Toxicology

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Clinical Chemistry
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1

toxicology

the study of adverse effects of xenobiotics in humans

2

xenobiotics

chemicals and drugs not normally found or produced in the body; exogenous agents that may have adverse effects on a living organism; environmental or drug exposures; medications

3

poisons

have an adverse effect on biological system; used when describing animal, plant, mineral, or gas; arsenic, lead, CO, poison ivy

4

toxins

substances that are biologically synthesized in living cells or microorganisms; bacteria, mycobacterium, S. aureus, snakes

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mechanistic

cellular and biochemical effects of toxins; context of dose-response relationship

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descriptive

uses results of animal experiments to predict what level of exposure will cause harm in humans; risk assessment

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regulatory

used data from mechanistic and descriptive to establish standards regarding acceptable levels of exposure; oversees human safety issues associated with therapeutic drugs, cosmetics, and food additives

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forensic

primarily medical and legal consequences of chemical or drug exposure

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suicide attempts

50% of poisoning cases

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accidental exposure

30% of poisoning cases

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ingestion, inhalation, and transdermal absorption

three exposure routes

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pH, rate of dissolution, gastric motility, resistance to degradation in GI tract

factors affecting absorption

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effective dose

dosage determined to be effective in 50% of the population

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toxic dose

dosage determined to be toxic to 50% of the population

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lethal dose

dosage determined to be lethal to 50% of the population

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interfere with enzyme actions and systems, block oxygen usage and transport, interfere with cell function, and cause hypersensitivity

four mechanisms of toxicity

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screening tests

rapid, simple, qualitative procedure to detect specific substances or classes of toxicants; good analytic sensitivity, but lack specificity

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confirmatory testing

immunoassays, TLC, and GC/MS

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alcohol

CNS depressant (changes membrane properties) causing disorientation, confusion, and euphoria; unconsciousness, paralysis, and death at high concentrations; changes in membrane properties to exert immediate effect

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alcohol -> aldehyde -> acid (ADH + ALDH)

biotransformation of alcohols

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ethanol

most commonly consumed alcohol; long term health effects include alcoholic hepatitis and cirrhosis, lipid deposition in the liver

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EtOH -> Acetaldehyde -> Acetate -> Acetaldehyde adducts

ethanol mechanism

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acetaldehyde adducts

EtOH product that changes structure and function of proteins in the body

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cirrhosis

fibrosis in liver affecting hepatic funciton

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AST/ALT ratio >2.0

highly specific for ethanol-related liver disease

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increased MCV

hematology impact due to EtOH consumption

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high serum HDL

impact on lipid panel caused by EtOH consumption

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GGT

...

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AST

...

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methanol MeOH

common solvent used as cleaning solution and a liquor contaminant; leads to severe acidosis and blindness; converted into formaldehyde and formic acid leading to death

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isopropanol

converted into acetone which has a longer half life and longer affects than EtOH; similar effects to ethanol

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ethylene glycol

ingestion leads to toxic byproducts (oxalic and glycolic acid) and crystal deposits (calcium oxalate) in tubules causing severe metabolic acidosis and renal tubular damage

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alcohol testing method

uses gas chromatography; enzymatic methods using ADH and measurement of NADH-specific for EtOH

34

carbon monoxide

a colorless, odorless, tasteless gas rapidly absorbed into blood from inspired air; considered highly toxic due to its affinity for and binding to hemoglobin, displacing oxygen; produced by incomplete combustion of carbon-containing substances of primary environmental sources: gasoline engines, improperly vented furnaces, and wood or plastic fires; symptoms: SOB (without strenuous exercise), severe headaches, fatigue, impaired judgment

35

differential spectrophotometry

used to measure carboxyhemoglobin against regular hemoglobin since different forms of hemoglobin (hgb, A1c, CoHb) absorb at different wavelengths

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0.5

CoHb of healthy adult

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5-15

CoHb of smoker

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40-50

CoHb leading to confusion and fainting

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60-70

CoHb leading to unconsciousness

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80

CoHb that is immediately fatal

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gas chromatography

reference method for carboxyhemoglobin measurement since it is accurate and precise

42

pulmonary edema, shock, death

toxicology of aspiration

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perforations in esophagus and GI tract

toxicology of ingestion

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rapid development of metabolic acidosis or alkalosis

risk of caustic agents

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cyanide

found in industrial processes, insecticides, rodenticides; produced by burning of some plastics; common suicide agent; associated with fires and smoke inhalation; binds heme, decreasing oxygen, depleting ATP; increases in cellular oxygen tension and venous pO2 occur as a result of lack of oxygen utilization causing headaches, dizziness, respiratory depression, leading to seizure, coma, and death

46

binding to heme iron, uncoupling oxidative phosphorylation and depleting ATP

how cyanide expresses toxicity

47

ISE and photometric

techniques used to measure cyanide

48

thiocynate

can be measured in urine for low level exposures to cyanide

49

arsenic

exists in both naturally occurring and manmade substances; binds to proteins affecting function; measured with AAS; short time in blood so urine is specimen of choice-90% in 6 days

50

cadmium

electroplating and galvanizing; mining and processing of many other metals; environmental pollutant found in tobacco shellfish and vegetables; binds to proteins with major effects on the renal system; AAS in whole blood or urine

51

lead

common constituent of household paints before 1972; byproduct of many industrial processes; plumbing materials; slow elimination so it builds up in the body over time; children very sensitive; measurement chromogenic-AAS

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abdominal and neurological impact, cerebral edema and ischemia

acute exposure to lead impacts

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behavioral changes, hyperactivity, ADD, IQ

subclinical exposure to lead impacts

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vitamin D metabolism and heme synthetic pathway

key impacts of lead exposure on enzymatic activity

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increased zinc protoporphyrin and basophilic stippling

testing strategies to find lead toxicity

56

mercury

inhalation and accidental ingestion of inorganic and organic forms in industrial settings; consumption of contaminated foods is major source of exposure; causes toxicity due to protein binding leading to GI issues, renal impact, behavioral changes, loss of balance, hypotension, bradycardia, and others; analysis by AAS using whole blood

57

pesticides

substances intentionally added to environment to kill or harm insects or plants impacting something else; contamination of food is major route of exposure; inhalation, transdermal and ingestion are exposure routes; lead to wide range of toxicity, both chronic and acute, and death

58

measurement of pseudocholinesterase (SChE) activity

more common measurement for pesticide toxicity

59

erythrocytic acetylcholinesterase activity

used for the detection of organophosphate exposure to pesticides-less common

60

salicylates-aspirin

used as an analgesic, antipyretic, and anti-inflammatory drug; decreases thromboxane and prostaglandin formation through inhibition of cyclooxygenase interfering with platelet aggregation and GI function in high amounts; toxic effects include metabolic acidosis (can lead to death), hyperventilation, respiratory alkalosis, acid-base disturbance, inhibition of Krebs cycle, resulting in excess conversion of pyruvate to lactate, and excess ketone body formation; measured by GC, LC, immunoassays, some chromogenic assays

61

acetaminophen

analgesic drug; overdose associated with severe hepatotoxicity, accumulation of reactive intermediates and free radical leading to toxic cell effect and necrosis of liver-onset usually 3-5 days after ingestion; initial symptoms are vague, nonspecific, and not predictive of hepatic necrosis; tested by immunoassay and high-performance liquid chromatography

62

amphetamines

therapeutic drugs used for narcolepsy and attention deficit disorder; stimulants with a high abuse potential; produce initial sense of increased mental and physical capacity and perception of well-being; initial effects followed by restlessness, irritability, and possible psychosis; OD: hypertension, cardiac arrhythmias, convulsions, and death; testing through urine, immunoassay screening, confirmed by LC or GC

63

methylenedioxymethamphetamine (MDMA)

an illicit amphetamine derivative commonly referred to as ecstasy

64

anabolic steroids

group of compounds related chemically to male sex hormone testosterone; increase muscle mass and can improve athletic performance; toxic hepatitis, accelerated atherosclerosis, abnormal platelet aggregation leading to stroke or MI; enlargement of heart leads to ischemia, cardiac arrhythmias, and possible sudden death; testicular atrophy, sterility, and impotence in males, masculine traits, breast reduction, and sterility in females

65

cannabinoids

group of psychoactive compounds found in marijuana; smoked or ingested, produces sense of well-being and euphoria; associated with impairment of short-term memory and intellectual function; OD not specific to physiologic toxic outcomes; immunoassay to screen, GC/MS to confirm

66

tetrahydrocannabinol (THC)

most potent and abundant cannabinoid

67

cocaine

effective as local anesthetic with few adverse effects at therapeutic concentrations; high concentrations is potent CNS stimulator that elicits sense of excitement and euphoria; high abuse potential; injected or inhaled (crack); half life is brief-30-60 minutes; toxic effects are hypertension, arrhythmia, seizure, and MI; detected by immunoassay to screen GC with MS to confirm

68

benzoylecgonine

analyte measured to detect cocaine in urine

69

half life

time it takes for a drug to decrease by 50%

70

opiates

a class of substances capable of analgesia, sedation, and anesthesia; high abuse potential; derived from opium poppy; leads to respiratory acidosis, myoglobinuria, cardiac damage, and death by cardiopulmonary failure

71

heroin

chemically modified opiate

72

phencyclidine

illicit drug (never therapeutic) with stimulant, depressant, anesthetic, hallucinogenic properties; high abuse potential; leads to agitation, hostility, and paranoia; toxic effects are stupor and coma; IA screening, mass GC spec confirmatory

73

sedative-hypnotics

CNS depressants including tranquilizers; wide range of therapeutic roles; barbs and benzos commonly abused; toxic effects include lethargy, slurred speech, coma, respiratory depression, and hypotension; includes lithium, adovan, valium; GC mass spec or LC