Biomedical Toxicology Notes Lecture 1 Toxicology and Dose - Dose = poison - Amount: magnitude of the dose - Frequency: how often exposure occurs - Duration: how long was the total exposure - Subject variability: sex, age, weight, genetic characteristics - Route of exposure: how was the individual exposed o Inhaled o Ingested o Injected o Transdermal - Target within organism – organ tissue cell type protein/nucleic acid/lipid - Bioavailability/bioaccumulation o Often gained from a look at metabolism and physical properties (pka) Distribution and Bioavailability - The proportion of a substance that enters the general circulation when introduced into the body and is able to have an active effect - Exposure - Solubility o Water soluble – stays in circulation o Lipid soluble – crosses cell membrane - Physical state o Liquids – solids – vapour o Mercury vapour is readily absorbed into circulatory system - Chemical state o Methyl mercury is more toxic than metallic mercury o Ethyl mercury is less toxic than methyl mercury o Lowest to highest: ethyl mercury, metallic mercury, methyl mercury Methyl Mercury of Ethyl Mercury - MeHg-L cysteine conjugate is actively transported across blood brain barrier - Mercury is in an electrophilic setting, will bind nucleophilic substances - MeHg stimulates extracellular glutamate levels and over activation of glutamate receptors o Increases Ca influx into neurons, activations important apoptotic pathways - In vivo, a distinct toxicokinetic profile exists between MeHg and EtHg o EtHg = shorter blood half life o Less compartment distribution
o Greater elimination of EtHg compared to MeHg Systematic Overview - Organism is exposed to toxicant - Toxicant is absorbed by oral, pulmonary, IV or dermal routes - Toxican is delivered to critical target tissue by way of blood stream and interacts with target molecule o Distribution of normal homeostasis - Sometimes, original form of toxicant is bioactivated to toxicologically active form - Countering possible toxicity, the toxicant is detoxified metabolically or excreted in feces, urine, or by exhalation What determines if toxicosis occurs? CONCENTRATION OF CHEMICAL AT BODY TARGET (SITE OF ACTION) Case Study 1: Lead Exposure - Very toxic - Oxidative stress - Disrupts calcium channels (nervous system toxicity) - Bind to cellular proteins and inhibits protein synthesis - Affects heme (anemia, low RBC) - Neurological toxicity from ROS and Ca mimicry - Cognitive defects in children - Anticipated human carcinogen - Children are much more at risk than adults – why? o Absorb more lead than adults (15% vs 42%) o CNS is still developing o More cognitive development still going on – lead also looks like calcium to the body o Developing children don’t have fully developed blood brain barrier, don’t have same defence mechanisms o Metabolic capacity is lower - Environmental risk factors (low income) o Poor nutrition, not enough Ca and Fe (compete for same transporters) o Living near major roadways (lead fumes) o Lead pipes Lecture 2 Nov 5 Attributes of Target Molecule -
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- Spring '14