Rodenticide Resistance

What PMPs Need to Know about Resistance to Anticoagulant Rodenticides
Pest Management Professional
Oct 1, 2001

Anticoagulants are not simply rodenticides. They have also been used for more than 50 years as human drugs to prevent blood clotting following injury, after surgery and as a consequence of certain diseases. A substantial amount of clinical experience and medically related research on anticoagulants has developed during this time-the results of which have implications for the use of these compounds in pest management.

Anticoagulant resistance and pesticide resistance are two different phenomena. Anticoagulant resistance is a medical concept that includes any inherited (genetic) or acquired (physiological) process that reduces the effectiveness of a drug. "Resistance" in the medical sense can usually be overcome by a relatively slight increase in the dose of the drug. Pesticide resistance, on the other hand, is an evolutionary concept that includes only inherited processes that reduce the effectiveness of a pesticide.

"Resistance" in the evolutionary sense cannot be overcome by a slight increase in dose, and a several-thousand-fold increase in dose is often required to kill resistant houseflies, cockroaches and other pests. A difference in response that would be classified by a physician as "resistance" in a human patient would fall within what an entomologist would consider to be the normal limits of susceptibility to an insecticide.

 
"Super Rats" Aren't so Super In practical terms, managing a population of anticoagulant-resistant rodents, or so-called "super rats," is no more difficult than managing a population of cockroaches that requires the "clean-out rate" of an insecticide. The difference is that, unlike most sprays, anticoagulant baits cannot be used in two strengths-a lower strength for "normal" populations and a higher strength for "less susceptible" populations. Every strain of "resistant" rodent tested so far can be killed with a higher dose of the same anticoagulant to which it is "resistant."

In addition, there is no fundamental difference in the activity of "single-feed" and "multiple-feed" anticoagulants. Their biochemical action at the target site is the same. Single-feed anticoagulants merely remain in the rodent's body for a longer period of time (Poche, 1984) so that the rodent "doses itself" (Jackson, 2000) without having to eat more bait. This is why dogs and other non-target animals that ingest single-feed anticoagulants must be treated with vitamin K (antidote) for weeks or months instead of a few days, as is the case for multiple-feed anticoagulants.

A child that accidentally ingested a second-generation anticoagulant required antidotal treatment for seven months (Watts, et. al., 1990), and an adult who attempted suicide with a second-generation anticoagulant was treated with vitamin K for eight months (Lipton and Klass, 1984). These differences in the duration of vitamin K therapy suggest that the optimal anticoagulant bait, from the standpoint of safety to children, pets and wildlife, may not be one that contains a low concentration of the most potent single-feed ingredient as do the most popular products on the market today.

A better option might be bait containing enough of a first-generation anticoagulant to kill "resistant" rodents after a single feeding. Such bait would not require long-term vitamin K therapy if ingested by a pet or child. The fact that highly acceptable baits containing first-generation anticoagulants at labeled rates can pass the United States Environmental Protection Agency (EPA) protocol for a single-feed rodenticide suggests that such baits are possible.

Reasons for Resistance Experience with human patients shows that not all forms of anticoagulant resistance are inherited. Some people become resistant to anticoagulants after being exposed to them over an extended period (Barnett and Hancock, 1975). This suggests that individual rats and mice may also become less susceptible to anticoagulant baits over time. This possibility has not been investigated, although it could be important in situations in which rodents consume small doses of bait, as when preferred alternative foods are available.

Although red squill, zinc phosphide and several other non-anticoagulant rodenticides can cause bait shyness (conditioned taste aversion) in rodents, anticoagulants are generally believed to be free from this problem. One reason for this belief is that the best documented cases of alleged taste aversions due to anticoagulant baits occurred in the early days of warfarin's use, and turned out to be due to an impurity, Alice's ketone, in the active ingredient. The problem disappeared when the process was adjusted to reduce the amount of ketone in the final warfarin bait. This result, combined with the absence of bait shyness in baits containing fumarin, a warfarin-like compound that could never contain Alice's ketone, convinced the industry that anticoagulants were incapable of inducing taste aversions in rodents.

More recent studies, however, reveal that sub-lethal doses of anticoagulant rodenticide can, in fact, produce taste aversions in Norway rats under laboratory conditions (Smith et. al., 1994). This bait shyness appears within the first day after dosing. Researchers have yet to check for taste aversions caused by sub-lethal doses of modern anticoagulants under practical field conditions.

The Dose Makes the Antidote Clinical experience with humans (Kempin, 1983, Stackley, 1984) and laboratory experiments with Norway rats (MacNicoll and Gill, 1993) show that both vitamin Kl and its precursors such as Vitamin K3 (menadione) will protect mammals from poisoning by anticoagulants. Nevertheless, there are differences of opinion among pest management professionals (PMPs) concerning the importance of Vitamin K3 in dog food and other sources. Rotramel (1989) and Brooks (2001) warn that Vitamin K3 in pet food can protect mice from anticoagulant baits.

On the other hand, Marshall (2000) argues that Vitamin K3 "is not an antidote for anticoagulants" and Bruesch (2001) states that Vitamin K3 "basically does nothing," and is "less effective than if the rodent were eating broccoli."

Both perspectives are correct, however, because the effectiveness of Vitamin K3 as an antidote depends on the ratio of Vitamin K3 ingested to anticoagulant ingested. The dose makes the antidote, just like the dose makes the poison. Even a weak antidote like Vitamin K3 can protect a mouse, if the mouse eats a lot of dog food and very little bait. This is the situation that can occur when weatherized anticoagulant baits are pitted against an open dish of pet food in a home or other pest management account.

The dose is also the reason why Vitamin K1, not Vitamin K3, is listed as the antidote on anticoagulant rodenticide labels. Vitamin K1 simply works more quickly, and at a lower dose.

Treatment Implications The mechanisms underlying resistance to anticoagulants in humans and rodents are essentially identical. Activity can be decreased or prevented entirely by the addition of vitamin K or vitamin K precursors as an antidote in the diet. Activity can decrease in the same individual over time as a result of increased levels of cytochrome p450 enzymes in the liver and other tissues. These enzymes degrade the anticoagulant before it can take effect. Activity can decrease due to a taste aversion that results in decreased consumption. In addition, activity can be prevented by inherited changes in the target enzyme that make it less susceptible to inhibition by the anticoagulant.

To guard against anticoagulant resistance from whatever cause-an altered target, increases in degradation enzymes, acquired taste aversion or the presence of an antidote in the diet-rodent management programs should never rely on anticoagulant baits alone. Every program should include at least one additional bait that contains a non-anticoagulant such as bromethalin or zinc phosphide in a carrier with a different base (taste) than the anticoagulant bait. The two baits can be used simultaneously, or switched around in a relay system.

The pest management industry could use a simple, cost-effective way to identify anticoagulant-resistant rodents in the field. The standard research protocol for anticoagulant resistance requires live trapping rodents, caging them and feeding them on test and control diets for several weeks.

The specialized facilities and support staff required to conduct these studies are available in only a few laboratories around the world, however. A cost-effective protocol for field surveys of resistance was developed as part of the federal government's "War on Rats" (Mortenson and Rotramel, 1976). This procedure used an indicator bait that contained a vital dye (DuPont Oil Blue A), in addition to a first-generation anticoagulant.

When the bait was ingested, the dye translocated to the pinnae (outer projecting portion) of the rodents' ears and the soles of their feet. The concentration of dye and the concentration of anticoagulant in the bait were balanced, so that all susceptible animals died before their ears and feet turned blue. The presence of resistant rodents could then be confirmed by trapping, and rats and mice with blue ears and blue feet were presumed resistant. If manufacturers of anticoagulant baits could formulate their products with an indicator dye, PMPs could identify anticoagulant resistance in all of their accounts.

References Barnett, D.B. and B.W. Hancock, 1975. Anticoagulant resistance: unusual case. British Medical Journal. I (Mar. 15): 608-609.

Brooks, A. 2001. Pet Food Could be Factor in Bait Resistance. Pest Control. Apr. p. 4.

Bruesch, T. 2001 Thinking inside and outside the box: What they don't teach you at pest control school. Proceedings of LiphaTech Technical Symposium. Sept. 13-14, 2000: 58-71

Jackson, W.B., 2000. Vitamin K effects on rodenticides/resistance management. Proceedings of LiphaTech Technical Symposium. Sept. 13-14, 2000: 72-93.

Kempin, S.J. 1983. Warfarin resistance caused by broccoli. New England Journal of Medicine. 308:1229-1230.

Lipton, R.A. and E.M. Klass. 1984. Human ingestion of a "superwarfarin" rodenticide resulting in a prolonged anticoagulant effect. Journal of the American Medical Association. 252: 3004-3005.

MacNicoll, A.D. and l.E. Gill, 1993. Vitamin K3 in Feedstuffs: Antidotal effects in captive anticoagulant-resistant rats and mice. J. Wildlife Management. 57(4):835-841.

Marshall, E. 2001. All Vitamin Ks are Not Created Equal. Pest Control. June. pp. 4, 5.

Mortenson, W.W. and G.L. Rotramel, 1976. A Regional Approach to Rodent Control in the San Francisco Bay Area. Proc. Seventh Vertebrate Pest Conference. 1976:235-241.

Poche, R.M., 1984. Personal communication (Nov. 30, 1984). Director of Technical Services, Lipha Chemicals Inc.

Rotramel, G.L., 1989. New Pet Foods a Concern in Rat and Mouse Control. Pest Control Technology. Dec. p. 56.

Smith, P., I.R. Inglis, D.P. Cowan, G.M Kerins and D.S. Bull. 1994. Symptom-dependent taste aversion induced by an anticoagulant rodenticide in the brown rat (Rattus norvegicus). Journal of Comparative Psychology. 108(3):282-290.

Stackley, I., 1984. Warfarin resistance caused by over-the-counter drugs, food supplements and vegetables. Pharm. Int. 5:165-167.

Watts, R.G., R.P. Castleberry and J.A. Sadowski. 1990. Accidental poisoning with a superwarfarin compound (brodifacoum) in a child. Pediatrics. 86 (Dec.): 883-887.

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