maneb 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

Skeletons of CD-1 mice exposed in utero during days 6 to 15 of gestation by gavage of their dams with 1200 mg/kg/day of Maneb in 1.0% carboxymethylcellulose (CMC), were examined between 60 and 65 days postnatal (DPN) for the 88 variants of the skeletal variant assay system (SVAS). Of the 58 variants that appeared, 13 differed (P less than 0.01) from untreated (UNTD), and 15 from vehicle-treated (VEH), despite absence of malformations at birth, weaning, or time of sacrifice. Major changes in frequencies of Parted Frontals, Abnormal Metoptic Roots, Reduced Articular Processes of the Thoracic (Th) Vertebrae, and Carpal Fusions occurred. Several variants affecting the Spinous Process of Th2 occurred in significant proportions as an unusual effect of this compound. In a series of 20 Maneb-treated litters dissected at 18 days post coitus (DPC), of 168 live fetuses, 9 had minor abnormalities, one was exencephalic, and 14 showed growth retardation. Prenatal mortality (20%) was higher than in UNTD (7.5%); litter size and litter weight were not significantly reduced. Ossification of cervical vertebral centra, and caudal vertebrae were significantly reduced, sternebra and limb ossification were not. Occurrence of 14-Ribs was increased. Although maternal mortality complicates interpretation, both traditional prenatal and postnatal examination focusing primarily on the skeleton revealed effects of exposure in the absence of frank malformations.

Topics: Abnormalities, Drug-Induced; Animals; Bone and Bones; Female; Litter Size; Maneb; Mice; Mice, Inbred Strains; Ossification, Heterotopic; Pregnancy

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

Rats, dose-dependent on maneb during pregnancy and lactation (20, 110, 200 or 290 ppm maneb in their food) obtained water or 20 percent alcohol to drink. The animals given pure water indicated no effect. Alcohol in combination with the same concentrations of maneb in the food raised embryotoxicity and produced retardation of the skeletons and postnatal growths in the F1-generation. There was dose-dependent coergistic effect in the breeding results from the alcoholic mothers. The practical significance of this over 15-fold higher susceptibility of alcoholic animals is discussed.

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Drug Synergism; Embryo, Mammalian; Ethanol; Female; Maneb; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains; Thiocarbamates

The effects of the fungicide Maneb 80 (manganese ethylenebisdithiocarbamate, 80% active ingredient) on the regenerating limb of the adult crested newt, Triturus cristatus carnifex, was studied. Female newts were exposed percutaneously to 5 ppm Maneb 80. One group of control newts was exposed to the inert ingredients of Maneb 80 (sodium lignin sulfonate and n-butylnaphthalene sulfonate), and another control group was kept in tap water. The limbs were examined histologically at weekly intervals throughout the regeneration period and at the end of the experiment (10-12 wk postamputation). The regenerating limbs of all the animals exposed to Maneb 80 showed growth retardation and skeletal abnormalities. Histological examination provided evidence that vascular disturbances are important for the genesis of the developmental abnormalities induced by Maneb 80. The inert ingredients had a promoting effect on limb growth and had no teratogenic effects under our experimental conditions. There were no histological differences between the two control groups.

Topics: Abnormalities, Drug-Induced; Animals; Blood Vessels; Extremities; Maneb; Regeneration; Salamandridae; Thiocarbamates

The potential of the fungicide maneb and two of its metabolites, ethylenebisisothiocyanate sulfide (EBIS) and ethylene thiourea (ETU), to induce perinatal toxicity in four species of rodents was investigated. The compounds were admininistered to rats and mice during the period of organogenesis, and ETU was also administered to rats and mice during the period of organogenesis, and ETU was also administered by oral gavage for a similar period to hamsters and guinea pigs. Treatment also continued through the lactational period in groups of rats that were allowed to give birth. Fetuses were examined for signs of toxicity, including terata, and neonates for reflex developement and open-field behavior. Maneb produced hydrocephalus in fetuses in litters of rats receiving 480 mg/kg . d. No fetotoxic effects were noted in litters of rats receiving EBIS at doses at high as 30 mg/kg . d. ETU proved to be a potent teratogen in the rat. Among the effects seen at doses of 40 mg/kg . d or greater were hydrocephalus, encephalocele, kyphosis, and various defects of the digits. Neither maneb (up to 1500 mg/kg . d), ETU (up to 200 mg/kg . d), nor EBIS (up to 200 mg/kg . d) elicited signs of fetal toxicity in the mouse. ETU also failed to result in fetal toxicity when administered to the hamster (100 mg/kg . d) or the guinea pig (100 mg/kg . d). Neither maneb nor EBIS produced significant dose-related alterations in the behavioral development of perinatally exposed rat neonates. At doses that also produced neonatal hydrocephalus, ETU produced significant increases in the open-field activity of the neonates. In addition to the perinatal effects noted above, both maneb and EBIS caused maternal limb paralysis in the rat, an effect not noted in the mouse at much higher doses.

Topics: Abnormalities, Drug-Induced; Animals; Behavior, Animal; Cricetinae; Ethylenethiourea; Female; Fetus; Gestational Age; Guinea Pigs; Imidazoles; Maneb; Mesocricetus; Mice; Pregnancy; Rats; Species Specificity; Thiocarbamates; Thiocyanates

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

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