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Biomedical Toxicology

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University of Guelph
TOX 2000
Aaron Witham

Principles of Toxicology Biomedical Toxicology Lecture 1 October 31, 2012 - toxicant: any substance that causes an adverse biological effect (toxic response) - toxicosis: chemically caused disease; toxic response; poisoning - drug: substance that can have pharmalogical effects or toxic effects - endogenous substances: normal components in the body - xenobiotics: chemicals not normally present in the body (exogenous substances) - common myth is that man-made substances are more dangerous than natural ones o untrue many tests, lots of regulation on man-made not on natural Toxicology Principle 1 # All substances, natural or man-made, are poisons (toxicants) if the right dose is given. # Toxicology Priciple 2 Every toxicant has a threshold dose. - threshold dose: dose below which no adverse effect occurs o factors: response being measured (acute vs. chronic) sensitivity of measurement number of individuals studied Toxicology Principle 3 # Due to genetic variability, not every indivudal is affected the same way by a given dose of a given substance. Note: Toxicology Principle 4 # Dose vs. Dosage: Toxic response increases with increased dose (graded response). Dose refers only to a - individuals: dose = effect, symptom severity, death weight of substance that - populations: number affected individuals should be taken. Dosage - exceptions: immunological reactions refers to the dose per body weight. Hormesis - stimulation of biological systes at low doses, inhibition at high doses - non-nutritional substances may have beenfical effects at low doses o example: vitamins, radiation, alcohol, flurorine - implications of low dose extrapolation o not always accurate Measures of Toxicity - toxicity: amount of chemical required to cause adverse effect under specific conditions o expressed as dosage: mg toxicant per kg of body weitht equalizes size variability - toxic endpoints: effects used as predictors o death LD 50 o adverse biological effect Toxic Dose (TD) of a given effect example: TD he50toxicity or TD neur1toxicity most sensitive effect should be used Determining Safety - non-toxic endpoints: used to determine safe levels o NOAEL o LOAEL - safety margin: magnitude of difference between the dose required to produce a maximum therapeutic effect and that which produces a toxic effect o bigger is better (safer) - safety margins are used instead of non-toxic endpoints because of statistical uncertainty o 90% are in the middle small dose range requires extrapolation - chemical use decision must way risks and benefits o benefit determination: subjective assessment changes between people and societies o risk: probability of toxicosis following exposure to a hazardous substance potential of exposure inherent toxicity experimentally determined - biomedical toxicology: portion of toxicology that studies the inherent toxicity/hazard of toxicants Exposure and Toxicosis - toxicokinetic parameters and concentration of chemical at site of action determine toxicosis - lead exposure o lead causes cognitive defects, low RBC count, anaemia, visual toxicity, and cancer o children more at risk absorb more lead than adults central nervous system (CNS) still developing blood brain barrier (BBB) not fully developed damage dirty hands dermal exposure o inner city children poor nutrition (Ca and Fe ) 2+ live near major roadways lead pipes Case Study 1: Lupinosis - toxicokinetics at play - lupine contains anagyrine o lipophilic, stable, natural teratogen o quinolizidine alkaloid group o affinity for nictotine receptors (parasympathetic nervous system) - acute symptoms: o lethargy o frequent urination o breathing rate; can lead to respiratory paralysis o blood flow to GI tract - chronic symptoms: o deformations due to poor tendon/muscle development caused by movement of fetus in womb - exposure occurred form goats milk and cheese o goats ate lupines absorption of angyrine in the milk # Lecture 2 November 2, 2012 Review Questions - woman died of hypernatremia induced heart block (C) - compund B is less toxic to the heart than compound A (E) Chemical and Body Membranes Characteristics - chemical movement in the body is determined by: o biological membranes: barriers to movement, compartmentalization o principles of lipid/water solubility of chemicals in body fluid and tissues pH varies by compartment many toxicants are weak acids/bases, so movement can be related to ionization state - biological membranes: bimolecular layer of phospholipids o components: phosphatidycholine and phosphatidylethanolamine structural and functional proteins signaling and cell adhesion molecules - membrane barriers: o organs (ex: skin) o tissue (ex: epithelium) o cells (ex: cell membrane) o cell organelles (ex: nucleus) - extracellular barriers o intercellular junctions o tight junctions o basement membrane (anchors the epithelium)
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