zineb 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

Exposure of Japanese medaka (Oryzias latipes) embryos and adult males to sublethal concentrations of two commonly used fungicides, Acrobat MZ and Tattoo C, had varying effects on development and adult male behavior. During embryolarval assays, medaka exposed to Acrobat exhibited decreased heart rates throughout embryonic development and were smaller at hatching than controls. Differences in hatching size were not apparent with Tattoo although some decrease in heart rate was observed at higher concentrations. Tail lesions and abnormal spinal development was a problem common to embryos exposed to Acrobat. Neither time to hatch nor early growth was affected by exposure to either fungicide. Adult males that had been exposed to high concentrations of Acrobat or Tattoo over a 28-day period were less likely to approach females during behavioral trials. The absence of other behavioral effects, particularly those related to reproductive performance, may have been due to females being sexually unreceptive during behavioral trials. No other behavioral modifications were apparent for adult males exposed to either fungicide. Information about developmental and behavioral responses to sublethal concentrations of pesticides is important for establishing environmental guidelines concerning their use.

Topics: Abnormalities, Drug-Induced; Animals; Behavior, Animal; Carbamates; Copulation; Embryo, Nonmammalian; Female; Fungicides, Industrial; Growth; Heart Rate; Larva; Male; Maneb; Morpholines; Nitriles; Oryzias; Pregnancy; Prenatal Exposure Delayed Effects; Sexual Behavior, Animal; 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

Topics: Abnormalities, Drug-Induced; Animals; Embryo, Nonmammalian; Maneb; Ranidae; Thiocarbamates; Zineb

The hygienic significance of the studies on pesticides from the aspect of their "long-term" effects upon the individual and the generations are emphasized. The basic methods and approaches used in the Laboratory of long-term effects with chemical etiology at the IHOH, Sofia, are discussed, namely for detecting the changes in gonads, reproduction and generation, embryotoxic and teratogenic effects, and changes in cardiovascular system. The results are discussed, namely: fundasol--the effect on gonads, generations, embryotoxic and teratogenic effects, changes in the cardiovascular system; endodan--changes in gonads, reproduction, embryotoxicity; basfungin--embryotoxic and teratogenic effects. All of these studies were performed for the purpose of threshold levels, establishment hygienic standardisation and prognosis of the potential risk for human.

Topics: Abnormalities, Drug-Induced; Animals; Benzimidazoles; Cardiovascular System; Dose-Response Relationship, Drug; Embryo, Mammalian; Ethylenethiourea; Female; Fungicides, Industrial; Imidazoles; Liver; Male; Mice; Pregnancy; Rats; Reproduction; Sulfides; Thiazoles; Thiocarbamates; Time Factors; 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

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Bone and Bones; Corpus Luteum; Dose-Response Relationship, Drug; Embryo Implantation; Environmental Exposure; Female; Fetal Diseases; Fetus; Fungicides, Industrial; Hydrocephalus; Maneb; Maternal-Fetal Exchange; Microcephaly; Pregnancy; Rats; Reproduction; Thiocarbamates; Time Factors; Zineb