Abstract:
Diclofenac was responsible for the death of millions of Gyps vultures (G. bengalensis, G. indicus and G. tenuirostris) in the Indian sub-region with the safety of the other members of nonsteroidal anti-inflammatory drugs (NSAIDs) being questionable. This has resulted in calls to test all the available NSAIDs for their vulture toxicity potential especially as studies have shown meloxicam to be safe; and ketoprofen, carprofen, flunixin and phenylbutazone as toxic. Unfortunately, due to the cost of testing, the time taken to establish toxicity reliably and the questionable ethics of repeat toxicity testing in an endangered species, an alternate method of and model for testing is needed. For this study, we evaluated an OECD recommended method for determining the avian toxic potential of environmentally applied pesticides. We exposed young-adult Japanese quails (Coturnix japonica), Muscovy ducks (Cairina moschata) and domestic pigeons (Columba livia) as per model requirements to diclofenac at various doses. This was coupled to the evaluation of the plasma toxicokinetics of the mentioned drug. The aim of this study was to look at the potential of the OECD models, as a predictive tool for diclofenac’s environmental toxic effect. Intoxication was noted in Japanese quails and Muscovy ducks which appeared to be identical to the clinical signs that were previously reported in vultures viz. depression and death within 48 – 92 h of dosing; while the domestic pigeon was insensitive| not susceptible. For the birds that died, necropsy revealed signs of nephrosis with resultant urate deposits in the kidney, spleen, pericardium and liver, once again as previously seen in the vulture. The pharmacokinetic profile in the domestic pigeon showed that the drug was well absorbed and distributed with a T1/2 generally below 6 h. The toxicokinetic profile in Japanese quails demonstrates that toxicity was related to metabolic capacity, with a T1/2 and MRT above 6 h and 8 h respectively being associated with signs of intoxication. While the quail result is consistent with previous studies, poisoning in the Muscovy ducks was not related to metabolic constraint but elevated plasma uric acid concentration as they all demonstrated rapid metabolism [T1/2 (1-2 h) and MRT (2-3 h)] irrespective of survival or death. This was also reflected by their almost intact micro-hepatic structure as opposed to the other species. Interestingly, some of the Muscovy ducks recovered even though they had elevated plasma uric acid concentrations reported to kill Gyps vulture. To better understand this, plasma from Muscovy duck, Cape Griffon vulture (Gyps coprotheres) and domestic chicken (Gallus gallus) were subjected to a uric-acid saturation test which proved the former’s higher tolerance to elevated plasma uric acid concentration. Despite evidence of intoxication from this study, the estimated oral LD50 was very high at 405 mg/kg and 190 mg/kg in Japanese quails and Muscovy ducks respectively. The latter was also substantially higher than the LD50 of 0.1 mg/kg extrapolated for Gyps vultures. We therefore conclude that these bird species are not suitable as surrogates for NSAID toxicity testing. More importantly the results suggest that the toxicity of diclofenac in vultures is idiosyncratic and thus completely unpredictable using current laboratory models prescribed by the OECD.
