Lecture 29 Flashcards
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
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
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
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
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)
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
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
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
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
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
Symmetrical poliomyelomalacia
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)
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
stilts
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
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
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
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
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
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
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
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
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
chronic toxicosis
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
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
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
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!
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
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
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
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
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
Plants Causing Secondary
Photosensitization
See hepatobiliary system for additional
examples of plants/toxins/toxicants causing
2o photosensitization
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
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
agave
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
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
Photosensitization
Sheep: Protected by
Thick Fleece Except…
Whole body is affected if recently sheared
Facial Eczema
Caused by the mycotoxin sporidesmin which produces severe
cholangitis and pericholangitis biliary obstruction
restriction of excretion of phylloerythrin photosensitization
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
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
