-
L-Acetylcysteine used for CCL4 toxicity because
the sulfhydryl group acts like glutathione to deactivate CCL4
-
Petroleum and solvent distillates are commonly used in
- plastic
- agriculture & chemical industry
-
Petroleum distilates are commonly used as
-
CNS and respiratory depression results from petroleum and solvent distillates because
cardiac stimulation from sensitization to catacholamines
-
Peroleum distilates are usually introduced by
-
concentration for a normal 8 hr work day or 40 hour work week to which workers may be repeatedly exposed without adverse effects
TWA value
-
maximum concentration that should not be exceeded at any time during a 15 minute exposure period
STEL value
-
STEL value is normally ____ than TWA value because
- higher
- individual is only allowed to be exposed for 15 min by law.
-
-
Benzene use
- solvent properties
- synthesis of other chemicals
- not present in house hold products
-
Benzene mechanism of toxicity
CNS depression
-
Exposure to Benzene 7500 ppm for 20 min can cause
fatality
-
exposure to benzene at >3000 ppm can cause
- euphoria
- nausea
- locomotor problems
- coma
-
Exposure to benzene at 250-500 ppm may cause
- vertigo
- drowsiness
- headache
- nausea
-
Chronic exposure to benzene can cause
- injury to bone marrow
- plastic anemia
- leukopenia
- pancytopenia
- thrombocytopenia
-
Bone marrow cells are most sensitive to benzene during
early stages of development
-
Benzine is ACGIH category
- A1
- human carcinogen
- causes leukemia
-
Another mechanism of toxicity to benzene
sensitization of the myocardium to arrhythmogenic effects of catecholamines
-
A typical smoker inhales _____ mg of benzene daily.
1-2 mg
-
EPA maximum contaminant level (MCL) of benzene in water is
5 ppb
-
Antidote for benzene
no specific antidote
-
Toluene
- no myelotoxic properties
- not associated with leukemia
- causes CNS depression
-
Exposure to 800 ppm toluene results in
severe fatigue and ataxia
-
Exposure of 10,000 ppm toluene leads to
rapid loss of consciousness
-
Chronic effects of long term toluene exposure
unclear
-
Xylene
- three isomers used as components in petroleum hydrocarbon solvents
- frequent source of lab exposure
-
commercial xylene
75-85% p-isomer
-
toxicity of xylene
- similar to toluene
- well absorbed via inhalation and skin contact
- mild hematopoietic toxicity
- Lethal dose in 15 mL of gasoline
-
Xylene metabolism
- metabolized via oxidation of the methyl group in the O, M, or P position
- excreted as O, M or P methylhippuric
-
Treatment of xylene ingestion
- diazepam to control convulsions
- supportive therapy
- monitor hematiopoietic elements
-
Halogenated unsaturated hydrocarbons
vinyl chloride
-
Vinyl chloride uses
- starting material for plastic
- polyvinyl chloride (PVC)
- aerosol propellant
-
Major routes of exposure to vinyl chloride
-
Acute signs of vinyl chloride exposure
- CNS depression
- dizziness, light headedness
- nausea
- headache
- dulling of senses
-
Chronic exposure to vinyl chloride
- raynaud's phenomenon (changes of blood supply to periphery by degradation of small vessels)
- skin changes
- changes in bones of the hands
- liver damage or hemangiosarcoma
-
Metabolism of vinyl chloride
- undergoes metabolic activation when metabolized by P450 to reactive intermediates which can alkylate DNA and lead to cancer
- metabolism is saturable
-
chloroethylene oxide or chloroacetaldehyde
reactive intermediate formed from vinyl chloride
-
shows correlation with vinyl chloride exposure
urinary excretion of cysteine metabolite and thiodiglycolic acid
-
Tumor incidence with vinyl chloride correlates to
amount metabolized rather than dose
-
Household products
- bleach
- hydrocarbon solvents (turpentine)
- antifreeze (ethylene glycol)
- methanol
- formaldehyde
-
Most common substance involved in poison cases by oral ingestion
bleach
-
Oral ingestion of bleach
- burning of mouth, throat and esophagus
- tissue damage results in edema of pharynx and larynx
-
Bleach in the stomach
- generates hypochlorus acid and CL2 gas in the presence of HCL
- CL2 may be inhaled causing dmg in the lungs
-
Hydrocarbon solvents
- turpentine
- white spirit
- used for cleaning paint brushes
-
Aspiration of hydrocarbon solvents leads to
chemical pneumonitis
-
toxic constituents of antifreeze
-
Ethylene glycol
- dihydric alcohol
- sweet tasting
- similar CNS effects as ethanol
- sometimes consumed by alcoholics
-
lethal amount of antifreeze
1 cup
-
toxicity of ethylene glycol
requires metabolism to metabolic products which lead to oxalic acid
-
oxalic acid
- toxic metabolite of ethylene glycol
- can chelate calcium that is important for enzyme fx
- crystallizes in the brain
- forms calcium oxalate in kidney tubules (stones) leading to kidney damage
-
Intermediate acidic metabolites of ethylene glycol cause
acidosis by increasing NADH levels which increases lactic acid production
-
First step in metabolism of ehtylene glycol involves
- alcohol dehydrogenase
- blocked by the presence of ethanol
-
Treatment of ethylene glycol poisoning
- administer ethanol PO or IV
- Hemoperfusion/dialysis
-
Methanol found in
- sometimes in antifreeze
- methylated spirits
-
Methanol toxicity comes from
metabolism to formaldehyde and formic acid
-
Most likely cause of organ toxicity with methanol poisoning
- formic acid
- inhibits cytochrome oxidase activity resulting in tissue hypoxia
- increased lactic acid formation resulting in metabolic acidosis
-
Formaldehyde may cause
- blindness if the dose of MeOH is not rapidly fatal
- pt will see "snow flakes"
-
Treatment of methanol poisoning
- same as ethylene glycol
- administer ethanol po or iv
- correct metabolic acidosis
-
Formaldehyde properties
- gas at room temp
- used in lab as 37% solution
- solution contains 15% methanol
-
formaldehyde uses
- manufacture of synthetic resins
- paper and fabric
- wood products
- preservatives
- disinfectants
-
exposure to formaldehyde
- occupational exposure by inhalation or direct skin contact
- residential exposure from release of formaldehyde fumes from synthetic foam insulation in exterior walls
-
TLV is ____ in air for formaldehyde
2 ppm
-
Odor threshold for formaldehyde is
1 ppm
-
Formaldehyde reacts with all cellular proteins but binds 4x as much to
erythrocytes
-
Metabolism of formaldehyde
oxidized to formic acid in erythrocytes and in the liver
-
Results of exposure to formaldehyde
- mucous membrane irritation
- lacrimation
- cough
- inflamation of bronchi
- pulmonary edema
- death
-
Direct skin contact with formaldehyde results in
- dermatitis
- sensitization occurs with repeated exposure
-
Ingestion of formaldehyde results in
- death
- corrosive dmg to stomach and SI
- circulatory collapse
- kidney dmg
-
biological indicator of formaldehyde exposure
formic acid in the urine
-
Major solvent found in glues that causes narcosis
toluene
-
Halogenated solvents found in aerosol products (as propellants) are more hazardous and may cause
- sensitization of myocardium to catecholamines leading to ventricular arrhythmias
- sudden death from heart attack especially uner certain conditions such as fright
-
solvents are found in household products such as
- glues, paint, paint strippers
- aerosols
- varnishes
- cleaning supplies
- fire extinguishers
-
Acute toxic effects of toluene abuse
- narcosis or anesthesia
- serious myocardial sensitization
-
chronic effects of toluene abuse
- personality changes
- general morbidity
-
Methanol uses
- antifreeze
- paint remover
- denaturant in denatured alcohol
-
Metabolism of methanol
- toxicity of methanol is probably due to conversion to formaldehyde
- methanol=(alcohol dehydrogenase)=>Formaldehyde
- Formaldehyde=(aldehyde ")=>formic acid
-
Formaldehyde causes selective injuries on ____ sx include
- retinal cells
- visual disturbances
- acidosis
- death (usually due to respiratory suppression)
-
Treatment of formaldehyde poisoning
- emesis or lavage
- 50% ethanol IV
- treat acidosis with sodium bicarbonate
- fomepizole
-
fomepizole (4 mehtylpyrazole) acts by
inhibiting alcohol dehydrogenase
-
Ethanol uses
- beverage
- solvent antiseptic
- chemical intermediate
-
Ethanol is more hazardous as
a beverage
-
kinetics of ethanol
well absorbed and distributed in TBW
-
90-95% of ethanol metabolized in the liver by
- EtOH =(alcohol DHase)=> acetaldehyde
- Acetaldehyde =(aldehyde DHase)=> acetate
-
Ethanol is metabolized to aldehyde by three enzymes
- Alcohol dehydrogenase (major)
- catalase (10%)
- CYP2E1 (minor)
-
catalase uses
hydrogen peroxide supplied by NADPH oxidase and xanthine oxidase
-
CYP2E1 is the principal component of
hepatic microsomal ehtanol oxidizing system
-
Levels of EtOH obtained through normal "cocktail usage" result in
stimulating microsomal enzymes
-
Levels of EtOH obtained in heavy drinking result in
inhibition of microsomal enzymes
-
EtOH can influence metabolism of
drug metabolized by microsomal oxidative enzymes
-
Alcohol dehydrogenase
- cytosolic NAD dependant enzyme
- found mainly in liver and gut
-
Gut metabolism of EtOH
- lower in females than in males
- accounts for metabolism of low to moderate doses
-
Limited supply of _____ results in ____ order kinetics for metabolism of EtOH
- coenzyme NAD
- Zero order kinetics
-
Fixed capacity of EtOH metabolism is about
7-10 g/hr
-
Chronic alcohol use results in
use of NAD resulting in depletion of the coenzyme for its normal metabolic functions
-
avg adult can metabolize ___ of whiskey or ___ of beer per hour
- 1 oz. whiskey
- 1 can of beer
- 10ml ethanol/hr
- zero order kinetics
-
Aldehyde dehydrogenase
- acetaldehyde => acetate
- 50% of asians have inactive ALDH
- may cause flushing, headache, n/v, tachycardia and hyperventilation with EtOH ingestion
-
Acute effects of EtOH ingestion
- CNS depression
- impaired judgement
- loss of inhibition
- slurred speach
- ataxia
-
Treatment of EtOH ingestion
- maintenance of vital signs
- prevention of aspiration of vomit
- administration of dextrose to adjust e- balance
-
Chronic effects of EtOH ingestion
- tolerance/dependance
- peripheral neuropathy
- loss of liver fx with hepatitis/cirrhosis
- gynecomastia
- testicular atrophy
-
Fetal alcohol syndrome
most common preventable cause of mental retardation and congenital malformation
-
Diagnostic criteria for fetal alcohol syndrome
- heavy maternal EtOH consumption during pregnancy
- pre- & post-natal growth retardation
- cranifacial malformation (microcephaly)
- mental retardation
-
Less complete manifestations of gestational EtOH exposure are referred to as
- fetal alcohol effects
- alcohol related neurodevelopmental disorder
-
Used to treat alcohol dependance
disulfiram (aldehyde dehydrogenase inhibitor)
-
Isopropyl alcohol (rubbing alcohol) symptoms
- cns depression
- renal damage
-
Isopropyl alcohol treatment
-
Ethylene glycol is converted to ____ by alcohol dehydrogenase which causes _____
- oxalic acid
- acidosis
- nephrotoxicity
-
methanol is converted to ____ by alcohol dehydrogenase which causes _____
- formaldehyde and formic acid
- severe acidosis
- retinal damage
-
ethanol is converted to ____ by alcohol dehydrogenase which causes _____
- acetaldehyde
- n/v, headache, hypotension
-
Competitive substrates for alcohol dehydrogenase
- ethylene glycol
- methanol
- ethanol
-
inhibitors of aldehyde dehydrogenase
disulfiram
|
|
