nabam and Abnormalities--Drug-Induced

Risk assessment is currently based on the no observed adverse effect levels (NOAELs) for single compounds. Humans are exposed to a mixture of chemicals and recent studies in our laboratory have shown that combined exposure to endocrine disrupters can cause adverse effects on male sexual development, even though the doses of the single compounds are below their individual NOAELs for anti-androgenic effects. Consequently, we have initiated a large project where the purpose is to study mixture effects of endocrine disrupting pesticides at low doses. In the initial range-finding mixture studies, rats were gavaged during gestation and lactation with five doses of a mixture of the fungicides procymidone, mancozeb, epoxyconazole, tebuconazole and prochloraz. The mixture ratio was chosen according to the doses of each individual pesticide that produced no observable effects on pregnancy length and pup survival in our laboratory and the dose levels used ranged from 25 to 100% of this mixture. All dose levels caused increased gestation length and dose levels above 25% caused impaired parturition leading to markedly decreased number of live born offspring and high pup perinatal mortality. The sexual differentiation of the pups was affected at 25% and higher as anogenital distance was affected in both male and female offspring at birth and the male offspring exhibited malformations of the genital tubercle, increased nipple retention, and decreased prostate and epididymis weights at pup day 13. The results show that doses of endocrine disrupting pesticides, which appear to induce no effects on gestation length, parturition and pup mortality when judged on their own, induced marked adverse effects on these endpoints in concert with other pesticides. In addition, the sexual differentiation of the offspring was affected. This as well as the predictability of the combination effects based on dose-additivity modelling will be studied further in a large dose-response study.

Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Bridged Bicyclo Compounds; Endocrine Disruptors; Epoxy Compounds; Female; Fungicides, Industrial; Imidazoles; Litter Size; Male; Maneb; Maternal Exposure; Mortality; No-Observed-Adverse-Effect Level; Parturition; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Sex Differentiation; Triazoles; Zineb

The teratogenic effects of lead acetate (Trial 1) and the possible teratogenic effect of this compound administered in combination with a fungicide containing 80% mancozeb (Trial 2) were studied in rats. The test substances were administered by gavage on Days 6-15 of gestation. In Trial 1, five groups were treated with lead acetate administered at doses of 0.1, 0.5, 1.0, 10.0 and 1000.0 mg/kg body weight (bwkg), respectively. In Trial 2, lead acetate was applied at doses of 0.1, 10.0 and 1000.0 mg/bwkg, respectively. In the latter case the dose of the pesticide was 750 mg/bwkg in all treated groups. Lead acetate was not teratogenic after a single administration. Combined administration of lead acetate and mancozeb gave rise to the following toxic effects: average maternal weight decreased during pregnancy, the ratio of live fetuses decreased after the two lowest doses, and fetal mortality increased in the lowest and in the highest dose groups. The ratio of fetal resorption was higher in all the treated groups than in the control group. A significant decrease occurred in average fetal and placental weight in each treated group as compared to the control. Maternal toxicity was expressed in paralysis of the hindlimbs in the two lowest dose groups. Maternal mortality was between 16.7 and 23.3% at the three dose levels. Phocomelia and hernia cerebri occurred as characteristic fetal developmental anomalies in all the treated groups. It is concluded that the joint administration of lead acetate and a mancozeb-containing fungicide can cause maternal toxicity, embryotoxicity and characteristic teratogenic effects.

Topics: Abnormalities, Drug-Induced; Animals; Dose-Response Relationship, Drug; Drug Interactions; Female; Fungicides, Industrial; Maneb; Organometallic Compounds; Pregnancy; Rats; Rats, Wistar; Teratogens; Zineb

Crl:CD rats were exposed (whole body) to mancozeb by inhalation at 0, 1, 17, 55, 110, 890, or 1890/500 mg/m3 for 6 hr/day from Day 6 through 15 of gestation (sperm-positive vaginal smear considered Day 1). Dams were killed 1 day prior to natural delivery and fetuses were examined externally, viscerally, and skeletally for any alterations. Maternal toxicity, as evidenced by significantly decreased body weight gain, hindlimb paralysis, general debilitation, and death or termination in extremis, was noted among rats exposed to mancozeb at concentrations of 500 to 1890 mg/m3. Dams from the 55 and 110 mg/m3 groups exhibited decreased body weight gain and hindlimb weakness. There was no maternal toxicity for dams exposed at a concentration of 17 mg/m3. Embryofetal toxicity, as evidenced by a significantly increased incidence of totally resorbed litters, external hemorrhage, and wavy ribs, was noted at concentrations of 55 mg/m3 and above. The embryofetal toxicity occurred only at concentrations toxic to the dam. Among the groups exposed to mancozeb, the incidence of major malformations was not dose related. Hence, under the test conditions of this study, mancozeb was not found to be teratogenic and produced no toxicity unique to the conceptus.

Topics: Abnormalities, Drug-Induced; Animals; Atmosphere Exposure Chambers; Body Weight; Female; Fetal Resorption; Fetus; Maneb; Maternal-Fetal Exchange; Particle Size; Pregnancy; Rats; Teratogens; Zineb

Oral administration of high dosages of the dithiocarbamate pesticides maneb and mancozeb was teratogenic in rats but not in mice. The malformations, severe limb and craniofacial defects, were pronounced after maneb treatment but less so after mancozeb and propineb, zinc-containing compounds. The teratogenic effect of maneb was progressively reduced by simultaneously administering increasing amounts of zinc acetate. The mechanism of the teratogenic effect may involve the compounds being chelating agents, trapping zinc required for many important enzyme systems.

Topics: Abnormalities, Drug-Induced; Acetates; Animals; Female; Fetal Resorption; Maneb; Mice; Pregnancy; Rats; Thiocarbamates; Zinc; Zineb

Fertile White Leghorn chicken eggs were injected on the tenth day of incubation with either 0, 10, 20, 30, 40 or 50 p.p.m. Aldrin or 0, 5, 10 or 15 p.p.m. Nabam and allowed to hatch. Aldrin neither did induce any deformities nor had any effect on hatchability, thyroid weight and histology. However, within three days after hatching, there was greater mortality in chicks treated with higher concentrations of the pesticide. Aldrin at higher concentrations significantly reduced 125I uptake by the thyroids. This was evident in the iodine fractions after chromatographic separation of the thyroid extracts. Nabam not only reduced hatchability but also induced deformities in the higher concentration groups. The thyroids showed an increase of resorption vacuoles in the colloid. Even though the thyroid weights increased in all experimental groups, a significant increase in 125I uptake was seen only in the 15 p.p.m. injected animals. This group also showed a reduction in radioactivity of thyroxine fraction but an increase of 125I in tyrosines. The significance of these results are discussed.

Topics: Abnormalities, Drug-Induced; Aldrin; Animals; Chick Embryo; Chickens; Eggs; Ethylenebis(dithiocarbamates); Fungicides, Industrial; Incubators; Iodine; Poultry Diseases; Thiocarbamates; Thyroid Gland; Thyroxine

Topics: Abnormalities, Drug-Induced; Animals; Chromatophores; Digestive System Abnormalities; Ear; Ethylenebis(dithiocarbamates); Eye Abnormalities; Female; Fungicides, Industrial; Maneb; Melanins; Microscopy; Microscopy, Electron; Pregnancy; Thiocarbamates; Xenopus