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TOXICOLOGY

TOXICOLOGY:- Study of poisons and their harmful effects. TOXINOLOGY:- Study of toxins.
Poison/Toxicant:- Any substance that depress health or entirely destroys life Toxin/Biotoxins:- Poisons produced by living organisms Eg: Phytotoxins,zootoxins,Mycotoxins,Bacterial toxins HISTORY Bhopal gas tragedy:- December 1984-By accidental release of Methyl Iso Cyanate. Ebers Papyrus:- Ancient document which contains disease conditions and prescriptions employed in Egyptian medicine. MJB Orfila :- Father of Modern Toxicology Paracelsius:- Concept of dose dependancy of toxic effects(Every substance is a poison.It is the dose which distiguishes toxin from a remedy)

Malicious/Intentional poisoning :- Abrus,strychnine etc

PESTICIDE POISONING Insecticides:Organophosphorous compounds 1. Direct acting :- Do not need activation in the body 2. Indirect acting:- Need activation in the body Parathion ->Paraoxon,Malathion-> Malaoxon,Diazinon-> Diazoxon Mechanism of Action:Acute toxicity Irriversible inhibition of AchE- Accumulation of Acetyl choline AchE has 2 main reactive sites Anionic site(Negatively charged) Esteratic site

OP compounds react only with esteratic site(Except Ecothiopate) Ecothiopate binds with both anionic and Esteratic site Clinical signs of acute toxicity are mainly Muscarinic signs,Nicotinic signs and CNS signs.) Delayed / Chronic toxicity:- Appears 7-30 days after disappearance of acute symptomsby inhibition of neurotoxic esterases.This delayed toxicity is called OPIDN(Organophosphorous Induced Delayed Neuropathy/ Dying back axonopathy) TREATMENT Antimuscarinic agent Atropine (Dog 0.2 2 mg/Kg) (Cattle- 0.2 0.5 mg/Kg) Choline esterase reactivators binds with anionic site of phosphorylated enzyme. Eg:- Oximes

Examples of OP Compounds:Malathion,Parathion,Ecothiopate,Dichlorvos(DDVP),Tabun,Sarin(N erve gases),Chlorpyrifos,Diazinon,Dimethoate,Monocrotophos. CARBAMATES:Reversible inhibitors of AchE. Occupy both anionic and esteratic site(So ChE reactivators are not effective in carbamate poisoning) TREATMENT Atropine (Antimuscarinic) Eg:-Naphthy carbamates- CARBARYL(SEVIN) Phenyl carbamates- PROPOXUR(Present in Baygon) Carbofuran(FURADAN) ORGANOCHLORIDE COMPOUNDS Eg:- DDT group-DDT, Methoxychlor Aryl Hydrocarbons- Benzene hexachloride(BHC) Cyclodienes :- Endosulphan

Cats are more susceptible to OC poisoning. Oc compounds are converted to more toxic epoxides . Lindane- Gamma isomer of BHC MECHANISM Inerfere with sodium channel -> prolong depolarisation -> Increased neuronal excitability. Primary targets for cyclodienes and lindane in mammalian brainGABA receptorsand inhibit binding of GABA results in uncontrolled excitation. No specific treatment Convulsions are treated with CNS depressants(barbiturates)

HERBICIDES 1. Chlorophenoxy acetic acid :- 2,4-D 2. Dinitrocompounds :- DNOC(Dinitro otho cresol) (Uncouplers of oxidative phosphorylation) 3.Bipyridyl compounds :- Paraquat,Diaquat (Pulmunotoxicant) 4. Glyphosate Present in ROUNDUP
RODENTICIDES Inorganic rodenticides :- Zinc phosphoides- Decompose rapidly in stomach to Zinc and Phosphine (PH3).Acute toxicity by Zinc phosphide is due to Phosphine. More toxic in full stomach.

ORGANIC RODENTICIDES

1.Anticoagulants Most commonly used Eg:Warfarin,Brodifacuom,Bromadilone,Pindone,Chlorphacinone MECHANISM Inhibition of Vitamin K dependant blood clotting factors (Factors II,VII,IX,X). Specific treatment Phytomenadione/Phylloquinone-specific antidote(Vit K1-present in plants)
2. ALPHA NAPHTHYL THIOUREA(ANTU) It has selective action on lungs

SODIUM FLOURACETATE As such non toxic.But inside the body converted to Flourocitrate (Toxic)- Examaple for Lethal Synthesis. Flouracetate copetes with citrate for the enzyme Aconitase and inhibit Krebs cycle CHOLECALCIFEROL(Vitamin D3) Promotes Calcium retention High dose-> Hypercalcemia->calcium salts are deposited in soft tissues . STRYCHNINE :- An alkaloid from the seeds of Strychnos nuxvomica competitively antagonise the action of inhibitory neurotransmitters like glycine-> strong convulscent

RED SQUILL :- Obtained from the bulb of sea onion (Urginia maritima) contains scillirocide cardioactive glycoside more toxic to feamale rats. FEED ADDITIVES NPN compounds UREA. In human , urea is converted to ammonia by the action of Urease enzyme.Normally Ammoni a produced in rumen is utilised by rumen bacteria for amino acid synthesis whichis required for further protein synthesis. If Ammonia is produced in high concentraion leads to urea poisoning Alkaline pH increases release ammonia from urea Ruminants more susceptible

Mechanism:- Toxicity is due to NH3 which is a primary inhibitor of TCA cycle Treatment Acetic acid/vineger- 2-8 lnintraruminally ENVIRONMENTAL POLLUTANTS I. Air pollutants:- Particles with diameters < 1m enters alveoli 2.Primary air pollutants :Carbon monoxide(52%),Sulphuroxides,Hydrcarbon 3.Secondary air pollutants :- Ozone,Peroxyacetylnitrate(PAN) 4.Carbon Monoxide :- Combines with Hb -> Carboxy haemoglobin(cannot carry oxygen) TREATMENT :- Artificial respiration Oxygen therapy 90-95% O2 with 5-10% CO2

WATER POLLUTANTS Polyhalogenated biphenyls(Chlorinated- PCBs,PBBs) Polycyclic aromatic hydrocarbon (PAHS) Benzopyrenes Benzanthracenes Carcinogenic ,mutagenic Benzopyrenes produces Benzopyrene diepoxide which is carcinogenic and mutagenic . FOOD AND FEED CONTAMINANTS Dioxim

TOXIC PLANTS
Cyanogenetic plants-Contain cyanoglycosides - releases HCN in rumen- by the action of Beta glycosidases Eg:- Bitter almond and wild cherry contain amygdalin Sorghum,Jowar etc contain Dhurrin Linseed,White clover contain Linamarin Mechanism of Action:- Inhibits cytochrome P450 enzyme Treatment:- NaNO2,Na2S2O3 Lathyrism:- Neurolathyrosis,Osteolathyrosis Bracken fern poisoning:Pteridium contains thiaminase,(Aplastic anemia factor,Hematurea factor etc)

OXALATE POISONING:- Oxalate seen in plants like oxalis MOA:-Complexes with serum Calcium results in hypocalcemiacalcium oxalate crystal deposition-organ damage PHOTOSENSITIZATION 1)Primary :-Occurs when photodynamic toxin ingested Eg:- Plants like Hypericum,Fagopyrum Drugs like Phenothiazine,Sulfonamides 2) Secondary-Hepatogenic-hepatotoxicand accumulation of photodynamic substances like phylloerythrin Eg:- Crotolaria,Lantana DATURA POISONING-Atropine,Hyoscine(Parasympatholytics) Produced by Datura strammonium and Atropa belladona,Physalis

CASTOR BEAN ,ROSARY PEA POISONING Contains Lectins,ricin and Abrin-Inhibit protein synthesis IPOMOEA POISONING Caused by Jalopor morning glory Toxic principle-Jalapin MOA :- Irritant,cathartic action NUXVOMICA POISONING Strychnos- contain Strychnine,Brucine-Competitive inhibitor of glycine-Seizures

METAL POISONING
1.Arsenic:Trivalent,Pentavalent are main inorganic form.Trivalent is more toxic MOA:Trivalent As- Binds to sulphydryl groups of enzymes Pentavalent As:-Uncoupling of mitochondrial oxidative phosphorylation Organic Arsenicals cause demyelination and gliosis of nerves Clinical symptoms:- Rice gruel Diarrhoea and enteritis CNS symptoms ,paralysis in organic As poisoning TREATMENT Dimercaprol as i/m ,Sodium thiosulphate,D-pencillamine

2) LEAD:-Plumbism/Painters colic Oral LD50 :-50-600mg/Kg,get deposited in bones and visible as lead line in x rays.Can cross BBB MOA:- Cross BBB and cause cerebral oedema and haemorrhage Competes with Cu,Fe,and Znfor mitochondrial enzymesClinical signs:- CNS symptoms with cerebrocortical necrosis and Poliomalacia TREATMENT Disodium Ca EDTA D-Penicillamine Dimercaprol

3) MERCURY Minamata disease or Nigata disease due to methyl mercury poisoning- Japan-Enviromental pollution Most toxic mercury vapoura crosses BBB .Inorganic mercury causes caustic lesions in GI tract MOA:- Mercury combine withsulphydryl groups interfers protein synthesis Clinical signs Mercurial ptyalism,Gasteroenteritis Treatment Raw egg/raw milk to prevent gastric damage Dimercaprol 3mg/Kg i/m

4)Selenium:-Toxic level in diet Above 5ppm Organic form Se is more toxic and selenium accumulating plants are divided into a)Obligate accumulator/Indicator:-In Se rich soil upto 15,000ppm b)Facultative accumulator-25-100ppm accumulates Se in soil C)Non accumulator plants contain 1-25 ppm MOA :-Replacement sulphur of aminoacids leading to abnormal protein production-inhibition of enzymes Clinical signs:Chronic Blind staggers,Alakali disease results in deformities of skin,hair,hooves and horn TREATMENT:-Supportive therapy

5)COPPER Most susceptible breed:- Bedlington terrier Most susceptible species:-Sheep MOA:- Inhibit Dihydrolipoyl dehydrogenase enzyme Clinical signs:-Deep green colour of diarroea Gun metal kidneys TREATMENT D-Pencillamine,Ascorbicacid,Sodium molybdate and Sodium sulphate

6)Flourine
MOA:- Delayed and impaired mineralisation of teeth and bone Treatment:- Supportive therapy

7)PHOSPHORUS:Yellow P is more toxic Protoplasmic poison Direct cardiotoxic action Phossy jaw in affected animals TREATMENT:-Non absorbable mineral oil,Supportive treatment 8)NITRATE AND NITRITE Nitrite more toxic than nitrates MOA:- Formation of methemoglobinin large quantity-reduced oxygen carrying capacity Clinical signs:-Bluish mucous membrane,chocolate brown blood TREATMENT:-Methylene blue-1%soln in NS

9) Nacl poisoning Pig and poultry most susceptible Oral lethal dose:-2.2g/Kg in farm animals MOA:- Purgation,cerebral oedema,hypertonicity,,capillary layer shrinkage Clinical signs:CNS symptoms mainly,cerebral muscular endothelialproliferation,distended perivascular space with oesiniphils-pathegnomonic Treatment :- Small quantity water at frequent intervals

MYCOTOXINS
1) AFLATOXIN:-A.flavus,A.parasiticus Important toxins:-B1(most toxic),B2,G1,G2 Ducks are most susceptible LD50 of B1:- 0.3-9mg/Kg Clinical sypmtom:-Centrilobular necrosis in liver Treatment:-Supportive 2)RUBRATOXIN Pencillium rubrum,P.purpurogenum Rubra toxin A and B( most toxic)

ERGOT:- Claviceps purpurea Alkaloids:-Ergotamin,Ergotoxin,Ergometrine 2 types A)acute-nervous/convulsive form B)Chronic /Gangrenous form MOA:-Vasoconstriction,CNS stimulation ZEARLENONE:-Fusarium roseum Potent nonsteroidal oestrogen Clinical signs:-Nymphomania,Abortion,Infertility in males
OCHRATOXIN:-Aspergillus ochraceous Causes mycotoxic nephropathy

Trichothecenes:- Cytotoxic mycotoxins Botulism:- C.botulinum


Neurotoxin-flaccid paralysis of muscle