References Casarett & Doull’s: Essentials of Toxicology, 2nd Ed., 2010 by Curtis Klaassen and John Watkins III Poisoning and Drug Overdose, 6th Ed., 2012 by Kent R. Olson Goldfrank's Toxicologic Emergencies, 10th Ed. 2014 by Lewis R. Goldfrank Emergency Toxicology, 2nd Ed., 1998 by Peter Viccellio
Department of Biopharmaceutics & Clinical Pharmacy Toxicology (1203562) (2 credit hours) Dr. Khawla Abu Hamour Department of Biopharmaceutics & Clinical Pharmacy University of Jordan
TOXICOLOGY IN PERSPECTIVE Introduction: TOXICOLOGY IN PERSPECTIVE
DEFINITIONS & TERMINOLOGY Toxicology: (toxicum) & (logia)….the Study of Poisons (The science of poisons, including their source, chemical composition, action, tests, and antidotes). Poisons: are drugs that have almost exclusively harmful effects However, Paracelsus (1493–1541) famously stated that “THE DOSE MAKES THE POISON” a substance that, on ingestion, inhalation, absorption, application, injection, or development within the body, in relatively small amounts, may cause structural or functional disturbance. Called also toxin biologic origin, ie, synthesized by plants or animals, in contrast to inorganic poisons (lead and iron) Toxicology: is the branch of pharmacology that deals with the undesirable effects of chemicals on living systems Toxin a poison, especially a protein or conjugated protein produced by certain animals, higher plants, and pathogenic bacteria
Disciplines of Toxicology
TOXICOLOGY DISCIPLINES Applied Toxicology. Environmental toxicology: study the effects of chemicals that are contaminants of food, water, soil, or the atmosphere Industrial (occupational) toxicology: Toxic exposure in the work place or during product testing Clinical (medical) toxicology: focus on the diagnosis, management and prevention of poisoning or ADEs due to medications, occupational and environmental toxins, and biological agents Applied Toxicology. This includes the various aspects of toxicology as they apply in the field or the development of new methodology or new selective toxicants for early application in the field setting
TOXICOLOGY DISCIPLINES Veterinary toxicology** Forensic toxicology: is the use of toxicology to aid medical and legal investigation of death Nanotoxicology: is the study of the toxicity of nanoparticles (<100 nm diameter). Because of large surface area to volume ratio, (nanomaterials have unique properties compared with their larger counterparts) **is the diagnosis and treatment of poisoning in animals
What is a Poison?? “What is there that is not poison? All things are poison and nothing without poison. Solely, the dose determines that a thing is nota poison” Paracelsus (1493-1541)
Water Intoxication? Water poisoning….fatal disturbance in brain functions when the normal balance of electrolytes in the body is pushed outside of safe limits (e.g., hyponatremia) by overhydration Water, just like any other substance, can be considered a poison when over-consumed in a specific period of time Intravenous LD50 of distilled water in mouse is 44ml/kg Intravenous LD50 of isotonic saline in mouse is 68ml/kg LD stands for "Lethal Dose". LD50 is the amount of a material, given all at once, which causes the death of 50% (one half) of a group of test animals
What is a Poison?? Poisoning or exposure?? Many people consider that poisoning start the moment exposure occurs In reality, we are exposed to a wide variety of toxic substances each day from food and water that we ingest, and air that we breath We do not display toxic symptoms, we are not actually poisoned
Exposure is defined as: Actual or suspected contact with any substance which has been ingested, inhaled, absorbed, applied to, or injected into the body, regardless of toxicity or clinical manifestation. Poisonings happen when the exposure results in an adverse health reaction; when a substance interferes with normal body functions after it is swallowed, inhaled, injected, or absorbed.
What is Response? Change from normal state – could be molecular, cellular, organ, or organism level……the symptoms The degree and spectra of responses depend upon the dose and the organism Immediate vs. Delayed (carcinogenic) Reversible vs. Irreversible (liver vs. brain, teratogenic effect) Local vs. Systemic Graded vs. Quantal……degrees of the same damage vs. all or none Allergic Reactions & Idiosyncratic Reactions….ADRs Idiosyncratic drug reactions, also known as type B reactions, are drug reactions that occur rarely and unpredictably amongst the population
Dose The amount of chemical entering the body This is usually given as: mg of chemical / kg of body weight = mg/kg The dose is dependent upon: The environmental concentration The exposure pathway The length of exposure The frequency of exposure The properties of the toxicant
i.v > inhalation > i.p > i.m > oral > topical Exposure: Pathways Routes and Sites of Exposure: Ingestion (GIT), (first pass effect) Ex. Lidocaine and Verapamil (antiarrhythmic drugs) Inhalation (Lungs): rapid absorption, because of large alveolar surface area Dermal/Topical (Skin), absorption varies with area of application and drug formulation, but usually absorption is slower than other routes Injection Intravenous, intramuscular, intraperitoneal Typical response of Routes and Sites of Exposure: i.v > inhalation > i.p > i.m > oral > topical Intraperitoneal injection or IP injection is the injection of a substance into the peritoneum (body cavity).
Exposure: Duration Toxicologists usually divide the exposure of experimental animals to chemicals into 4 categories……: Acute < 24hr Usually 1 exposure Sub-acute 1 month Repeated exposure Sub-chronic 1-3 months Chronic > 3 months Lethal injection is the practice of killing a person using a lethal dose of drugs administered intravenously. Two methods of lethal injection exist today, one using a three-drug protocol and another using one large dose of a barbiturate. At the warden's signal, the execution chamber is exposed to witnesses in an adjoining room, and in states that use the three-drug protocol the inmate is injected with sodium thiopental or pentobarbital, anesthetics intended to put the inmate to sleep. Presumably after a member of the intravenous team determines the inmate is sufficiently unconscious, he is then injected with pancuronium bromide, which paralyzes the entire muscle system and stops the inmate's breathing. In most cases, the inmate's consciousness is again checked, and finally potassium chloride stops his heart. In ideal circumstances, death results from anesthetic overdose and respiratory and cardiac arrest while the condemned person is unconscious Over time, the amount of chemical in the body can build up, it can redistribute, or it can overcome repair and removal mechanisms Lethal injection by capital punishment…..
Exposure = Intensity x Frequency x Duration The other time-related factor that is important in the temporal characterization of repeated exposures is the frequency of exposure Exposure = Intensity x Frequency x Duration Exposure = How much x How often x How long
Dose Response Relationship The magnitude of drug effect depends on the drug concentration at the receptor site, which is in turn determined by the dose of drug administered and by factors of the drug pharmacokinetic profile There is a graded dose-response relationship in each individual and a quantal dose-response relationship in a population
Graded-dose response relationship The response to a drug is a graded effect, meaning that the measured effect is continuous over a range of doses Graded dose response curves are constructed by plotting the magnitude of the response against increasing doses of a drug (or log dose)
Dose-Response Relationship As the dose of a toxicant increases, so does the response Steep curve….relative small dose changes cause large response changes
Graded-dose response relationship Two important properties of drugs can be determined by the graded dose response curves: Potency Maximal toxicity
‘U’ Shape of the Dose-Response Curve
Quantal-dose response relationship The quantal (all or none) dose-effect curve often characterizes the distribution of responses to different doses in a population of individual organisms Median toxic dose(TD50): the dose at which 50% of individuals/population exhibit a particular toxic effect If the toxic effect is death of the animal, a median lethal dose (LD50) may be experimentally defined Median effective dose (ED50) is the dose that produces a quantal effect (all or nothing) in 50% of the population that takes it
LD50 The dose of chemical required to produce death in 50% of the organism exposed to it LD50 is not an absolute description of the compound toxicity in all individuals…..Variations it’s possible to take more than the lethal dose and live, and take less of the lethal dose and die. the LDLo (Lethal Dose Low) is the lowest dose known to have resulted in fatality in testing, whilst the LD100 (Lethal Dose 100%) is the dose at which 100% of the test subjects are killed.
Quantal-dose response relationship No. of individuals Resistant Hyper susceptible Majority Sever Response Mild Response Dose or log dose
Toxicity rating chart Rating Oral Lethal Dose Partially non toxic >15 g/kg Slightly toxic 5-15 g/kg Moderately toxic 0.5-5 g/kg Very toxic 50-500 mg/kg Extremely toxic 5-50 mg/kg Super toxic <5 mg/kg
Assumptions in Deriving the Dose-Response Relationship Confirms that a chemical is responsible for a particular effect Establishes the lowest dose for which an effect occurs – threshold effect (µg’s….g’s) Individuals vary in their response to a certain dose of xenobiotic The magnitude of the response is related to the dose………!!!!!
!!!……Molecular Target Concept Agonist Antagonist
Toxicodynamics & Kinetics
Toxicodynamics Toxicodynamics refers to the molecular, biochemical, and physiological effects of toxicants or their metabolites in biological systems These effects are result of the interaction of the biologically effective dose of the ultimate (active) form of the toxicant with a molecular target
Toxicokinetics: Disposition (ADME) Toxicokinetics is the quantitation of the time course of toxicants in the body during the processes of absorption, distribution, biotransformation, and excretion or clearance of toxicants In other words, toxicokinetics is a reflection of how the body handles toxicants as indicated by the plasma concentration of that xenobiotic at various time points The end result of these toxicokinetic processes is a biologically toxic concentration of the toxicant/s Toxicokinetics is the quantitation of the time course of toxicants in the body during the processes of absorption, distribution, biotransformation, and excretion or clearance of toxicants. In other words, toxicokinetics is a reflection of how the body handles toxicants as indicated by the plasma concentration of that xenobiotic at various time points The end result of these toxicokinetic processes is a biologically effective dose of the toxicant