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Home , Bromadiolone, Difethialone, Pindone, Rodenticide

TOXICOLOGY BRIEF

PEER-REVIEWED : Deadly for pests, dangerous for pets Valentina Merola, DVM

t’s fall, and mice and are able as grain-based pellets, wax heading indoors to escape the blocks, dusts, and tracking pow- Icooler weather, making them- ders and in a variety of other for- selves unwanted visitors. Many mulations and colors (Table 1). people put out baits to Some people assume that if they keep these pests from becoming see a blue-green pellet it is an anti- permanent residents. Anticoagu- coagulant rodenticide. But be care- lant rodenticides are popular ful, because not every blue-green choices. But these rodenticides pellet is an anticoagulant rodenti- can harm other animals in the cide and not every anticoagulant house as well. The prognosis for rodenticide is a blue-green pellet. pets that have ingested anticoagu- Other rodenticide baits that contain lant rodenticides depends on the , , or length of time between exposure can be indistin- and treatment, so you must diag- guishable from an anticoagulant nose and institute appropriate rodenticide. Second-generation an- therapy immediately. ticoagulant rodenticides are most commonly found at a concentra- Origin compound marketed as an antico- tion of 0.005% ( is First-generation anticoagulant ro- agulant rodenticide. be- found at 0.0025%), while denticides were initially developed came resistant to the first-generation is most commonly found at during the 1940s and 1950s by the compounds over the next few 0.025%.3 When an animal is ex- Wisconsin Alumni Research Foun- decades, so second-generation anti- posed to an anticoagulant rodenti- dation (WARF). WARF was founded coagulant rodenticides, such as cide, always examine the package in 1925 as a nonprofit agency with , diphacinone, and to determine the concentration of the purpose of promoting, aiding, , were produced. The the active ingredient so that a dose and encouraging scientific research second-generation compounds can be calculated and appropriate and investigation at the University of were developed to work more treatment undertaken (Table 2). Wisconsin-Madison. Dicumarol was quickly and with greater efficacy the first anticoagulant that could be than the first-generation products. Risk factors and susceptibility given orally to people, and warfarin They were also formulated to be Dogs allowed to roam may be (named after WARF) was the first highly palatable to rodents.1 Be- more likely to encounter cause of this, second-generation baits. These baits may be improp- “Toxicology Brief” was contributed by anticoagulant rodenticides are both erly placed in areas pets have ac- Valentina Merola, DVM, Department of appealing and extremely toxic to cess to, or rodents may drag baits Veterinary Biosciences, College of nontarget species, especially do- into these areas. Pets that live in Veterinary Medicine, University of mestic dogs (Table 1). rural or urban areas where rodent Illinois, Urbana, IL 61802. The depart- control is frequently used are also ment editor is Petra A. Volmer, DVM, Available products more likely to be exposed. An ani- MS, DABVT, College of Veterinary are the most com- mal owner may be unaware that a Medicine, University of Illinois, Urbana, mon type of rodenticide produced operator has placed IL 61802. Dr. Volmer is also a diplomate 2 of the American Board of Toxicology. and used in the United States. An- these baits if the owner lives in a ticoagulant rodenticides are avail- rental property or has recently

716 OCTOBER 2002 Veterinary Medicine TOXICOLOGY BRIEF

moved to a new home. In general, toxicosis is possible in an animal interaction can cause more of either rodent baits are used most often in that frequently preys upon rodents drug to be available.3 The plasma the fall when rodents are most in an area where these baits are half-life varies among products. The likely to enter buildings. Finally, commonly used.3 first-generation rodenticides have a keep in mind that rodenticides are Animals that are elderly or juve- half-life of about 14 hours in dogs; commonly used in malicious poi- nile and those with disease, the second-generation rodenticides sonings, and must be considered if hypothyroidism, or other underly- have a half-life of up to six days.1 the clinical signs are consistent, ing illnesses are more susceptible The rodenticides are metabolized in even in animals that are thought to to anticoagulant rodenticides. the liver and excreted in the urine. be unlikely to have encountered the agent. Toxicokinetics Mechanism of action Relay toxicosis, the intoxication Anticoagulant rodenticides are K is a necessary cofactor in by ingestion of a previously poi- rapidly and well-absorbed orally. activating clotting factors II, VII, IX, soned animal, is unlikely to occur They are highly protein-bound in and X by carboxylation (Figure 1). with these agents, because only a plasma. In an animal receiving an- Without , these coagula- small amount of the rodenticide is other drug that is highly protein- tion proteins will remain in a non- in a rodent’s gut (in general, the bound, such as a nonsteroidal anti- functional, precursor state. Antico-

LD50 in rodents is lower). But relay inflammatory drug, the displacement agulant rodenticides interfere with

TABLE 1 Common Anticoagulant Products and Their Active Ingredient Concentrations, Formulations, and Acute LD50*

Active Common Common Trade Names Ingredient Generation Concentrations Formulations Acute LD50 Rodex, Blitz, Rid-a-, Warfarin First 0.025%–0.03% Pellets, others 20–300 mg/kg (dogs); Eagles, and many more** 5–30 mg/kg (cats) D-Con, Havoc, Jaguar, Brodifacoum Second 0.005% Chunks, blocks, 0.2–4 mg/kg (dogs); Warrior Chunks, Enforcer, pellets, others unknown in cats and many more Hawk, Maki, Boot Hill, Bromadiolone Second 0.005% Blocks, bars, 11–15 mg/kg (dogs); Just One Bite, Tomcat pellets, others unknown in cats Ultra, and many more D-Cease, Generation, Difethialone Second 0.0025% Pellets, others 4 mg/kg (dogs); Hombre > 16 mg/kg (cats) Assassin, Tomcat, Ditrac, Diphacinone Second 0.005%–0.2% Blocks, bars, powder, 0.9–8 mg/kg (dogs); Exterminator’s Choice, liquid concentrates 15 mg/kg (cats) and many more Enforcer Rat Bait, Second 0.03% Pellets, others 5–75 mg/kg (dogs); Duocide** unknown in cats

*Source: References 1, 3, 4, and 12. **Products containing warfarin and pindone are older, and most have been replaced. But these older products could still be in use.

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Continued

TABLE 2 An Example of a Rodenticide Dose Calculation and Interpretation

A 75-lb dog is seen consuming 4 oz of a bait that contains 0.005% brodifacoum.

To calculate the dose of brodifacoum the dog ingested in mg/kg:

1. Convert the animal’s weight to kilograms: 75 lb 2.2 lb/kg 34 kg 2. Calculate how much bait the dog ingested: 1 oz approximately 30 g; 4 oz 30 g 120 g 3. Calculate the amount brodifacoum in each gram of bait: 0.005% 0.05 mg brodifacoum/g bait 4. Calculate how much brodifacoum the dog ingested: 0.05 mg/g 120 g 6 mg of brodifacoum ingested 5. Calculate the dosage in mg/kg: 6 mg 34 kg 0.18 mg/kg

This dose is approaching the low end of the LD50 range (0.2–4 mg/kg; see Table 1). The LD50 is defined as the dose at which 50% of an experimentally exposed population will die. This means that nearly half of the exposed individuals die

below the LD50. Because some animals are sensitive to doses between the LD50 1 10 and / of the LD50, it is recommended that any animal that received a dose in that range be decontaminated and monitored. In this case, the dose is high enough to warrant aggressive decontamination, monitoring, and treatment. 1 2 Animals that received doses less than / of the LD50 (in this case, less than 0.1 mg/kg) should be decontaminated, and the PT should be monitored every day

for 72 hours. Previous administration of vitamin K1 may result in misleading PT results. In general, to be cautious and prevent clinical signs in the most sensi- tive individuals, it is recommended to decontaminate and monitor any animal that received a dose above 0.02 mg/kg.

the activation process by inhibit- tive form. The net result is a coag- ing an animal’s ability to conserve ulopathy that begins as the natural vitamin K. Vitamin K is consumed breakdown of the clotting factors by carboxylation of the proteins occurs. The half-lives of factors II, and is present as vitamin K epox- VII, IX, and X are 41, 6.2, 13.9, and ide, which cannot activate clotting 16.5 hours, respectively; thus fac- proteins.4 Normally, the body con- tor VII will be depleted first.4 If an verts vitamin K epoxide back to external source of vitamin K is active vitamin K via the enzyme provided to an animal, normal ac- vitamin K epoxide reductase. Anti- tivation of the proteins can occur, coagulant rodenticides inhibit this and no clinical signs will develop. enzyme, resulting in a lack of ac- tive vitamin K.4 As a result, con- Clinical signs centrations of the clotting factors Clinical signs in an exposed ani- decrease, since no more precursor mal usually develop one to seven protein can be converted to an ac- days after ingestion as the active

718 OCTOBER 2002 Veterinary Medicine TOXICOLOGY BRIEF

clotting factors are depleted, with FIGURE 1 three to five days being the most

common time frame, depending CO2 on the agent consumed.1 The clin- ical signs can vary, but they are al- Precursor factor II, VII, IX, X Functional factor II, VII, IX, X ways due to the coagulopathy. Animals may present with nonspe- cific signs such as lethargy, an- Vitamin K Vitamin K expoxide orexia, or lameness due to intra- articular hemorrhage. In a recent retrospective study, dyspnea, coughing, lethargy, and hemopty- sis were the most common clinical signs.5 Any type of bleeding can occur, and hematuria, hemateme- Epoxide reductase sis, melena, hyphema, or epistaxis Vitamin K quinone (enzyme inhibited by may be seen.1 Petechia and ecchy- the anticoagulants) mosis of any mucosal surface or the skin are other possible find- 1. A diagram of the role that vitamin K plays in ings. Acute bleeding into the tho- Diagnosis activating coagulation factors and the route through rax or abdomen can cause ane- The one-stage prothrombin time which it is recycled. mia, shock, and death.4 If rapid (PT), activated partial thromboplas- bleeding into the brain or spinal tin time (APTT or PTT), and acti- lation tests (PT and APTT) for de- cord takes place, it may be mani- vated clotting time (ACT) will all be tecting bleeding tendencies and fested as ataxia, seizures, or death. elevated before hemorrhage oc- are a valuable aid in rapidly diag- Sometimes an animal will present curs, but the PT is the most sensi- nosing anticoagulant rodenticide with no history of exposure, and tive test.4 The PT is the first test to intoxication.7,8 the only sign is incessant bleeding become elevated and the first test In general, a threefold increase from a wound. Another presenta- to return to normal after ingestion in PT or PIVKA is highly suggestive tion can be of a dog with a vague of an anticoagulant rodenticide, be- of anticoagulant rodenticide toxico- history of nonspecific signs that cause of the shorter half-life of fac- sis.6 Prior administration of vitamin bleeds and forms a large hema- tor VII (Figure 2). K1 can cause the PT to be mislead- toma after venipuncture.2 Clotting PIVKA (proteins induced by vita- ingly normal, as new clotting fac- abnormalities can persist for 14 min K1 absence or antagonism), or tors can be synthesized six to 12 days in animals poisoned by a first- Thrombotest (Axis-Shield), is an- hours after treatment. In an animal generation product and for 30 days other test that can be used to that is hemorrhaging, a complete or longer with second-generation screen for the anticoagulant roden- blood count may show regenera- rodenticides.4 The extended dura- ticides. In a recent study, dogs tive anemia. A decrease in plasma tion of the clinical signs is related with prolonged PTs had prolonged proteins or in platelet number is to the rodenticides’ long half-lives, PIVKA times, regardless of the also sometimes found. Urinalysis especially of the second-generation cause of the prolonged bleeding may also be helpful, but keep in compounds, and depends on the time.6 The PIVKA times seem to be mind that hematuria is not specific amount of the agent consumed. more sensitive than routine coagu- for anticoagulant rodenticide toxi-

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Continued

FIGURE 2 thrombocytopathy, and inherited disorders such as hemophilia and The Coagulation Pathway von Willebrand’s disease can usu- ally be differentiated based on the Intrinsic Extrinsic results of the coagulation screenings System System (Table 3) and a patient’s history and ➞ ➞ Factor XII ➞ Factor XIIa Factor VII Factor VIIa* clinical signs. Coagulopathies due ➞ ■ to liver disease can usually be de- • Factor XI ➞ Factor XIa termined based on elevated liver ➞ enzyme activities.10 Canine ehrlich- Factor IX ➞ Factor IXa* iosis can likewise usually be distin- ➞ Factor VIII Factor VIIIa guished from other problems by PTT PT the results of a complete blood ACT PIVKA count and serum chemistry profile Common (e.g. thrombocytopenia, anemia, System leukopenia [or leukocytosis later in ➞ the disease], hyperglobulinemia, Factor X ➞ Factor Xa* proteinuria, mildly elevated blood Factor V ➞ Factor Va* nitrogen, creatinine, and total ➞ bilirubin concentrations and liver Factor II ➞ Factor IIa (thrombin)* enzyme activities) and serologic ➞ ■ testing. • Factor I ➞ Factor Ia (fibrin) Treatment In patients that present soon after *Vitamin K-dependent factors exposure, perform decontamina- tion measures. If the exposure oc- curred less than four hours prior, cosis, and a negative result does to a potentially lethal dose and not induce emesis followed by acti- not rule it out. have any changes in its laboratory vated charcoal and a cathartic to Radiography is another impor- parameters for the first few days. limit gastrointestinal absorption.1 tant ancillary test that can aid in On necropsy, liver as well as Do not induce emesis in species diagnosis. Many dogs will have blood or stomach contents can be that are unable to vomit, such as evidence of thoracic or abdominal tested for anticoagulant rodenti- rabbits and rodents. At this point effusions. Tracheal narrowing or cides at many veterinary diagnostic you must decide whether vitamin 4 soft tissue opacity in the medi- laboratories. K1 therapy should be started. If the astinum may be present if bleed- ingested dose is small or deconta- ing occurs in those locations.9 Differential diagnoses mination was successful, it may be It is important to remember that Other causes of hemorrhage must sufficient to monitor the PT or an animal that has been acutely ex- be differentiated from anticoagu- PIVKA at 24, 48, and 72 hours. If posed (less than one to two days) lant rodenticide toxicosis. Immune- the PT or PIVKA remains normal at

may not have any of these findings. mediated thrombocytopenia, dis- 72 hours, and no vitamin K1 was An animal may have been exposed seminated intravascular coagulation, administered, further treatment is

720 OCTOBER 2002 Veterinary Medicine TOXICOLOGY BRIEF

TABLE 3 Expected Results of Coagulation Tests in Various Coagulopathies*

APTT ACT PT PIVKA Anticoagulant ingestion Marked Marked Marked Marked elevation elevation elevation elevation Immune-mediated Normal Marked Normal Normal thrombocytopenia elevation DIC Marked Marked Marked Marked elevation elevation elevation elevation Thrombocytopathy Normal Marked Normal Normal elevation Hemophilia Marked Marked Normal Normal elevation elevation von Willebrand’s Slight to Slight to Normal Normal disease moderate moderate elevation elevation

*Source: References 4, 8, and 10.

11 not necessary. If you are not sure larger. Vitamin K3 can also be how much rodenticide a patient nephrotoxic and cause anemia.11 has ingested, it is safest to assume The length of time for treatment

it was a large dose. with vitamin K1 depends on the In cases of large ingestions, type of anticoagulant rodenticide

begin phytonadione (vitamin K1) ingested. For first-generation anti- therapy (3 to 5 mg/kg orally di- coagulants, treatment with vitamin 5 vided b.i.d.). Treat pocket pets at K1 for 14 days is usually sufficient. the high end of this dosage For second-generation anticoagu- range. Make sure to tell owners lants, treatment should be insti- that the vitamin K1 must be pre- tuted for at least 30 days. If the scription strength and that vita- class of anticoagulant is un- min supplements do not contain known, vitamin K1 therapy enough vitamin K1 to be effective. should be instituted for 30 days. Over-the-counter supplements Vitamin K1 is well-absorbed contain micrograms of vitamin K1, orally, and absorption is en- but milligrams are needed. Do hanced when a fatty meal is fed

not use vitamin K3 (menadione) at the same time the dose is for treatment; it is poorly stored given. Oral administration is

and requires metabolism for activ- ideal, because vitamin K1 will be ity, so the onset of action is longer delivered directly to the liver and the amount required is through the portal circulation

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Continued

where the clotting factors are acti- continued at a dosage of 3 to 5 REFERENCES vated. In all patients, check the PT mg/kg orally divided twice a day 1. Murphy, M.J.; Talcott, P.A.: Anticoagulant rodenticides. Small Animal Toxicology (M.E. or PIVKA 48 hours after stopping vi- for an appropriate period of time. Peterson; P.A. Talcott, eds.). W.B. Saunders, tamin K1 therapy, and if the test re- or anorectic patients or Philadelphia, Pa., 2001; pp 406-419. sult is prolonged, continue vitamin pocket pets that may be difficult to 2. Woody, B.J. et al.: Coagulopathic effects 1 and therapy of brodifacoum toxicosis in K1 treatment for another week. treat orally may require subcuta- dogs. J. Vet. Intern. Med. 6 (1):23-28; 1992. Again, a patient must be tested for neous injection of vitamin K1, but 3. Dorman, D.C.: Toxicology of selected adequate clotting 48 hours after vit- bleeding could occur at the injec- , drugs, and chemicals. Antico- 5 agulant, cholecalciferol, and bromethalin- amin K1 therapy has been discon- tion site. If possible, vitamin K1 based rodenticides. Vet. Clin. North Am. tinued. Exercise restriction during should be given orally, and intra- (Small Anim. Pract.) 20 (2):339-352; 1990. treatment is recommended. In a symptomatic animal, decont- amination by using emetics and Check the PT or PIVKA 48 hours activated charcoal is generally not necessary or beneficial because of after stopping vitamin K1 therapy. the length of time between expo- sure and the development of clini- muscular or intravenous routes 4. Mount, M.E.: Diagnosis and therapy of anticoagulant rodenticide intoxications. cal signs. Aim treatment at pre- should be avoided because of the Vet. Clin. North Am. (Small Anim. Pract.) venting further hemorrhage by risk of hematoma formation or 18 (1):115-130; 1988. providing clotting factors and vita- anaphylaxis if given intravenously. 5. Sheafor, S.E.; Couto, C.G.: Anticoagu- lant rodenticide toxicity in 21 dogs. min K1, as well as appropriate sup- A patient that is bleeding into the JAAHA 35 (1):38-46; 1999. portive care. Handle all patients thoracic cavity may require thora- 6. Rozanski, E.A. et al.: Thrombotest gently to avoid inducing further cocentesis or pericardiocentesis (PIVKA) test results from 25 dogs with ac- quired and hereditary coagulopathies. J. bleeding. Monitor patients closely, and oxygen therapy in addition to Vet. Emerg. Crit. Care 9:73-78; 1999. and if anemia becomes severe, a plasma and vitamin K1. Intravenous 7. Center, S.A. et al.: PIVKA clotting blood transfusion may be re- fluids may be needed to support times in dogs with suspected coagu- lopathies (abst.). Proc. ACVIM, ACVIM, quired. Polymerized bovine hemo- the blood pressure, and broad- San Diego, Calif., 1998. globin glutamer-200 (Oxyglobin— spectrum should be 8. Mount, M.E.: Proteins induced by vita- min K absence or antagonism (“PIVKA”). Biopure) could also be used in a used when indicated. Nutritional 1 Current Veterinary Therapy IX Small Ani- severely anemic animal to help support should be provided, if mal Practice (R.W. Kirk, ed.). W.B. Saun- provide oxygen to tissues, but it necessary. ders, Philadelphia, Pa., 1986; pp 513-515. will not supply needed clotting fac- 9. Berry, C.R. et al.: Thoracic radio- graphic features of anticoagulant rodenti- tors. Animals that are bleeding Prognosis cide toxicity in fourteen dogs. Vet. Radiol. should be given plasma to provide The prognosis for animals with an- Ultrasound 34:391-396; 1993. clotting factors until enough time ticoagulant rodenticide toxicosis is 10. Staus, J.H.: Bleeding disorders and epistaxis. Quick Reference to Veterinary has passed for the animal to begin variable depending on the stage of Medicine (W.R. Fenner, ed.). Lippincott producing clotting factors, based illness at the time of presentation. If Williams & Wilkins, Baltimore, Md., 2000; on clinical signs (bleeding), treatment is instituted before clini- pp 70-90. 11. Puls, R.: Vitamin K. Vitamin Levels in changes in the hematocrit, and PT cal signs develop, the prognosis is Animal Health. Sherpa International, results.5 good to excellent. Otherwise, the Clearbrook, B.C., 1994; pp 116-117. In symptomatic patients, vitamin prognosis is guarded to good, de- 12. Liphatech Worldwide: The veterinar- ian’s guide to managing poisoning by anti- K1 should be given at a loading pending on the type and severity coagulant rodenticides. http://www dose of 2.5 to 5 mg/kg orally and of bleeding. .liphatech.com/vetguide.html; July 2002. ■

722 OCTOBER 2002 Veterinary Medicine