Evaluation of new toxins for mustelid control

Published byDepartment of ConservationP.O. Box 10-420Wellington, New Zealand DOC Science Internal Series is a published record of scientific research carried out, or advice given,by Department of Conservation staff, or external contractors funded by DOC. It comprises progressreports and short communications that are generally peer-reviewed within DOC, but not alwaysexternally refereed. Fully refereed contract reports funded from the Conservation Services Levy (CSL)are also included.
Individual contributions to the series are first released on the departmental intranet in pdf form.
Hardcopy is printed, bound, and distributed at regular intervals. Titles are listed in the DOC SciencePublishing catalogue on the departmental website http://www.doc.govt.nz and electronic copies ofCSL papers can be downloaded from http://csl.doc.govt.nz Copyright July 2002, New Zealand Department of Conservation This report originated from work carried out under Department of Conservation investigation no.
3125. It was prepared for publication by DOC Science Publishing, Science & Research Unit; editing byLynette Clelland and layout by Ruth Munro. Publication was approved by the Manager, Science &Research Unit, Science Technology and Information Services, Department of Conservation, Wellington.
C.E. O’ConnorLandcare Research, PO Box 69, Lincoln 8152, New Zealand Sustainable, humane, and cost-effective stoat control is essential in NewZealand to protect our native fauna from predation. The long-term aim of thisresearch is to develop a new tool for conservation that is designed withspecificity and humaneness as the most important attributes. This project beganby evaluating the sensitivity of captive stoats and ferrets to a range of potentialmustelid toxicants. Ferrets and stoats were susceptible to MNT (a compoundbeing developed for predator control in Australia). Preliminary observationsindicate that death from MNT is relatively humane in mustelids, with noobvious signs of distress or pain observed. The non-target species tested wereall susceptible to MNT but for possums and wallabies this was at higherconcentrations than for stoats and ferrets, whereas for ducks it was similar.
Further research, to determine the toxicity and relative humaneness of MNT tostoats and susceptibility of non-target species, is required to develop this toxininto an effective stoat control tool.
Keywords: stoat control; target-specific toxicants; non-target susceptibility;humaneness.
July 2002, New Zealand Department of Conservation. This paper may be cited as:O’Connor, C.E. 2002: Evaluation of new toxins for mustelid control. DOC Science Internal Series 56.
Department of Conservation, Wellington. 14 p.
The susceptibility of target and non-target animals to potentially mustelid-specific toxicants was evaluated by Landcare Research, Lincoln, for theDepartment of Conservation from July 1998 to June 2001.
Mustelids, especially stoats (Mustela erminea) and ferrets (M. furo), are majorpredators of many bird species in New Zealand. Control strategies for mustelids,using poisoned baits, have previously relied on the use of sodium monofluoro-acetate (1080) or anticoagulant rodenticides. While effective, the widespreaduse of 1080 is controversial, due to its lack of target specificity, and anticoagu-lants are under increasing scrutiny as a result of persistent environmentalresidues. The Department of Conservation (DOC) has indicated a need for amore target-specific toxicant for mustelid control and, as a first step towardsachieving this goal, Landcare Research prepared a report for them in 1998entitled ‘Mustelid-specific toxicants’. This report identified a range of com-pounds to which mustelids appear to be particularly susceptible. These were,typically, veterinary products or human pharmaceuticals (medicines) that werereported to have caused death in individual pets, mainly ferrets.
In particular, some methaemoglobin-inducing agents (oxidants) and non-steroidalanti-inflammatory agents (NSAIDs) were identified as promising. In at least onestudy, ferret erythrocytes (red blood cells) were reported to be relatively sensitiveto oxidative stress, leading to the conversion of haemoglobin to methaemoglobin,which is incapable of binding oxygen (Davis et al. 1993).
• To evaluate the sensitivity of captive stoats and ferrets to new, potentially mustelid-specific toxicants in single-dose acute toxicity studies.
• To evaluate the sensitivity of captive stoats, possums, wallabies, and ducks to O’Connor—Evaluation of new toxins for mustelid control Approvals from the Landcare Research Animal Ethics Committee (99/4/1,99/5/1, 00/6/6, 01/3/3) were obtained before beginning each part of thisresearch.
A C U T E T O X I C I T Y I N F E R R E T S First-generation captive-bred, adult ferrets were used in all these tests. Ferretswere individually housed in cages (50 × 50 × 100 cm) under an outside shelter atthe animal facility at Landcare Research. Each ferret was supplied with a hessiansack for nesting and extra protection from the weather, and fed a rotation ofdead day-old chick, mince and dog roll in the afternoon, with free access to water.
Initially, ferrets were tested in toxin susceptibility studies to determine theirrelative sensitivity to each of four compounds. Four treatment groups ofanimals were tested at different dose levels and a control. The toxicant wasadministered in the morning prior to the animals being fed, as a solution, by oralgavage (stomach tubing) in an appropriate vehicle, under light anaesthesia withfluothane. Animals were closely monitored for 30 days and all mortality andtimes to death recorded. Any animal showing greater than 25% body weight lossor behavioural signs of extreme distress or pain was euthanased immediately byanaesthesia with fluothane and then cardiac puncture with an overdose ofPentobarb 300.
Humaneness of each new toxicant was evaluated in the groups of animals usedin the efficacy trials. Preliminary behaviour observations were made to recordprimary signs of toxicosis and, particularly, any behaviours indicating pain ordistress. If there were not high mortalities at the initial doses tested, othercompounds were investigated.
AcetaminophenThe first agent tested was a methaemoglobin-inducing agent acetaminophen. Thereare known species differences in susceptibility to acetaminophen with the hamsterand mouse being more sensitive than the rat, guinea pig, rabbit (Davis et al. 1974)and possum (Eason et al. 1999). Cats are the most susceptible of any species studiedwith an LD < 40 mg/kg (Wickstrom & Eason 1999). The LD of most other species is in the range 150–1000 mg/kg (St Omer & McKnight 1980; Gaunt et al. 1981).
Acetaminophen would only prove useful as a species-specific toxicant if mustelidswere in the highly susceptible range (< 200 mg/kg).
Twenty-one ferrets (11 male, 10 female; mean weight: 0.98 ± 0.04 kg) weretested in groups of five (six at the highest dose) at reasonably lowconcentrations of acetaminophen: 0, 50, 100, and 200 mg/kg. The humanpharmaceutical, Panadol double-strength, colour-free liquid (SmithKlineBeecham) was the test solution at a concentration of 250 mg acetaminophen/5 ml. Nanopure water at the equivalent volume for 200 mg/kg (4 ml/kg), wasused for the control animals. The limit of 200 mg/kg was chosen as the upper limit to include ferrets as ‘a susceptible species’ and hence ensure minimal risksto other, non-target, species, which generally have a much higher LD . The mean air temperature was 16.4°C during testing.
Non-steroidal anti-inflammatory agentsThe second types of compound tested, as above, were the non-steroidal anti-inflammatory agents. The compounds tested were acetylsalicylic acid, as ExtraStrength Aspro® Clear (Roche) 500 mg tablets dissolved in nanopure water, andNurofen® for children (Boots Healthcare) containing 100 mg ibuprofen/5 mlsuspension. There are few data available on the sensitivity of other species tothese compounds, although in children doses of acetylsalicylic acid over150 mg/kg are considered an overdose (Meyers et al. 1980). Three females foreach treatment group of 250 and 500 mg/kg doses for each compound (mediumto high doses: Wickstrom 1998) were tested. These pilot trials were aimed atdetermining the toxicity to ferrets of concentrations that could, practically, beincluded in a bait. The mean air temperature was 8.5°C during testing.
MNTBecause ferrets were susceptible to acetaminophen (see results), a compound(Mustelid New Toxin: MNT) being developed for predator control in Australia(which we believed had a similar toxicological effect) was tested. (The ‘inprinciple’ agreement in place during these trials has led to the preparation of aMemorandum of Understanding between the Department of Natural Resourcesand Environment, Victoria, Australia; Landcare Research; and DOC to test thiscompound on mustelids.) Forty-seven ferrets (15 male, 32 female; mean weight: 0.90 ± 0.04 kg) weretested at six dosages of MNT (0, 12.5, 25, 30, 40 and 50 mg/kg (Table 1)), afteran initial pilot trial with six animals showed promise. Ferrets were dosed with0.5–2.5 ml/kg MNT, in a crystalline form, dissolved in monopropylene glycol(MPG). Control animals were dosed with MPG. The mean temperature on thedays of testing ranged from 4.2 to 17°C.
A C U T E T O X I C I T Y I N S T O A T S Wild-caught stoats were housed in cages (60 × 150 × 90 cm) under an outsideshelter at the animal facility at Landcare Research. Each stoat was supplied witha nest box (40 × 33 × 15 cm) containing shredded paper as nesting material.
Stoats were fed a rotation of dead day-old chicks, chicken pet mince andmutton/beef pet mince in the afternoon, and had free access to water.
The most promising toxicants were tested in the same manner as on ferrets.
With stoats, only two groups of five to six animals were tested, one control andone treatment group, as information on the appropriate dose level wasprovided from the ferret data. There is little comparable toxicology databetween these two species, but it was assumed that because they are closelyrelated (the same genus), they would have similar susceptibility to toxicants.
Five stoats (3 male, 2 female; mean weight: 260 ± 32 g) were dosed withacetaminophen at 200 mg/kg, alongside five stoats dosed with water (2 male, 3 O’Connor—Evaluation of new toxins for mustelid control female; mean weight: 265 ± 14 g), as controls. Twelve stoats were tested with MNT,six at 25 and six at 50 mg/kg (10 male, 2 female; mean weight: 302 ± 19 g) alongsidenine control stoats dosed with MPG (8 male, 1 female; mean weight: 310 ± 23 g).
The mean temperature on the days of testing ranged from 9.5–17.6°C.
Again, humaneness of each potential toxicant was evaluated in the groups ofanimals used in the efficacy trials. Detailed observations of behaviour weremade for signs of toxicosis and, particularly, any indication of pain or distress.
N O N - T A R G E T A N I M A L S U S C E P T I B I L I T Y T O M N T At DOC’s request the emphasis of this project in the final year (00/01) waschanged, from the original objective to evaluate the relative humaneness ofthese new toxicants in captive stoats and ferrets, to evaluating the sensitivity ofthree non-target species to MNT. This was conducted as part of the agreementDOC (and Landcare Research) has with the Australian group. The humanenessresearch is still viewed as important, but is proposed for future years.
The relative susceptibility of three non-target species (possums, wallabies andducks) to MNT was tested. Groups of six animals were tested at a time, in eithera treatment or control group. All animals were orally gavaged, under lightanaesthesia (or restraint for ducks), and closely monitored for signs oftoxicosis. Control animals were dosed with the carrier solution only (MPG).
The first treatment group (n = 6) received a dose of 500 mg/kg, 100 times theLD recorded for cats (5.6 mg/kg). In general, highly susceptible species have an LD < 20 mg/kg and most species tested have an LD 100–200 mg/kg. If there were no deaths then testing ceased, and the lethal dose would have beenrecorded as > 500 mg/kg. If there were any deaths, further groups of six animalswere tested at a dosage incrementally decreasing (i.e. 250, 125, 62.5 mg/kg .)until a dose level was found where no deaths were recorded. The number, andtime, of deaths were recorded for each dosage level.
Approximate LD values for MNT were calculated for those species where sufficient data were available. The LD values and their 95% confidence intervals were estimated from logistic regression models fitted in SYSTAT 7.0.
A C U T E T O X I C I T Y I N F E R R E T S AcetaminophenThere was 50% mortality at the highest (200 mg/kg) dosage tested, and nomortality at any of the other doses. The three ferrets died within 2 days ofdosing. Lethargy and inappetance were observed in most ferrets in the 24–48hours following dosing at all concentrations (except 0 mg/kg).
Non-steroidal anti-inflammatory agentsThere were no signs of illness and no deaths following acetylsalicylic aciddosing in ferrets. Ferrets dosed with 500 mg/kg ibuprofen were lethargic within2 hours, one animal vomited and another was unconscious for several hours,but there were no deaths.
MNTThere were no deaths at the lowest dose (12.5 mg/kg), 55% of ferrets died at 25mg/kg and 91% at 50 mg/kg MNT (Table 1). The estimated LD for ferrets from these data was 29 mg/kg (95% CI: 22–37 mg/kg). There was no evidence of a sexdifference in susceptibility to MNT.
At all doses of MNT, ferrets generally recovered from the anaesthesia within 5minutes, showed some reduced coordination initially before progressing fromlying, to sternal recumbent to a prostrate posture 50 minutes after dosing.
Animals also showed changes in breathing from rapid breathing initially toshallow, slow breathing nearer death. The mean time to death was 149 minutes.
None of these postural or breathing changes are indicators of pain. All animalsbecame pale and many shivered, including those that recovered (recovery wasseen approximately 5 hours after dosing).
O’Connor—Evaluation of new toxins for mustelid control A C U T E T O X I C I T Y I N S T O A T S AcetaminophenThere were no signs of illness and no deaths following acetaminophen dosing instoats.
The NSAIDs were not tested on stoats because they showed no toxicity in ferrets.
MNTThere was one death in the control group (2 days after dosing) and in the 50mg/kg group (death in 4 minutes), where the effects of anaesthesia combinedwith oral gavaging can not be ruled out. All five of the other 50 mg/kg treatedstoats died within 50 minutes (mean: 41 ± 2.6 minutes). At 25 mg/kg MNT all sixstoats died, also within 50 minutes (mean: 37 ± 3.6 minutes).
Stoats dosed with MPG (controls) recovered from the anaesthetic within 3 minutes,and immediately showed normal active behaviours, including grooming, beforelying in a curled posture. Stoats showed a very consistent pattern after dosing withMNT. For example, stoat 172 dosed at 25 mg/kg woke from anaesthetic at 4minutes and was uncoordinated, lay curled (normal posture) 5 minutes, distinctiveblue colouration to lips by 10 minutes, lying/prostrate from 10 minutes, labouredbreathing from 22 minutes, and dead 31 minutes later. Again, there were noindications of stoats feeling any pain with only postural or breathing changesobserved.
N O N - T A R G E T A N I M A L S U S C E P T I B I L I T Y T O M N T PossumsEighteen acclimatised wild-caught brushtail possums (Trichosurus vulpecula),were used in this trial (9 male, 9 female; mean weight: 3.3 ± 0.2 kg). Possumswere housed in individual wire cages (350 × 20 0 × 200 cm) in temperature-controlled rooms (19 ± 5°C) under natural-day-length fluorescent lighting.
The possums tested had 50% mortality at 500 mg/kg MNT (1 male, 2 female),and no deaths at 0 or 250 mg/kg MNT (Table 2).
All possums dosed with MNT became pale with a distinct ‘blue’ nose 30–60minutes after dosing. Those animals that succumbed lay prostrate within 5hours of dosing, dying 24–48 hours later (animals were unconscious for at leastsome of this time). Two animals that recovered had some external bleeding,from the nose or anus, 12–24 hours after dosing.
WallabiesForty-eight male dama wallabies (Macropus eugenii) (mean weight 5.5 ± 0.4 kg)were captured in the Rotorua district and transported to Guus Knopers’ farm,Te Puke. Wallabies were housed in an enclosed pasture pen (6 × 6 m) with anenclosed shed (2 × 6 m) for shelter, and fed calf muesli and carrots for theduration of the trial. The mean temperature on the days of testing ranged from15 to 23°C.
TABLE 2. NUMBER OF POSSUMS, WALLABIES, AND DUCKS WITH PERCENTMORTALITY FOR EACH MNT DOSE TESTED, AND APPROXIMATE LD50 VALUES There were mortalities at all doses of MNT tested, except 0 and 31.25 mg/kg (Table2). These data indicate an LD of 89 mg/kg (95% CI: 63–118) for wallabies.
The symptoms seen in wallabies following dosing with MNT were blue mouthand excessive salivation, with breathing becoming more shallow and irregularcloser to death. Most wallabies remained comatose until death (on average20 ± 6 hours later). There was occasional limb flexing in some comatoseanimals. The animals that recovered appeared to have impaired coordination forvarying lengths of time (< 24 hours) before recovering.
DucksForty-eight Pekin ducks (Anas platyrhynchos) (18 male, 30 female; meanweight: 2.34 ± 0.1 kg) were housed in groups of at least six in pens (32 × 3 × 2m) outside at the animal facility at Landcare Research. Their diet consisted of agrain mix, duck pellets and fruit with free access to water. The meantemperature on the days of testing ranged from 2.7 to 17.6°C.
There were mortalities at all doses of MNT tested (Table 2); hence the LD50 estimated from these data is 38 mg/kg (95% CI: 20–73). The high susceptibilityof ducks to MNT was unexpected, as much higher LD values (133 to > 300 mg/kg) have been estimated in other bird species.
Within 5 minutes of dosing, ducks went and sat in shade/shelter, already with someincoordination whilst walking. After 10 minutes they had laboured breathing (beakopen gasping for air) and were lethargic until death 2–12 hours later. Some ducksappeared distressed with head waving and neck arching observed.
O’Connor—Evaluation of new toxins for mustelid control • Ferrets, but not stoats, were susceptible to acetaminophen at the low doses • Human non-steroidal anti-inflammatory agents (acetylsalicylic acid and ibuprofen) were not toxic to ferrets at the doses tested.
• Ferrets were susceptible to MNT with an approximate LD of 29 mg/kg (95% • Stoats were highly susceptible to MNT, with 100% mortality at 25 mg/kg.
• Preliminary observations indicate that death from MNT is relatively humane in mustelids, with no obvious signs of distress or pain observed.
• The non-target species tested (possum, wallaby and duck) were all susceptible to MNT. The lethal dose for possums and wallabies was higher than for stoatsand ferrets, but that for ducks was similar.
This research has identified a potential new toxin for stoat control. Thedevelopment of MNT as a new, humane, effective toxin for stoat control, withlow non-target risks, requires further research to:• determine the toxicity of MNT to captive stoats to calculate an accurate LD , • evaluate the relative humaneness of MNT in captive stoats;• estimate the susceptibility of non-target species to MNT, initially by desk-top extrapolation of available data to identify key information gaps, and criticalspecies for future testing; • determine the palatability and effectiveness of a toxic bait, containing MNT, I thank Grant Morriss and Andrea Rhodes for assisting with the trials; Guus andHeddie Knopers for providing facilities, wallabies and wallaby care; and JulieTurner, Penny Willcock, Siobhan Kay and Michael Wehner for the husbandryand care of all other animals. Thanks also to Ray Webster for statistical advice,Penny Fisher, Elaine Murphy and Charles Eason for comments on earlier drafts,Christine Bezar for editing, and Wendy Weller for final word processing of thisreport.
Davis, D.C.; Potter, W.Z.; Jollow, D.J.; Mitchell, J.R. 1974: Species differences in hepatic glutathione depletion, covalent binding and hepatic necrosis after acetaminophen. Life Sciences 14:2099–2109.
Davis, J.A.; Greenfield, R.E.; Brewer, T.G. 1993: Benzocaine-induced methemoglobinemia attributed to topical application of the anaesthetic in several laboratory animal species.
American Journal of Veterinary Research 54: 1322–1326.
Gaunt, S.D.; Baker, D.C.; Green, R.A. 1981: Clinicopathologic evaluation of N-acetylcysteine therapy in acetaminophen toxicosis in the cat. American Journal of Veterinary Research 42: 1982–1984.
Eason, C.T.; Wright, G.R.G; Gooneratne, R. 1999: Pharmacokinetics of antipyrine, warfarin and paracetamol in the brushtail possum. Journal of Applied Toxicology 19: 157–161.
Meyers, F.H.; Jawetz, E.; Goldfien, A. 1980: Review of medical pharmacology. California, Lange St Omer, V.V.; McKnight, E.D. 1980: Acetylcysteine for treatment of acetaminophen toxicosis in the cat. Journal of the American Veterinary Medical Association 176: 911–913.
Wickstrom, M.L.; Eason, C.T. 1999: Literature search for mustelid-specific toxicants. Pp. 57–63 in: Department of Conservation 1999: Progress in mammal pest control on New Zealandconservation lands. Science for Conservation 127, 74 p.
O’Connor—Evaluation of new toxins for mustelid control

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