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
