Acute and long-term effects of exposure to sodium monofluoroacetate (1080) in sheep.

Acute and long-term effects of a single, relatively high oral dose (0.25 and 0.30 mg/kg) of sodium monofluoroacetate (1080) on the survival and productivity of sheep were evaluated to establish a better understanding of 1080 poisoning and identify more specific changes diagnostic of toxicosis. In survivors, clinical signs of acute 1080 toxicosis such as salivation and lethargy were generally very mild. Fasted animals were more prone to 1080 toxicity. In animals that died, more severe signs, including tachypnoea, dyspnoea, and tremors occurred for 15-20 min prior to death. 1080 concentrations were highest in the blood > heart > skeletal muscle > liver. 1080 could not be detected in any of these organs of the animals that survived. Serum citrate concentrations were elevated for 4 days after dosing. No clinical or biochemical abnormalities were found in any animal after 4 days. Histopathological lesions were most marked in the heart and lung with inflammation, necrosis, and scattered foci of fibrous tissue in the myocardium, pulmonary oedema and inflammation of the lung. No adverse long-term effects on general health or reproductive performance were observed in any sheep that survived the first 4 days following exposure to 1080. The most reliable diagnostic indicators of 1080 exposure in sheep were measurement of its residues in blood, skeletal muscle and ruminal contents, increased serum citrate concentration, elevated heart rate, and characteristic electrocardiograph changes (up to 4 days after exposure). Death from 1080 is most likely to occur within 96 h, and animals that survived this period appeared normal.

Behavioural, biochemical, and pathological responses of possums (Trichosurus vulpecula) poisoned with phosphorus paste.

AIM: To investigate the behavioural, biochemical and pathological responses of possums following poisoning with phosphorus paste, in order to assess the implications for the welfare of possums. METHODS: After ingestion of phosphorus paste by wild-caught possums (18 high dose, nine low dose, and 12 non-poisoned controls), behavioural observations were made at 15-min intervals for 24 h or until death. Serum biochemistry, and gross and microscopic pathology were assessed at 3-hourly intervals in a further 21 possums. RESULTS: Possums that ingested phosphorus paste developed an abnormal posture (high incidence of crouching after 4-8 h), mild congestion of the gastric mucosa, and elevated levels of creatine kinase (CK) in serum after 3-6 h. Retching was observed in 67% possums, and 44% vomited at least once. Possums were prostrate from about 18 h after eating the poison, and the response to handling, an indicator of consciousness, was lost at about 24 h, followed by death at 25 h. CONCLUSION: The main welfare concern was the possibility of discomfort or pain caused by the congestion of the gastric mucosa, as indicated by the crouched posture adopted by poisoned possums. Retching and vomiting may also have caused pain and distress. The degree of pain or discomfort would depend on the degree of congestion of the gastric mucosa, which was typically mild, and on the duration and severity of retching and vomiting, which were typically short and mild. Possums remained conscious until 1 h before death, implying that they were able to experience pain and distress from the effects of ingestion of phosphorus for almost the entire period of illness, which lasted for approximately one day.

Animal welfare and ethical issues relevant to the humane control of vertebrate pests.

Vertebrate pests and pest control impact on people, animals and the environment, so any ethical consideration of vertebrate pest control must incorporate the interests of all three. The necessity of intervention, whether it involves killing animals or not, must be properly evaluated. Justification for pest control is only tenable if all of the negative impacts (harms) on people, animals and the environment are minimised and all of the positive impacts (benefits) are maximised as far as can be feasibly achieved. In all cases, the most humane control methods possible must be used; we must actively seek ways to improve the humaneness of existing methods and to find new methods that are more humane. There are six major principles that guide the design and execution of ethically sound vertebrate pest control programmes. (1) The aims or benefits and the harms of each control programme must be clear. (2) Control must only be undertaken if the aims can be achieved. (3) The methods that most effectively achieve the aims of the control programme must be used. (4) The methods must be applied in the best possible way. (5) Whether or not each control programme actually achieved its precise aim must be assessed. (6) Once the desired aims or benefits have been achieved, steps must be taken to maintain the beneficial state. An ideal pest control method would be effective and easy to use, affordable, safe for human users and for people exposed to it, humane, specific to the target species or individuals, and safe for the environment. Although such a gold standard is difficult to achieve, we can only retain ethical credibility if we conscientiously strive to make incremental improvements towards that gold standard.

Development of antidotes for sodium monofluoroacetate (1080).

Baits containing sodium monofluoroacetate (1080) are commonly used in New Zealand during feral pest control operations. However, each year, a number of domestic dogs are unintentionally killed during these control operations, and a suitable antidote to 1080 intoxication is required. The primary toxic mechanism of 1080 is well known. However, as with other pathologies where energy deprivation is the main effect of intoxication, the cascade of effects that arises from this primary mechanism is complex. At present, putative antidotes for 1080 are generally unable to address the primary mechanism of intoxication but such agents may be able to control the cascade of secondary effects, which can result during intoxication. Part of the reason for this is that targeting the cascade can provide a longer window of time for antidote success. We have undertaken studies that identified some of the central nervous system (CNS) and systemic pathophysiological cascades caused by 1080 intoxication. Using this information we designed antidotes, on the basis of preventing different steps in this cascade. In the chicken model targeting systemic changes, in particular reducing effects of nitric oxide derivatives generated in cardiac muscle, proved successful in reducing fatality associated with 1080. In rats and sheep, targeting the CNS with a number of compounds including: glutamate; calcium and dopamine antagonists; gamma amino butyric acid agonists, and astressin-like compounds reduced fatalaties. However, to be successful in the rat and sheep model a given antidote needed to move quickly from systemic circulation across the blood brain barrier and into the CNS. The work also suggests ways in which specific biomarkers of 1080 exposure may be developed with respect to different species.

Sorption of fluoroacetate (compound 1080) by Colestipol, activated charcoal and anion-exchange in resins in vitro and gastrointestinal decontamination in rats.

The sorption of sodium fluoroacetate (FA) by activated charcoal (AC) and 5 anion exchange resins (AERs) was tested in 2 simulated gastrointestinal (GI) fluids. Each sorbent was incubated with FA in a shaker-water-bath at 37 C for 24 h. Supernatant was removed and filtered, and the concentration of FA was determined by gas chromatographic detection of the dichloroaniline derivative. Under simulated gastric conditions (0.1 M HCl at approximately pH 1.5), the sorbents removed the following proportions of FA from solution: Carbosorb AC, 87 +/- 2%; cholestyramine, 28 +/- 7%; colestipol, 96 +/- 0%; Amberlite IRA-96, 70 +/- 2%; DEAE-Sephadex, 7 +/- 4%; Chitosan, 66 +/- 2%. Under simulated intestinal conditions (0.05 M sodium phosphate at approximately pH 7.4), binding was as follows: Carbosorb AC, 68 +/- 4%; cholestyramine, 53 +/- 5%; colestipol, 46 +/- 2%; AmberliteIRA-96, 10 +/- 20%; DEAE-Sephadex, 64 +/- 7%; Chitosan, 5 +/- 2%. All findings differed significantly from control, with the exception of Amberlite IRA-96 and Chitosan in phosphate buffer, and DEAE-Sephadex in HCI. In a second study, rats were given 5 mg FA/kg, and then gavaged with 2 g/kg Carbosorb AC, colestipol or bentonite. Over 4 h, the area under the curve of serum FA versus time (AUC) decreased by 39% in the rats treated with colestipol and 42% in those treated with bentonite. In contrast, Carbosorb AC did not affect the AUC,yet increased Tmax In another study, mortality was assessed 96 h after rats were orally dosed with 5 mg FA/kg followed by gavage with 2 g/kg Carbosorb AC, colestipol or water immediatey or 30 min after dosing. When the sorbents were given immediately, mortality was the same as control (75%). Surprisingiy, the 30-min delay resulted in lower mortality in colestipol-treated rats, (approximately 38%) compared to 100% in the group treated with Carbosorb AC. Before any recommendation can be made regarding the use of colestipol as a GI decontaminant, the latter findings require confirmation in an intensive care setting. The potential for synergistic effects with 2 or more sorbents also warrant investigating.

Pharmacokinetics of antipyrine, warfarin and paracetamol in the brushtail possum.

The plasma pharmacokinetics of antipyrine, warfarin and paracetamol have been studied in the Australian brushtail possum (Trichosurus vulpecula). The plasma elimination half-lives (t1/2) were 1.2 h for antipyrine, 11.9 h for warfarin and 5.2-12.9 h for paracetamol. Our data indicate that the clearance of these three xenobiotics in the possum is similar to that reported in eutherian mammals. There was no dose-dependent increase in paracetamol plasma t1/2 over the dose range 100-1000 mg kg(-1), indicating a lack of capacity saturation. This observation may in part explain the unusual resistance of the possum to the hepatotoxic effect of high doses of paracetamol.

Effect of potassium cyanide on behaviour and time to death in possums.

AIM: To assess the sickness behaviours of possums after eating a lethal dose of potassium cyanide. METHOD: Spontaneous behaviour and the time to loss of physical responses were examined. RESULTS: Cyanide ingestion caused a short-lasting period of mild respiratory stimulation. There was no salivation, retching or vomiting. Convulsions occurred in 73% of the possums. After the ingestion of cyanide, the average time to onset of ataxia was 3 minutes, the average time to overall loss of consciousness was 6.5 minutes, and the time to cessation of breathing was 18 minutes. CONCLUSION: Cyanide is a rapid-acting toxin with few undesirable signs from the welfare perspective.

Fluoroacetate content of some species of the toxic Australian plant genus, Gastrolobium, and its environmental persistence.

Gas chromatography confirmed the relatively high concentrations of fluoroacetate found in toxic Gastrolobiums, a genus of indigenous Australian plants. Fluoroacetate concentration in these plants ranged from 0.1 to 3875 micrograms/g (ppm) dry weight, with young leaves and flowers containing the highest concentrations. However, there was considerable intrastand variation between individual plants of at least two species with coefficients of variation ranging from 94% to 129%. Despite the high concentrations of fluoroacetate in many species, only one of nine soil samples collected from beneath these plants contained fluoroacetate. None of the 16 water samples collected from nearby streams and catchment dams contained fluoroacetate. This suggests that fluoroacetate does not persist in this environment. Fluoroacetate was also found in the genus Nemcia, and very low levels of fluoroacetate (ng/g) were detected in the foodstuffs, tea and guar gum. The latter indicates that other plant species may produce biologically insignificant amounts of fluoroacetate.

Persistence of sodium monofluoroacetate in rabbits and risk to non-target species.

1. Sodium monofluoroacetate (1080), a vertebrate pesticide used in New Zealand, was administered orally to rabbits at two dose levels (sub-lethal and lethal) to determine how long 1080 would persist in plasma, liver, kidney, and muscle so that the risk of consumption of meat from lethally or sub-lethally poisoned rabbits by non-target species could be assessed. 2. The plasma elimination half-life in rabbits receiving a sub-lethal dose was 1.1 h. Retention of 1080 in tissue was greater in rabbits dosed with a lethal dose than in those that received a sub-lethal dose. Irrespective of the dose level, concentration of 1080 in muscle, kidney, and liver was substantially lower than in the plasma. 3. Poisoning of dogs is possible because of their extreme susceptibility to 1080. Poisoning of birds is less likely. The risk of secondary poisoning is reduced as the concentration of 1080 declines in putrefying carcasses.

Persistence of sodium monofluoroacetate in livestock animals and risk to humans.

1. Sodium monofluoroacetate (1080), a vertebrate pesticide widely used in New Zealand, was administered orally to sheep and goats at a dose level of 0.1 mg kg-1 body weight to assess risk to humans of secondary poisoning from meat. Blood, muscle, liver, and kidney were analysed for 1080 residues. 2. The plasma elimination half-life was 10.8 h in sheep and 5.4 h in goats. Concentrations of 1080 in muscle (0.042 microgram g-1), kidney (0.057 microgram g-1), and liver (0.021 microgram g-1) were substantially lower than those in plasma (0.098 microgram ml-1) at 2.5 h after dosing. 3. Only traces of 1080 (< 0.002 to 0.008 microgram g-1) were found in sheep tissues after 96 hours. 4. Livestock are normally excluded from areas where 1080 is being used for pest control, reducing the risk of secondary poisoning. Even with accidental exposure to a sublethal dose 1080 would not persist in tissues for more than a few days because it is cleared rapidly from the body. Therefore the occurrence of 1080 in meat intended for human consumption is highly unlikely.

The plasma pharmacokinetics of iophenoxic and iopanoic acids in goat.

1. The comparative plasma pharmacokinetics of two organic iodine-containing compounds were evaluated in the goat for their suitability as markers in wildlife studies. 2. After oral administration of a single dose, the plasma elimination half-life for iopanoic acid was considerably more rapid (t1/2 of 1-2 days) than that of iophenoxic acid (t1/2 of 81 days). 3. Similar peak plasma concentrations were obtained after administration of iophenoxic acid (1.5 mg/kg) and iopanoic acid (25 mg/kg); however, the AUC0----infinity for iopanoic acid at doses of 25, 50, and 100 mg/kg were 201 +/- 39, 604 +/- 225, and 1292 +/- 721 (micrograms h/ml +/- SD), respectively, which were less than the value of 36,600 +/- 6387 for the oral administration of iophenoxic acid at 1.5 mg/kg. 4. Iophenoxic acid was chosen as a suitable marker because of its persistence at detectable concentrations in the plasma for 5 months.

The importance of pharmacokinetic and receptor studies in drug safety evaluation.

The importance of pharmacokinetic and receptor studies in the preclinical and clinical safety evaluation of candidate drugs is reviewed with reference to a number of recently developed drugs. Different aspects of the relationships between pathways of metabolism, pharmacokinetics, receptor interactions, and drug toxicity are illustrated. The failure of animal toxicity studies to predict drug toxicity in humans, due to species differences in metabolism and pharmacokinetics, is illustrated by reference to the anti-inflammatory antiviral terpenoid carbenoxolone, the antiasthmatic candidate drug FPL 52757, and the cardiotonic drug amrinone. The false prediction of adverse effects in man from toxicity manifested in experimental animals, due to species differences in pharmacokinetics or receptor activities, is exemplified with reference to the antiepileptic valproic acid, the hypolipidemic drug ciprofibrate, the antipeptic ulcer drug, omeprazole, and the progestogen lynestrenol. Finally, the importance of adequate, repeat-dose, clinical pharmacokinetic studies in patients as distinct from healthy volunteers to evaluate any effect of the disease state, in the elderly and the young to examine the effects of age, and in sufficiently large populations to detect genetic anomalies and idiosyncrasies is illustrated by reference to the anti-rheumatoid drug benoxaprofen, the antiangina drug perhexiline, and the diuretic tienilic acid.

A comparison of the effects of three positive inotropic agents (amrinone, milrinone and medorinone) on platelet aggregation in human whole blood.

Amrinone, milrinone and medorinone inhibit platelet aggregation in human whole blood. They are particularly potent inhibitors of arachidonic acid induced aggregation, inhibiting by 50% (IC50) at concentrations of 1.5 microM (milrinone), 7.5 microM (medorinone) and 48 microM (amrinone). Each drug was less potent at inhibiting ADP and collagen-induced aggregation. The rank order for inhibition of arachidonic acid - induced aggregation correlated well with the rank order of cyclic AMP phosphodiesterase inhibition for these drugs when compared to the response of a reference cAMP phosphodiesterase inhibitor (CI-930) and a reference cGMP phosphodiesterase inhibitor (M & B 22948). Since inhibition of platelet aggregation in vitro occurred at clinically relevant concentrations, it is evident that these agents have potentially beneficial antithrombotic properties.