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ENVHLTH 417 test I
Principles of Toxicology test I
Question | Answer |
---|---|
Paracelsus (1493-1541) | "The dose makes the poison. All substances are poisons; there are none which is not a poison. The right dose differentiates a poison from a remedy." |
Wiley Bill (1906) | First food and drug law passed; established inspections for meat packing plants |
Copeland Bill (1938) | Helped establish the FDA; required all drugs be tested for safety before going on the market |
Delaney Cause (1958) | Chemicals found to be carcinogenic could be not be added to U.S. food supply; not strictly enforced since "zero risk" is not realistic |
Love Canal | A canal used as a chemical waste site caused major health problems and eventually an evacuation of the whole town |
Descriptive toxicology | seeks to characterize the toxicity associated with a chemical (ADME) |
Mechanistic toxicology | seeks to determine the cellular, biochemical, or molecular mechanisms that result in a toxic response |
Regulatory toxicology | seeks to draw conclusions about the safety of a chemical, based on data from descriptive and mechanistic studies |
Saccharin | descriptive: found it caused bladder cancer in rats mechanistic: determined that the carcinogenic levels were not attainable in humans regulatory: determined that sacchrin was low risk for humans |
Toxicant | "man made" toxic substance |
Toxin | naturally produced toxic substances |
LD_50 | Dosage usually expressed in mg/kg; studies are usually short with one dose administered |
Limitations of LD_50 | vary from species to species, route of administration, formulation of the chemical; only describe toxic potential, not other toxic effects |
Toxic effect | an effect that is life threatening (death, organ failure, cancer, birth defects) |
Side effect | undesirable effect that results from normal action of a chemical (headache, nausea, etc) |
Haptens | Chemicals which combine with endogenous protein to become antigenic (allergic reaction) |
Local toxicity | Occur at site of first contact |
Systemic toxicity | Toxicant must be absorbed into bloodstream and distributed to a distant site where toxic effects occur (usually 1-2 target organs) |
Intravenous exposure | usually results in the greatest effect and most rapid response to a toxic agent |
Duration of exposure | Many chemicals exhibit different toxicities in single exposures and multiple exposures. It is important to get a full spectrum of effects from different exposure levels |
ED/TD/EC_50 | effective/toxic (responses to toxic agents)/effective dose/concentration (theraputics) required for 50% response |
Therapeutic Index (TI) | TI = TD_50/ED_50; approximates the relative safety of a drug; drugs with large TI (>10) are considered relatively safe |
NOAEL | no obserbed adverse effect level; "apparent" thresold which is considered "safe" |
LOAEL | lowest observed adverse effect level; helps determine threshold |
Threshold | level below which no response occurs |
U-shaped dose response curve | typically a substance which is required at low doses but is toxic at high doses. e.g. vitamins and minerals |
Hormesis/J shaped dose response curve | Phenomenon where some toxic substances impart a beneficial/stimulatory effect at low doses but toxic at high doses. e.g. alcohol, ionizing radiation |
Intensity of a toxic effect | Depends on the concentration and persistence of the ultimate toxicant at its site of action |
Ultimate toxicant | the chemical species hat produces the toxic effect, could be: the parent compound, a metabolite, a reactive oxygen or nitrogen species generated as a byproduct when compound is meetabolized |
Concentration of ultimate toxicant at target site will be influenced by 1: | concentration: absorption (into circulation), distribution (to target site), reabsorption (target site --> blood), toxication/metabolic activation |
Concentration of ultimate toxicant at target site will be influenced by 2: | presystemic elimination (removed before reaching blood?), distribution away from target, excretion (removed to external environment), detoxication/metabolic inactivation |
ADME | absorption, distribution, metabolism (biotransformation), excretion. define how a compound interacts with the rest of the body to cause activity and toxicity |
What depends on ADME? | the formation of the ultimate toxicant and the ability of a toxicant to reach its site of action |
Toxicity is influenced by.. (in regards to absorption) | the ability of a chemical to cross multiple cell membranes to reach the target site |
Passive transport | most chemicals cross membrane this way; movement depends on size (small) and lipid (lipidphilic) solubility |
Most toxicants are _____ organic molecules with _______ degrees of lipid solubility | large, differing |
diffusion trapping | when a chemical is absorbed into a cell where the pH differs and causes the chemical to ionize is no longer able to cross the cell membrane |
main sites of absorption | GI tract, skin, lungs |
absorption by GI tract | occurs all along the GI tract; toxicants don't cause much of a problem until they are absorbed |
absorption by skin | not very permeable. toxicants muc past through epidermis and several cell layers to reach blood. |
rate determining barrier of skin | stratum corneum |
rate determining barrier of the lungs | blood-gas partition coefficient |
absorption by lungs | gases, small particles |
blood-gas partition coefficient | ratio of concentration of a chemical in the blood to concentration in gas phase; essentially a solubility ratio and is unique for each gas |
subcutaneous (sc), intramuscular (im) | absorbed slowly directly into bloodstream |
intraperitoneal (ip) | rapid absorption because of rich blood supply and surface area of peritoneal cavity. absorbed through hepatic portal circ then to bloodstream |
first-pass metabolism/effect | ingested materials are sent through hepatic portal circ --> liver --> systemic circ. can be beneficial or dentrimental |
potential consequences of first-pass metabolism | 1. enzymes in liver may activate the chemical 2. enzymes may deactivate the chemical but this can hurt the liver 3. chemical may be excreted after detoxification |
distribution of a toxication | translocation of the toxicant after it enters the blood tends to be rapid. rate of diffusion depends on blood flow, rate of diffusion from capillaries to tissues |
3 compartments of water toxicants can be distributed into | 1. plasma water, interstitial water (between cells), and intracellular water |
what determines where a chemical will accumulate? | rate of blood flow, can toxicant bind to proteins expressed on certain cells/tissues, is the toxicant highly soluble at a site, is the chemical a substrate for active transport proteins that are expressed in cells of certain tissues |
protective accumulation | site of accumulation is different than the site of toxicity |
detrimental accumulation | site of accumulation and toxicity sites are the same |
as a chemical is removed from the body by biotransformation, ____ chemical is released from storage site | more |
where can toxicants be stored? | plasma proteins, liver and kidneys, fat, bone |
plasma proteins bind ________ compounds as well as ________. | endogenous, xenobiotics |
toxicants and plasma proteins | cannot cross capillary walls. some have high affinity for binding to plasma proteins which may cause interactions w/ other compounds that also bind plasma proteins |
drugs and toxicants that bind plasma proteins can displace _______ from ______, resulting in toxicity | bilirubin, albumin |
liver & kidney as storage depots | high capacity for binding toxicants and concentrating them. enter through simple diffusion, active transport, binding to tisue components in these organs |
fat as a storage depot | stable, lipophilic organic compounds can easily cross membranes and become concentrated in adipose tissue. this is protective. |
bone as storage depot | entering: depends on surface chemistry. leaving: depends on surface chemistry and osteoclast activity |
blood-brain barrier | tightly joined capillary endothelial cells in CNS; tight junctions prevent toxicant from entering and transport proteins actively pump toxicants out of the endothelial cells |
biliary excretion | main route of excretion. contributes to fecal excretion and the liver puts toxicants into the bile |