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51 Cards in this Set

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how is toxicity data extrapolated among/between species?
10x factor for intraspecies variability (gender/age based differences, susceptible subpopulations), 10x factor for interspecies extrapolation, safety factor approach will often lead to a 100 fold margin for toxicity data. Unfortunatly, safety factor will lead to excessive treatment of most animals exposed to common poisons
why do we use a 10x factor?
3x for pharmacokinetic differences, 3x for pharmacodynamic differences
what factors influence toxicity?
animal factors, dietary factors,
what animalf factors influence toxicity?
physiologic state, health at time of exposure, individual variation, nutrients, contaminants
what is an example of a toxin influenced by physiological state?
white snakeroot is excreted via milk which protects the lactating dam but puts the nursing animal at great risk
what is an example of a toxin influenced by health at time of exposure?
bufo toad poisoning is more hazardous to old animals with preexistant heart dz
what dietary factors influence toxicity?
nutrients, contaminants, malnutrition
what is an example of a toxin influenced by nutrients?
decreased carbohydrate increases susceptibility of ruminants to urea toxicosis
what is an example of a toxin influenced by contamination?
natural toxins (aflatoxin), feed additives (monensin), manmade toxicants (pesticides)
what is an example of a toxin influenced by malnutrition?
increased ingestion of poisonous plants, may protect against toxic effects of some toxicants that are bioactivated by liver enzymes (carbon tetrachloride), toxicant may enhance or decrease palatability
what is toxicokinetics?
the time course of movement of chemical through the body
why is toxicokinetics important clinically?
disposition of toxicant
what influences the severity of toxicity?
disposition of the toxicant, biological reactivity of toxicant
what processes are involved in toxicokinetics?
absorption (substance enters body), Distribution (xenobiotic moves from siteof entry to other sites in body), Metabolism (body changes (transforms) xenobiotic into new forms (metabolites)), Excretion (xenobiotic (metabolites) leave the body)
what factors influence the disposition of xenobiotic?
duration/concentation of substance at portal of entry, rate of absorption, distribution in the body, concentration at specific body sites (tissue dose), efficiency of biotranformation and nature of the metabolites, ability of zenobiotic to cross cellular membranes, extent of tissue storage of the chemical or metabolites, rate and sites of excretion,
what is absorption?
process whereby toxicants gain entrance into the body
how does absorption apply to ingested and inhaled materials?
still considered outside the body until they cross the cellular barriers of the gastrointestinal tract or respiratory system, to exert an effect on internal organs it must be absorbed, although local toxicity, such as irritation may occur (portal of entry effects)
what are portal of entry effects?
to exert an effect on internal organs, toxicant must be absorbed, although local toxicity such as irritation may occur
how does absorption affect skin, oral, and respiratory exposure?
exposure dose is only a fraction of the absorbed dose, xenobiotic must cross several membranes in order to go from one area of the body to another
how does absorption affect injected substances?
exposure dose = absorbed or internal dose
how does absorption vary?
route (Hg inhale vs ingest, DDT oral vs dermal)
what mechanisms are used to cross membranes?
passive transfer, facilitated transport, active transport, endocytosis (phagocytosis/pinocytosis)
what factors affect GI absorption?
absorption site, period of time that the substance remains at the site, pH of stomach or intestinal contents at the site
how are xenobiotics absorbed within the mouth and esophagus?
poorly except nicotine, nitroglycerin
what type of xenobiotics are absorbed in the stomach?
stomach pH = 1-3, significant site for absorption of weak organic acids, weak bases will be highly ionized and are poorly absorbed
what type of xenobiotics are absorbed in the small intestine?
pH 5-8, large surface area and slow transit time facilitates diffusion, facilitated and actve transport mechanisms exist to move certain substances across the intestinal cells into the body
what factors influence the absorption rate from respiratory tract?
solubility in the blood (high = well absorbed, low = limited absorption: blood becomes saturated quickly), absorptiong through alveolar membrane is by passive diffusion, rate and depth of breathing, rate of blood flow to the lungs
how does skin affect dermal absorption?
relatively impermeable to most ions as well as aqueous solutions
what chemicals cross skin and induce systemic toxicity?
organophosphate pesticides, carbon tetrachloride, hexane
which layer of skin provides the primary barrier?
epidermis (stratum corneum) is primary, dermis and subcutaneous tissue secondary
where is the stratumcorneum thickest and thinnest?
thick on palms and soles, thin on arms, back, legs, abdomen, thinnest on axillary, inguinal, scrotum
what is dermal absorption enhanced by?
damage to stratum corneum: abrasions, scratches, cuts, acids, alkalis, corrosives, skin burns, dermatitis
how does dermal absorption occur?
passive diffusion (no known active transport mechanism), water-soluble chemicals diffuse through the outer surface of the hydrated keratinized layer, lipid soluble chemicals dissolve in and diffuse through the lipid material
what are the species differences in dermal absorption?
species similar to people (monkey, pig, guinea pig), more permeable (rat, rabbit), less permeable (cat)
what are other sites of dermal absorption?
small amounts of chemicals may be absorbed through the sweat glands, sebaceous glands, and hair follicles
how can a toxicant distribute?
enter local tissue cells, enter blood capillaries and the blood circulatory system, enter the lymphatic system…is affected by plasma protein binding (free substance is available to pass through the capillary membranes), once a chemical is in the blood stream it may be excreted, stored, biotransformed into different chemical (metabolites may be excreted or stored), chemical or its metabolites may interact or bind with cellular components
how does biotransformation affect route of exposure?
if a chemical goest to the liver before going to other parts of the body much of it may be biotranformed quickly, GI tract absorption and intraperitoneal injection (blood directly to the liver by the portal system, 'first pass effect' for propranolol is aobut 70%), absorbed through the lung or skin enter blood and go directly to the heart and systemic circulation (not subject to this first pass effect)
half life (t1/2)
the amount of time required for the disappearance of half the compound: first order kinetics (constant fraction is eliminated per unit of time) or zero-order kinetics (constant amount is eliminated per unit of time)
explain all forms of toxicant distribution?
in blood stream: excreted, stored, biotransformed into different chemicals (metabolites may be excreted or stored), chemical or its metabolites may interact or bind with cellular components
toxicokinetics can influence toxicity in biotranformation
biotransformation (a substance that is biotransformed into a more toxic metabolite (bioactivated) is a greater hazard than a substance that is biotransfored into a less toxic metabolite (detoxified), biotransformation reactions are categorized by the normal sequence with which they tend to react with a xenobiotic (phase I reactions add a functional structure: oxidation, reduction, hydrolysis and phase II enzyme conjugates: glucuronide conjugation-most important, sulfate conjugation-important reaction, acetylation, amino acid conjugation, glutathione conjugation, methylation
biotransformation sites
primary sites (liver > kidneys/lungs (10-30% of the liver's capacity) > skin/intestines/testes/placenta), microsomal enzymes (most phase I reactions, glucuronidation enzymes), cytosolic enzymes (most phase II reactions, some oxidation and reduction enzymes)
modifiers of biotransformation
species, age, gender, genetic variability, nutrition, disease, exposure to other chemicals that can inhibit or induce enzymes, and dose levels, fetuses and neonates have limited abilities for xenobiotic biotransformations, phase II acetylation reaction is influenced by genetic differences in humans (slow acetylators)
excretions
polar substanced eliminated more rapidly, main routes of excretion are urine, feces, and exhaled air
urinary excretion
primary route of excretion of toxicant, functional unit of the kidney responsible for excretion is the nephron, processes involved in urinary excretion (filtration, secretion, reabsorption)
hepatobiliary excretion
transport to liver via portal vein, gall bladder to bile duct, biliary excretion
fecal excretion
biliary route (Active secretion > passive diffusion, transport systems: organic bases, organic acids, and neutral substances, some heavy metals are excreted in the bile-arsenic, lead, mercury, substanced excreted via the bile are comparatively large, ionized molecules, such as large molecular weight conjugates > 300 daltons, enterohepatic circulation, some drugs (eg phenobarbital) can produce an increase in bile flow rate)
exhalation
important route of excretion for xenobiotics (and metabolites) that exist in a gaseous phase in the blood, excreted by passive diffusion from the blood into the alveolus, can be a very efficient route of excretion for lipid soluble substances
milk excretion
simple diffusion, basic substances and lipid-soluble compounds can be excreted into milk, milk is more acidic (pH ~6.5) than blood plasma, substances that are chemically similar to calcium can also be excreted into milk along with calcium
What differences should be noted on exposures?
age-related differences in absorption, species differences,
what are age related differences in absorption?
intestinal enzyme activity (neonate<adult), intestinal motility (neonate<adult), gastric acid secretion (neonate<adult), pre-ruminant vs. ruminant (microbes in the rumen metabolize many xenobiotics), infant BBB is much more permeable than in the adult, several metabolic enzymes are very low or virtually absent the first few weeks of life, infant has lower glomerular filtration rate, milk as the major source of nutrition (persistent, fat soluble toxicants), disease of old age are common in dogs, cats, some horses (decreased glomerular filtration rates and reduced metabolic capacity)
what are species differences in absorption?
monogastrics (tend to have low pH in the stomach ie 3-4 in dogs and pigs), posterior fermenters tend to have a higher gastric pH (ie 5.5 for horses), ruminants tend to have a slightly acid ruminal pH (ie 5.5-6.5 but diet dependent increase in grain lowers pH), birds have very high respiratory rates, metabolic rates of birds is very high, birds, at least some straings of domestic fowl, have comparatively low glomerular filtration rates, liver metabolism (fast-slow acetylation has been demonstrated in humans, monkeys, rabbits & dogs are relatively poor at N-acetylation of aromatic amines, swine have low fulfotransferase activity and thus little ability to cnjugate xenobiotics to sulfate, dogs are relatively poor at N-acetylation of aromatic amines, domestic cats are relatively poor at glucuronidation), urine pH influences the rate of elimination of specific xenobiotics via the urine (ruminant urine pH ~8-9, human urine pH ~5-7, dog urine pH ~6-9), dogs have a relatively poor ability to excrete organic acids (their organic anion excretion system is poorly developed), the milk of cows (slightly acidic pH of 6.5-6.9 vs plasma pH of 7.2 to 7.4, contains considerable milkfat, milk tends to concentrate basic, as well as fat soluble drugs and toxicants)