Poisons, People and the EnvironmentTarget Organ ToxicityTarget Organ ToxicityNot all organs are affected in the same manner by a toxicantA toxicant can have several target organsDifferent toxicants can have the sametarget organThe target organ may not have the highest concentration of a toxicantThe concentration of the toxicant in a target organ is the “sum” of all toxicokinetic processesTarget Organs in the Human BodyWhat is Neurotoxicity?Neurotoxicity occurs when exposure to naturalor manmade toxic substances (neurotoxicants)alters the normal activity of the nervous system.Cognitive Effectsmemory, learning, confusionMotor Effectsweakness, convulsion, paralysisSensory Effectsvision, auditory, touch, balanceMood and Personality Effectssleep, depression, irritability, excitabilityGeneral Effectsloss of appetite, fatiguebrainbrainaxons and cell bodiesComponents of the Nervous System CNS – Central Nervous System PNS – Peripheral Nervous System Blood brain barrier Neuronal cells Neurotransmitters & receptors 10-100 billion cells with 1015 connectionsImage from Purves et al., Life: The Science of Biology, 4th Edition,NeuronNeurotransmittervesiclesSynapticcleftMotorend plateSkeletal muscle fibergyMyelinAxon of motorneuronMitochondriaNeurotransmitterreceptorsAdapted from: Casarett and Doull’s Toxicology: A Basic Science of Poisons and A Small Dose of Toxicology by S. GilbertNormalNeuronopathyAxonopathyMyelinopathyTransmissionsynapseaxonMyelinating cellneuronNeurological and Behavioral Effects of Exposure to Toxic Substances Cognitive Effects - Memory problems,confusion, speech impairment, learningimpairment Motor Effects - Convulsions, weakness, tremor, twitching, lack of coordination, unsteadiness, paralysis, reflex abnormalities, activity changes Sensory Effects - Equilibrium changes, visiondisorders, pain disorders, tactile disorders, auditorydisordersNeurological and Behavioral Effects of Exposure to Toxic SubstancesMood and personality effects - Sleep disturbances, excitability, depression, irritability, restlessness, nervousness, tension, delirium, hallucinationsGeneral effects - Loss of appetite, depression of neuronal activity, narcosis stupor, fatigue, nerve damageSite of actionNeurotoxic changeNeurotoxic chemicalCorresponding disorderNeuron cell body NeuronopathyMethylmercury Quinolinic acid 3-AcetylpyridineMinamata disease Huntingtons disease Cerebellar ataxiaNerve terminal Terminal destruction1-methyl,4-phenyl 1,2,3,6tetrahydropyridine (MPTP) (dopaminergic)Parkinson’s diseaseSchwann cell myelin Myelinopathy HexachloropheneCongenital hypomyelinogenesisCentra-peripheral distal axonDistal axonopathyAcrylamide, carbon disulfiden-hexanePeripheral neuropathyCentral axons Central axonopathy ClioquinolSubacute myelooticoneuropathyProximal axon Proximal axonopathy B,B-IminodipropionitrileMotor neuron diseaseBiotransformation of Mercuryhttp://www.usgs.gov/themes/factsheet/146-00/http://www.teratology.org/jfs/Agricultural.htmlTable 1. Various Indices showing the Threshold Value for Onset of Symptoms inHuman Body(Source: "IPCS Environmental Health Criteria No.101 Methylmercury",etc.)Mercury ToxicityAverage daily intake 3-7 µg/kgBody burden15-35mg(50kg weight)Total mercury concentration in blood 20-50µg/100mlTotal mercury concentration in hair 50-125µg/gFetal Alcohol SyndromeMany compounds affect brain function!!NormalExposedLiver ToxicityOverall there are three principal liver functions Storage Glucose is converted to glycogen Fat and fat-soluble vitamins and other nutrients Metabolism Carbohydrates, Proteins, Amino acids, Fatty acids, Steroids and Xenobiotics Biosynthesis Enzymes, plasma proteins LipoproteinsExogenous toxic substanceDistal GI Excretion LungsSkinGastrointestinal tractVascular SystemHepatic MetabolismRenal ExcretionRenal ExcretionLiver StructurePortal CanalBile ductCentral veinsPortal Veinhttp://biology.bangor.ac.uk/images/bsx1016/liver_structureHEPATIC PARENCHYMAepithelial working tissueSINUSOIDSINUSOIDPlate of hepatocytesEndothelial cellsKupffercellPlate of hepatocytesSpacebloodadapted fro m http://wberesford.hsc.wvu.eduSpace of DisseSmooth ERRERMitochondrionBile canaliculusTight junctionGlycogenGolgicomplexPeroxisomeLysosomeMicrovilliadapted fro m http://wberesford.hsc.wvu.eduFactors influencing the toxicity of compounds in the liver Age Ethnicity and race Gender Nutritional status Underlying liver diseaseRenal functionPregnancyDuration and dosage of drugEnzyme inductionDrug- drug interactionEnvironmental Agents Causing Liver Injury Home Poisons: rat poisons, cleaning solutions, medicines, paint (lead) Air Pollution: automobile exhaust, environmental soot, cigarette smoke, asbestos Rural toxic substances: pesticides and herbicides, fungal spores on grains, fertilizers Industrial toxicity: solvents, metals, chemicals Food additives: oils, red dye, saccharine, cyclamates, nitrates Drugs: antibiotics, anesthetics, analgesics,stimulants, depressants, hormones, chemotherapeuticagents, ethyl alcoholCirrhosis A progressive disease resulting from the combination of diffuse fibrosis and nodules of regenerating liver cells Caused by:• Excessive alcohol (or chemical) consumption(nutrition)• Hepatitis B Characterized by deposition of collagen fibers throughout the liver. Considered “active” ifnecrosis, inflammatory infiltration and parenchymalcell loss are evident. Results inRestriction of blood flowChanges in normal metabolic processesChanges in detoxication processLiver failureCirrhosisThe disparity between the typical cirrhosis of chronic viral hepatitis (small liver,big nodules) and alcohol related liver diseases (big liver, small nodules) is particularly evident here. These patients were both autopsied the same day (photograph by T.H. Kent, M.D.).What is the Endocrine System?The endocrine system consists of 3 main parts:GlandsHormonesTarget cellsEndocrine Toxicity?Endocrine hormonesare released by the thyroid, parathyroid, adrenal, reproductive tissues and other glands.Where are Hormones Produced?Hypothalamus: Secretes the "supervisory" hormones that regulate the pituitary gland.Pineal: Secretes melatonin, a hormone involved with daily biological rhythms.Pituitary: This is the master gland. It secretes hormones that influence other glands and organs and