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ENVHLTH 417 test I

Principles of Toxicology test I

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
Created by: AngryEggplant