Is Vitamin D Rat Poison

Is Vitamin D Rat Poison

Cholecalciferol

Yoshihiko Ohyama , Toshimasa Shinki , in Handbook of Hormones, 2016

Signal Transduction Pathway

Cholecalciferol does not control gene expression via VDR. After two sequential hydroxylation reactions of vitamin D ₃, the product of 1,25(OH)₂D₃ acquires affinity to VDR. 1,25(OH)₂D₃-binding VDR forms a heterodimer with the retinoid X receptor (RXR), and then binds to vitamin D response element(s) [VDRE(s): a direct repeat of the AGGTCA motif separated by three nucleotides] that are identified in promoters of many target genes, such as calbindin, osteocalcin, and CYP24 (see Subchapter 97A, Calcitriol).

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Cholecalciferol

Wilson K. Rumbeiha DVM, PhD, DABVT, DABT , in Small Animal Toxicology (Third Edition), 2013

Sources

Cholecalciferol (vitamin D ₃) is naturally synthesized in mammalian skin from its precursor, 7-dehydrocholesterol, in the presence of ultraviolet light. ¹ This process is tightly regulated, and toxicosis from natural oversynthesis of cholecalciferol in mammalian skin has not been reported to date. A common source of vitamin D toxicosis in small animals is accidental ingestion of rodenticides containing cholecalciferol as the active ingredient. ³ Rodenticide baits containing cholecalciferol as the active ingredient are sold over the counter. Some common proprietary names of these rodenticides include Muritan, Mouse-B-Gone Mouse Killer, Quintox Mouse Seed, Ceva True Grit Rampage, Quintox Rat and Mouse Bait, and Rampage Rat and Mouse Bait. These products are available in different formulations (e.g., granules, flakes, tablets, cakes, or briquettes) containing 0.075% cholecalciferol.

The other common source of vitamin D toxicosis in small animals is accidental ingestion of human medications. ⁴ Medications containing vitamin D are currently used for the treatment of a number of human diseases, including hypophosphatemic disorders, hypoparathyroidism, osteomalacia, osteoporosis, and renal failure. Newly discovered functions of vitamin D in cell differentiation and immune function have recently ushered in a new generation of vitamin D medications for prophylactic treatment of cancer and immunosuppression. For example, Dovonex (calcipotriene or calcipotriol), an analogue of 1,25(OH)₂D₃, is currently used for the treatment of psoriasis in humans. Ingestion of antipsoriasis petroleum-based creams containing calcipotriene has become a potential source of vitamin D intoxication in dogs. ⁴ Other vitamin D analogues of similar therapeutic uses include 1α(OH)D₃, 1α(OH)D₂, dihydrotachysterol, calcitriol (a 1,25(OH)₂D₃ analogue), and tacalcitol. Some of these vitamin D analogues have potent calcemic and phosphatemic properties and are potentially lethal when ingested at much smaller doses than the parent vitamin D compounds. The recent surge in interest in the therapeutic potential of vitamin D drugs for inflammatory and immune-mediated disorders will likely increase the potential for pet exposure, and these drugs may become the major source of vitamin D toxicosis in pets in the future.

In the past few years there have been outbreaks of vitamin D poisoning in dogs associated with feeding of pet foods that had high levels of vitamin D. One case in 2010 involved dogs that had been fed three Brands of Blue Buffalo pet food that were found to be tainted with 25-hydroxy vitamin D₃ (HyD®). This particular brand of vitamin D is not approved for use in pet food and inadvertently contaminated the pet food as a carryover. However, inadvertent oversupplementation of pet food with cholecalciferol has also sickened or killed dogs in the recent past. ³¹ In 1999 there was a recall of DVM Nutri-Balance High protein dog food and Golden Sun Feeds Hi-Pro Hunter dog food. In February 2006 there was a recall of ROYAL CANIN Veterinary Diet™. Other sources of vitamin D toxicosis in dogs include iatrogenic oversupplementation of diets in the treatment of dogs with hypoparathyroidism and ingestion of diets containing high concentrations of vitamin D, such as fatty fish, eggs, milk, or liver. Vitamin D₂ and cholecalciferol (vitamin D₃) are fat soluble. Therefore, suckling animals, which are more sensitive to vitamin D toxicosis than adults, are at risk of exposure through milk. To date there has been no report in dogs or cats of an equivalent form of Williams syndrome, an idiopathic form of juvenile hypercalcemia in human infants characterized by exaggerated production of 25(OH)D₃ in the presence of normal dietary vitamin D content. ⁵ It is not clear at the present time whether this condition exists in dogs or cats. However, an idiopathic disease in 3- to 10-week-old puppies of several breeds of dogs, characterized histologically by extensive soft tissue mineralization—especially of the lungs, stomach, and kidneys—has been recognized recently. Granulomatous diseases, such as blastomycosis, result in an endogenous increase in 1,25(OH)₂D₃ in humans and animals. However, these granulomatous disease-related hypercalcemias have not been widely reported in small animals. Vitamin D–containing plants, such as Solanum malacoxylon and Trisetum flavescens, pose little risk of toxicosis for pets because of the large amount of plant material a pet has to consume to induce a poisoning. There are also reports in the literature of Cestrum diurnum (e.g., common names jasmine and jessamine) poisoning. This plant may be used as an ornamental plant and presumably contains 1,25 dihydroxyvitamin D₃. ⁸

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Volume 2

Lei-Wen Xiang , ... Ivanhoe K.H. Leung , in Encyclopedia of Food Chemistry, 2019

Vitamin D

Vitamin D₃ is a fat-soluble vitamin found to bind to both the calyx and surface hydrophobic pocket of β-lactoglobulin. The binding of vitamin D₃ to β-lactoglobulin appeared to improve the stability of the vitamin when the vitamin is exposed to UV light (Diarrassouba et al., 2014). The resistance of β-lactoglobulin-vitamin D₃ complex to protease-catalysed denaturation was also increased. The authors also showed that the β-lactoglobulin-vitamin D₃ complex has led to improved bioavailability of vitamin D₃, as the complex managed to cross cell membranes (Diarrassouba et al., 2014). These findings are useful in food applications, offering the possibility for using the β-lactoglobulin-vitamin D₃ complex to improve the intake of vitamin D₃ (Diarrassouba et al., 2014).

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Calcium and Phosphorus Homeostasis I

Joseph Feher , in Quantitative Human Physiology (Second Edition), 2017

Vitamin D Has Two Forms of Equal Potency in Humans

Cholecalciferol is known as vitamin D ₃ for historical reasons. The chemical structure of vitamin D₂ was worked out earlier than that of D₃ because of the availability of ergosterol, a sterol derived from fungus. UV light converts ergosterol to ergocalciferol, an analogue of cholecalciferol. It is known as vitamin D₂ and equals vitamin D₃ in preventing rickets. One international unit of vitamin D=0.025   μg; 400   IU or 10   μg of irradiated ergosterol are typically added per quart of milk. The US RDA (recommended dietary allowance) for vitamin D is 400   IU   day⁻¹. The structures of ergosterol and ergocalciferol are shown in Figure 9.7.8. Ergocalciferol differs from cholecalciferol by a double bond and an extra methyl group.

Figure 9.7.8. Structure of ergosterol and vitamin D₂, ergocalciferol.

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Gastrointestinal Toxicology

T.J. Evans , S.B. Hooser , in Comprehensive Toxicology, 2010

10.16.10.1 Cholecalciferol (Vitamin D₃) Toxicosis

Cholecalciferol (vitamin D ₃) toxicosis in dogs and cats has occurred through ingestion of rodenticides containing cholecalciferol as the active ingredient. The effect of ingestion of large amounts of cholecalciferol is to increase the concentrations of calcium in the blood through increased bone resorption and intestinal transport (Dorman 1990). Hypercalcemia due to cholecalciferol ingestion results in metastatic calcification of tissues throughout the body, particularly in the stomach, renal tubules, and blood vessels. These lesions lead to diarrhea and vomiting, which can contain blood from the stomach damage. Due to severe kidney and blood vessel damage which also occur, this toxicosis is often fatal (Dorman 1990; Gunther et al. 1988; Thomas et al. 1990).

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Non-Anticoagulant Rodenticides

Ramesh C. Gupta , in Veterinary Toxicology (Third Edition), 2018

Introduction

Cholecalciferol is a form of vitamin D, also called vitamin D ₃, that is commonly used as rodenticide. Vitamin D₃ is a secosteroid, and structurally similar to other steroids, such as cholesterol, testosterone, and cortisol. It has chemical formula C₂₇H₄₄O, with a molecular weight of 384.64. Its structural formula is shown in Fig. 47.3. Cholecalciferol has other names, and is marketed as a rodenticide under the brand names Quintox, True Grit Rampage, and Ortho Rat-B-Gone; it is also marketed as a feed additive under the name Viactive.

Figure 47.3. Structural formula of cholecalciferol.

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Non-anticoagulant rodenticides

Ramesh C. Gupta , in Veterinary Toxicology, 2007

Toxicity

Cholecalciferol is of low toxicity to mammalian species, as it is classified as a Class III toxic chemical. The oral LD ₅₀ of cholecalciferol in rats is 43.6 mg/kg and in mice is 42.5 mg/kg. The dermal LD₅₀ in rabbits is 2000 mg/kg. Studies suggest that cholecalciferol is of low toxicity to birds (oral LD₅₀ = >2000 mg/kg in mallard ducks and dietary LC₅₀ = 4000 ppm in mallard ducks, and 2000 ppm in bobwhite quail).

Pets, such as dogs are poisoned by ingesting rodenticide bait, while the farm animals are affected by overdose of additive vitamin D₃ in the feed. Signs and symptoms of poisoning are similar to hypercalcemia, such as anorexia, fatigue, headache, itching, weakness, nausea, vomiting, and diarrhea. In acute cases, cholecalciferol causes severe polyneuropathy. Dogs poisoned with cholecalciferol-containing rodenticide bait usually show the signs of depression, anorexia, vomiting, bloody diarrhea, cardiac irregularities, hypertension, seizures, and death. In dogs, signs of poisoning may occur with as little as 2 mg/kg dose, and death may occur with 10 mg/kg dose of cholecalciferol.

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Rodenticides

Alain F. Pelfrène , in Hayes' Handbook of Pesticide Toxicology (Third Edition), 2010

(a) Absorption, Distribution, and Excretion

Cholecalciferol after absorption from the intestine is transported to the liver, where it is metabolized to 25-hydroxycholecalciferol by an NADPH-dependent reaction. This metabolite is then transferred to the kidney and converted to 24-, 25-, or 1,25-dihydrocholecalciferol by mitochondrial mixed-function oxidases ( McClain et al., 1980). After their intestinal absorption, ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃) undergo an identical metabolic C pathway (Fournier et al., 1985). The metabolism and pharmacokinetics of one metabolite of cholecalciferol, 24,25-dihydrocholecalciferol have been reviewed by Jarnargin et al. (1985); the excretion curve shows an initial fast phase with a plasma half-life of 0.55   h and a second slow phase with a plasma half-life of 73.8   h in the rat. The clearance from plasma, liver, and kidney but not intestine follows a two-compartment model. The most potent form of vitamin D₃, 1,25-dihydrocholecalciferol, has been shown to be responsible for the stimulation of intestinal absorption of calcium and the metabolism of calcium in bone. However, Frolick and Deluca (1973) have shown that when given orally to rats, 1,25-dihydrocholecalciferol is rapidly modified during its passage through the intestine, thus reducing its physiological activity to a large extent.

Orally administered high doses of cholecalciferol (37.5   μg/day for 14 days followed by an 88-day observation period) to female Wistar rats rapidly increase the plasma cholecalciferol level to reach a steady-state. Plasma 25-hydroxyvitamin D (25-OH-D) and adipose tissue levels of cholecalciferol increased linearly for 2 days after treatment. Subsequently, half-lives of plasma cholecalciferol and 25-OH-D and perirenal and subcutaneous adipose tissue were: 1.4, 22.5, 97.5, and 80.9 days, respectively. Fasting, as compared with ad libitum feeding, caused increased plasma free fatty acids, weight loss and increased adipose tissue cholecalciferol. It did not affect plasma cholecalciferol immediately after treatment but raised 25-OH-D. Fasting at the end of the study decreased plasma cholecalciferol and increased 25-OH-D. The authors concluded that orally administered cholecalciferol rapidly accumulates in adipose tissue and that it is very slowly released (Brouwer et al., 1998).

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Avian Clinical Biochemistry

J.T. Lumeij , in Clinical Biochemistry of Domestic Animals (Sixth Edition), 2008

6 Calcium and Vitamin D3 Toxicity

Oversupplementation of the diet with calcium and vitamin D₃ is the most common cause of true hypercalcemia in birds.

Vitamin D₃ (1,25-dihydroxycholecalciferol) regulates the absorption of calcium by the gut (Lumeij, 1994c). Birds can synthesize vitamin D in their skin from 7-dehydro-cholesterol and therefore only need dietary vitamin D₃ when they lack ultraviolet light (Lumeij, 1994c; Nott and Taylor, 1993). One can easily oversupplement a bird's diet because most commercial diets contain abundant vitamin D₃ (Dumonceaux and Harrison, 1994; Macwhirter, 1994). Vitamin D3 is considered to be in the toxic range at 4 to 10 times the recommended dose (Brue, 1994). Avian species that have been reported to be susceptible to hypervitaminosis D₃ are the macaw, cockatoo, African grey parrot, toucan, dove, and cardinal (Phalen et al., 1990; Takeshita et al., 1986; Dumonceaux and Harrison, 1994; Lumeij, 1994b). In literature on hypervitaminosis D in birds, there seldom is discrimination between vitamin D₃ and D₂. Because vitamin D₂ (ergocalciferol) is 30 times less active than vitamin D₃ (Nott and Taylor, 1993), an excess of vitamin D₃ occurs most easily. When amounts of vitamin D are expressed in international chicken units (ICU), they refer to vitamin D₃. The baby macaws described by Takeshita et al. (1986) showed symptoms when fed a diet containing 1000 to 4000 ICU vitamin D₃/kg. Other workers reported that toxic effects will appear when the birds are fed a diet containing more than 2500 ICU vitamin D₃/kg diet (Brue, 1994; Harrison, 1991). The diet of the two birds reported by De Wit et al. (2003) contained more than 25,000 ICU vitamin D₃/kg.

Recommended calcium concentrations for maintenance in avian diets are 5 to 10   g/kg. A level of 30   g calcium/kg diet will result in toxicity (Shane et al., 1969). A high calcium intake alone can cause calcifications in the kidneys (Macwhirter, 1994). Nutritional errors can be prevented by the use of balanced commercial diets.

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Vertebrate Pesticides

Rosalind Dalefield BVSc PhD DABVT DABT , in Veterinary Toxicology for Australia and New Zealand, 2017

Toxicokinetics

Cholecalciferol is rapidly absorbed from the gastrointestinal tract and is transported by a specific protein to the liver, where it is metabolized to 25(OH)D ₃ (calcifediol). Cholecalciferol in excess of that which can be metabolized in the liver is stored in adipose tissue, so although the plasma half-life is 19–24   hours, cholecalciferol actually persists in the body for weeks or months. Calcifediol is the principal metabolite in circulation, and has a functional half-life of 29 days in the circulation because of continued mobilization of cholecalciferol from adipose tissue and metabolism in the liver. Calcifediol is further metabolized in the kidneys to 1,25(OH₂)D₃ (calcitriol) and 24,25(OH₂)D₃. Metabolites are principally excreted by the biliary route.

Clinical signs of cholecalciferol poisoning may develop as soon as 14   hours after ingestion, but more commonly are delayed for 18–48   hours.

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Is Vitamin D Rat Poison

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