q3A[R2]) for cardiotoxicity studies, ensuring accurate dosing (ABT Handbook, Domain I.A; Web: FDA, 2024).
53
How does acrylamide’s mechanism cause vascular toxicity? (Domain II)
Acrylamide forms adducts with hemoglobin, impairing endothelial function via oxidative stress (ABT Handbook, Domain II.D; Document: Neuro Tox; Web: NIH, 2025).
54
What is the role of PBPK modeling in cardiac dose-response assessment? (Domain III.C)
PBPK models predict cocaine’s cardiac distribution, refining dose-response for arrhythmias (ABT Handbook, Domain III.C; Web: EPA, 2023).
55
How does applied toxicology address emerging cardiac risks from nanomaterials? (Domain IV)
Nanosilver’s cardiotoxic potential is evaluated via in vitro studies, developing safety standards (ABT Handbook, Domain IV.B; Web: NIH, 2025).
56
How are systemic and local cardiac effects distinguished in study interpretation? (Domain I.C)
Systemic effects (e.g., lead hypertension) involve multi-organ toxicity, while local effects (e.g., doxorubicin cardiomyopathy) are cardiac-specific (ABT Handbook, Domain I.C; Web: ATSDR, 2024).
57
What factors increase vascular susceptibility to PAHs? (Domain II)
Genetic polymorphisms (e.g., CYP1A1) and smoking increase PAH-induced atherosclerosis risk (ABT Handbook, Domain II.C; Document: Chemical Carcinogenesis; Web: ATSDR, 2024).
58
How is the precautionary principle applied to cardiac risk management? (Domain III.D)
Conservative exposure limits for solvents (e.g., toluene) are set when data is uncertain, prioritizing safety (ABT Handbook, Domain III.D; Web: ECHA, 2024).
59
What clinical signs indicate cardiotoxicity in poisoning incidents? (Domain IV)
Signs include tachycardia, hypotension, or arrhythmias, guiding treatments like beta-blockers for cocaine overdose (ABT Handbook, Domain IV.K; Web: NIH, 2025).
60
How does green chemistry reduce cardiotoxicity risks in product design? (Domain IV)
Safer solvents (e.g., replacing benzene) reduce vascular toxicity in industrial products (ABT Handbook, Domain IV.G; Web: EPA, 2023).
61
What are the regulatory standards for cardiotoxicity testing? (Domain IV)
ICH S7B and FDA require hERG and telemetry studies for drugs, ensuring cardiac safety (ABT Handbook, Domain IV.L; Web: FDA, 2024).

DABT 2025 (16 decks)

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