Toxicokinetics & Toxicodynamics PDF

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impa stectivetoxicity exerobiotic Toxicant cases nodeff EEEIE.EE antitypes iIIIiIii c TOXICOKINETICS TOXICODYNAMICS Toxicokinetics I an m sites o I ii  frequency isinsp cuzdetermine if accumulateeleminated Toxicokinetics O e.EE The relationship between dose and ÉIEF concentration at the target site under a different conditions of dose frequency yesss and elimination rate i as are TTi E 8sepiinee novel Chemical B, elimination half-life equal to the dosing frequency, toxic artieofnextdose concentration at target site (=2 units) is not reached until the fourth dose Chemical A, elimination rate much slower than the dosing interval, the toxic concentration is reached with only two doses Chemical C, elimination rate much faster than the dosing interval, the toxic concentration will never be reached regardless of how many doses are administered ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION OF TOXICANTS (ADME) Absorption: the ability of a chemical agent to enter the blood. Similar blood levels are more likely to give similar effects than similar administered doses. Intravenous No limiting factors in absorption (100% bioavailable) tomato Inhalation Must penetrate alveolar sacs of lungs but then into capillary bed Ingestion Requires absorption through GI tract and is subject to 1st pass effect Eiti Intraperitoneal Like ingestion (still 1st pass effect) but does not require absorption through the GI tract Dermal/Topical Requires absorption through the skin Distribution: EE EFaneeoose the process in which a chemical agent translocates throughout the body. The blood carries the agent to and from its site of action, storage depots, organs of biotransformation, and organs of elimination. The rate of distribution – rapid, determined by blood flow and chemical characteristics of the toxicant (its Is IF Enom affinity for the tissue and the partition coefficient). The distribution of a chemical may change over time. Storage: DDT in Fatty tissues iiee.ie my iritis e volume of a biologicalffluid rom non nots Lead and Fluoride in Bone reservesstorerased The volume of distribution, Vd: corresponds to the apparent in which a xenobiotic is diluted, expressed in units of volume (mL or L of blood, plasma, or plasma water) Hydrophilic Xenobiotics exhibit smaller volumes of distribution (often close to 0.6 L/kg). a Lipophilic Xenobiotics exhibit a marked affinity for tissue or fat depots have large Vd, leading to low plasma concentrations. To Substances that are highly bound to plasma proteins have large Vd. attestorians  ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION OF TOXICANTS (ADME) Metabolism: (biotransformation) the process by which administered chemicals (parent compounds) are modified by the Ease organism, usually via enzymes. The primary objective of metabolism is to make chemical agents more Episggywater soluble and easier to excrete by: Decreasing lipid solubility  Decreased amount that reaches target Increasing ionization  Increased rate of excretion  Decrease toxicity In some situations, biotransformation results in the formation of reactive metabolites—Bioactivation. (e.g., acetaminophen  NAPQI) Whether it is the parent compound or the metabolite, it is the active compound that does the damage. Excretion: Toxicants are eliminated from the body by several routes. Urinary excretion: Water soluble products are filtered out of the blood and excreted into the urine. Is nonation a unties Exhalation: Volatile compounds are exhaled through breathing Biliary Excretion via Fecal Excretion: Compounds can be extracted by the liver, biotransformed, and excreted into the bile. The bile drains into the small intestine where the eliminated compound can be excreted into the feces. Fecal excretion also rids the body of non-absorbed compounds which pass through the GI tract. Dose-Response Relationship (Toxicodynamics) a very important concept in toxicology: ⇒ Determining if a drug produces a certain desired or undesired effect (e.g. median effective, toxic, lethal dose) ⇒ Determining potency or dose required to produce effect (ED50, LD50, TD50) ⇒ Comparing one drug with others (efficacy, potency, safety) ⇒ used to set standards for human exposure (NOAEL, ADI, TLV)  Types of Dose-Response RelationshipsTDsoEDs LDso Graded report oses ▪ effect of various doses of a drug on an individual ▪ Continuous response (↑dose →↑effect) ▪ inhibition of an enzyme, reduction of BP, degree of liver damage.. ▪ TD50 Quantal ▪ effect of various doses of a drug on a population ▪ All-or-none response (responders or non-responders) __ ▪ e.g lethality or presence of tumor I ▪ LD50 siamoidalcurve Graded Dose-Response Relationship 0-1= no or low adverse effect level (NOAEL or LOAEL) LOAEL 2-3 = linear portion of the curve NOAEL 4 = maximal response or damage  Threshold dose: the dose below which there is no detectable response o  NOAEL (no observed adverse effect level): is the highest dose of an agent which does not produce an observable adverse effect  LOAEL (low observed adverse effect level): is the lowest dose which produces an it observable adverse effect. a  NOAEL is important for setting exposure limits, e.g. Acceptable Daily Intake (ADI) a e additives/contaminantsmm factor that determine safe intake of food is based on NOAEL a2 t.a.mn (divide NOAEL by a safety factor of 100). Tman  Threshold Limit Value (TLV): used to set occupational exposure limits in industry www.T  Quantal Dose-Response Relationship Using mortality as the response, the dose that is lethal to 50% of the population, o curve. of 0 or the median lethal dose (LD50) can be derived from the LD50 is a quantal measure of acute toxicity. Usually derived from an acute single exposure study. LD50 is not an exact value (unreliable), may not accurately reflect the full spectrum of toxicity (e.g. some chemicals with low acute lethality may have carcinogenic or teratogenic effect at doses that produce no acute lethality) Animal LD50 values can be used to estimate lethal amounts for humans by multiplying the LD50 by human weight. E.g., If the LD50 is 50 mg/kg, then: the lethal amount for a child weighing 10 kg would be 50 mg/kg multiplied by 10 kg, which equals 500 55 mg (about 1/8 tsp.), and the lethal amount for an adult weighing 70 kg would be 50 mg/kg multiplied by 70 kg, which is 3,500 mg (about 3/4 tsp.) Useful for relative safety comparisons the toxic agent with the lowest LD50 is the most potent The toxic agent with the lowest LD50 is the most potent toxic agent o Ferrous sulfate 1,500 kills s 1915 L  Shapes of Dose-Response Curve 1) Traditional monotonic slope - increasing “uphill” (A) 2 - decreasing “downhill” (B) 2) Nonmonotonic  biphasic response: - U-shape (C), inverted U-shape (D), J-shape (E), and upwin ushape erupe variable slope (F). U-shaped Dose-response curve At low dose, adverse effects are observed since inverted downhin vague oncethere is a deficiency of these nutrients to maintain homeostasis (e.g. Vitamins, essential elements). I e As dose increases, homeostasis is achieved, and the bottom of the U-shaped dose-response curve is reached severity As dose increases to exceed the amount required to maintain homeostasis, overdose toxicity can develop. Thus, adverse effects are seen at both low and high dose I High doses of vitamin A can cause liver toxicity e vitamin A deficiency is and birth defects, and lethal. J- Shaped DRC (hormesis concept) a Some non-nutritional toxic substances - An be beneficial effects at low doses, but at higher doses, produce adverse effects. - This concept is called “hormesis”. - For example, Alcohol! there is substantial evidence that low to moderate consumption of alcohol reduces the incidence of coronary heart disease and stroke, although chronic alcohol consumption increases the risk of esophageal cancer, liver cancer and liver cirrhosis at relatively high doses. I.it  The Dose Estimates the Effects TDzo 20 TDg LD50: the dose that produces 50% mortality in a population 18 3 TD50: the dose that produced 50% toxicity in a population ED50: the dose that produces 50% therapeutic effects in a population ED90: the dose that produces 90% therapeutic effects in a population Determining the safety of a drug Therapeutic Index (TI) or – is the ratio of the median toxic dose TD50 (or LD50) and median effective dose (ED50) TI = TD50/ED50 – used as an index of comparative toxicity of two different materials; approximate statement of the relative safety of a drug – compare the therapeutically effective dose to the toxic dose of a pharmaceutical agent. o – The larger the ratio, the greater the relative safety. Margin of safety (MS) o ED99 (the effective dose in 99% of the test animals) MS = TD1/ ED99 o – is the ratio of the TD1 (the dose that causes toxicity in 1% of the test animals) and the apemientiiss – a more accurate estimate as it takes into consideration the slope of the curve. g o – The larger the ratio, the greater the relative safety 3  Determining the safety of a drug: TI o  The larger the TI, the safer the drug  Drugs with narrow TI should be monitored  Drugs with narrow TI given in smaller doses  However, TI does not reflect the influence of slope of the dose- response curve o Tee steeparaterouses so so 1000 1 100 Alsager  - o - ②100 8 Steep slope  sharp increase in response with increasing dose more toxic response. Flat slope  gradual increase in response with increasing dose less toxic effect. - - _ PRACTICE ON DRC QQ.Q.io Understanding LD50 Graphs Lethal dose data is shown below for two toxic chemical compounds: arsenic and sodium cyanide. Graph each and determine their LD50 levels. Sodium Cyanide ( Sample size = 190 ) Dose Number of Death (mg/kg) Deaths Rate (%) 1 8 4% 2 16 8% 3 30 16 % 4 48 25 % 5 68 36 % Eg 6 89 50 % 7 119 63 % Iii 8 140 74 % 9 173 91 % 10 190 100 %  Sodium Cyanide 100 95 90 eat.tt e 85 80 75 Death Rate % 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0 1 2 3 4 5 6 7 8 9 10 LD50= 6 mg/kg Dose (mg/Kg) Arsenic ( Sample size = 210 ) I Dose Number of Death (mg/kg) Deaths Rate (%) 2 2 1% 4 6 3% 6 11 5% E 8 22 11 % 10 41 20 % 12 72 34 % 14 131 62 % 16 198 94 % Iiii 18 210 100 % 1. What is the LD50 of sodium cyanide? 2. What is the LD50 of arsenic?13.2susing 3. Which is more dangerous based on the data, arsenic, or sodium cyanide? Foam 8 51 7su 4. Calculate the human lethal dose for each chemical for a human weighing 70 Kg. 77 5. What is the type of this DR curve? Arsenic 100 95 90 85 80 75 70 Death Rate % 65 60 55 50 45 40 35 30 25 20 15 10 5 0 2 4 6 8 10 12 14 16 18 20 Dose (mg/Kg) LD50= 13 mg/kg References  Casarett and Doull's Toxicology: The Basic Science of Poisons. Chapter 2. Principles of Toxicology.  Harrison's Principles of Internal Medicine. Chapter 50. Poisoning and Drug Overdosage.  Dipiro et al., Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 10. Clinical Toxicology.  Goldfrank's Toxicologic Emergencies, 10e. Chapter10.  Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. Chapter 4. Drug Toxicity and Poisoning.