Term
| What is methemoglobinemia? |
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Definition
| the accumulation of methemoglobin in the blood - methemoglobin is formed when Fe2+ (ferrous iron) in the blood oxidizes to Fe3+ (ferric iron), which cannot bind O2 in the blood but binds H2O instead |
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Term
| Signs and symptoms of methemoglobinemia |
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Definition
3-15% MetHb = some discoloration :: 15-20% MetHb = ? healthy adults with normal activity are fine
20-50% MetHb = light headed, confused, chest pain, headache, dyspnea, heart palpitations |
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Term
| normal % MetHb in the blood |
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Definition
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Term
| 2 ways methemoglobin can be formed |
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Definition
| Copper and Nitrates/Nitrites |
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Term
| how are methemoglobin levels in the body normally regulated? |
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Definition
| methemoglobin reductase -- reduces Fe3+ (ferric iron) back to Fe2+ (ferrous iron) |
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Term
| ___ is used as an antidote for methemoglobinemia. how does this work? |
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Definition
| methylene blue - converts MetHb back to Hb by reducing Fe3+ to Fe2+. Methylene blue reductase creates a cycle to quickly reduce all the Fe3+ |
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Term
| What is hereditary methemoglobinemia? |
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Definition
| a deficiency in MetHb reductase that results in the patient having constantly elevated levels of MetHb |
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Term
| Other effects of aniline toxicity (other than MetHb) |
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Definition
| CNS effects - aniline pips = shakes, liver damage, hemolytic anemia |
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Term
| Effects of Nitrobenzene other than MetHb |
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Definition
| CNS depression, immunotoxicity, animal carcinogen |
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Term
| Toxicology of plastics is usually related to what? |
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Definition
| additives - the pure plastic polymers are usually inert |
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Term
| 2 areas of concern with plastic toxicity |
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Definition
| solid state carcinogenesis and implantation of silastic-based medical devices |
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Term
| _____ is plastic toxicity that is not related to additives and results in tumors (fibrosarcomas) on the surface of an implant in rodents |
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Definition
| solid state carcinogenesis |
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Term
| problems with silicone breast implants |
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Definition
| toxicity emerged in women about 10-15 years after they had been implanted -- results in acute and chronic inflammation and fibrosis around the implant, and potential auto-immune condition after silica leaks out of the implant ... has an adjuvent-like action |
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Term
| Toxicity of plastic monomers |
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Definition
| vinyl chloride - angiosarcoma in PVC plant workers, Kupffer cell sarcoma ... and acro-osteolysis in vat cleaners called vat cleaners disease - tips of bones dissolved |
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Term
| mechanism of vinyl chloride genotoxicity |
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Definition
| forms an epoxide via CYP2E1 (a liver cytochrome) and a reactive intermediate that reacts with DNA by forming a DNA adduct and results in cancer |
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Term
| toxicity of flame retardants used in plastics -- TRIS |
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Definition
| Tris-(2,3_dibromopropyl)phosphate flame retardant in kid's pajamas turned out to be mutagenic and carcinogenic and can accumulate in the environment -- make up a high % of plastics by weight |
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Term
| Toxicity of flame retardants in plastics -- Melamine |
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Definition
| used in combination with cyanuric acid -- illegally added to pet and baby food to make it appear to have higher protein content -- results in melamine cyanurate which produces crystalluria in kidney and may lead to kidney failure |
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Term
| What are plasticizers and when are they of most concern? |
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Definition
| largest class of additives to plastics, used to impart flexibility, can migrate out of plastic matrix (especially in heat and over long periods of time) -- biggest concern for dialysis patients because it's used in IV tubing |
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Term
| ____ are the main plasticizers of concern |
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Definition
| phthalate esters, mainly DEHP - di(2-ethylhexyl)phthalate (or bis-) |
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Term
| Implications of DEHP toxicity |
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Definition
| plasticizer - probably not much risk to humans bc it is metabolized quickly but is endocrine disruptor in animals by inhibiting testosterone synthesis and causing small testes |
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Term
| ___ is a plasticizer used in food grade PVC products like cling wrap and seems to produce some developmental toxicity in rats (but probably not humans) |
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Definition
| DEHA - di-(2-ethylhexyl)adipate |
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Term
| ___ is used to make nalgene bottles, baby bottles, and dental fillings. What are the effects of it? |
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Definition
| endocrine disruptor in rodents that produces developmental and reproductive toxicity -- no consistent findings of effects in humans. |
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Term
| ___ is the component of methanol metabolism that actually causes the blindness |
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Definition
| formate - builds up because we are formate dehydrogenase and tetrahydrofolate deficient as a species, and foods are often supplemented with folate to offset our natural folic acid deficiency (??) |
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Term
| primary concerns with methanol exposure |
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Definition
| acute toxicity - BLINDNESS also: CNS effects (dizziness, headache) and acidosis (increases in formate and lactate increase the pH of the blood) |
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Term
| treatment for methanol poisoning |
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Definition
| give bicarbonate to offset the acidosis and give fomepizole and ehtanol (beer) for several days to competitively inhibit the enzymes that bind methanol |
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Term
| long term effects of methanol poisoning |
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Definition
| possible reproductive tox, but probably not |
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Term
| ___ is a heat transfer agent (antifreeze) that causes CNS effects and inebriation. as well as kidney damage |
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Definition
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Term
| all alcohol compounds produce what toxicity? |
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Definition
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Term
| treatment for ethylene glycol toxicity |
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Definition
| ethanol, fomepizole, and hemodialysis for acidosis |
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Term
| How are glycol ethers reproductive toxins |
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Definition
| especially methyl and ethyl (cellosolves) - in rats and rabbits: testicular atrophy, degeneration of seminiferous tubules, decrease sperm count |
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Term
| butyl glycol ethers do not cause reproductive effects, but do cause ____. |
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Definition
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Term
| primary target tissues of halogenated solvents |
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Definition
| CNS (brain), liver, kidney, and heart |
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Term
| target tissues of carbon tetrachloride |
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Definition
| acute: CNS (necrosis, headache, dizziness, stupor), liver (enlarges, jaundice, centrolobular necrosis), kidney (anuria) .. chronic: liver (fibrosis and cirrhosis), kidney (cell death and loss of function) |
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Term
| ___ is the most toxic halogenated solvent |
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Definition
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Term
| ____ are metabolized by an oxidative breakdown |
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Definition
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Term
| ___ can sensitize the myocardium to epinephrine and induce arrhythmias at high doses, diagnosed by an abnormal PQRST complex |
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Definition
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Term
| ___ is used as a substitute for carbon tetrachloride because it is not as toxic to the liver |
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Definition
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Term
| Chronic risks associated with trichloroethylene |
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Definition
| liver tumors in mice, kidney tumors in rats via glutathione conjugation of mercapturic acids resulting in cysteine adducts |
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Term
| key words for trichloroethylene toxicity |
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Definition
| Kidney cancer --> mercapturic acids --> glutathione conjugation --> GSH-transferase --> cysteine adduct activation --> B-lyase |
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Term
| biggest concern with the use of tetrachloroethylene (PERC)? |
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Definition
| kidney tumors in rats - very similar to trichloroethylene |
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Term
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Definition
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Term
| what does the metabolism of dichloromethane need? |
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Definition
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Term
| What are the carcinogenic effects of dichloromethane in mice as compared to humans? |
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Definition
| mice: liver and lung ... humans: possibly biliary tract and glial cells |
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Term
| IRIS says dichloromethane is what kind of carcinogen? |
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Definition
| probable human carcinogen |
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Term
| subchronic effects of n-hexane (straight chain hexanes) exposure |
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Definition
| peripheral neuropathy, axonapathy (swollen axons decrease transport), begins as numbness, loss of reflexes, weakness of limbs |
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Term
| How does unleaded gas cause kidney tumors in male rats? |
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Definition
| chemical binds to a2u-globulin, which changes the structure of the protein and decreases its lysosomal catabolism by increasing the size of it's lysosomes.this results in accumulation of a2u, lysosomal overload, and cytotoxicity (DNA damage). If exposure is chronic, the DNA is damaged enough to cause kidney tumors. |
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Term
| acute effects of benzene exposure |
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Definition
| CNS depression, liver and kidney effects (?) |
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Term
| Absorption and excretion of benzene |
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Definition
| absorption: orally, skin (local effect), inhalation (rapid equilibrium) :: Excretion: some exhaled, most metabolized and excreted in urine |
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Term
| chronic effects of benzene |
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Definition
| aplastic anemia (decreased WBC, RBC, and thrombocytes) and leukemia (acute myeologenous leukemia) |
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Term
| key words in the metabolism of benzene |
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Definition
| sulfate and glucaronide conjugation, GSH, p450-dependent |
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Term
| ___ is a common substitute for benzene, but may have it's own health effects such as ? |
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Definition
| toluene - CNS, hearing loss and vestibular disturbance (ototoxicity) |
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Term
| synergistic effect of toluene |
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Definition
| in conjunction with noise -- effects are worse than either individually |
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Term
| 4 areas of carbon disulfide toxicity -- not on study sheet |
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Definition
| CNS, polyneuritis (nerve damage), hormonal damage, atherosclerosis |
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Term
| why is acute toxicity testing done? |
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Definition
| emphasis on acute effects and clinical signs other than on death (as with an LD50 study) -- mimic human exposure in animal model and study accidental human exposures -- 4 general reasons: biological, safety, governmental regulations, other |
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Term
| the primary species studied in acute toxicity testing is the ____. what is determined from this? |
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Definition
| rat (both sexes because males and females metabolize things differently) -- determinations are made as to damage to each organ system |
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Term
| other species used for acute toxicity testing (other than rat) |
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Definition
| dogs and rabbits - rabbits are a good indicator because their skin absorbs more than humans |
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Term
| in acute toxicity testing, ___ are generally used for an oral dose and __ are used for a dermal dose |
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Definition
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Term
| a subchronic study is ___ days |
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Definition
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Term
| reasons for doing subchronic studies in animals |
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Definition
| identify adverse effects not detected in acute studies and provide additional info on those that were detected... find NOAEL... provide info on dose selection for chronic studies... confirm/identify target organs .... provide basis for species selection for chronic studies... provide info for regulatory agencies... provide risk assessment data |
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Term
| Species selection for studies should be based on what 2 things? |
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Definition
| pharmacodynamics (how the animal responds compared to humans) and pharmacokinetics (how the animal metabolizes certain things) |
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Term
| prerequisites for chemicals for toxicity testing |
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Definition
| must be as pure as possible, have pilot data on the chemical to find doses other than the LD50 that are useful |
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Term
| 7 types of measurements taken during a subchronic study |
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Definition
| survival, growth rate, food consumption/absorption, daily observations of behavior and personal care, hematology (Hb, Hemoatocrite, etc), clinical chemistry (electrolytes, albumin, glucose, etc), urine analysis (volume, pH, etc) |
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Term
| subchronic study data to be obtained after an animal has died |
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Definition
| complete pathology including weights of many tissues (enlarged organs = toxicity) |
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Term
| species used in subchronic testing |
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Definition
| rats and dogs (both sexes of each) |
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Term
| for the national toxicology program carcinogenicity studies, what species are used and how long do the studies run? |
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Definition
| Fischer 344 rats and B6C3F7 mice (50-80 of each sex and species) -- 2 year studies + 3 years to analyze data |
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Term
| for the National Toxicology Program carcinogenicity studies, what doses are used? |
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Definition
| 2-3 doses and a control... the top dose is called the maximum tolerated dose (MTD) and must be very sensitive and precise to ensure that it doesn't kill the rats but is still toxic enough to cause cancer |
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Term
| 5 categories of evidence in NTP carcinogenicity studies |
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Definition
| clear evidence, some evidence, equivocal evidence (maybe, maybe not), no evidence, and inadequate study |
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Term
| the process of evaluating alternative regulatory option and selecting among them. answers the question, "what do we do about a risk?" |
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Definition
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Term
| the qualitative or quantitative characterization of the potential health effects of particular substances on individuals or populations.... answers the question, "what is the risk?" |
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Definition
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Term
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Definition
| hazard identification (does the agent cause the adverse effect? or is there an impurity causing it?) ... dose-response assessment (what is the relationship between dose and incidence in humans?) ... exposure assessment (what exposures are currently experienced or anticipated under different conditions?) ... these all lead to: Risk Characterization (what is the estimated incidence of the adverse effect in a given population?) |
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Term
| The 'bottom line' to risk assessment is? |
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Definition
| risk characterization (what is the estimated incidence of the adverse effect in a given population?) |
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Term
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Definition
| development of regulations, evaluation of public health, economic, social, and political consequences of the regulations |
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Term
| threshold for carcinogens |
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Definition
| none - no allowable risk for people to get cancer |
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Term
| an estimate of a daily exposure to the human population (including sensitive subgroups) that is likely to be wtihout appreciable risk of deleterious effects during a lifetime |
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Definition
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Term
| RfD must consider de minimus ... |
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Definition
| that a substance has a very low risk but it still must be considered |
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Term
| Modifying factors in RfD's |
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Definition
| "fudge factor" - determined based on how good the study is. Default is 1, for a good study |
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Term
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Definition
| drinking water exposure level - MCL for substances in water - accounts for the fact that you might be exposed to something other than thru water |
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Term
| the ____ approach is a better way of analyzing dose-response data to come up with an effective dose. These doses are based on a point of departure and are represented by a percentage. |
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Definition
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Term
| carcinogenicity potency factor (q1) ... why? when? how? |
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Definition
| because carcinogens have no threshold.. used with known and probable carcinogens... calculated as # cancers/given dose (1/100 = 1 cancer case/100 people) |
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Term
| Most compounds use the EPA classification system, that covers what 5 groups? |
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Definition
| Group A-E :: known human carcinogen, probable, possible, not classified, and evidence of non-carcinogenicity |
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Term
| 2 types of flame retardants discussed |
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Definition
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Term
| 3 types of plasticizers discussed |
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Definition
|
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Term
| exision repair of DNA damage |
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Definition
| cut out 14-30 nucleotides from DNA adduct, use corresponding strand to repair damaged strand |
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Term
| What is Unscheduled DNA synthesis (UDS) and how is it measured? |
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Definition
| when a piece of DNA is repaired by exision repair, the repaired piece is labeled with tritiated thymine. We then measure the incorpartion of these in the DNA and use them to look for repaired cells. see notecard |
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Term
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Definition
| when DNA is damaged, it breaks into pieces. isolate the DNA on a slide and then attach it to an anode. The DNA will migrate toward the anode and the broken pieces will trail behind -- looks like a comet |
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Term
| the comet assay is what kind of assay |
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Definition
| single cell gel electrophoresis |
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Term
| purpose of the Ames (salmonella) test |
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Definition
| to detect mutagenic activity using chemicals that require metabolic activation |
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Term
| 2 Salmonella strains used in the Ames assay |
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Definition
| TA-98 (frameshift) and TA-100 (base pair substitution) |
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Term
| if a salmonella species is Ames-positive, what does that mean? |
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Definition
| it is a mutagen, and you don't want to use it in other tests |
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Term
| one drawback to the Ames assay |
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Definition
| may overestimate carcinogenicity |
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Term
| the mouse lymphoma assay detects ___ mutations by using ___ activity |
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Definition
| forward mutations by using thymidine kinase activity |
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Term
| basis of mouse lymphoma thymidine kinase assay |
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Definition
| use TK+/- cells (with active thymidine kinase) and mutate them to TK -/- cells (with no TK activity). The TK -/- cells are preferred because they don't produce toxic metabolites and allow the cells to live |
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Term
| the sister chromatid exchange assay is used to detect agents that are ____. |
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Definition
| clastogenic (break chromosomes) |
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Term
| in an SCE test, what is meant by a "harlaquin" chromosome? |
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Definition
| a chromosome that has switched material |
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Term
| basis of the micronucleus test |
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Definition
| a chemical is added to a cell and is allowed to incubate for 24 hrs, the bone marrow is analyzed for fragments of immature RBCs and you will see chromosomal fragments during anaphase and telophase, indicating damage |
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Term
| what is the purpose of genotoxicity/mutation assays? |
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Definition
| to find out if a chemical is genotoxic or causes mutations |
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Term
| what species is used for the Draize skin irritation assay? |
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Definition
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Term
| what species is used for the Draize test for hypersensitivity potential/allergenicity of a chemical? |
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Definition
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Term
| what 2 things are measured in the dermal irritation assay using the Draize test? |
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Definition
| erythema and edema -- both on a scale of 0-4 -- 0 being none, 4 being beet redness (for erythema) and more than 1mm raising (for edema) |
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Term
| what animal is used for the local lymph node assay (LLNA) |
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Definition
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Term
| for the LLNA (Local Lymph node assay), when is a chemical considered a skin sensitizer? |
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Definition
| when it has an SI of 3 or more at at least one concentration put on the mouse's ear |
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Term
| what species is used in the eye irritation studies? |
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Definition
|
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Term
| what measurements are taken in the eye irritation study? |
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Definition
| corneal opacity, iris, and redness/swelling of the conjunctiva |
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Term
| end products of methanol metabolism |
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Definition
| CO2, and tetrahydrofolate (cycle begins again) |
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Term
| End products of ethylene glycol metabolism |
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Definition
|
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Term
| End products of dichloromethane metabolism |
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Definition
|
|
Term
| what solvent? treated wtih bicarbonate, ethanol, and fomepizole |
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Definition
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Term
| what solvent? causes kidney damage, CNS effects, acidosis, and eventual death from respiratory failure. treated with ethanol, fomepizole, and hemodialysis |
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Definition
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Term
| what solvent? causes CNS effects. methyl and ethyl forms cause reproductive tox, butyl form causes hemolytic anemia |
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Definition
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Term
| what solvent? causes CNS necrosis, centrolobular necrosis, jaundice, increase in serum enzymes, proximal tubule damage, anuria, lipid peroxidation, cirrhosis and fibrosis of liver, and kidney cell death? |
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Definition
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Term
| what solvent? causes kidney tumors via glutathione conjugation of mercapturic acids |
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Definition
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Term
| only solvent discussed that does not cause CNS effects? |
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Definition
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