Lecture 25 Flashcards
Toxicant exposure is via inhalation and/or pulmonary circulation
_________ cardiac output passes through lungs
______ diffusion barriers that facilitate ____
exchange facilitate _______ uptake
_______ surface area for gas exchange = large surface area for _______ uptake
Total cardiac output passes through lungs
Thin diffusion barriers that facilitate gas
exchange facilitate toxicant uptake
Large surface area for gas exchange = large
surface area for toxicant uptake
Name the pulmonary defenses
Pulmonary defenses: mucus barrier,
mucociliary escalator system, active
immune system (bronchial associated
lymphoid tissue), toxicant metabolism, high
repair capacity
Name the acute, toxic responses:
◦ Airway reactivity
◦ Edema
Name the chronic, toxic responses:
◦ Emphysema
◦ Fibrosis
◦ Asthma
◦ Neoplasia
List the signs of respiratory toxicosis
Coughing
Nasal discharge
Epistaxis
Dyspnea, apnea, hypopnea, hyperpnea
Increased heart rate
Grunting
Weakness, confusion, fatigue, coma, death
List the sources of Ammonia
◦ Toxic air pollutant most frequently found in
________ concentrations in animal facilities
◦ Most common where _____ and other ______ are allowed to accumulate and decompose on solid floor
_____ hygiene conditions
The species most at risk are ______ and ______.
◦ Toxic air pollutant most frequently found in
high concentrations in animal facilities
◦ Most common where feces and other wastes are allowed to accumulate and decompose on solid floor
Poor hygiene conditions
Pigs and poultry
Name the species at risk of ammonia toxicosis
most, esp. poultry and pigs
What is the MOT of ammonia toxicity?
NH3 dissolves in ______ layer in the ____
and ______ respiratory tract to form ______
which is caustic and causes:
◦ Irritation of ___________ epithelium
◦ __________ of cells through disruption of cell
membrane ______ → __________ response
At concentrations found in animal facilities
(<_____ ppm) it causes chronic _______ to the
respiratory tract → secondary _______ infections and _______ growth
NH3 dissolves in aqueous layer in the eye
and upper respiratory tract to form NH4OH
which is caustic and causes:
◦ Irritation of respiratory epithelium
◦ Necrosis of cells through disruption of cell
membrane lipids → inflammatory response
At concentrations found in animal facilities
(<100ppm) it causes chronic stress to the
respiratory tract → 2o bacterial infections
and reduced growth
What are the clinical signs of ammonium toxicity?
Excessive tearing, shallow breathing, clear or
purulent nasal discharge
Increased secondary respiratory infections e.g.,
Bordetella rhinitis in pigs
Chickens may develop keratoconjunctivitis, corneal
opacity and tracheatis
Reduced production
Death at very high (>2500 ppm) exposure
concentrations
How do you Dx ammonium toxicity?
History
Field observations
How do you prevent and control ammonium toxicityT?
Adequate ventilation
Good sanitary conditions
What is the most common cause of human poisoning in the US?
Carbon monoxide
List the sources of Carbon Monoxide
◦ Odorless and colorless gas
◦ Byproduct of incomplete combustion of
hydrocarbon fuels esp. in the internal
combustion engine
◦ Gas water heaters, space heaters, or
furnaces in poorly ventilated spaces e.g.
farrowing houses and lambing sheds
◦ Fires
What is the MOT of carbon monoxide toxicity?
- Competes with O2 for binding sites on
__________
◦ Affinity of ____ for CO is 250× that for O2
◦ O2 carrying capacity of ___ is severely reduced
◦ Capacity to give off CO2 in the lungs is ______ - Increases affinity of O2 for ____ and the
stability of O2-___ bond
◦ O2 dissociation curve shifts to the _____
◦ Release of O2 from ___ to tissues is ______
Net effect = ______ availability of O2
to cells
Competes with O2 for binding sites on
hemoglobin (Hb)
◦ Affinity of Hb for CO is 250× that for O2
◦ O2 carrying capacity of Hb is severely reduced
◦ Capacity to give off CO2 in the lungs is reduced
Increases affinity of O2 for Hb and the
stability of O2-Hb bond
◦ O2 dissociation curve shifts to the left
◦ Release of O2 from Hb to tissues is impaired
Net effect = Reduced availability of O2
to cells
The Hb-O2 Dissociation Curves explains?
Explains how blood carries and releases oxygen
Mechanisms of Toxicity Cont.
Impairment of O2 transport by myoglobin
in a similar fashion as for Hb
Binds to cytochrome c oxidase in
mitochondria → interferes with cellular
respiration and causes generation of
reactive oxygen species → oxidative stress
Cytochromc C oxidase: Complex IV of the mitochondrial electron transport chain
What are the clinical signs of CO toxicosis
Signs @ >25% COHb; death @ >/= 60% COHb
Reflect hypoxia of tissues. Tissues with high
O2 demand (brain, heart and skeletal muscle)
are most impacted
Initially: drowsiness, nausea, vomiting, lethargy,
weakness, deafness (cats & dogs),
incoordination and cardiac arrhythmias
Cherry-red color to blood, skin and mucous
membranes due to high [COHb]
Severely affected animals: dyspnea, terminal clonic spasms, coma and acute death
Abortion
◦ CO crosses the placental barrier → fetal hypoxia
Chronic exposure to low levels results in
exercise intolerance and disturbances in
postural and position reflexes
How do you Dx CO toxicosis?
History suggestive of ____ exposure, e.g.,
_________ or faulty fuel burning ______
Clinical signs of _____ death and ______
Measure ____ in suspect environment
Measure _____ in blood
History suggestive of CO exposure, e.g.,
unvented or faulty fuel burning heaters
Clinical signs of acute death and hypoxia
Measure CO in suspect environment
Measure COHb in blood
How do you treat CO toxicosis?
Main goal: restore adequate _____ supply
particularly to the _____ and _____
◦ Decontaminate: move patient to an area of ____ air
◦ Establish and maintain _______ airway
◦ Provide artificial _______ if necessary
◦ Give _________ oxygen
◦ Give blood _________ for _______ Hb
Main goal: restore adequate oxygen supply
particularly to the brain and heart
◦ Decontaminate: move patient to an area of fresh air
◦ Establish and maintain patent airway
◦ Provide artificial respiration if necessary
◦ Give hyperbaric oxygen
◦ Give blood transfusion for functional Hb
Smoke is a complex mixture of vapors,
gases, fumes, heated air, particulates and
liquid aerosols
There is no typical smoke: composition of
smoke is highly variable
◦ Synthetic materials give rise to worse smoke in
terms of fume intensity and composition
Smoke inhalation is the leading cause of
deaths (>80%) from fires
◦ Primary cause of toxicity is carbon
monoxide inhalation
Other adverse effects associated with
smoke inhalation include:
◦ Thermal injury, cyanide exposure, inhalation
of other noxious gases, aerosols, and
particulates
What is the MOT of carbon monoxide toxicity?
Asphyxiation: due to decreased supply and
impaired transport of O2, occlusion of
airway, and central respiratory center
depression
Irritation of mucous membranes
What are the clinical signs of smoke inhalation toxicity?
Clinical Signs: reflect respiratory
___________ and/or ______ toxicity
◦ List the remaining clinical signs?
Clinical Signs: reflect respiratory
compromise and/or systemic toxicity
◦ Coughing, dyspnea, tachypnea, tachycardia,
dizziness, unconsciousness, CNS signs, death
How do you Dx smoke inhalation toxicity?
Presence of _____ smoke odor on _____
Perform __________/_____________
◦ Reveals ______/_______ of injury
Perform pulse __________
Measure ______ blood gas, _______ and ______ levels
Evaluate _____ of blood
Radiography to assess ?
Presence of acrid smoke odor on haircoat
Perform laryngoscopy/bronchoscopy
◦ Reveals extent/severity of injury
Perform pulse co-oximetry
Measure arterial blood gas, COHb and
metHb levels
Evaluate color of blood
Radiography to assess atelectasis, edema,
hemorrhage or infection
How do you treat smoke inhalation toxicity?
Decontaminate
◦ _______ animal from smoke-filled environment
Best left to professional firefighters!
◦ Irrigate _____ and _______ immediately
Maintain airway _______ (key to therapy)
◦ Immediately undertake endotracheal _______ or _________ for animals with signs of ______ airway injury, _________, ______ or _______
Perform procedure early because airway _______ may make intubation difficult or impossible
Decontaminate
◦ Remove animal from smoke-filled environment
Best left to professional firefighters!
◦ Irrigate eyes and skin immediately
Maintain airway patency (key to therapy)
◦ Immediately undertake endotracheal intubation or tracheostomy for animals with signs of upper airway injury, obstruction, coma or burns
Perform procedure early because airway edema may make intubation difficult or impossible
Provide adequate ventilation and oxygen
supplementation
◦ It is assumed CO poisoning has occurred
Suction airway frequently to remove secretions,
debris and necrotic material
β2-adrenergic agonists (e.g., albuterol, terbutaline,
epinephrine) for bronchospasm and
bronchoconstriction
Treat cyanide poisoning with hydroxocobalamin
Control and prevention: avoid exposure, provide
adequate ventilation, use smoke detectors
Hydrogen Sulfide (H2S)
A colorless gas with distinct rotten-egg
smell and is heavier than air
What are the sources of hydrogen sulfide?
Sources: anaerobic bacterial decomposition
of protein and other sulfur containing
organic matter
H2S
Accumulates in manure pits, holding tanks
and other low areas in animal facilities
Released when manure is agitated to suspend
solids before pumping
Name the species at risk of hydrogen sulfide toxicity
mainly swine, also cattle and
poultry
What is the MOT of hydrogen sulfide toxicity?
Irritation → ___________ of mucous
membranes of the _____ and _________ tract
At higher levels it causes _______ toxicity
(________ system, ______, ________ muscles)
◦ Stimulation of ________ in the carotid body (Regulate ________ activity: maintain arterial ?) → __________, ______, _______
◦ Paralyzing effect on the ________ and __________ centers chemoreceptors.
Irritation → inflammation of mucous
membranes of the eye and respiratory tract
At higher levels it causes systemic toxicity
(nervous system, heart, skeletal muscles)
◦ Stimulation of chemoreceptors in the carotid body (Regulate respiratory activity: maintain arterial PO2, PCO2 & pH)→ hyperpnea, acapnia and apnea
◦ Paralyzing effect on the respiratory and olfactory centers chemoreceptors
What are the clinical signs of hydrogen sulfide toxicity?
Increased secretions in the eye and
respiratory tract due to irritation, pulmonary
edema, respiratory and olfactory paralysis
Nervous stimulation (spasms, convulsions),
collapse, semicomatose state and death
Note: humans detect low conc. of H2S (<0.025ppm)
as rotten egg smell. High conc. depress olfactory
sensory apparatus blocking odor detection
How do you Dx H2S toxicity?
History of acute death and manure pit
agitation
Clinical signs
How do you treat H2S toxicity?
______ animals from H2S source and
provide good ventilation
Provide __________ support and __________
◦ Breathing ________ re-establishes spontaneously after H2S-induced respiratory paralysis
Treat pulmonary ______ if present
Remove animals from H2S source and
provide good ventilation
Provide cardiorespiratory support and
resuscitation
◦ Breathing never re-establishes spontaneously after H2S-induced respiratory paralysis
Treat pulmonary edema if present
List the sources of the pesticide paraquat
A contact herbicide now
restricted in US.
◦ Still used in many countries (<50,000 kg used in
Canada annually)
◦ Contaminated vegetation, improperly stored or
disposed pesticides, access to spills
◦ Malicious poisoning (dogs)
Which species are at risk of paraquat toxicity?
All. Dogs and cattle are poisoned
most often
What is the ADME of paraquat toxicity?
Rapid but incomplete (dog: ___-___%)
absorption _____ with peak plasma conc. in ____ min.
Broken down _____ in GI tract
Preferentially concentrated in type __ & __
alveolar cells by a ________-_______
transport system
Excreted in _____ (largely __________)
Bioavailability is ________ by binding tightly to _____ → environmental persistence
Rapid but incomplete (dog: 25-28%)
absorption orally with peak plasma conc. in
75 min.
Broken down slowly in GI tract
Preferentially concentrated in type I & II
alveolar cells by a diamine-polyamine
transport system
Excreted in urine (largely unchanged)
Bioavailability is reduced by binding tightly to soil → environmental persistence
What is the MOT of paraquat toxicity?
Paraquat is an ______ and a __________
Paraquat undergoes ______ cycling →
production of _____ → oxidation of _______
and other reductants → oxidation of cellular
__________ (oxidative ____) → cell ____
Toxic dose: 22-262mg/kg bw. Oral LD50,
mg/kg bw = 25-50 (dogs) and 40-50 (cats)
Paraquat is an irritant and a vesicant
Paraquat undergoes redox cycling →
production of ROS → oxidation of NADPH
and other reductants → oxidation of cellular
macromolecules (oxidative stress) → cell
death
Toxic dose: 22-262mg/kg bw. Oral LD50,
mg/kg bw = 25-50 (dogs) and 40-50 (cats)
What are the clinical signs of paraquat toxicity?
Local toxicity: erythema, ulceration and blistering
Acute poisoning from oral exposure occurs in three phases:
◦ First phase: irritant/caustic action causes GI tract pain, anorexia, vomiting, diarrhea
◦ Second phase: renal failure and centrilobular hepatocellular necrosis
◦ Third phase: pulmonary edema with dyspnea,
and tachypnea. Toxicosis progresses to a proliferative stage with extensive pulmonary fibrosis
poor prognosis
Subacute/chronic paraquate Toxicosis
Results from lower dose exposures
Manifests as hyperplasia of type II
alveolar epithelial cells with healing by
fibrosis
◦ Cyanosis develops when poisoned
animals are exercised
Due to mismatch between ventilation and perfusion, increased
arterial O2 gradient and desaturation of Hb with O2
How do you dx paraquat toxicity?
History of consumption of herbicide or
spraying of herbicide in an enclosed space
Clinical signs and gross and histologic
lesions
Analysis of paraquat in urine, plasma
and lung
◦ Highest concentration is found in the lung
(target tissue for chronic poisoning)
How do you treat paraquat toxicity?
Decontamination
◦ ______ within 1 h of exposure or gastric lavage
◦ Administer adsorbent. __________ _________ is
preferred to kaolin, clay or bentonite because it is more effective in reducing the _____ and ______ of the toxicosis
◦ Administer a cathartic if within ___ h of exposure; IV administration of large volumes of _______ fluids and ________
◦ Perform forced _______ and charcoal
___________ with Hemocol cartridge
Caution: Forced diuresis may ________ pulmonary edema
Decontamination
◦ Emesis within 1 h of exposure or gastric lavage
◦ Administer adsorbent. Activated charcoal is
preferred to kaolin, clay or bentonite because it is more effective in reducing the severity and fatality of the toxicosis
◦ Administer a cathartic if within 12 h of exposure. IV administration of large volumes of isotonic fluids and diuretics
◦ Perform forced diuresis and charcoal
hemoperfusion with Hemocol cartridge
Caution: Forced diuresis may aggravate pulmonary edema
Supportive and symptomatic therapy
◦ Maintain _______ and protect ________
◦ Monitor ____ signs and blood ____ frequently
◦ _____ management
◦ Prevent/treat ______ failure
◦ ________ blood losses
◦ Treat _____ complications and _______ signs
◦ Supplemental oxygen is contraindicated (oxygen appears to aggravate ________ damage)
Supportive and symptomatic therapy
◦ Maintain circulation and protect airway
◦ Monitor vital signs and blood gases frequently
◦ Pain management
◦ Prevent/treat renal failure
◦ Replace blood losses
◦ Treat cardiac complications and neurological signs
◦ Supplemental oxygen is contraindicated (oxygen
appears to aggravate pulmonary damage)
L-Tryptophan
Causes acute bovine pulmonary edema and
emphysema (ABPE)/acute respiratory distress
syndrome (ARDS)/Fog Fever
How are animals exposed to L-tryptophan
◦ Occurs when hungry adult cattle are moved from
dry pastures to rapidly growing lush, green forage
(foggage) high in L-tryptophan or when dry hay is
replaced with lush, green forage
No fog, no fever! Name is derived from foggage
Which species are at risk of L-tryptophan toxicosis
cattle (adult beef mostly) and other
ruminants, horses
What is the MOT of Tryptophan toxicity
L-tryptophan is metabolized by ruminal
_________ to _____ → absorbed and concentrated in the ____
3-MI is metabolized by _________ ____ or
prostaglandin __ _______ (in ___ cells and
______, and type __ pneumocytes to a
lesser extent) to a toxic metabolite, _____
3-MEIN preferentially destroys ___ cells and
type __ pneumocytes → proliferation of type __ pneumocytes to restore the ______ epithelium
◦ During the proliferation period, type __ pneumocytes have ________ ability to synthesize and secrete functional surfactant. The surfactant produced does not effectively ______ surface tension
There is ________ alveolar permeability
resulting in edema
The alveolar damage is followed by ______
resulting in ______ interstitial pneumonia
a typical == No response to conventional therapy
L-tryptophan is metabolized by ruminal
microbes to 3-methylindole (3-MI) →
absorbed and concentrated in the lungs
3-MI is metabolized by cytochrome P450 or
prostaglandin H synthetase (in club cells and
macrophages, and type II pneumocytes to a
lesser extent) to a toxic metabolite, 3-
methyleneindolenine (3-MEIN)
3-MEIN preferentially destroys club cells and
type I pneumocytes → proliferation of type II
pneumocytes to restore the alveolar epithelium
◦ During the proliferation period, type II pneumocytes
have decreased ability to synthesize and secrete
functional surfactant. The surfactant produced does
not effectively lower surface tension
There is increased alveolar permeability
resulting in edema
The alveolar damage is followed by fibrosis
resulting in atypical interstitial pneumonia
a typical == No response to conventional therapy
3-MEIN preferentially destroys club cells and
type I pneumocytes → proliferation of type II
pneumocytes to restore the alveolar epithelium
◦ During the proliferation period, type II pneumocytes
have decreased ability to synthesize and secrete
functional surfactant. The surfactant produced does
not effectively lower surface tension
There is increased alveolar permeability
resulting in edema
The alveolar damage is followed by fibrosis
resulting in atypical interstitial pneumonia
a typical == No response to conventional therapy
What are the clinical signs of l-tryptophan toxicity?
Occur 5-10 days after move to lush pasture
Severe dyspnea with open-mouth breathing and
reluctance to move. Coughing is not a
prominent feature of this toxicosis
Animals stand with their feet wide apart, head
and neck extended and lowered, and the
nostrils flared
Animals then become recumbent and die
Less severely affected animals: depression, loud
expiratory grunt, wheezing and frothy salivation
No fever
Late summer & early fall
“panters” or “lungers”
L-tryptophan pathology
Cranial lung lobes are _____, deep-_____,
______ when cut, and do not _______
Lungs are ____, _______ and ________
Air ________/gas _____ throughout the lung
Pulmonary ______, particularly ________
Gelatinous yellow fluid oozes from ____
surfaces and airways are filled with _____
Microscopically: Alveolar epithelial
_________ (= _________ appearance)
Cranial lung lobes are heavy, deep-purple,
glisten when cut, and do not collapse
Lungs are firm, rubbery and distended
Air bubbles/gas bullae throughout the lung
Pulmonary edema, particularly ventrally
Gelatinous yellow fluid oozes from cut
surfaces and airways are filled with froth
Microscopically: Alveolar epithelial
proliferation (= glandular appearance)
How do you Dx L-tryptophan toxicity?
History e.g., change in pasture
Clinical signs and lesions
Tx: none is effective
NSAIDs, diuretics, bronchodilators and
antihistamines have had little success
Prevention and control
Avoid sudden introduction of lush pasture to
cattle diet
Ionophores may provide partial protection by
inhibiting growth of bacteria that convert L-
tryptophan to 3-MI
List the sources of Furans
◦ Perilla ketone (______ plant, perilla frutescens)
◦ 4-ipomeanol in _____ sweet ______ (infested with fungi of Fusarium sp.)
4-ipomeanol is formed from 4-hydroxymyoporone, a _____ metabolite produced by sweet ______ with Fusarium fungal infestation
◦ Peanut vine hay and green beans infested with fungi of Fusarium sp.
◦ Perilla ketone (mint plant, perilla frutescens)
◦ 4-ipomeanol in moldy sweet potatoes (infested with fungi of Fusarium sp.)
4-ipomeanol is formed from 4-hydroxymyoporone, a stress metabolite produced by sweet potatoes with Fusarium fungal infestation
◦ Peanut vine hay and green beans infested with fungi of Fusarium sp.
Which species are at risk of Furan toxicity?
mainly cattle
Perilla frutescens (Mint Plant)
Ornamental, grows
around hog pens and in
shaded areas along
rivers/creeks
Widespread in
southern USA
Greatest risk: late summer (flower and seed stage)
What is the MOT of the mint plant?
Perilla ketone and 4-ipomeanol damage ________ cells → ____ permeability → ______
They also destroy type ___ pneumocytes → formation and proliferation of type ___ pneumocytes
Perilla ketone and 4-ipomeanol damage endothelial cells → ^ permeability → edema
They also destroy type I pneumocytes → formation and proliferation of type II pneumocytes
What are the clinical signs of the mint plant toxicity?
atypical interstitial pneumonia (AIP)
◦ Acute onset of dyspnea with open-mouth breathing,
extension of head and neck, loud expiratory grunt,
froth in the mouth and nose, subcutaneous
emphysema along the neck and back, minimal
coughing
How do you Tx Furans toxicity?
Antibiotics, antihistamines, corticorsteroids,
NSAIDs, and diuretics may not alter the
outcome of AIP
Severely affected animals may collapse and
die during handling and restraint
