Lecture 29

Question 1

Toxicant Absorption via Skin
 The skin is an enclosing barrier and provides
environmental protection. It regulates temperature,
produces pigment and vitamin D, and has a role in
sensory perception
 Pathways of toxicant absorption:
◦ Transappendageal route
◦ Epidermal route
 Skin is also a barrier to toxicants:
◦ Structural (physical)
◦ Biochemical

Question 2

Question 3

Selenium
 A nonmetallic element
 Has 4 oxidation states: -2: selenides; 0:
elemental; +4: selenites and +6: selenates
 Essential nutrient
◦ A component (as selenocysteine) of >30
selenoproteins
 Iodothyronine deiodinases, glutathione peroxidase,
thioredoxin reductase, etc.
 Plays a role in immune function, reproduction,
biotransformation reactions and
neurotransmitter turnover

Answer 3

Question 4

Selenium (Se)
 Sources: plants
◦ Obligate indicator plants: require high
concentrations of Se to grow
 Xylorhiza (woody aster), Oonopsis (goldenweed), Stanleya
(prince’s plume), Astragalus (locoweeds)
◦ Facultative indicator plants: survive in high
Se and accumulate high levels of Se but do not
require high levels of it to grow
 Other asters, Atriplex (saltbush), Sideranthus (ironweed)
Machaeranthera, Gutierrezia (snakeweed)
◦ Non-accumulator plants: other plants growing
on seleniferous soils

Answer 4

Question 5

Answer 5

Question 6

Sources Contd.
CA maritime provinces: Se deficiency, acidic soils render Se unavailable

 High Se soils in western Canada, AZ, CO, SD,
ND, ID, KS, NE, NV, NM, UT
◦ Low rainfall areas with alkaline soils
 Errors in food formulation (rare but can
occur anywhere)
 Iatrogenic: Associated with Se use for
prevention of musculoskeletal disorders
(white muscle disease)
 Mine wastes esp. from Cu or Ag mines

Question 7

ADME
 Se absorption occurs in the duodenum and to a
lesser extent in the jejunum and ileum
 Absorption depends on the chemical form
◦ Low absorption for elemental Se; high absorption for
selenomethionine, selenocysteine and selenite
◦ Selenite is absorbed by passive diffusion via brush-
border membranes
◦ Selenate is absorbed via sodium cotransport system
◦ Selenomethionine and selenocysteine are absorbed
via amino acid transport mechanisms
 Eliminated in urine, feces and expired air
Garlic odor (dimethylselenide)

Question 8

Toxicity
 The toxic dose varies with species and
route of exposure
 Oral MLD in dogs and cats is 1.5-3 mg/kg
 Oral LD50 (selenite) is 1.9-8.3 mg/kg in
ruminants
 Oral LD50 for poultry is 33 mg/kg
 IM LD50 for injectable Se is 0.5 mg/kg in
lambs

Question 9

Mechanisms of Toxicity
 Se reacts with thiols leading to generation of
ROS  oxidative stress  cellular damage
(e.g., membrane lipid peroxidation)
 Depletion of GSH and S-adenosylmethionine
 Se replaces sulfur in proteins  impaired
enzyme activity & cellular functions (cell
division & growth)
◦ Keratinocytes & the sulfur-containing keratin they
produce are the most susceptible  weakening of
hooves and hair

Question 10

Mechanisms of Toxicity Contd.
 Embryotoxicity in birds is possibly due to
inhibition of DNA and RNA polymerases
 Induction of focal symmetrical
poliomyelomalacia of ventral horns of spinal
cord in swine

Question 11

Clinical Signs
 Species: all, horses are most sensitive
 Acute selenosis: depression,
weakness, dyspnea, cyanosis, anorexia, non-
responsiveness, garlicky odor to breath,
nasal discharge, salivation, teeth grinding,
watery diarrhea, head down, droopy ears,
prostration, mydriasis, fever, incoordination,
sweating, tachycardia, tetanic spasms,
paralysis, dog-sitting (pigs).
 Death in 2h to 7d

Answer 11

Question 12

Clinical Signs Contd.
 Subchronic selenosis
◦ Ataxia, posterior paralysis, quadriplegia, sternal
recumbency, some coronary band separation and
alopecia. Occurs in swine

Ingestion of 20-25 ppm Se in diet

Question 13

Answer 13

Symmetrical poliomyelomalacia

Question 14

Chronic Selenosis (Alkali
Disease)

Consumption of 5-15 ppm Se in diet

 Seen in cattle, horses,
sheep, pigs, poultry
 Affected animals exhibit
decreased vitality,
anaemia, joint stiffness,
lameness, rough hair coat,
hair loss (tail and mane in
horses), horn and hoof
overgrowth/deformities,
but no anorexia (animals
graze on their knees)

Question 15

Answer 15

Question 16

Teratogenesis
↑Se in irrigation drainage water,
San Joaquin Valley, California
 Occurs in waterfowl
and poultry
 Manifests as:
◦ Underdeveloped feet
◦ Underdeveloped or
missing lower and
upper beak
◦ Underdeveloped or
missing eyes

Question 17

Answer 17

stilts

Question 18

Dx
 History of access to Se source or Se
administration to animals
 Compatible clinical signs and lesions
 Se detection by chemical analysis
◦ Blood and urine
◦ Liver, kidney and spleen

Question 19

Tx
 Acute toxicosis
◦ Terminate exposure
◦ IV fluids, supplemental oxygen, assist ventilation
◦ Administer vitamin E or N-acetylcysteine
◦ Treat symptoms
 Chronic toxicosis
◦ Add arsenic salt to feed to accelerate biliary Se
excretion (in poultry, cattle and pigs)
◦ Add substances that antagonize Se to feed
◦ Eliminate source of Se and provide Se-deficient
rations
◦ Increase protein content of feed to bind free Se

Question 20

Molybdenum Toxicosis –
Copper Deficiency
 Molybdenum (Mo) is an essential nutrient
for all animals
◦ It is a component of important metalloenzymes
 Xanthine oxidase, xanthine dehydrogenase, aldehyde
oxidase, sulfite oxidase
 Purine metabolism  uric acid (an antioxidant) production,
sulfur-containing amino acids metabolism, metabolism of drugs
and toxicants
◦ Mo binds to α-macroglobulin in RBC membranes
and enhances resistance of the membranes to
rupture

Question 21

Sources
 Mo occurs naturally in copper, lead and tungsten
ores but not as an element
 Combustion of fossil fuels releases Mo
 High [Mo] in forage
◦ High soil Mo, e.g., in FL, OR, NV, CA
◦ Use of Mo fertilizers to increase nitrogen fixation
in legumes
◦ Pastures in the vicinity of metal mining or
aluminum and steel alloy production plants
 Usually a concomitant Cu deficiency is present

Question 22

ADME
 Mo and sulfate share a common transport
pathway in the intestine and kidney
◦ Sulfate competitively inhibit Mo uptake
 Mo absorption ranges from 40-90%
 Mo is eliminated in bile (cattle) or urine
(lab animals)
 Mo is also excreted in milk in ruminants
 Species: Mo toxicosis is most often
seen in ruminants and has been reported in
horses, swine and rabbits

Question 23

Toxicity and Risk
 Cattle are more susceptible than sheep and
young animals are usually more sensitive
than adults
 Dietary Cu:Mo ratio is the single most
important factor driving Mo toxicity
◦ Desired ratio of Cu to Mo is 4:1 to 10:1
 High dietary sulfur levels exacerbate Mo
toxicity because sulfur decreases Cu
absorption

Question 24

Pathophysiology/MOT
3-way interaction of Mo–Cu–S
 Dietary S is converted to sulfide in the rumen
which binds Cu  Cu absorption
◦ ↑Mo in diet increases conversion of S to sulfide
 Mo and S form thiomolybdates in the rumen
which bind Cu  insoluble Cu thiomolybdates
 Cu absorption
 When rumen Cu is low thiomolybdates are
absorbed and impair systemic Cu metabolism by
i). Increasing biliary and urinary loss of Cu  Cu
availability in blood

Answer 25

Question 26

Clinical Signs
 Clinical signs of acute and chronic
toxicoses are different
Acute toxicosis (cattle and sheep)
◦ Feed withdrawal, lethargy, weakness, hind limb
ataxia that progresses to front limbs and
recumbency
◦ Profuse salivation, ocular discharge and mucoid
feces in cattle
◦ Lesions: hydropic degeneration of hepatocytes
and renal tubules

Question 27

Chronic Toxicosis
 Severe, persistent diarrhea (peat scours)
◦ Green, liquid feces containing gas bubbles
 Achromotrichia and alopecia –> Due to depletion of tyrosinase and reduced melanin synthesis

 Emaciation, decreased milk production, delayed
puberty, decreased fertility and libido, abortions,
bone fractures, lameness, anemia, limb
deformities, muscular degeneration
 Swayback/enzootic ataxia in lambs
◦ Stiffness of the back and legs with difficulty rising
 Microcytic hypochromic anemia can occur

Question 28

Answer 28

chronic toxicosis

Question 29

Dx
 Important: Distinguishing between 1o Cu
deficiency and 2o Cu deficiency related to
excessive Mo exposure
 Clinical signs in a herd and concentration
of Mo in blood, liver and kidney
◦ Mo levels that result in toxicosis depend on the
levels of Cu and S
 Levels of Cu and Mo (ratio) in feeds/forages
 Levels of Cu and Mo in tissues
◦ There is a poor correlation between tissue
levels of Cu and clinical disease

Question 30

DDx
 Disease syndromes characterized by:
◦ Emaciation or unthriftiness
 Parasite infections, selenosis, fluorosis, ergotism
◦ Diarrhea
 Metals poisonings, GI infections
◦ Lameness or bone abnormalities
 Fluorosis, selenosis, ergotism, lead poisoning

Question 31

Tx
 Addition of Cu to diets to achieve 4:1 to
10:1 Cu-to-Mo ratio
◦ Additional Cu is necessary to cater for effects of
dietary S. The S-to-Mo ratio should be <100:1
 Administer Cu orally or parenterally
◦ Injectable products include copper glycinate or
copper edetate (Cu-EDTA)
◦ If dietary exposure is not eliminated, treatment
with copper products may be futile

Question 32

Photosensitization
 An abnormal sensitivity of skin to UV light
caused by endogenous or exogenous factors
 Affects all animals, but mostly herbivores
Classification
 Type 1: Primary photosensitization
 Type II: Aberrant endogenous pigment
synthesis (porphyria)
 Type III: Secondary/hepatogenous
photosensitization
 Type IV: Idiopathic (unknown etiology)
Not sunburn!

Question 33

Pathogenesis
 In nonpigmented skin, photodynamic compounds
are activated by absorption of light (UV) of
appropriate   higher energy state  reaction
with biological substrates or molecular oxygen 
free radicals (1O2, O2-; HO; etc.)
 The free radicals cause oxidative damage of
macromolecules (amino acids, cell membrane
lipids, proteins, DNA) and damage to organelles
(lysosomes, mitochondria, nucleus)
 Damaged cell and organelle membranes results in
increased permeability and release of lytic
enzymes and cytoplasmic extrusion
lambda = wavelength

Question 34

Pathogenesis Contd.
 The consequence of the photosensitivity
reaction is edema, cell death and ulceration
 Superficial blood vessels and epidermis are
the primary targets
◦ Epidermal cell death  skin ulceration  skin
sloughs off

Question 35

Primary Photosensitization
 Photodynamic compounds ingested, injected, or
absorbed through the skin react with light in
non-pigmented skin to cause a severe dermatitis
 Plants causing primary photosensitization:
 Fagopyrum esculentum (buckwheat)
 Hypericum perforatum (St. John’s wort)
 Ammi majus (bishop’s weed)
 Chemically induced e.g. by phenothiazines Polycyclic aromatic hydrocarbons
, Polycyclic aromatic hydrocarbons PAHs,
sulfonamides, tetracyclines, antifungals, NSAIDs

Answer 36

Answer 37

Answer 38

Question 39

Type II: Aberrant Pigment
Metabolism
 Occurs in cattle and cats
 The photosensitizing agent is porphyrin, an
endogenous pigment
◦ Arises from inherited or acquired defective
functions of enzymes involved in heme synthesis
◦ Bovine/feline congenital erythropoietic porphyria
and bovine erythropoietic protoporphyria are
the most common diseases in this category

Question 40

Type III: Secondary/hepatogenous
Photosensitization
 Phylloerythrin, a microbial breakdown
product of chlorophyll in the GI tract, is the
photosensitizing agent
◦ Hepatic disease/dysfunction or occlusion of the
biliary system prevents excretion of
phylloerythrin  concentration increases in
circulation. On reaching the skin, phylloerythrin
is activated by light  phototoxic reaction
 Hepatogenous photosensitization is most
common type of photosensitivity in livestock
and has a poor prognosis

Question 41

Plants Causing Secondary
Photosensitization
 See hepatobiliary system for additional
examples of plants/toxins/toxicants causing
2o photosensitization

Question 42

Panicum virgatum
(Switch grass)
 Panicum sp. are
collectively known as
panic grasses
 Toxic principle:
Lithogenic saponins
(diosgenin)
 Species affected:
cattle, goats, sheep
Stone-forming: crystalize in bile ducts

Question 43

Answer 43

Question 44

Agave (
Agave lecheguilla)
 Location: TX, NM
 Toxic principle:
diosgenin
 Species affected:
cattle, goats, sheep
Puncture vine (Tribulus terrestris) and beargrass
(Nolina texana) also contain diosgenin

Question 45

Answer 45

agave

Question 46

Clinical Signs of Photosensitivity
 Signs are similar regardless of the cause
 Skin areas affected most include those with little
or no hair, and areas with light-colored skin:
◦ Skin around the lips, nose, eyes and coronary band
of the hooves
◦ White skin on the face, back and legs
◦ Udder, teats and tongue
 Severe phylloerythrinemia and bright sunlight
can induce lesions even in black-coated animals

Question 47

Clinical Signs Contd.
 Initially: photophobia, excessive tearing, and
swelling, redness and increased sensitivity of
nonpigmented skin
 Later: pruritus, blister formation, ulceration
and exudation, scab formation, cutaneous edema,
fissuring of epithelium, necrosis and sloughing of
non-pigmented exposed skin, 2o bacterial
infections. Licking behavior in cattle and deer
results in glossitis with ulceration and deep
necrosis. Corneal edema and blindness may
occur
 Signs of liver disease, e.g., icterus may be present
in hepatogenous form

Question 48

Answer 48

Photosensitization

Question 49

Answer 49

Sheep: Protected by
Thick Fleece Except…
Whole body is affected if recently sheared

Question 50

Answer 50

Facial Eczema
Caused by the mycotoxin sporidesmin which produces severe
cholangitis and pericholangitis  biliary obstruction 
restriction of excretion of phylloerythrin  photosensitization

Question 51

Dx
 History or evidence of exposure to
photosensitizing agents or hepatotoxins
 Clinical signs and lesions restricted to lightly
pigmented areas with sparse hair cover
 Liver serum enzymes and histologic signs of
disease support 2o photosensitization Dx
 Porphyria Dx
◦ Signalment (sex, breed, age),
◦ Clinical signs
◦ Porphyrin levels in blood, feces and urine

Question 52

Tx
 Supportive and symptomatic care are the
only options
 Provide ample shade/sheltering during the
day
◦ Allow grazing only in darkness
 Parenteral corticosteroids in the early
stages may be helpful
 Basic wound management (lavage,
debridement, closure)
◦ Prevent 2o bacterial infections with antibiotics