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102 Cards in this Set
- Front
- Back
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What is target organ toxicity?
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-damage to a specific organ in response to a chemical insult.
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What is the target organ/tissue for priaquine?
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blood (erythrocytes)
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What is the taqrget organ/tissue for clhorenphenical?
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bone marrow
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What is the target organ/tissue for MPTP?
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brain (substantia nigra)
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What is the target organ/tissue for furosemide?
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ear (cochlea)
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what are target tissue/organ for streptomycin?
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ear (vestibular apparatus)
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What is the target organ/tissue for uv radiation?
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eye (lens)
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What is the target organ/tissue for chloraquine
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eye (retina)
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What is the target organ/tissue for NSAIDs?
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GI tract (stomach/duodenum)
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What is the target tissue/organ for doxorubicin?
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heart
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What is the target tissue/organ for cephaloridine?
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kidney
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What is the target tissue/organ for acetaminophen?
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-liver
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What is the target tissue/organ for paraquat?
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-lung
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What is the target tissue/organ for cyclophosphamide?
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-ovaries
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What is the target tissue/organ for uv radiation?
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-eye (lens) and skin
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What is the target tissue/organ for 1,2-dibromo-3-chloropropane?
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-testes
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What factors influence target organ toxicity?
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-disposition of chemical through tissue accumulation and distribution
-unique physiology/biochemistsry of organ -age -gender -species -metabolism of parent compound versum metabolites -response to injury such as regeneration, fucntional reserve/compensation , etc |
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What is disposition of toxin?
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-severity of response usually determined by concentration of chemical and duration of exposure
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What is tissue distribution of toxin?
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-must reach target site to have a toxic effect
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How does cephloridine accumulate in the kidney?
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-uptake by anion transport system
binds to melanin |
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How does chloroquine accumulate in the eye?
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-binds to melanin?
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How does 6-hydroxydopamine accumulate in the adrenergic nerves?
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-structual similarity to dopamine
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How doe paraquat accumulate in the lung?
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structural similarity to endogenous polyamines
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How does streptozotocin accumualate in the pancreas?
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-affinity for B-cells due to glucose moiety
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How does the physiology of bone marrow affect toxicity?
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-rapidly growing cells are susceptible to damage
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How does the reabsorption and secrtion in the kidney affect toxicitiy?
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-uptake and concentration of toxic species
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How does metabolism in the liver affect toxicity?
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toxification of chemicals
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How does respiration in the lungs affect toxicity?
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exposed to high O2 tension
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How does the glucose-6-phosphate dehydrogenas pathway in blood affect toxicity?
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-deficiency- susceptibility of RBCs to hemolysis
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How does the superoxide dismutase, catalase pathway ain the heart affect toxicity?
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-deficiency- cardiotoxicity of doxorubicin
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How does cysteine conjugate beta-lyase pathway in the kidney affect toxicity?
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presence- nephrotoxicity of some cysteine conjugates
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How does cytochrome p450 pathway in the liver affect toxicity?
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presence- toxicity of acetaminophen
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How does DNA repair in skin affect toxicity?
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deficiency- increased susceptibility to skin cancer
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How is age a factor for toxicity?
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-lead can cause toxicity in children due to incomplete developed blood brain barrier
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How is gender a factor for toxicity?
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acetaminophen affects livers in female mice more than males
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How is route of exposure a factor in toxicity?
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-toxicity can only be seen orally for cycasin in the liver/kidney
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How is species a facor in toxicity?
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-there's more toxicity in mice than rats for acetaminophen in the liver
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How is strain a factor in toxicity?
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toxicity (rats) F344 > SD for acetaminophen in the kidney
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How is type of exposure a factor in toxicity?
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acute- CNS
chronic- bone marrow for benzene toxicity |
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How can a parent compound be toxic?
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-directly toxic to target organ, no effect in non-target organ (not accumulated, may be detoxified, etc.)
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How is reactive metabolite toxic?
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-reacts in organ where generated (parent compound is non-toxic), no effect in non-target organ (not generated, may be detoxified, etc.)
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How is stable metabolite toxic?
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generated in one organ and then transported to another, may be directly toxic to target organ or further metabolism may be required (parent compound is non-toxic), no effect in non-target organ
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What are the functions of the skin?
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-protective barrier from exposure to external injury and chemicals (also acts as a shock absorber)
-thermoregulation -sensory organ for pain and "itching" -immunological system with specialized white blood cells |
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What is the epidermis of the skin?
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-avascular
-thickness varies (shaped into a brick-like barrier) -main cell types: -keratinocytes (start in stium germinativium, divide and differentiate rapidly) -melanocytes (create pigment) -Langerhans cells (macrophages) -Merkel cells (nerve cells) -sub divided into 4 layers |
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What is the dermis of the skin?
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-highly vascularized
-loose connective tissue -epithelial appendages -sweat glands -hair follicles -sebaceous glands |
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What is percutaneous absorption of the skin?
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-passage of substances through the epidermis with subsequent diffusion into dermis and entry into circulation
-includes transepidermal and transappendageal |
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What is transepidermal percutaneous absorption?
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-substance penetrates through stratum corneum
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What is transappendageal percutaneous absorption?
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-substance enters skin through sweat glands and hair follicles to bypass stratum corneum
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What are the transport processes in the skin?
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-no active transport
-only diffusion |
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What are factors that affect percutaneous absorption?
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-integrity of skin
-physicochemical properties of chemical (lipophilicity is important) -vehicle (DMSO a good solvent) -surface water (cells can swell from being in water) -skin site (thicker skin protects more) -dermal circulation/temperature (as temp. increases, increase in blood flow, removes from dermis more) -species (best model is pig, most used is rabbit) -age (infants and elderly have thinner skin |
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What is metabolism in the skin?
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-qualitatively similar to the liver but is actively smaller
-epidermis is more active due to vascularization |
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What is irritant contact dermatitis (ICD)?
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-contact dermatitis
-localized inflammatory response -symptoms include redness and swelling -many causative agents- detergents, organic solvents, UV radiation, etc. -mechanism involves keratinocytes and other cells, no antigen recognition |
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What is a chemical burn?
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-contact dermatitis
-severe injury/tissue death -produced by caustic substanced |
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What is the pathway of the mechanism of action for irritant contact dermatitis?
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-activated keratinocyte releases chemotaxins which brings about neutrophils and monocytes that migrate into the skin
-it also releases Interleukon 1a and tissue necrosis factor alpha which brings about t-cells which leads to mast cell degranulation -histamine, prostglandins, thromboxanes, bradykinin are releases which leads to increased vascular permeability (swelling), increased blood flow (redness and heat), and stimulation of nerve endings (pain) |
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What is allergic contact dermatitis (ACD)?
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-symptoms include swelling, redness, blisters, etc.
-causative agents include plant sensitizers, benzocaine, etc. -cross-reactivity may occur -mechanism is type IV hypersensitivity (antigen + T-cells) |
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What is the pathway of the mechanism of action of allergic contact dermatitis?
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-parent toxin enters protein and modifies it to antigen
-where it is then processed by the langerhans cell and a t-cell binds to becomes activated -macrophages and t-killer cells are activated and recruited -leads to tissue damage |
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What is photosensitization?
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-toxicity enhanced by exposure to uv or visible light
-includes UV radiation, phototoxicity, and photoallergy |
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What is UV radiation of the skin?
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-can penetrate skin
-UV-A (320-400 nm)- constant throughout day -UV-B (290-320 nm)- most intense from ~10:00 AM to 2:00 PM |
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What is phototoxicity of the skin?
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-similar to irritant response
-primarily involves UV-A -causative agents- usually via systemic exposure (e.g. antibiotics) -mechanism includes topical or systemic exposure of caustic agents with exposure to UV radiation -leads to reactive species and causes inflammation and cell damage |
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What is photoallergy of the skin?
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-similar to allergic response
-primarily involves UV-A -causative agents- usually via topical exposure (halogenated salicylanilides, oxybenzone) -mechanism includes topical or systemic exposure to caustic agent with UV radiation -leads to allergic response and tissue damage |
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What are toxic responses of the skin?
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-contact dermatitis
-photosensitization -physical dermatitis (fiberglass) -hair damage/loss (anti-cancer drugs) -pigmentation disorders (hydroquinone and coal tar) -urticaria (hives from latex gloves) -toxic epidermal necrolysis (carbamazepine) -chloracne (halogenated aromatic hydrocarbons) -skin cancer (UV radiation) |
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What is the draize test?
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-chemical is applied to intact and abraded skin
-after 24 hours reactions are evaluated against standard charts -results are usually subjective, highly variable -difficult to extrapolate to humans from animal models -use the patch test for humans. |
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What are the general functions of the liver?
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-numerous biological functions including:
-anabolic (synthetic) -catabolic (degradative) -storage -excretion -metabolism -clearance and immune responses -large functional reserve (liver can compensate for damaged parts) |
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What is the cellular composition of the liver?
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1. hepatocytes (most numerous, basic functional cells)
2. endothelial cells 3. Kupffer cells (macrophages) 4. Ito (stellate) cells (synthesize collagen) |
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What is the anatomy of the liver?
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1. subdivided into lobes
2. receives both arterial and venous blood |
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What is the morphology of the liver?
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-hepatocytes arranged in “cords” around central vein
a. sinusoid b. bile canaliculi c. portal triad -metabolites are secreted into blood or bile |
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What is the liver lobule as a functional unit?
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a. centered around branch of central vein
b. sub-divided into periportal (PZ), centrilobular (CZ), mid zones (MZ) |
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what is the damage frequency of the different zones of the liver?
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-zone 3 (CZ) > zone 1 (PZ) > zone 2 (MZ)
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What are the characteristics of necrosis?
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-conditions: pathological only
-ATP-dependent:no -effects: multiple cells -cell morphology: swelling -DNA damage: random fragments -toxicant dose: high -tissue response: inflammation |
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What are the characteristics of apoptosis?
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-conditions: pathological/physiological
-ATP-dependent: yes -effects: single cells -cell morphology: shrinkage -DNA damage: small fragments -toxicant dose: low -tissue response: little or no inflammation |
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What are the mechanisms of necrosis?
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a. covalent binding (reactive metabolite --> damage to critical macromolecules)
b. lipid peroxidation (free radicals --> cell membrane damage) c. elevation of intracellular Ca2+ levels (activation of endonucleases, proteases and lipases) d. mitochondrial damage (inhibit oxidative phosphorylation --> decrease ATP synthesis) |
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What is the potential role of inflammation in hepatic damage?
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a. tumor necrosis factor alpha (TNF-a) is a central mediator
b. results in exacerbation of intial lesion |
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What is the pathway for the role of inflammation in necrosis?
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-chemical enters body
-necrosis of hepatocytes (focal) -kupffer cell activation -with TNF-1a and IL-1 leads to hepatic inflammation which leads to hepatic damage |
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What is steatosis? Possible mechanisms?
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-accumulation of lipids in hepatocytes
-Fatty liver (microvesicular vs. macrovesicular) -Hepatic lipid metabolism -Increased lipid influx or synthesis -Decreased oxidation -Impaired efflux |
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What is cholestasis? possible mechanisms?
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-Decreased/absent bile flow
-Hepatic bile formation/secretion -Altered bile salt transport -Leaky paracellular junctions -Decreased canalicular contractions -concentration of toxicants in canaliculi |
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What is cirrhosis? Etiology?
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-proliferation of collagen fibers, irreversible damage
-Progressive, chronic injury: steatosis → necrosis → fibrosis → cirrhosis -Proliferation of collagen -Alters hepatic morphology -direct effects on heptatocytes from ethanol and acetaldehyde -involvement of Kupffer cells |
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What is the purpose of the assessment of hepatotoxicity?
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-detect subtle damage
-determine type -follow recovery |
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What are the different measurements of assessing hepatotoxicity?
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-measure hepatic elimination rate
-measure biosynthetic ability -measure blood levels of substances released by injured hepatocytes -morphological assessment |
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What is the hepatic elimination test as an assessment of hepatotoxicity?
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-Measure clearance from blood
-Exogenous substances: -dyes (bromosulfophthalein, indocyanine green) -drugs (metabolism of 14C-aminopyrine, etc.) -Endogenous substances: -bilirubin -bile salts |
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What is dye excretion used for in assessment of hepatotoxicity?
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bromosulfophthalein (BSP- adminisered iv and monitor blood levelss
-indocynine green (ICG)-eliminaed i bile -measures clearance fortests for steatosis |
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What is amino pyrene metabolism used for in assessment of hepatotoxicity?
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-measure radioactive CO2 in breath
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What is serum bile/ bilirubin used for assessment in hepatotoxcicity?
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-bile (serum) levels will increase after hepatic damage
-bilirubin (serum or urine) increase suggests hepatic damage |
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What are biosynthetic tests in assessment of hepatotoxicity?
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-synthesis of prothrombin and fibrinogen clotting time may increase
-synthesis of serum albumin decrease may indicate damage -Measure plasma concentrations, etc. -Relatively insensitive -Serum albumin -Blood clotting proteins -prothrombin -fibrinogen |
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What are enzyme tests in assessment of hepatotoxicity?
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-Measure enzyme activities in blood
-Highly sensitive -Aminotransferases -alanine aminotransferase (ALT, a.k.a. SGPT) -aspartate aminotransferase (AST, a.k.a. SGOT) -Other enzymes: -sorbital dehydrogenase (SDH) -alkaline phosphatase (AP) -good for detecting necrosis |
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What are the functions of the kidney?
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excretion:
-waste products of cellular metabolism -drug/chemical metabolites: regulation/reabsorption: -extracellular fluid volume -plasma acid-base balance -filtration/reabsorption Synthesis/Secretion: -hormones (i.e. Epo) -vitamins (i.e. vitamin D3) |
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What is the effect of molecular weight on filtration in the kidney?
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-as molecualr weight of a substance increases, percent filtered decreases
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What is the effect of molecular charge on filtration in the kidney?
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-filtration decreases as carge becomes more negative
-vice-versa for more ositve charged substances |
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What is acute renal failure (ARF)? Causes?
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-Characterized by decreased GFR
-caused by constriction of afferent arterioles -backleakage of glomerular filtrate - and tubular obstruction |
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How can the kidney conduct adaptation following injury or acute renal faliure?
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-kidneys can compensate for damage
-ex. unilateral nephrectomy (removal of kidney) -intially decrease in GFR and EPO synthesis -can lead to anemai i does not compensate -levels return to normal eventually |
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What s chronic renal failure (CRF)?
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-may occur with long-term exposure
-initial injury triggers secondary damage -possibly due to rheumatoid arthrtitis drug or litium use |
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What are factors that can lead to susceptibility of the kidneys to injury?
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-high blood flow/small mass(more suscpetible than liver)
-concentration of tubular fluid -presence of active transporters -metabolic capability of the nephron -extrarenal factors |
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What damage to the glomerulus can lead to susceptibility of the kidneys to injury?
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Site selectivity:
-location in nephron -anatomy of glomerular basement -membrane Mechanisms -altered filtration size/charge selectivity -impaired filtration -immune complex-mediated damage |
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What is the pathway for gloerulonephritis or imuune complex-mediated damage to the kidneys?
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-drug-modified antigen combines with antibodies to become immune complexes
-they become trapped in the glomerulus basement membrane -this casues an imune response that leads to glomerular damage |
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What damage to the proximal tubule can lead to suscpetibility of the kidneys to injury? mechanisms?
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-most common site for renal injury
-site selectivity -high blood flow -intracellular accumulation (via tubular reabsorption and/or tubular secretion) -ex: cortical uptake and nephrotoxicity of cephalosporins -concentration of non-reabsorbed chemcials in tubular fluid -distribution of metabolic enzymes (cytochrome p450 and renal cystein conjgate beta-lyase activity) -altered tubular reabsorption/secretion -formation of toxic metabolites |
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What damage to the distal tubule can lead to suscetibility of the kidneys to injury?
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-less common than proximal tubular damage
-site selectivity- distribution of metabolic enzymes -damage observed as impaired concentrating ability -ex. some tetracyclines |
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What dmaage to the renal medulla and papilla can lead to susceptibility of the kidneys to injury?
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medulla (loop of Henle, collecting ducts):
-damage observed as impaired concentrating ability -site selectivity due to concentrative function of medulla? ex. methoxyflurane (hepatic metabolism) -->fluoride ion papilla: -susceptible to damage from chronic, abuse of analgesics (“analgesic nephropathy”) -site selectivity due to concentrative function of papilla? -mechanism uncertain |
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What is the purpose of the assessment of nephrotoxicity?
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-detect subtle damage
-determine type -follow recovery |
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How is measurement of glomerular filtration rate an approach to the assessment of nephrotoxicity?
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-inulin clearane
-creatinine clearance -ex. effect of aminoglycosides (AG) on glomerular filtration rate in rats |
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How are hemolytic measurements as approach to the assessment to nephrotoxicity?
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-blood urea nitrogen (BUN) level
-serum creatinine level -correlation with GFR -ex. chloroform nephrotoxicity |
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How is urinalysis measurements an approach to the assessmnt of nephrotoxicity?
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-easy & non-invasive
-change in volume -urine contents: -protein content (proteinuria) -glucose content (glucosuria) -enzyme content (enzymuria) |
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How is morphology an approach to the assessment of nephrotoxicity?
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-site, nature and severity of injury
-ex. effect of probenecid on cephaloridine accumulation and nephrotoxicity |
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What is significant about the nephrotoxicity of N-(3,5-dichlorophenyl)succinimide (NDPS)? How is it used in assessment?
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-agricultural fungicide
-nephrotoxic in rats (proximal tubular damage) -model compound for chemically-induced kidney damage - used for urinalysis/hematology -used to measure renal morphology after toxicity |
