Ten 3-day-old chicks were submitted from a flock experiencing high mortality. Necropsy revealed lacrimation, diarrhea, pleural effusion, hemorrhage and ulceration of the proventriculus, and swollen, hemorrhagic livers. Numerous yellow granules were present in the crop. Assayed crop contents contained 39 ppm diazinon [O,O-diethyl O-(2-isopropyl-4-methyl-6-pyrimidyl)phosphorothioate]. The insecticide had been applied to the litter to control fire ants. The high mortality abated after new litter was added on top of the old litter. Diazinon toxicosis was traced to ingestion of diazinon-impregnated granules and was reproduced experimentally.

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ABSTRAC~The genotoxic and oncogenic potentials of methotrexate were studied in Sprague-Dawley rats. The rats received 0.1, 0.2, or 0.4 mg/kg of methotrexate as dietary admixtures on a 5 days on, 9 days 0% regimen for 23 months. In the females of the high-dose group, there was a significant increase in mortality starting at 18 months. Significant increases in the number of rats with focal pulmonary interstitial fibrosis were seen in both sexes at the high-dose level. At the mid-and high-dose levels of both sexes, there was a significantly increased number of rats with myeloid and erythroid bone marrow hypoplasia. There was no evidence of either early onset or increased incidence ofany tumor type in the treatment groups. Therefore, it is concluded that methotrexate does not have oncogenic potential. Also, at terminal sacrifice, bone marrow cells were harvested from selected animals on the last day of the 5-day dosing cycle and cytogenetic evaluation was performed. No significant increase in chromosomal aberrations was seen in any dose group relative to the control group. This observation further substantiates the absence of oncogenic potential due to methotrexate in rats. INTRODUC~IONMethotrexate is an antimetabolite which acts as a folic acid antagonist (1 1). It is one of the few drugs whose mechanism of action has been extensively studied and well characterized. Methotrexate, also known as amethopterin, is a potent inhibitor of dihydrofolate reductase which converts dihydrofolate to tetrahydrofolate. Tetrahydrofolate and subsequent folic acid derivatives serve as cofactors in the transfer of single carbon atoms in the synthesis of purines and thymidylic acid required for DNA synthesis.Methotrexate has been recognized for many years as one ofthe most effective chemotherapeutic agents for certain leukemias, choriocarcinoma and Burkitt's lymphoma as well as other neoplastic diseases (22). More recently, it has been successfully used for the treatment of severe recalcitrant psoriasis (3, 10) and rheumatoid arthritis (5) for durations longer than normally used in patients with cancer. In order to determine the oncogenic potential or the genetic liability of methotrexate, a 2-year lifetime bioassay in rats was performed. This paper describes the results of the carcinogenicity study as well as chromosomal analysis from rats in the lifetime bioassay. Furthermore, we have reviewed the Iiterature on the carcinogenic, co-carcinogenic and mutagenic potentials of methotrexate. Based on all these studies, an overall safety of methotrexate has been assessed. METHODS ClieniicalMethotrexateO,' N-[4-[[(2,4-diamino-6-pteridinyl)methylJmethylamino]benzoyIJ-l-glutamic acid (Fig. 1) is a bright yellow-orange, odorless, crystalline powder with a molecular weight of 454.5. AnimalsSprague-Dawley rats were obtained from Charles River Breeding Laboratories. The rats weighing approximately 75 g at the start of the study were assigned to different groups using a table ofrandorn numbers. All animals were individually identified by a system ...