|Anticoagulant rodenticides are absorbed through the gut and work by preventing the normal clotting of blood, leading to fatal haemorrhage. Their main effect is in the liver where they inhibit production of the enzyme Vitamin K Epoxide Reductase, so that Vitamin K cannot be recycled or regenerated by the body.
There are four clotting proteins that require the presence of Vitamin K. Without Vitamin K, these are not formed and the blood cannot clot. As a consequence the animal dies of internal bleeding.
Haemostasis is the process by which mammals stop bleeding when an injury to the vascular tissue occurs. There are two key processes involved,platelets and the coagulation cascade.
The first step involves the formation of a platelet plug. Initially the blood vessel wall will constrict to decrease the flow of blood. At the same time, theexposed vascular wall will attract platelets to adhere to its surface. Think of this step as simply “putting your finger in the hole of the dike”. It will stop the flow of blood for a short period oftime, but as soon as the platelets are no longer present, the haemorrhage will recommence.
The second step is the coagulation cascade. This results in the formation of a fibrin clot to seal the injured blood vessel wall. The chemicals in the coagulation cascade consist of many different blood clotting proteins referred to as factors (and excitingly numbered from I to XII), as well as several different co-factors. These co-factors assist the process and include Vitamin K, which assists in the production of someof these clotting factors. The coagulation cascade is a complicated process that begins with the platelets which serve as ‘scaffolding’ for the clotting factors to bind and begin the process ofdepositing the fibrin. The clotting factors in combination with the various co-factorsbegin to activate each other in a cascading fashion (Factor XII activatesFactor XI which activates Factor IX,etc.) until Factor I is activated and becomesfibrin. The fibrin is deposited and forms a seal over the hole in the vascular wall.
Vitamin K instigates the production of four of these blood clotting proteins, Factors II, VII, IX and X.(The actual production of the four factors occurs through gamma-carboxylation of glutamic acid residues of precursorproteins.)
At the same time as these four proteins are formed, the active form of Vitamin K is converted to aninactive epoxide compound. Some of this is excreted, but the majorityis reactivated by an enzyme, Vitamin K Epoxide Reductase. The reactivated Vitamin K recycles and represents the major source of Vitamin K in the animal. Small losses of Vitamin K are replaced by Vitamin K from gut bacteria and fromfood (Fig. 1).
All anticoagulant rodenticidesshare the same siteof action; they block the production of Vitamin K Epoxide Reductase Enzyme.The recycling of activated Vitamin K istherefore stopped, and there is insufficient VitaminK left in the system.
As a consequence, the production ofthe four blood clotting proteins (factors) is critically reduced, and eventuallythe blood clottingmechanism fails and internal haemorrhaging (bleeding) begins.
Since the mechanism is common to all products, there islittle difference in the time to death between the different anticoagulants,once the enzyme is blocked. What does differ is thetime taken to achieve this.
Similarly, due to the common mode of action, the treatment of poisoning in the case of an accident is the same for all rodenticides. The synthesis of the four blood clottingfactors can be restarted by the addition of appropriate amounts of Vitamin K. Frequent administration, usually by intravenous infusion, is required until all residues of the anticoagulant are cleared. Different anticoagulants requiredifferent treatment periods dependent upon their half-lives atthe site of action, varying from some hours for warfarin,and sometimes up toseveral weeks for the more potent products.
One of the major benefits associated with the anticoagulant rodenticides when they were introduced, in comparison to the acute products used previously, was improved safety. This was primarily due to the availability of Vitamin K asan antidote; and their slow mode of action, which generally provides adequate time for diagnosis and treatment.
As with allpesticides, the use of anticoagulant rodenticides does carry a degree ofrisk, particularly with the second generation products. This is exacerbated by the close proximity in which rodents live with humans, and the fact that they are mammalian toxins. Nonetheless there is a long and relatively safe history of use.
Litovitz in the USA has produced the most detailed study on accidental exposure to harmful substances in a paper presented in 1989, which showed that, of more than one million human exposures, only3.8% were associated with pesticides; a category which includesrodenticides as only a minor component. Exposures toanalgesics, cleaning agents and cosmetics by far exceededthe number of exposures to pesticides!
Of more interest is the demographic profile of these incidents withthe vast majority being via theoral route, and involving children under the age of six. (I would suggest that these were mostly non-professional applications too!)A major advance in protecting children, and people in general, from the effects of these compounds has been the use of a human taste deterrent inmodern rodenticides. Denatonium benzoate is undetectable by rodents, but it renders the products highly objectionableto humans.
Companion animals, especially dogs may also be exposed to rodenticides. The key to safety in all aspects of non-target accidental poisoning is to take great care in bait placement, and to make use of lockablebait stations which can be anchored in place.
The area of most concern with the use of the anticoagulants is the hazard they may pose to animals or pets that prey upon poisoned rodents, or scavenge their dead bodies. Contrary to some reports, all the second-generation compounds are equally persistent, and even some of the earlier compounds are retained in animal tissues, most usually the liver, at sub-lethal levels for relatively long periods (Parmar et al. 1987, Huckle et al. 1989).
Five highly potent second generation anticoagulants have been commercialised and three of them, brodifacoum, flocoumafen and difethialone, each to a greater or lesser extent, can be said to possess the capability of killing rodents after a single feed. A common misunderstanding of the secondary aspects of the toxicity of these products has lead some to recommend the use of the less potent anticoagulants, where one or more feeds may be required by the rodent. Yet studies presented in PPC in the UK have shown brodifacoum, the most potent of the modern anticoagulant rodenticides, requires less than a quarter of the bait consumption to kill rats compared to difenacoum, and typically 80% less than bromadiolone, suggesting lesser amounts present in the rodent carcasses too.
The primary criteria for professional pest managers in their selection of rodenticides should be to select products that are going to provide the most effective kill of the primary target pest; in the most palatable form available. Good bait consumption is critical to the success of any rodenticide program. Safety is then ensured by careful bait placement using lockable stations.
Given that anticoagulants are mammalian toxicants, they have a long history of safe and effective use world-wide, and with the cost of developing new compounds; it seems likely that those currently available will continue to dominate the practice of rodent control for many years to come.