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Cartap is extensively used to control agricultural pests. Pertinent literatures have indicated that it causes no eye irritation [D.E. Ray, Insecticides derived from plants and other organisms, in: W.J. Hayes, E.R. Laws (Eds.), Handbook of Insecticide Toxicology, Classes of Insecticides, vol. 2, Academic Press, New York, 1991, p. 611; C. Tomlin, Cartap, in: C. Tomlin (Ed.), The Insecticide Manual, 12th ed., British Crop Protection Council, Surrey, UK, 2000, p. 144]; however, the instillation of a little cartap through the eye has caused death in rabbits. The aim of this study was to determine the ocular toxicity of cartap in New Zealand White rabbits. Cartap was directly instilled into the low conjunctival sac of eyes, at doses of 0, 5, 7.5, 10 and 12.5 mg/kg body weight. The changes in the enzymes and isoenzymes of creatine kinase (CK), lactate dehydrogenase (LD), as well as pathological changes in the muscles of the heart, thigh and diaphragm were determined in the cartap-treated rabbits. Moreover, the neuromuscular effect of cartap was examined using the isolated rabbit phrenic-nerve diaphragm model. The results indicated that rabbits developed severe signs and they died within 20 min of ocular instillation. The ocular LD50 of cartap was 8.1 mg/kg body weight. Treatment with cartap increased the activities of CK and LD enzymes and their isoenzymes, CK-1, CK-2, and CK-3 in serum, and CK-3 and LD-5 in the diaphragm. Microscopically, hypercontraction bands and the rupture of myofibers of the diaphragm were observed in dead rabbits. Cartap did not affect nerve-evoked twitch but induced irreversible contracture and twitch depression on the isolated rabbit's diaphragm. These results indicate that the rabbit is susceptible to cartap toxicity; the effect of cartap caused contracture and damage to the diaphragm might play a pivotal role in respiratory paralysis and death of rabbits during intoxication.

The purpose of this work is to evaluate the pulmonary toxicity of purified thuringiensin in Sprague–Dawley rats. Rats were intratracheally instillated with 0, 0.4, 0.8, 1.6, 3.2, 6.4 and 9.6 mg/kg body weight of thuringiensin. The results indicated that the acute pulmonary LD 50 of thuringiensin for rats was 4.4 mg/kg. The total number of inflammatory cells and lactate dehydrogenase (LDH) activity in the bronchoalveolar lavage (BAL) fluid increased in a dose-dependent manner after thuringiensin instillation. Furthermore, an effective dose of 1.6 mg/kg was selected for the time course study of pulmonary toxicity. The treated animals showed a significant increase in the weights of the lungs, hydroxyproline levels in the lungs and total number of cells in BAL fluid 2, 4, 7, 14, 28 and 56 days after treatment. In comparison with the control, the total protein concentrations in BAL fluid were increased by 361, 615, 116, 41, 34 and 41%, after 2, 4, 7, 14, 28 and 56 days, respectively. The LDH activity in BAL fluid showed a significant increase after 1, 2, 4, 7, 14, 28 and 56 days. The increases in fibronectin levels were 164, 552, 490, 769, 335, 257 and 61% at the corresponding times, but neither tumor necrosis factor nor interleukin-1 increased. The treated rats presented abnormal histology including distributed inflammation in the bronchioles and alveoli, bronchial cellular necrosis on days 1 and 2, and areas of septal thickening with cellular infiltration and collagen deposit in the intestinal and alveolar spaces on days 4–56. Based on these biochemical and pathological parameters, intratracheal instillation of purified thuringiensin might cause significant pulmonary toxicity in rats.

Our previous study has demonstrated that instead of neuromuscular blockage cartap, an organonitrogen insecticide, could cause a marked irreversible Ca2+-dependent contracture in both isolated mouse and rabbit phrenic nerve-diaphragms. We further examined the potential of direct myocytotoxicity of cartap and the possible roles of calcium ion and oxidative stress on cartap-induced muscle cell injury using the mouse myoblast cell line, C2C12. Cartap exerted a dose- and time-dependent cytotoxic effect in C2C12 cells measured by MTT colorimetric assay and trypan blue dye exclusion. The extracellular activities of both creatine kinase (CK) and lactate dehydrogenase (LDH) were elevated in the cartap-treated groups at or greater than 100 microM. The isoenzymatic profiles showed that the elevations were mainly due to CK-3, LDH-3, and LDH-4. Following the addition of 0.5-2.5mM EGTA, a Ca2+ chelator, or 30-100 microM verapamil, an L-type Ca2+ channel blocker, the cartap-induced reduction in MTT metabolic rate of C2C12 cells was significantly restored in a dose-dependent manner in both EGTA and verapamil-treated cells. Furthermore, EGTA could significantly reduce the cartap-induced elevation in the levels of total extracellular CK and LDH activities. Additionally, cartap significantly increased the level of endogenous reactive oxygen species (ROS) in C2C12 cells in a dose- and time-dependent manner. The cartap-induced ROS generation could be significantly inhibited by antioxidants, including Vitamins C and E, catalase, and superoxide dismutase, with catalase the most effective. EGTA could significantly inhibit cartap-induced ROS generation in a dose-dependent manner. The results suggested that cartap could induce ROS generation in C2C12 cells via a Ca2+-dependent mechanism resulting in subsequent cytotoxicity, at least partially, to C2C12 cells. It is speculated that both Ca2+ and Ca2+-induced ROS may also play the central role on the myogenic contracture and myofiber injury of the diaphragm leading to respiratory failure and subsequent death in rabbits exposed ocularly to cartap.