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### 83 Cards in this Set

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 Define Dose. the amount of a substance administered at one time What parameters are needed to characterize the exposure to xenobiotics The most important are the number of doses, frequency, and total time period of the treatment. Give 3 examples of parameters needed to characterize an exposure to xenobiotics. 1. 650 mg Tylenol as a single dose 2. 500 mg Penicillin every 8 hours for 10 days 3. 10 mg DDT per day for 90 days Define 'exposure dose'. The amount of a xenobiotic encountered in the environment. Define 'absorbed dose'. The actual amount of the exposed dose that enters the body. Define 'administered dose'. The quantity administered usually orally or by injection. Define 'total dose'. The sum of all individual doses. Explain Fractionating. Fractionating a total dose usually decreases the probability that the total dose will cause toxicity. The reason for this is that the body often can repair the effect of each subtoxic dose if sufficient time passes before receiving the next dose. In such a case, the total dose, harmful if received all at once, is non-toxic when administered over a period of time. Give an example of Fractionating. For example, 30 mg of strychnine swallowed at one time could be fatal to an adult whereas 3 mg of strychnine swallowed each day for ten days would not be fatal. The units used in toxicology are basically the same as what? The units used in toxicology are basically the same as those used in medicine. What is the standard unit in toxicology. The gram is the standard unit. However, most exposures will be smaller quantities and thus the milligram (mg) is commonly used. For example, the common adult dose of Tylenol is 650 milligrams. The clinical and toxic effects of a dose must be related to what? The clinical and toxic effects of a dose must be related to age and body size. For example, 650 mg is the adult dose of Tylenol. That would be quite toxic to young children, and thus Children's Tylenol tablets contain only 80 mg. A better means to allow for comparison of effectiveness and toxicity is the amount of a substance administered on a body weight basis. What is a common dose measurement for this. A common dose measurement is mg/kg which stands for mg of substance per kg of body weight. Another important aspect is the time over which the dose is administered. This is especially important for what? Give an example. This is especially important for exposures of several days or for chronic exposures. The commonly used time unit is one day and thus, the usual dosage unit is mg/kg/day. What is the consequence since some xenobiotics are toxic in much smaller quantities than the milligram? Smaller fractions of the gram are used, such as microgram (µg). 1 kg equals how many grams? 1000g = 10^3g 1 mg equals how many g? 0.001g = 10^-3g 1mcg equals how many g? 0.000,001g = 10^-6g 1ng equals how many g? 0.000,000,001g = 10^-9g 1pg (picogram) equals how many g? 0.000,000,000,001g = 10^-12g 1fg (femtograms) equals how many grams? 0.000,000,000,000,001g = 10^-15g. Environmental exposure units are expressed as what? Environmental exposure units are expressed as the amount of a xenobiotic in a unit of the media. mg/liter (mg/l) for liquids mg/gram (mg/g) for solids mg/cubic meter (mg/m3) for air Environmental exposure units are expressed as the amount of a xenobiotic in a unit of the media. mg/liter (mg/l) for liquids mg/gram (mg/g) for solids mg/cubic meter (mg/m3) for air Smaller units are used as needed, e.g., µg/ml. What are some other commonly used dose units for substances in media? parts per million (ppm), parts per billion (ppb) and parts per trillion (ppt). The dose-response relationship is a ? and ? concept in toxicology The dose-response relationship is a fundamental and essential concept in toxicology What does the dose-response relationship correlate? It correlates exposures and the spectrum of induced effects. Generally, the higher the dose, the more severe the response. What is the dose-response relationship based on? The dose-response relationship is based on observed data from experimental animal, human clinical, or cell studies. Knowledge of the dose-response relationship establishes what three things? Knowledge of the dose-response relationship: 1. establishes causality that the chemical has in fact induced the observed effects 2. establishes the lowest dose where an induced effect occurs - the threshold effect 3. determines the rate at which injury builds up - the slope for the dose response. Within a population, the majority of responses to a toxicant are similar; however, a wide variance of responses may be encountered, some individuals are susceptible and others resistant. As demonstrated above, a graph of the individual responses can be depicted how? Within a population, the majority of responses to a toxicant are similar; however, a wide variance of responses may be encountered, some individuals are susceptible and others resistant. As demonstrated above, a graph of the individual responses can be depicted as a bell-shaped standard distribution curve. Dose responses are commonly presented as what? Dose responses are commonly presented as mean + 1 S.D. (standard deviation), which incorporates 68% of the individuals. Two standard deviations, incorporates what % of the responses? Two standard deviations, incorporates 95% of the responses. What does a large standard deviation indicate? A large standard deviation indicates great variability of response. Which of these responses indicate more variability: 15+8 mg or 15+2 mg. A response of 15+8 mg indicates considerably more variability than 15+2 mg. The dose-response curve normally takes the form of a what? The dose-response curve normally takes the form of a sigmoid curve. It conforms to a smooth curve as close as possible to the individual data points. For most effects, small doses are what? For most effects, small doses are not toxic. What is the threshold dose level. The point at which toxicity first appears is known as the threshold dose level. At the point of the threshold dose level on a curve what happens? At the threshold dose level the curve increases with higher dose levels. A threshold for toxic effects occurs at what point? What does it mean that for most organs there is a reserve capacity? Give an example. A threshold for toxic effects occurs at the point where the body's ability to detoxify a xenobiotic or repair toxic injury has been exceeded. For most organs there is a reserve capacity so that loss of some organ function does not cause decreased performance. For example, the development of cirrhosis in the liver may not result in a clinical effect until over 50% of the liver has been replaced by fibrous tissue Knowledge of the ? and ? of the dose-response curve is extremely important in predicting the toxicity of a substance at specific dose levels. Knowledge of the shape and slope of the dose-response curve is extremely important in predicting the toxicity of a substance at specific dose levels. Major differences among toxicants may exist not only in the point at which the threshold is reached but also where? Major differences among toxicants may exist not only in the point at which the threshold is reached but also in the percent of population responding per unit change in dose (i.e., the slope). The quantity of a substance administered to an individual over a period of time or in several individual doses is known as the: Exposure Dose Absorbed Dose Total Dose The total dose is the quantity of a substance administered to an individual over a period of time or in several individual doses. It becomes particularly important when evaluating cumulative poisons. Fractionation of a total dose so that the total amount administered is given over a period of time usually results in: Decreased Toxicity Increased Toxicity Fractionation of a total dose so that the total amount administered is given over a period of time usually results in decreased toxicity. This applies to most forms of toxicity. It may not necessarily apply to carcinogenicity and mutagenicity. The usual dosage unit that incorporates the amount of material administered or absorbed in accordance with the size of the individual over a period of time is: PPM/hour mg/kg/day kg/100 lb/week The usual dosage unit that incorporates the amount of material administered or absorbed in accordance with the size of the individual over a period of time is mg/kg/day. In some cases, much smaller dosage units are used, e.g., µg/kg/day. A milligram represents: 1/100th of a gram 1/1000th of a gram 1000 grams A milligram represents 1/1000th of a gram. This is the most common unit employed in pharmaceuticals Knowledge of the dose-response relationship permits one to determine: Whether exposure has caused an effect, threshold for the effect, and the rate of buildup of the effect with increasing dose levels. The degree of metabolism of a xenobiotic. The relationship of exposure dose to absorbed dose Knowledge of the dose-response relationship permits one to determine whether exposure has caused an effect, threshold for the effect, and the rate of buildup of the effect with increasing dose levels. Rate of buildup of toxic effects is known as the "slope" of the dose-response curve The usual measure for variability of a toxic response is the standard deviation. One standard deviation represents: 95% of the responses. 35% of the responses. 68% of the responses One standard deviation represents 68% of the responses. One standard deviation is usually employed to indicate variability of response The dose level at which a toxic effect is first encountered is known as the: Threshold Dose First Dose Median Toxic Dose The dose level at which a toxic effect is first encountered is known as the threshold dose. Doses below the threshold dose are often referred to as "subthreshold doses." Dose-response curves are used to derive what? Dose-response curves are used to derive dose estimates of chemical substances. A common dose estimate for acute toxicity is what? A common dose estimate for acute toxicity is the LD50 (Lethal Dose 50%). What is LD50? This is a statistically derived dose at which 50% of the individuals will be expected to die LD0 represents what? LD0 represents the dose at which no individuals are expected to die. This is just below the threshold for lethality. LD10 refers to what? LD10 refers to the dose at which 10% of the individuals will die. For inhalation toxicity, what are used for exposure values. Explain? For inhalation toxicity, air concentrations are used for exposure values. Thus, the LC50 is utilized which stands for Lethal Concentration 50%, the calculated concentration of a gas lethal to 50% of a group. Occasionally LC0 and LC10 are also used. What are EDs? Effective Doses (EDs) are used to indicate the effectiveness of a substance Normally, effective dose refers to a ? effect. It might also stand for a ? effec. Normally, effective dose refers to a beneficial effect (relief of pain). It might also stand for a harmful effect (paralysis). Thus the specific endpoint must be indicated. ED0 means what? Effective for 0% of the population. ED10 means what? Effective for 10% of the population. ED50 means what? Effective for 50% of the population. ED90 means what? Effective for 90% of the population. What is a TD? Toxic Doses (TDs) are utilized to indicate doses that cause adverse toxic effects. TD0 means what? Toxic to 0% of the population. TD10 means what? Toxic to 10% of the population. TD50 means what? Toxic to 50% of the population. TD90 means what? Toxic to 90% of the population. The knowledge of the ? and ? dose levels aides the toxicologist and clinician in determining the relative safety of pharmaceuticals. The knowledge of the effective and toxic dose levels aides the toxicologist and clinician in determining the relative safety of pharmaceuticals. Two dose-response curves are presented for the same drug, one for effectiveness and the other for toxicity. What is TI? The Therapeutic Index (TI) is used to compare the therapeutically effective dose to the toxic dose. The TI is a statement of relative safety of a drug. It is the ratio of the dose producing toxicity to the dose needed to produce the desired therapeutic response. TI is the ratio of the ?to the ?. It is the ratio of the dose producing toxicity to the dose needed to produce the desired therapeutic response. What is the common method used to derive the TI? Give an example. The common method used to derive the TI is to use the 50% dose-response points. For example, if the LD50 is 200 and the ED50 is 20 mg, the TI would be 10 (200/20). A clinician would consider a drug safer if it had a TI of 10 than if it had a TI of 3. The use of the ED50 and LD50 doses to derive the TI may be what? The use of the ED50 and LD50 doses to derive the TI may be misleading as to safety, depending on the slope of the dose-response curves for therapeutic and lethal effects The use of the ED50 and LD50 doses to derive the TI may be misleading as to safety, depending on the slope of the dose-response curves for therapeutic and lethal effects. How might this deficiency be overcome? To overcome this deficiency, toxicologists often use another term to denote the safety of a drug - the Margin of Safety (MOS). How is Margin of Safety (MOS) calculated? The MOS is usually calculated as the ratio of the dose that is just within the lethal range (LD01) to the dose that is 99% effective (ED99). The MOS = LD01/ED99. A physician must use caution in prescribing a drug in which the MOS is of what value? A physician must use caution in prescribing a drug in which the MOS is less than 1. Due to differences in slopes and threshold doses, low doses may be what? Due to differences in slopes and threshold doses, low doses may be effective without producing toxicity. Although more patients may benefit from higher doses, this is may be offset by what? Although more patients may benefit from higher doses, this is offset by the probability that toxicity or death will occur. Knowledge of the slope is important in comparing what? Knowledge of the slope is important in comparing the toxicity of various substances. For some toxicants a small increase in dose causes a large increase in response (toxicant A, steep slope). For other toxicants a much larger increase in dose is required to cause the same increase in response (toxicant B, shallow slope). In general terms, what are NOAEL and LOAEL? Two terms often encountered are No Observed Adverse Effect Level (NOAEL) and Low Observed Adverse Effect Level (LOAEL). They are the actual data points from human clinical or experimental animal studies. Define NOAEL? The highest data point at which there WAS NOT an observed toxic or adverse effect. Define LOAEL? Lowest data point at which there WAS an observed toxic or adverse effect. Sometimes what terms may be found in the literature that do not necessarily imply toxic or harmful effects and may be used to describe beneficial effects of chemicals as well. Sometimes the terms No Observed Effect Level (NOEL) and Lowest Observed Effect Level (LOEL) may also be found in the literature. NOELs and LOELs do not necessarily imply toxic or harmful effects and may be used to describe beneficial effects of chemicals as well. The NOAEL, LOAEL, NOEL, and LOEL have great importance in the conduct of what? The NOAEL, LOAEL, NOEL, and LOEL have great importance in the conduct of risk assessments. The LD50 represents The effect level resulting from a threshold dose of 50 mg. The point at which the liver is 50% destroyed. The estimated dose level that will produce 50% deaths in groups of animals administered a specific dose. The LD50 represents the estimated dose level that will produce 50% deaths in groups of animals administered a specific dose. It has been used to compare the acute toxicity of various chemicals for many years. Other measures of acute toxicity are now being employed as well. The Therapeutic Index is used to: Compare the lethal dose to the minimally toxic dose. Compare the 50% response to a pharmaceutical in terms of therapeutically effectiveness (ED50) and toxicity (LD50). Compare the lethal dose levels for different pharmaceuticals. The Therapeutic Index is used to compare the 50% response to a pharmaceutical in terms of therapeutically effectiveness (ED50) and toxicity (LD50). Since the slopes for effectiveness and toxicity may be quite different, a low Therapeutic Index should alert the clinician to use caution when prescribing the drug. The Margin of Safety is: A comparison of the minimally lethal dose (LD01) to the maximally effective dose (ED99). The amount of a pharmaceutical that can be given before toxicity first appears. The difference between the ED50 and LD50. The Margin of Safety is a comparison of the minimally lethal dose (LD01) to the maximally effective dose (ED99). This indicates a higher level of safety to the clinician or risk assessor than that provided by the Therapeutic Index. A drug that has a 99% effective dose of 20 mg/kg and a 1% lethal dose of 100 mg/kg has a margin of safety (MOS) of: 0.2 5000 20 5 A drug that has a 99% effective dose of 20 mg/kg and a 1% lethal dose of 100 mg/kg has a margin of safety (MOS) of 5. The MOS is derived by dividing the LD01 by the ED99 which in this case is 100 mg / 20 mg = 5.