Cholecalciferol Poisoning
by
Carla Morrow, DVM
Cholecalciferol (vitamin D3) is found commercially in rodenticides and vitamin supplements. One IU of
vitamin D3 is equivalent to 0.025 μg of cholecalciferol.1 Table 1 lists some common products that contain
cholecalciferol.
Cholecalciferol is rapidly absorbed after ingestion. The parent compound and metabolites are fat soluble
and, thus, are stored in adipose tissue. Enterohepatic recirculation of cholecalciferol and its metabolites
occurs.2 With normal dietary intake, cholecalciferol is converted to 25-hydroxycholecalciferol (calcifediol)
by 25-hydroxylase in the liver. There is limited negative feedback of calcifediol on the activity of hepatic
25-hydroxylase, and its activity is not influenced by plasma calcium and phosphorus concentrations.3
Calcifediol becomes metabolically activated to 1,25-dihydroxycholecalciferol (calcitriol) in the kidneys by
1-α-hydroxylase. The rate of renal 1-α-hydroxylase activation depends on plasma concentrations of
parathyroid hormone, calcium, phosphorus, and calcitriol.3
After a massive cholecalciferol intake (i.e. after ingesting a cholecalciferol-containing rodenticide), excess
calcifediol is produced in the liver. Calcitriol is initially produced in the kidneys, but once a set plasma
concentration of calcitriol is reached, it exerts negative feedback on renal 1-α-hydroxylase, and no more
calcitriol is produced.3 However, because of the limited negative feedback on hepatic 25-hydroxylase,
calcifediol concentrations continue to increase, and the plasma concentrations of calcifediol become high
enough to exert metabolic effects.3
Because of their high lipid solubility, cholecalciferol and its metabolites are eliminated slowly from the
body. Cholecalciferol has a plasma half-life of 19 to 25 hours and a terminal half-life (the time needed for
the amount of a compound present in all body stores to decrease by half) of weeks to months.2 Calcifediol
has an experimental elimination half-life of 19 days.2 Metabolites are eliminated primarily (96%) through
the bile and feces.3
Mechanism of action
The metabolic activity of cholecalciferol and its metabolites is variable. Calcitriol is the most metabolically
active and binds to the vitamin D receptors 500 times greater than calcifediol does and 1,000 times greater
than cholecalciferol does.3
The active metabolites increase plasma calcium and phosphorus concentrations through two primary
mechanisms. First, they increase the amount of intestinal calcium-binding protein (calbindin). The amount
of calcium absorbed is directly related to the amount of calbindin in the enterocytes.4 Thus, more calcium is
absorbed from the intestines when calbindin is increased. Second, cholecalciferol metabolites stimulate
calcium and phosphorus transfer from bone to plasma.3
Clinical signs (vomiting, lethargy, muscle weakness) seen within the first 48 hours of cholecalciferol
overdose are due to the direct effect of increased plasma calcium concentrations on cells. These cellular
effects include altered cell membrane permeability, altered calcium pump activity, decreased cellular
energy production, and cellular necrosis.3 Specific organ effects include acute renal tubular necrosis,
gastrointestinal stasis, increased gastric acid secretion, decreased skeletal muscle responsiveness, and
decreased neural tissue responsiveness.3
With an unregulated increase in plasma calcium and phosphorus concentrations, the plasma calcium X
phosphorus product can rise above 60, which will likely cause soft tissue mineralization.5 Mineralization of
the kidneys, gastrointestinal tract, cardiac muscle, skeletal muscle, blood vessels, and ligaments causes
structural damage that leads to decreased functional capacity of these tissues and organs. This loss of
function contributes to the development of ongoing and end-stage clinical signs as well as long-term signs
in animals that survive.3
Toxicosis and risk factors
Any animal that ingests cholecalciferol-containing rodenticides has a greater risk of developing toxicosis
than does an animal that ingests supplements that contain vitamin D. Clinical signs can be seen at 0.5
mg/kg of cholecalciferol.6 This corresponds to 6 g (79 pellets or about ½ tbsp) of a typical 0.075%
cholecalciferol rat bait ingested by a 20-lb (9-kg) dog.7 The amount of cholecalciferol in most vitamin
supplements is not considered a risk for companion animals, even with massive ingestion. While a pet
ingesting large amounts of vitamin supplements may develop a self-limiting gastroenteritis, the signs can
be attributed to nonspecific gastrointestinal irritation. Relay toxicosis (i.e. toxicosis in an animal that has
ingested a rodent that died of cholecalciferol poisoning) with cholecalciferol baits has not been reported.
Clinical signs
Signs of acute toxicosis develop within 12 to 36 hours after ingestion.6 They include vomiting and diarrhea
(sometimes bloody),
anorexia, depression, and possibly polyuria and polydipsia.8,9 With high doses,
fulminant acute renal failure can occur within 24 to 48 hours. Death can result from acute renal failure in
severely affected animals. Animals that survive may lose renal or musculoskeletal function and may
develop cardiac arrhythmias.3 Clinical signs and subsequent treatment may last for weeks because of the
lipid storage and slow elimination of the cholecalciferol metabolites.
Clinical pathology
In cases of acute toxicosis, there is a moderate rise in the serum phosphorus concentration (up to 11 mg/dl)
and a more severe rise in the serum calcium concentration (up to 20 mg/dl).8-10 The calcium X phosphorus
product may easily exceed 130. These changes are seen between 12 and 72 hours after exposure.8-10
Secondary increases in blood urea nitrogen and creatinine concentrations may also occur in this time frame.
Urine specific gravity becomes isosthenuric.
Diagnostic testing
You must rule out other causes of hypercalcemia when a patient has an uncertain history of cholecalciferol
exposure. These causes include hypercalcemia when a patient has an uncertain history of cholecalciferol
exposure. These causes include hypercalcemia of malignancy (mediated through parathyroid hormonerelated
peptide), hypoadrenocorticism, chronic renal failure, primary hyperparathyroidism, feline idiopathic
hypercalcemia,11 and ingestion of human prescription skin products containing the vitamin D analogues
calcipotriene or tacalcitol.12,13 (For more information on calcipotriene poisoning, see “Calcipotriene
poisoning in dogs,” Oct. 2000, p. 770.)
A parathyroid hormone/parathyroid hormone-related peptide/calcifediol assay may help differentiate
among the various causes of hypercalcemia (Table 2).5 This assay should detect overexposure to
cholecalciferol products, since calcifediol is elevated during cholecalciferol toxicosis. However, easy and
routine assays for calcipotriene, tacalcitol, and calcitriol are lacking, making a definitive diagnosis through
chemical identification of these analogues difficult.
If you are submitting samples for a parathyroid hormone/parathyroid hormone-related peptide/calcifediol
assay, contact your diagnostic laboratory to confirm test availability. If the assay is unavailable,
antemortem serum analysis for parathyroid hormone/calcifediol and antemortem plasma analysis for
parathyroid hormone-related peptide can be performed at Michigan State University. Send chilled samples
to the Animal Health Diagnostic Laboratory, Endocrine Diagnostic Section, 619 W. Fee Hall B, Michigan
State University, East Lansing, MI 48824-1315. For more information call (517) 353-0621, or visit
www.ahdl.msu.edu.
Treatment
In cases in which the exposure is recent, an animal is asymptomatic, and there are no underlying
contraindications to emesis (e.g. underlying cardiac or seizure disorders, the patient is a lagomorph or
rodent), induce vomiting. All asymptomatic patients should receive activated charcoal (1 to 2 g/kg mixed
with 50 to 200 ml water administered orally; or 240 ml commercial slurry per 25- to 50-lb [11- to 23-kg]
animal) given with a cathartic. Many commercial slurries contain sorbitol as a cathartic. If a slurry does not
contain a cathartic, ¼ tsp Epsom salts (magnesium sulfate)/10 lb can be added. In cases of large or massive
ingestion, repeated doses of activated charcoal at half the initial dose and without a cathartic may be given
at six- to eight-hour intervals for 48 hours. Multiple doses of activated charcoal may help interrupt
enterohepatic recirculation of cholecalciferol and its metabolites.
Obtain baseline measurements of serum calcium, phosphorus, blood urea nitrogen, and creatinine
concentrations, and monitor these parameters daily for four days. If the values stay normal and the patient
remains asymptomatic, no further monitoring or treatment is necessary.12
In animals that develop clinical signs or elevations in serum calcium concentrations, initial treatment
consists of diuresis with intravenous 0.9% saline solution at two to three times the maintenance rate. Saline
is preferred because it contains no calcium, and the sodium ions reduce tubular calcium reabsorption,
leading to increased calcium excretion.3
Once an animal’s hydration status is normal, administer furosemide as a 5 mg/kg intravenous initial bolus
and then as a 5-mg/kg/hr constant-rate intravenous infusion3; 2 to 4 mg/kg furosemide given orally every
eight hours is another option.14 Furosemide decreases sodium and chloride reabsorption across Henle’s
loop, resulting in a diminished positive potential across the renal tubule. This diminished potential
increases renal calcium excretion.3 Carefully monitor hydration status, and reduce the amount of
furosemide in the constant-rate infusion if dehydration develops.3 Do not use thiazide diuretics, because
they are calcium-sparing.3
Administering prednisone at 1 to 2.2 mg/kg every 12 hours orally will decrease serum calcium
concentrations by decreasing bone resorption and intestinal calcium absorption and increasing renal
calcium excretion.3
Phosphate binders (aluminum hydroxide [Amphojel – Wyeth-Ayerst]; 30 to 90 mg/kg/day divided, given
orally with meals) and a low-calcium, low-phosphorus diet are recommended to decrease dietary mineral
absorption while a patient is being treated and monitored (generally four weeks).3 Affected animals should
avoid sunlight to prevent endogenous cholecalciferol formation. Carefully consider using activated
charcoal in symptomatic patients, weighing the risk of aspiration in a vomiting animal against the benefit of
activated charcoal.
Continue intravenous saline solution administration until serum calcium concentrations are normal.12
Furosemide and prednisone can be continued for one or two weeks after you discontinue the intravenous
saline solution and then gradually reduced.3 Monitor calcium concentrations daily for four days after
stopping fluids, twice a week for two weeks after that, and then weekly for two weeks.3
Severely affected animals, animals whose calcium concentrations do not respond to initial therapy, or
animals who relapse after fluid discontinuation may benefit from treatment with a bisphosphonate. The
bisphosphonate pamidronate disodium (Aredia – Novartis) has been used successfully in dogs for
cholecalciferol toxicosis. Pamidronate (1.3 to 2 mg/kg diluted with saline solution and given intravenously
over two hours) reduces serum calcium concentrations.15 Maintain the animal on therapeutic intravenous
saline solution (two to three times the maintenance rate) until the calcium concentrations are normal. Once
serum calcium concentrations return to normal, monitor them daily for four days. Pamidronate retreatment
five to seven days later may be necessary.
Bisphosphonates lower plasma calcium by inhibiting bone reabsorption of calcium through blocking
dissolution of hydroxyapatite and inhibiting osteoclastic bone resorption.15 While biphosphonates are
expensive, they may save a client money in the long run. They lower plasma calcium concentrations in 24
to 48 hours, allowing a patient to be treated on an outpatient basis instead of being hospitalized and
receiving intravenous saline solution for two to four weeks.
If a bisphosphonate is not available, salmon calcitonin (4 to 6 IU/kg t.i.d. subcutaneously) may be used to
lower serum calcium.3 Salmon calcitonin lowers plasma calcium concentrations by inhibiting osteoclastic
activity. But salmon calcitonin must be administered more frequently than bisphosphonates, and some
patients may become refractory to salmon calcitonin.15
Using bisphosphonates and salmon calcitonin in the same patient, either simultaneously or sequentially, is
controversial. Experimental animals that received both did worse than animals receiving one or the other.16
However, concurrent use of salmon calcitonin and bisphosphonates is the preferred treatment of emergency
hypercalcemia of malignancy in people.3
Prognosis
The prognosis is good for animals that are decontaminated promptly or that receive treatment to decrease
their serum calcium concentrations before soft tissue mineralization occurs. The prognosis is more variable
if soft tissue mineralization has occurred. Soft tissue mineralization is minimally reversible and can lead to
structural damage and decreased function of the renal, cardiovascular, gastrointestinal, and musculoskeletal
systems. The amount of function loss and, thus, the prognosis depend on the duration and severity of the
elevated plasma calcium X phosphorus product.12 When animals present with signs of cholecalciferol
toxicosis, inform clients of the seriousness of the situation and the cost and commitment required for
treatment.
Table 1 Products Containing Cholecalciferol
Product Name Concentration Formulations
Quintox – Bell Laboratories 0.075% cholecalciferol Pellets, seed mixtures, place
packs
Rampage Motomco Ltd. 0.075% cholecalciferol Pellets, place packs, bait chunks
Viactiv – Mead Johnson 100 IU (2.5 μg) vitamin D3;
500 mg calcium;
40 μg vitamin K (per chew)
Chews flavored as milk
chocolate, caramel, orange cream,
or mochaccino
Multivitamins Most products contain 400 IU (10
μg) of vitamin D2 or D3 (per
tablet)
Tablets
Table 2 Expected Results of Parathyroid Hormone/Parathyroid Hormone-Related
Peptide/Calcifediol Assay for Various Causes of Hypercalcemia
Disease Parathyroid Hormone
(serum)
Hormone/Parathyroid
Hormone-Related
Peptide (plasma)
Calcifediol (serum)
Cholecalciferol
toxicosis* Decreased Absent Increased
Hypercalcemia of
malignancy* Decreased Present Normal
Chronic renal failure* Increased Absent Unknown (normal)
Primary
hyperparathyroidism* Increased Absent Unknown (normal)
Feline idiopathic
hypercalcemia** Normal Absent Unknown (normal)
*Source: Kruger, J.M. et al.: Hypernatremia and renal failure: Etiology, pathophysiology, diagnosis and treatment. Vet.
Clin. North Am. (Small Anim. Pract.) 26 (6):1417-1445; 1996.
**Source: Midkiff, A.M. et al.: Idiopathic hypercalcemia in cats, J. Vet. Intern. Med. 14 (6):619-626; 2000.
References
1. Puls, R.: Vitamin D. Vitamin Levels in Animal Health: Diagnostic Data and Bibliographies. Sherpa
International, Clearbrook, British Columbia, Canada, 1994; pp 81-97.
2. Marcus, R.: Agents affecting calcification and bone turnover, Goodman and Gilman’s: The
Pharmacological Basis of Therapeutics, 9th Ed. (J. Hardman; L. Limbird, eds.). McGraw-Hill, New
York, 1996; pp 1519-1546.
3. Rosol, T. et al.: Disorders of calcium. Fluid Therapy in Small Animal Practice, 2nd Ed. (S. DiBartola,
ed.). W.B. Saunders, Philadelphia, Pa., 2000; pp 108-162.
4. Kutchai, H.: Digestion and absorption. Physiology, 4th Ed. (R. Berne et al., eds.). Mosby, St. Louis,
Mo., 1998; pp 647-676.
5. Kruger, J.M. et al.: Hypercalcemia and renal failure: Etiology, pathophysiology, diagnosis, and
treatment: Vet. Clin. North Am. (Small Anim. Prac.) 26 (6):1417-1445; 1996.
6. Dorman, D.C.: Toxicology of selected pesticides, drugs, and chemicals. Anticoagulant, cholecalciferol,
and bromethalin-based rodenticides. Vet. Clin. North Am. (Small Anim. Pract.) 20 (2):339-352; 1990.
7. Metts, B.C. et al.: Clinical Management of Poisoning and Drug Overdose, 3rd Ed. (L.M. Haddad et al.,
eds.). W.B. Saunders, Philadelphia, Pa., 1998; pp 864-875.
8. Dougherty, S.A. et al.:Salmon calcitonin as adjunct treatment for vitamin D Toxicosis in a dog.
JAVMA 196 (8):1269-1272; 1990.
9. Fooshee, S.K.; Forrester, S.D.: Hypercalcemia secondary to cholecalciferol rodenticide toxicosis in
two dogs. JAVMA 196 (8):1265-1268; 1990.
10. Gunther, R. et al.: Toxicity of a vitamin D3 rodenticide to dogs. JAVMA 193 (2):211-214; 1988.
11. Midkiff, A.M. et al.: Idiopathic hypercalcemia in cats. J. Vet. Intern. Med. 14 (6):619-626; 2000.
12. Volmer, P.: Oral toxicity of skin and eye products. Proc. ACVIM, ACVIM, Seattle, Wash, 2000; pp
45-47.
13. Hilbe, M. et al.: Metastatic calcification in a dog attributable to ingestion of a tacalcitol ointment. Vet.
Pathol. 37 (5):490-492; 2000.
14. Plumb, D.C.: Veterinary Drug Handbook, 3rd Ed. Pharma Vet Publishing, White Bear Lake, Minn.,
2000; pp 366-368.
15. Rumbeiha, W.K. et al.: Use of pamidronate disodium to reduce cholecalciferol-induced toxicosis in
dogs. AJVR 61 (1):9-13; 2000.
16. Rumbeiha, W. et al.: The use of pamidronate disodium for treatment of vitamin D3 toxicosis in dogs.
Proc. Am. Assoc. Vet. Lab. Diagnosticians, American Association of Veterinary Laboratory
Diagnosticians, Louisville, Ky., 1997; p 71.
“Toxicology Brief” was contributed by Carla Morrow, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.
Copyright 2001, Veterinary Medicine Publishing Group. Reprinted with permission from the December 2001
issue of Veterinary Medicine. All rights reserved. For more on Veterinary Medicine, visit
www.vetmedpub.com.
