A Comparison of the Acute Toxicity, Neuropathology, and Electrophysiology of N,N-Diethyl-m-toluamide and N,N-Dimethyl-2,2-diphenylacetamide in Rats

The insect repellent DEET and the structurally related herbicidediphenamid both cause ataxia associated with a spongiform myelinopathylargely confined to the cerebellar roof nuclei. This local myelinopathywas accompanied by the formation of neuronal cytoplasmic cleftsand was produced by a single dose of 1 to 3 g/kg N,N-diethyl-m-toluamide(DEET). These dose levels also produced a severe and often fatalprostration and clear electrophysiological signs of prolongedsuppressed seizure activity. Diphenamid produced an identicalmyelinopathy after doses of 0.8 to 1.5 g/kg but without thesevere prostration, suppressed seizures, or neuronal clefts.The effects of diphenamid were shown to be reversible over 3to 7 days by neuropathological, motor, and auditory evoked responseindices. Both compounds caused characteristic changes in auditoryevoked response which may be useful in clinical diagnosis. Sixother alkyl amides, two of which produce signs of CNS excitation,failed to produce myelinopathy at the maximum tolerated doses.Our findings show close parallels with a number of human casesof DEET poisoning and indicate that other amides, like diphenamid,also pose a potential hazard.     

Selective inhibition and induction of CYP activity discriminates between the isoforms responsible for the activation of butylated hydroxytoluene and naphthalene in mouse lung

1. Selective induction and inhibition experiments have been used to identify the cytochrome P450 (CYP) isoforms responsible for butylated hydroxytoluene (BHT) bioactivation in mouse lung. 2. Pre-treatment of BALB/c mice with O,O,O-trimethylphosphorothioate (OOOMeP(S)), which prevented all the signs of toxicity observed following BHT treatment,inhibitedthe pulmonary activity of pentoxyresorufin O-dealkylase (PROD) and coumarin hydroxylase but not 4-nitrophenol hydroxylase. 3. Pulmonary coumarin hydroxylase activity was greater inDBA thanin BALB/c mice but the severity of BHT-induced lung injury was similar. 4. Pre-treatment with pyrazole, which exacerbated BHT-induced lung injury, did not affect pulmonary coumarin hydroxylase or 4-nitrophenol hydroxylase activity but increased that of PROD. 5. Pre-treatment with OOOMeP(S) prevented the lethargy and weight-loss associated with naphthalene poisoning but not the pulmonary injury.Pre-treatment with pyrazole did not exacerbate naphthalene-induced injury. 6. Members of both CYP2F and 2B sub-families have been shown to exhibit PROD activity and 2F2 activates naphthalene in mouse lung. The current studies, however, indicate that 2F2 is unlikely to be a significant component of PROD activity in mouse lung. 2F2, like coumarin hydroxylase (2A5) and 4-nitrophenol hydroxylase (2E1), is not responsible for the pulmonary activation of BHT, which is largely attributable to an isoform of 2B, probably 2B10.     

EVOLUTION OF THE INTRACELLULAR CHANGES IN NEURONS CAUSED BY TRIMETHYLTIN

Rats have been given a single dose of trimethyltin (10 mg/kg) and the intracellular events have been followed particularly in hippocampus, cerebral cortex, cerebellum and spinal ganglion cells. The earliest change visible occurs 12 h after this dose and is found to be dense membrane-bound bodies, probably derived from branching tubulo-vesicular smooth endoplasmic reticulum formations. These occur in close connection with rought endoplasmic reticulum and polyribosomes and appear also to have some association with the Golgi complex. At 24 h there is a general vacuolation of Golgi cisterns and SER membranes, and the membrane-bound dense body formation is greatly increased. SER abnormalities are particularly conspicuous in Purkinje cells. In spinal ganglion cells, while vacuolation of Golgi cisterns is intense, dense bodies are inconspicuous and are replaced by increased autophagosomes, often of great complexity. By 48 h vacuolation of Golgi cisterns has waned, but accumulation of dense bodies and secondary lysosomes has steadily increased. In spinal ganglion cells autophagosomes only are increased as the Golgi vacuolation declines. At later times steady increases of lysosomal dense bodies is seen generally accompanied in hippocampal pyramidal cells and dentate fascia cells by abundant cell death. The suggestion is put forward that the Golgi complex may be the seat of the critical metabolic lesion and disturbances to protein transfer and protein synthesis follow. No explanation for the selective loss of hippocampal h1-5 (CA1-CA4 except Sommer's sector) pyramidal cells and of small dentate fascia neurons can be derived from these conclusions.     

THE TOXICITY AND NEUROPATHOLOGY OF DIMETHYLETHYLTIN AND METHYLDIETHYLTIN IN RATS

Triethyltin causes an increase in brain water with vacuolation of myelin sheaths, whereas trimethyltin is selectively damaging to neurons, especially of the hippocampal formations, causing chromatolysis, accumulation of cytoplasmic dense bodies and often cell death. The effects on rats of the analogues, dimethylethyltin and methyldiethyltin (oral LD50 14 mg/kg and 7.5-10.0 mg/kg respectively) are now reported. The dimethylethyl compound produces functional changes resembling those caused by trimethyltin, while the methyldiethyl compound causes responses similar to those produced by triethyltin. Structurally, however, the dimethylethyl compound, while producing marked nerve cell changes of the trimethyltin type also causes moderate vacuolation of myelin sheaths. By contrast, methyldiethyltin causes marked vacuolation of myelin sheaths of the triethyltin type and relatively minor neuronal changes of the trimethyltin type. These findings are discussed in terms of the structure-activity relationships of trialkyltin compounds.