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 toxinsHISTORYBhopal 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 ToxicologyParacelsius:- 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 POISONINGInsecticides:-Organophosphorous compounds1. Direct acting :- Do not need activation in the body2. Indirect acting:- Need activation in the body Parathion ->Paraoxon,Malathion-> Malaoxon,Diazinon-> DiazoxonMechanism 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 siteClinical 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”)

TREATMENTAntimuscarinic 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(Nerve 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 COMPOUNDSEg:- 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 brain- GABA 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-D2. 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,ChlorphacinoneMECHANISMInhibition 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 FLOURACETATEAs 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 Kreb’s cycleCHOLECALCIFEROL(Vitamin D3)Promotes Calcium retentionHigh 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 ureaRuminants – more susceptible

Mechanism:- Toxicity is due to NH3 which is a primary inhibitor of TCA cycleTreatmentAcetic acid/vineger- 2-8 lnintraruminallyENVIRONMENTAL POLLUTANTSI. Air pollutants:- Particles with diameters < 1µm enters alveoli2.Primary air pollutants :- Carbon monoxide(52%),Sulphuroxides,Hydrcarbon3.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 CONTAMINANTSDioxim

TOXIC PLANTSCyanogenetic plants-Contain cyanoglycosides - releases HCN in

rumen- by the action of Beta glycosidasesEg:- Bitter almond and wild cherry contain amygdalin Sorghum,Jowar etc contain DhurrinLinseed,White clover contain LinamarinMechanism of Action:- Inhibits cytochrome P450 enzymeTreatment:- NaNO2,Na2S2O3Lathyrism:- Neurolathyrosis,OsteolathyrosisBracken fern poisoning:- Pteridium contains thiaminase,(Aplastic anemia

factor,Hematurea factor etc)

OXALATE POISONING:- Oxalate seen in plants like oxalisMOA:-Complexes with serum Calcium results in hypocalcemia-

calcium oxalate crystal deposition-organ damagePHOTOSENSITIZATION

1)Primary :-Occurs when photodynamic toxin ingestedEg:- Plants like Hypericum,Fagopyrum Drugs like Phenothiazine,Sulfonamides2) Secondary-Hepatogenic-hepatotoxicand accumulation of

photodynamic substances like phylloerythrinEg:- Crotolaria,LantanaDATURA POISONING-Atropine,Hyoscine(Parasympatholytics)Produced by Datura strammonium and Atropa belladona,Physalis

CASTOR BEAN ,ROSARY PEA POISONINGContains Lectins,ricin and Abrin-Inhibit protein synthesisIPOMOEA POISONINGCaused by Jalopor morning gloryToxic principle-JalapinMOA :- Irritant,cathartic actionNUXVOMICA POISONINGStrychnos- contain Strychnine,Brucine-Competitive inhibitor of

glycine-Seizures

METAL POISONING1.Arsenic:- Trivalent,Pentavalent are main inorganic form.Trivalent is more

toxicMOA:-Trivalent As- Binds to sulphydryl groups of enzymesPentavalent As:-Uncoupling of mitochondrial oxidative

phosphorylationOrganic Arsenicals cause demyelination and gliosis of nervesClinical symptoms:- “Rice gruel Diarrhoea” and enteritisCNS symptoms ,paralysis in organic As poisoningTREATMENTDimercaprol as i/m ,Sodium thiosulphate,D-pencillamine

2) LEAD:-Plumbism/Painters colicOral LD50 :-50-600mg/Kg,get deposited in bones and visible as

lead line in x rays.Can cross BBBMOA:- Cross BBB and cause cerebral oedema and haemorrhageCompetes with Cu,Fe,and Znfor mitochondrial enzymesClinical

signs:- CNS symptoms with cerebrocortical necrosis and Poliomalacia

TREATMENTDisodium Ca EDTAD-PenicillamineDimercaprol

3) MERCURYMinamata disease or Nigata disease due to methyl mercury

poisoning- Japan-Enviromental pollutionMost toxic mercury vapoura crosses BBB .Inorganic mercury

causes caustic lesions in GI tractMOA:- Mercury combine withsulphydryl groups interfers protein

synthesisClinical signsMercurial ptyalism,GasteroenteritisTreatmentRaw egg/raw milk to prevent gastric damageDimercaprol 3mg/Kg i/m

4)Selenium:-Toxic level in diet Above 5ppmOrganic form Se is more toxic and selenium accumulating plants

are divided into a)Obligate accumulator/Indicator:-In Se rich soil upto

15,000ppmb)Facultative accumulator-25-100ppm accumulates Se in soilC)Non accumulator plants contain 1-25 ppmMOA :-Replacement sulphur of aminoacids leading to abnormal

protein production-inhibition of enzymesClinical signs:-Chronic – Blind staggers,Alakali disease results in deformities of

skin,hair,hooves and hornTREATMENT:-Supportive therapy

5)COPPERMost susceptible breed:- Bedlington terrierMost susceptible species:-SheepMOA:- Inhibit Dihydrolipoyl dehydrogenase enzymeClinical signs:-Deep green colour of diarroeaGun metal kidneysTREATMENTD-Pencillamine,Ascorbicacid,Sodium molybdate and Sodium

sulphate

6)FlourineMOA:- Delayed and impaired mineralisation of teeth and boneTreatment:- Supportive therapy

7)PHOSPHORUS:-Yellow P is more toxicProtoplasmic poisonDirect cardiotoxic actionPhossy jaw in affected animalsTREATMENT:-Non absorbable mineral oil,Supportive treatment8)NITRATE AND NITRITENitrite more toxic than nitratesMOA:- Formation of methemoglobinin large quantity-reduced

oxygen carrying capacityClinical signs:-Bluish mucous membrane,chocolate brown bloodTREATMENT:-Methylene blue-1%soln in NS

9) Nacl poisoningPig and poultry most susceptibleOral lethal dose:-2.2g/Kg in farm animalsMOA:- Purgation,cerebral oedema,hypertonicity,,capillary layer

shrinkageClinical 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:-Supportive2)RUBRATOXINPencillium rubrum,P.purpurogenumRubra 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 roseumPotent nonsteroidal oestrogenClinical signs:-Nymphomania,Abortion,Infertility in males

OCHRATOXIN:-Aspergillus ochraceousCauses mycotoxic nephropathy

Trichothecenes:- Cytotoxic mycotoxins

Botulism:- C.botulinumNeurotoxin-flaccid paralysis of muscle