Toxicology Exam 2

These flashcards cover key terms and concepts related to the fundamentals of toxicology and genetic toxicology, including types of mutations, their effects, and mechanisms of mutagenesis.

Genotoxicants

Agents that cause damage to the genetic information within a cell.

Somatic mutations

Mutations that occur in nonreproductive cells and are passed on during mitosis.

Germ-line mutations

Mutations that occur in reproductive cells and can be transmitted to the next generation.

Phenotypic effects of mutations

Changes in observable traits due to mutations, including missense, nonsense, and silent mutations.

Missense mutation

A mutation that results in a different amino acid being incorporated into a protein.

Nonsense mutation

A mutation that converts a codon into a stop codon, leading to premature termination of protein synthesis.

Silent mutation

A mutation that does not change the amino acid sequence of a protein.

Loss-of-function mutation

A mutation that results in a complete or partial absence of normal protein function.

Gain-of-function mutation

A mutation that leads to a protein with new or enhanced activity.

Conditional mutation

A mutation that exhibits its effects only under specific conditions.

Aneuploidy

An increase or decrease in the number of individual chromosomes.

Clastogenesis

Chromosomal breakage leading to structural abnormalities.

Mutagen

An environmental agent that increases the rate of mutation.

Ames test

A test used to assess the mutagenic potential of chemical compounds.

DNA methylation

An epigenetic mechanism that involves the addition of methyl groups to DNA, affecting gene expression.

RNA interference (RNAi)

A biological process that inhibits gene expression through the degradation of mRNA.

Chromosomal abnormalities

Changes in the structure or number of chromosomes, including deletions, inversions, and translocations.

What is usually the critical factor determining the respiratory tract region in which a particle or an aerosol will deposit?

Particle size

Asthma

Increased reacitivity of the brichial smooth muscle in response to exposure of irritants

Emphysema

the destruction of the gas-exchanging surface area results in a distended hyperinflated lung that no longer effectively exchanges oxygen and carbon dioxide.

4 Features of the Lung

1. Gas Exchange

2. Large Surface Area

3. Branching Structure

4. Pocketed Structure

2 Zones of the Lung

1. Conductive Zone (through the nasal and oral cavity)

2. Respiratory Zone (trachea and bronchi)

Type I Alveolar Cells

• squamous

• 95% of the alveolar surface

• involved in gas exchange

• permeable

• unable to replicate

• susceptible to toxic insult

Type II Alveolar Cells

• cover a small fraction of the alveolar surface

• secrete surfactant

• can proliferate and differentiate into type I cells

• found at the blood-air barrier

Atmospheric particles are typically categorized into two modes:

Accumulation and course

True or False: Clearance from the respiratory tract does not equate to removal from the body.

True

3 Components of the Lungs

1. Bronchial Smooth Muscle

2. Irritation

3. Mucus

7 Effects of Pulmonary Toxicology

1. Irritation

2. Cell Necrosis

3. Fibrosis

4. Emphysema

5. Sensitization

6. Cancer

7. Allergy

Silicosis

Cased by silica dust

Causes fibrosis

Asbestosis

Caused by asbestos exposure

Causes fibrosis and mesothelioma

Chronic Obstructive Pulmonary Disease (COPD)

A group of lung diseases including emphysema and chronic bronchitis, characterized by airflow limitation and breathing difficulties.

4 D’s of Pulmonary Toxicology

Dose

Dimension (size)

Distribution

Durability (in reference to particles and fibers)

Endocrine glands

Collections of specialized cells that synthesize, store, and release their secretions directly into the bloodstream.

Adrenal Cortex

Synthesizes and secretes steroid hormones that regulate salt and fluid balance, glucose homeostasis, and a long-term response to stress.

Adrenal Medulla

Secretes the catecholamines, epinephrine, and norepinephrine.

Pregnenolone

The basic precursor for the three major classes of adrenal steroids

Effects of Glucocorticoids

• Gluconeogenesis

• Protein catabolism

• Fat catabolism

• Increased bone resorption

• Altered mood

• Increased gastric acidity

Mineralcorticoids

Act primarily on intracellular receptors in kidney tubules to reabsorb sodium and water and excrete potassium and protons.

True or False; Xenobiotics, such as heavy metals, do not alter the thyroid glands’ structure.

False

Beta cells

Insulin producers

Alpha cells

Glucagon producers

4 Modes of Action of Endocrine-disrupting Chemicals

1. Serving as steroid receptor ligands

2. Modifying steroid hormone metabolizing enzymes

3. Perturbing hypothalamic-pituitary release of trophic hormones

4. Uncharacterized proximate modes of action

Sertoli cells

Intermediate sensitivity

Leydig cells

Resistant

Hematotoxicology

The study of adverse effects of chemicals on teh blood and blood-forming tissues.

In the human fetus, hematopoiesis can be found in the…

Liver, spleen, bone marrow, thymus, and lymph nodes

-emia

With reference to the blood

-penia

Decreased number of blood cells

-cytosis

Increased number of blood cells

Leukemias

Hematopoietic stem or progenitor cells in bone marrow undergo controlled proliferation and cannot differentiate normally into mature blood cells.

• lack of white blood cells (lack of mature wbc)

The 4 Major Types of Leukemia

Acute lymphoblastic leukemia (lack of lymphocytes)

Acute myeloid leukemia (lack of all other cells)

Chronic lymphoblastic/myeloid leukemia

PR interval

A measure of the time from onset of atrial activation to the onset of ventricular activation.

the QRS complex

Represents the conduction pathways through the ventricles.

the ST segment

The interval during which the entire ventricular myocardium is depolarized.

the QT interval

Electrical systole of the ventricles and mirrors the action potential duration of the mass of ventricular myocytes.

Phosphocreatine

Maintains a high phosphorylation potential to drive ATPase reactions under highly demanding conditions.

Toxicological cardiomyopathy

Myocardial cell death, leads to fibrotic scarring.

Cardiac hypertrophy

An adaptive response in which cardiac function changes to meet an increased demand of cardiac output.

Arrhythmogenenic cardiomiopathy (ACM)

Compromise of electrical conduction can lead to sudden death in an otherwise healthy individual.

Response of vascular endothelial cells to toxic insults

Nitrotyrosine adducts

Response of smooth mucle cells to toxic insults

Changes in vascular tone and atherosclerosis

Effects of vascular toxicity

• hyper/hypotension

• atherosclerosis

• edema

• hemorrage

Human health risk assessment endpoints

• cancer

• non-cancer

Risk characterization yields…

“the number!”

LOAEL

Lowest observed adverse effect level

NOAEL

No observed adverse effect level

MRL

An estimate of the daily human exposure to a substance that is likely to be without an appreciable risk of adverse, noncancer effects over a specified duration of exposure”

RfD

An estimate (with uncertainty spanning perhaps an order of magnitude) of daily exposure to the human population (including sensitive subgroups) that is likely to be without appreciable risk of deleterious effects during lifetime.

Risk management

The process of evaluating and if necessary, controlling sources of exposure and risk

QSAR

Prediction of chemical behavior and properties based on molecular structure and properties.

Neurotoxicity

An adverse change in the structure or function of the central and/or peripheral nervous system following exposure to a chemical, physical, or biological agent.

Adverse effects

Alterations from baseline or normal conditions that diminish an organism’s ability to survive, reproduce, or adapt to the environment.

Characteristics that increase nervous system vulnerability

• high energy requirements

• long spatial extensions (axons) and large cell volumes

Signs of peripheral/central neuropathies

• altered. myelin

• altered ion gradients

• decreased amplitudes of nerve action potentials

• parasthesias (foot fell asleep feeling)

• paralysis

• increased reaction time

Patterns of neurotoxic injury

Neuronopathy (neuron death)

Axonopathy (axon degenerates)

Myelinopathy (injury to Schwann cells or oligodendrocytes)

Chloramphenicol

inhibits DNA/protein synthesis

leads to neuronopathy

Methylmercury

acts on protein binding

leads to neuronopathy

Colchicine

acts on microtubules

leads to axonopathy

Acrylamide

alters axonal transport

leads to axonopathy

Ethidium bromide and trimethyltin

cause intramyelinic edema

lead to myelinopathy

Pesticides

Substances used to prevent, destroy, repel, or mitigate any pest

Organochlorine insecticides

derived from chlorinated hydrocarbons

associated with suppression of the immune system and cancer

ex: DDT

proceeds exceptionally slow

Lipophilicity is strongly related to…

chlorines

Organophosphates and carbamates

anticholinesterase agents

undergo extensive metabolism

Pyrethroids or pyrethrins

derived from natural sources

interfere with sodium channels (open)

Type I (no substituent) and Type II (with substituent)

Type I pyrethroids

open sodium channels for a short period of time

Type II pyrethroids

open sodium channels for a prolonged period of time

the most metabolically active organ

the liver

normal function of the liver

creates bile

hepatocytes

cells that make up the liver

metabolic functions of the liver

fat, protein, and carbohydrate metabolism

4 Types of Liver Cells

1. Hepatocytes

2. Kupffer cells (macrophages)

3. Hepatic stellate cell (ITO cells)

4. Sinusoidal endothelial cells

hepatitis

inflammation of the liver

fatty liver

when lipids accumulate in hepatocytes

cholestasis

obstruction of canaliculi leading to cell swelling, death, inflammation and decreased bile flow or bile salt formation

cirrhosis

accumulation of collagen fibers, permanent

Functions of the kidney

• excrete waste (urine)

• regulate fluid volume

• maintain acid-base balance

Urine Formation

1. ultrafiltration of plasma

2. reabsorption of water and solutes from the ultrafiltrate

3. secretion of selected solutes

Blood Urea Nitrogen (BUN)

a test that indicates renal function

tests to see if urea nitrogen is higher than normal

B lymphocytes

produce antibodies