Lecture 25

Question 1

Toxicant exposure is via inhalation and/or pulmonary circulation

Question 2

 _________ cardiac output passes through lungs
 ______ diffusion barriers that facilitate ____
exchange facilitate _______ uptake
 _______ surface area for gas exchange = large surface area for _______ uptake

Answer 2

 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

Question 3

Name the pulmonary defenses

Answer 3

Pulmonary defenses: mucus barrier,
mucociliary escalator system, active
immune system (bronchial associated
lymphoid tissue), toxicant metabolism, high
repair capacity

Question 4

Name the acute, toxic responses:

Answer 4

◦ Airway reactivity
◦ Edema

Question 5

Name the chronic, toxic responses:

Answer 5

◦ Emphysema
◦ Fibrosis
◦ Asthma
◦ Neoplasia

Question 6

List the signs of respiratory toxicosis

Answer 6

 Coughing
 Nasal discharge
 Epistaxis
 Dyspnea, apnea, hypopnea, hyperpnea
 Increased heart rate
 Grunting
 Weakness, confusion, fatigue, coma, death

Question 7

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 ______.

Answer 7

◦ 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

Question 8

Name the species at risk of ammonia toxicosis

Answer 8

most, esp. poultry and pigs

Question 9

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

Answer 9

 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

Question 10

What are the clinical signs of ammonium toxicity?

Answer 10

 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

Question 11

How do you Dx ammonium toxicity?

Answer 11

 History
 Field observations

Question 12

How do you prevent and control ammonium toxicityT?

Answer 12

 Adequate ventilation
 Good sanitary conditions

Question 13

What is the most common cause of human poisoning in the US?

Answer 13

Carbon monoxide

Question 14

List the sources of Carbon Monoxide

Answer 14

◦ 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

Question 15

What is the MOT of carbon monoxide toxicity?

1. 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 ______
2. 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

Answer 15

 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

Question 16

The Hb-O2 Dissociation Curves explains?

Answer 16

Explains how blood carries and releases oxygen

Question 17

Question 18

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

Question 19

What are the clinical signs of CO toxicosis

Answer 19

 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

Question 20

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

Answer 20

 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

Question 21

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

Answer 21

 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

Question 22

Question 23

Smoke is a complex mixture of vapors,
gases, fumes, heated air, particulates and
liquid aerosols

Question 24

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

Question 25

Smoke inhalation is the leading cause of deaths (>80%) from fires ◦ Primary cause of toxicity is carbon monoxide inhalation

Question 26

Other adverse effects associated with smoke inhalation include: ◦ Thermal injury, cyanide exposure, inhalation of other noxious gases, aerosols, and particulates

Question 27

What is the MOT of carbon monoxide toxicity?

Answer 27

 Asphyxiation: due to decreased supply and impaired transport of O2, occlusion of airway, and central respiratory center depression  Irritation of mucous membranes

Question 28

What are the clinical signs of smoke inhalation toxicity? Clinical Signs: reflect respiratory ___________ and/or ______ toxicity ◦ List the remaining clinical signs?

Answer 28

Clinical Signs: reflect respiratory compromise and/or systemic toxicity ◦ Coughing, dyspnea, tachypnea, tachycardia, dizziness, unconsciousness, CNS signs, death

Question 29

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 ?

Answer 29

 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

Question 30

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

Answer 30

 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

Question 31

 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

Question 32

Hydrogen Sulfide (H2S)  A colorless gas with distinct rotten-egg smell and is heavier than air

Question 33

What are the sources of hydrogen sulfide?

Answer 33

Sources: anaerobic bacterial decomposition of protein and other sulfur containing organic matter

Question 34

H2S Accumulates in manure pits, holding tanks and other low areas in animal facilities  Released when manure is agitated to suspend solids before pumping

Question 35

Name the species at risk of hydrogen sulfide toxicity

Answer 35

mainly swine, also cattle and poultry

Question 36

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.

Answer 36

 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

Question 37

What are the clinical signs of hydrogen sulfide toxicity?

Answer 37

 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

Question 38

How do you Dx H2S toxicity?

Answer 38

 History of acute death and manure pit agitation  Clinical signs

Question 39

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

Answer 39

 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

Question 40

List the sources of the pesticide paraquat

Answer 40

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)

Question 41

Which species are at risk of paraquat toxicity?

Answer 41

All. Dogs and cattle are poisoned most often

Question 42

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

Answer 42

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

Question 43

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)

Answer 43

 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)

Question 44

What are the clinical signs of paraquat toxicity?

Answer 44

 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

Question 45

Subacute/chronic paraquate Toxicosis

Answer 45

 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

Question 46

How do you dx paraquat toxicity?

Answer 46

 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)

Question 47

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

Answer 47

 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

Question 48

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)

Answer 48

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)

Question 49

L-Tryptophan  Causes acute bovine pulmonary edema and emphysema (ABPE)/acute respiratory distress syndrome (ARDS)/Fog Fever

Question 50

How are animals exposed to L-tryptophan

Answer 50

◦ 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

Question 51

Which species are at risk of L-tryptophan toxicosis

Answer 51

cattle (adult beef mostly) and other ruminants, horses

Question 52

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

Answer 52

 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

Question 53

 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

Answer 54

Question 55

What are the clinical signs of l-tryptophan toxicity?

Answer 55

 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”

Question 56

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)

Answer 56

 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)

Question 57

How do you Dx L-tryptophan toxicity?

Answer 57

 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

Question 58

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.

Answer 58

◦ 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.

Question 59

Which species are at risk of Furan toxicity?

Answer 59

mainly cattle

Question 60

Answer 60

Perilla frutescens (Mint Plant)  Ornamental, grows around hog pens and in shaded areas along rivers/creeks  Widespread in southern USA

Question 61

Greatest risk: late summer (flower and seed stage)

Question 62

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

Answer 62

Perilla ketone and 4-ipomeanol damage endothelial cells → ^ permeability → edema  They also destroy type I pneumocytes → formation and proliferation of type II pneumocytes

Question 63

What are the clinical signs of the mint plant toxicity?

Answer 63

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

Question 64

How do you Tx Furans toxicity?

Answer 64

 Antibiotics, antihistamines, corticorsteroids, NSAIDs, and diuretics may not alter the outcome of AIP  Severely affected animals may collapse and die during handling and restraint