Benlate. A medical and scientific controversy.

Benlate, a fungicide, has been used for over 20 years in Florida to treat agricultural crops and ornamentals. In the past few years, there have been reports of crop damage and health effects from exposure. Physicians should be aware of research findings regarding these effects.

Potentiation of ethyl methanesulfonate-induced germ cell mutagenesis and depression of glutathione in male reproductive tissues by 1,2-dibromoethane.

EDB significantly depressed GSH in caput and cauda epididymis, but not in testis, 2 hours following injection. This depression was dose-related. EDB enhanced EMS-induced dominant lethal mutations at mating weeks 2 and 3 (of 6). At mating week 2 the fetal death rate was increased two-fold, while at week 3, the fetal death rate had increased to nearly three-fold greater than the EMS-only controls. Enhancement of fetal death rate was confined to postimplantation loss. As with EMS alone, the EDB potentiation of EMS-induced mutations was limited to postmeiotic stages of spermatogenesis. EDB also enhanced alkylation of rat spermatozoa by labeled EMS. Depression of GSH in reproductive tissues is correlated with a potentiation of dominant lethal mutations, as well as an increase in the binding of EMS to sperm heads.

Depression of glutathione in male reproductive tissues and potentiation of EMS-induced germ cell mutagenesis by L-buthionine sulfoximine.

Buthionine sulfoximine (BSO) treatment significantly reduced testicular epididymal and vas deferens glutathione (GSH) levels in rats. Testicular levels of GSH were reduced by 20%, while epididymal GSH levels were reduced by more than 50%. BSO treatment correspondingly enhanced ethyl methanesulfonate (EMS)-induced dominant lethal mutations. EMS-induced resorption rates were doubled following BSO treatment. This effect was observed in mating wk 2 and 3 (d 8-19 following treatment), indicating effects on those germ cells which were in late testicular stages or were caput epididymal spermatozoa at the time of EMS treatment. The enhancement of the mutagenic action of EMS by BSO is restricted to the same time period (spermatid-spermatozoa transition, early epididymal maturation) as maximum sensitivity to the clastogenic action of EMS on male germ cells. The temporal pattern of EMS alkylation of rat spermatozoa correlated with the incidence of EMS-induced dominant lethal mutations. BSO depresses GSH in the male reproductive tract in a dose- and time-dependent manner. Perturbation of GSH in the male reproductive tract appears to influence chemical-induced germ cell mutations.

Germ-cell mutagenesis and GSH depression in reproductive tissue of the F-344 rat induced by ethyl methanesulfonate.

Sensitivity of male F-344 rats to the dominant lethal (DL) mutagenic effect of ethyl methanesulfonate (EMS) was studied in conjunction with an evaluation of EMS-induced depression of glutathione (GSH) in testis, epididymis and vas deferens. At the maximal effect, during week 3 (days 15-19 post-EMS), a dosage of 50 mg/kg caused 13.3% fetal death (FD) vs. 3.3% in controls, while 100 mg/kg caused 56.6% FD in the same interval. EMS maximally depressed GSH to 33%, 54% and 77% of control in vas, epididymis and testis respectively. The slope of the DL dose-response curve for EMS in rats shows a 3-4-fold greater sensitivity than that reported for mice. The steepness of this curve suggests that small perturbations in endogenous protective mechanisms, such as GSH depression, may exert a greater proportional effect on germ-cell mutagenesis in rats which should be more readily observable than in mice. EMS and other electrophilic toxicants may thus influence their own primary reproductive toxicity and/or that of other agents by depression of GSH in male reproductive tissue.

Cocaine-induced hepatotoxicity: lipid peroxidation as a possible mechanism.

In vitro experiments with hepatic washed microsomal preparations showed that malondialdehyde (MDA) formation was increased in a time- and concentration-dependent manner using COC or NC as the substrate. Though 1 mM COC or NC inhibited MDA formation, significant elevations were observed for 100, 10 or 1 microM concentrations. NC at 10 microM after a 30 minute incubation produced a 34% decrease in hepatic microsomal cytochrome P450 whereas 1 mM NC had no such effect. MDA formation in vivo, measured as total absorbance at 535 nm per gram liver, was found to be maximal 4 hours after 40 mg/kg NC ip. Elevations of serum transaminase (SGPT) however were not found until 6 hours after NC. We conclude from these studies that COC and NC induce lipid peroxidation in the liver of PB-pretreated Swiss-origin mice and that peroxidative attack may be a mechanism for hepatotoxicity of these compounds.