• inherent capacity of a substance to produce injury
• ex: LD50

• practical certainty that injury will occur when a substance is used in stated quantity and set of conditions
• proportionate risk

• the practical certaintly that injury will NOT occur when a substance is used in stated quantity and set of conditions
• acceptable risk

• definition- rapid exposure to high dose with rapid course of injury
• examples
  • homicidal/suicidal- ingestion
  • occupational- inhalation, dermal

• definition- slowly developing injury that is often progressive and irreversible
• examples
  • frequently occupational- cancer, dermatoses, delay neurological disease, obstructive lung disease, reproductive impairment
  • can be environmental- chronic bronchitis, excess cardiopulmonary mortality
• sources
  • bioaccumulation
  • air pollution
  • building materials
  • industrial accidents

• block oxygen transport or utilization
• alter enzyme activity
• alter selective permeability of membranes
• free radical formation and lipid peroxidation
• formation of reactive oxygen species
• binding to critical macromolecules
• hapten and antigen formation

• complexation with poison
• accelerate bioconversion to nontoxic metabolites
• block formation of more toxic metabolites
• accelerate excretion
• block or compete for essential receptors
• bypass effect of poison

• carbon monoxide forming carboxyHb
  • antidote- oxygen at high partial pressure displace CO from Hb
  • destroys coopertivity of Hb with oxygen
• nitrate/aromatic amines/nitro compounds forming methemoglobin
  • antidote- methylene blue acts as electron donor to reduce ferric in Hb back to ferrous

• cyanide react with ferric in cytochrome oxidase to disrupt cellular energy metabolism, causing CNS, cardiac dysfunction
• organophosphate poisoning (insecticide) blocks AChE, leading to accumulation of ACh

• two step process
  1. amylnitrate inhaled (for rapid action) and 3% NaNO₂ IV produce Met-Hb to compete with cytochrome oxidase for free CN and when form cyanomethemoglobin, its nontoxic
  2. sodium thiosulfate IV: in the presence of rhodanese reacts with CN to form thiocyanate ion which is relatively nontoxic and readily excreted

• three phase
  1. atropine sulfate block muscarinic R, so block ACh
  2. pralidoxine (PAM)
     1. dephosphorylates AChE and restores enzyme activity
     2. directly react with paraoxon rendering it inert

• solvents, petroleum distillates: hydrocarbon poisoning
  • kerosene
  • gasolene
  • diesel oil
  • paint thinner
• metals
  • iron
  • mercury
  • lead
  • cadmium
• corrosives

• via inhalation of vapors or ingestion of liquid
• intoxication leads to CNS depression similar to that of ethanol
  • incoordination
  • restlessness
  • respiratory arrest
  • death
• inhalation of vapors can:
  • sensitize myocardium and precipitate ventricular fibrillation
  • rapid CNS depression w/respiratory failure and death
• ingestion of liquid (esp. low viscocity):
  • aspiration can produce:
    • chemical pneumonitis
    • pulmonary edema

• mostly supportive
• because of danger of aspiration, should not consider:
  • emesis
  • gastric lavage
  • should only be considered if risks are justified by additional toxic substances in solvent
• ex: cathartics like MgSO₄ and Na₂SO₄ can be used

• routes of exposure
• duration of exposure
  • acute
  • chronic
• presence of mixture

• mechanism
  • react with essential functional groups, esp. sulfhydryl
  • this alter active or facilitating transport
• epidemiology
  • acute poisoning mostly in kids due to ingestion
  • occasionally adults are occupationally exposed

1. normally, ferrous is absorbed readily and converted to ferric form and bound to protein
2. when the binding sites become saturated, we get toxicity
3. leading to a corrosive action on GI mucosal cells leading to:
   • coagulative necrosis
   • hemorrhage
   • hypovolemic shock
   • hepatic dysfunction

• concentrated accumulation of a chemical as the chemical moves "up the food chain"
  • ex: little fish exposed to mecury, little fish eat big fish, we eat the big fish

speciation crucial to toxicity (bioaccumulation)

• elemental mecury- uncharged and easily crosses membranes, esp. BBB to target CNS (nontoxic when ingested)
• inorganic mecury (cation)- targets the kidney
  • use agriculture antifungal, dental amalgums, cathartic, rat poison, curaritve in felt hat industry
• organic mecury- targets CNS and kidney (lipid soluble)
  • example of bioaccumlation in food chain with acute exposure rate
  • created from inorganic mercury by anaerobic bacteria

Erethism- sudden attacks of anger, irritability, loss of memory, drowsiness, loss of interest in life, withdrawal from society

• linear model
• threshold model (hockey stick)- we have developed capacity to deal with chemicals to a certain extent, when we pass that point, we see toxicity
• hormetic model- good for you at low doses, but at high doses, things go wrong (ex: baby aspirin)

• occupational exposure to miners, smelters, foundry, battery workers
• environmental exposure is ubiquitous
  • household exposure with paint that is prior to 1977

• accumlation in bone, hairs, teeth
• can remobilize by factors affecting calcium metabolism
• see burtonian gingival lead line (blue line on the gums)
• recently associated with moderate to severe developmental learning disabilities
• inhibits ALA dehydratase and ferrochelatase, leading to excretion of ALA and proporphyrinogen III in urine and accumulation of protoporphyrin IX in RBC's

• extremely long half life
• inhibits many enzymes like alpha antitrypsin, leading to severe lung dammage
• osteomalacia
• immunosuppressant
• growth retardation
• testicular damage
• carcinogenesis

Epi- many industrial processes include electroplating

• calcium disodium EDTA
  • indications
    • lead poisoning
    • iron poisoning
  • long term use may cause arrhythmias
    • beware of hypocalcium and severe proximal nephron degeneration
• dimercaprol (BAL)
  • indication
    • mecury poisoning
    • lead poisoning
  • numerous side effects
• deferoxamine (chelation therapy) 
  • indication- specifically for iron poisoning
  • can provoke histamine release
• penicillamine
  • indication- numerous mettals, but not first choice
  • given for long term follow up of EDTA
  • caution: allergy

• bright pink skin (cherry red hypoxia)
• bracing headache

• chocolate brown blood
• gray cyanosis
• easily fatigability

ITS A VERY STEEP CURVE

• at 0.5-1: mild (rapid pulse, flush, headache)
• 1.0-2.5: moderate (stupor, tachycardia, tachypnea)
• 2.5 +: severe (comatose, unresponses, dilated pupules, death unless treated immediately)

• ingestation
  • burning pain in mouth, throat, abdomen
  • blood tinged vomit
  • bloody diarrhea
  • dysphagia
  • drooling
  • hypotension
• inhalation
  • bronchial irritation
  • frothy sputum
  • pulm. edema
  • moist rales
  • hypotension
  • dyspnea
• dermal- stain skin, burning pain
• ocular
  • conjunctivitis
  • corneal destruction
  • pain
  • lacrimation
  • photophobia

• halogenated HC's
  • carbon tetrachloride
  • trichloroethylene
  • trichloroethane
  • dichloromethane
  • chloroform

• can occur via inhalation of vapor, ingestion, or rarely percutaneous absorption
• inhalation exposure symptoms
  • init.- irritate eyes, nose throat; nausea and vomiting; dizziness; headache
  • continues: stupor, convulsion, coma, death from CNS depression
  • sudden death from ventricular fibrillation or medullary depression
• ingestion- abdominal pain, hematemesis, hepatic damage
• delayed hepatotoxicity and nephrotoxicity

• carbon tetracloride metabolized to free radical CCl₃ via P450 activation
• initiates a chain of organic free radical reactions
• leads to peroxsidation of lipids in ER and cellular membrane
• leads to breakdown in membrane structure and function

Source of inhibiting PCT function and hepatotoxicity

• there is a point in "phase 2" of iron poisoning where the patient appears to approve
• you must not send them home, and you must keep them for long term observation

• alloxan- pancreated beta cell destruction
• adriamycin- cardiotoxicity
• 6 hydroxy dopamine- nerve terminal destruction
• paraquat- pulmonary toxicity
• streptonigrin- bacteriolysis

• acetaminophen toxic after sulfation and glucoronidation are saturated and glutathione is depleted
• leads to hepatotoxicity due to accumulation of toxic metabolites
• tx- N-acetyl cysteine

• dont delay life saving or life supporting therapy
  • emesis
  • removal of absorbed poison from body
  • supportive therapy
• try to ID type of poison, how much and when
• utilize specific antidote if possible

• purpose- minimize further absorption of an ingested poison from GI tract
• success depends on time since ingestion of poison and its rate of absorption
• CI
  • corrosive poison (ex: strong acid or alkali can cause gastric perforation or esophageal necrosis)
  • pertrolium distalate (aspiration pneumonia)
  • CNS stimulant (provoke convulsions)
  • comatose patient

• syrup of ipecac
• apomorphine
• gastric lavage
• chemical absorption

• decrease time during which concentration of poison remains above the toxic levels
• thereby, reduce morbidity and mortility
• efficacy depends on concentration gradient of poison in blood and removal fluid
  • poison with large V_d or extensively bound to plasma protein impairs removal

• forced diuresis
• altered urinary pH
• peritoneal dialysis
• hemodialysis
• hemoperfusion
• exchange transfusion

• CNS depression
• convulsions
• cerebral edema
• hypotension
• cardiac arrhythmias
• hypoxia
• pulmonary edema