A teratological assessment of four trihalomethanes in the rat

Abstract

Four trihalomethanes were administered by gavage to Sprague‐Dawley rats from day 6 to day 15 of gestation. Chloroform (Ch) was administered at levels of 100, 200 and 400 mg/kg and bromoform (Br), bromodichloromethane (BDCM) and chlorodibromomethane (CDBM) were administered at levels of 50, 100 or 200 mg/kg/day. A separate control was used for each compound. Maternal weight gain was depressed in all groups receiving Ch and at the highest dose levels of BDCM and CDBM. Ch administration caused decreased maternal hemoglobin and hematocrit values at all dose levels and also produced increased serum inorganic phosphorus and cholesterol at the highest dose. Liver enlagement was observed at all dose levels of Ch but in no other treatment groups. Evidence of a fetotoxic response was observed with Ch, CDBM and Br but not BDCM. No dose‐related histopathological changes were observed in either mothers or fetuses as a result of treatment. None of the chemicals tested produced any teratogenic effects.     

Assessment of teratogenic potential of trichlorfon in mice and rats

Trichlorfon was evaluated for its teratogenic potential in the CD-1 mouse at doses of 200, 300 or 400 mg/kg/day administered by gavage on days 7-16 of gestation. In the CD-1 mouse, TCF was teratogenic, fetotoxic and lethal at the two highest dose levels which were also maternally lethal. At the lowest dose level which was not maternally lethal, there was a significant decrease in the number of calcified centers in the forepaws and hindpaws indicating fetotoxicity and a delay in maturation. TCF was administered at doses of 50, 100 or 200 mg/kg/day to CD rats by gavage on gestational days 7-19 (study I) or 8-20 (study II). In the CD rat in body study I and II, the highest dose level was maternally lethal. In study I, TCF was teratogenic with a shift in rib profile. In study II, TCF was teratogenic with an increased incidence in malformations of the urinary system. Additionally, TCF was fetotoxic with reduced ossification of the skulls at the lowest and highest dose levels.     

Effect of quinalphos on blood enzymes and its acute toxicity in bubalus bubalis

Abstract

The acute toxic effects of quinalphos (0,0‐diethyl 0–2‐quinoxalyl phosphorothioata) uere investigated in male buffalo calves. Quinalphos was administered in single oral doses of 5, 7.5, 8.5 and 10 mg/kg body wt. and its effects on erythrocyte and plasma cholinesterases, serum aspartate aminotransferase and blood glucose were studied at various time intervals. The lowest dose (5 mg/kg) produced no apparent toxic symptoms. All the animals given highest dose (10 mg/kg) died within 60–82 hours after dosing. Quinalphos at all the dose levels markedly inhibited the erythrocyte and plasma cholinesterases (68–100%) and significantly elevated the levels of serum aspartate aminotransferase and blood glucose. Seven days after the administration of quinalphos, the blood cholinesterases in survivors remained inhibited to the extent of 41–77% whereas the levels of serum aspartate aminotransferase and blood glucose were comparable to control values.     

Teratogenic evaluation of the pesticides baygon, carbofuran, dimethoate and EPN

Baygon was administered IG once daily to CD rats (5 to 50 mg/kg), on the 7th-19th day of gestation or to CD-1 mice (5 to 60 mg/kg) on days 6-16 of gestation. Baygon, at dose levels which were not maternally lethal, did not produce fetotoxicity, fetal lethality or malformations in the fetuses. Baygon was not teratogenic in the CD rat or CD-1 mouse at maternally nontoxic dose levels. Carbofuran was administered IG once daily to CD rats (0.05 to 5.0 mg/kg), on the 7th-19th day of gestation or to CD-1 mice (0.1 to 20 mg/kg) on days 6-16 of gestation. At dose levels which were not maternally lethal, carbofuran did not produce fetotoxicity, fetal lethality or malformations in the fetuses. Carbofuran was not teratogenic in the CD rat or CD-1 mouse at maternally nontoxic dose levels. Dimethoate was administered IG once daily to CD-1 mice (10 to 80 mg/kg), on the 6th-16th day of gestation. At dose levels which were not maternally lethal, dimethoate did not produce fetotoxicity, fetal lethality or malformations in the fetuses. Dimethoate was not teratogenic in the CD-1 mouse at maternally nontoxic dose levels. EPN was administered IG once daily to CD-1 mice (1.0 to 12.0 mg/kg) on the 6th-16th day of gestation. EPN, at dose levels up to those which were maternally lethal, did not produce fetotoxicity, fetal lethality or an increase in malformations. EPN was not teratogenic in the CD-1 mouse at maternally nontoxic dose levels.     

Effects of phosphorothionate on the reproductive system of male rats

Acute and Sub-acute toxic effects of a new pesticide phosphorothionate coded as RPR-V on testis of albino rat were studied. For the acute study, rats received a single dose of 30 mg/kg of RPR-V and sacrificed after 24 hours. For the Subacute study, 1.42 mg/kg/day was administered orally to rats for 10 days and 21 days. Acute exposure of rats to RPR-V brought no change either in the Gonadosomatic Index (GSI) or in the structure of testis or in the serum levels of Testosterone. Similarly, no significant change was observed in the Glutathione S-transferase (GST) activity. But, in testis there was significant increased in the reduced Glutathione (GSH) and Acid Phosphatase (AcP), whereas Alkaline Phosphatase (AkP) levels decreased significantly at 24hr post treatment. On 7th day (withdrawal period) after the cessation of the treatment the GSH, AcP, and AkP levels reached to near control. The sub-acute study revealed a significant post treatment. Due to RPR-V treatment the testis AcP levels increased significantly at 21st day of medication but AkP levels decreased both at 10th and 21st day of post treatment. Histopathological studies showed that after 10th day testis showed considerable loss of spermatozoids and at 21st day complete derangement of cellular organization was observed. Testosterone levels decreased significantly after 10th day and remained significantly low at 21st day. However, withdrawal studies showed a recovery in testis of rat treated with RPR-V. GST, GSH, GSI, AcP and AkP values were recovered, testosterone levels were also recovered but recovery in testis structure remained at a low profile.     

Teratologic assessment of maleic hydrazide and daminozide,and formulations of ethoxyquin,thiabendazole and naled in rats

Abstract

Teratogenicity studies were conducted in rats treated orally from days 6–15 of gestation with single daily doses of 400–1600 mg/kg of maleic hydrazide, 300–1000 mg/kg daminozide, 125–500 mg/kg ethoxyquin or thiabendazole, or 25–100 mg/kg naled. Dams were killed on the 22nd day of gestation, and fetuses were evaluated by routine teratologic methods. No adverse effect was related to any treatment other than an increased incidence of anomalous fetuses at the highest dose (500 mg/kg) of thiabendazole.     

Teratologic assessment of maleic hydrazide and daminozide, and formulations of ethoxyquin, thiabendazole and naled in rats

Teratogenicity studies were conducted in rats treated orally from days 6-15 of gestation with single daily doses of 400-1600 mg/kg of maleic hydrazide, 300-1000 mg/kg daminozide, 125-500 mg/kg ethoxyquin or thiabendazole, or 25-100 mg/kg naled. Dams were killed on the 22nd day of gestation, and fetuses were evaluated by routine teratologic methods. No adverse effect was related to any treatment other than an increased incidence of anomalous fetuses at the highest dose (500 mg/kg) of thiabendazole.     

Toxicity of organophosphorus esters to laying hens after oral and dermal administration

Fourteen organophosphorus esters (OPs) were evaluated for their potential to cause organophosphorus ester induced delayed neurotoxicity (OPIDN) when administered dermally and/or orally to white leghorn hens. The compounds were chlorpyrifos, DEF, dichlorvos, dimethoate, EPN, ethoprop, fenthion, isofenphos, leptophos, merphos, ronnel, tetrachlorvinphos, terbufos, and trichlorfon. DEF induced ataxia if given dermally or orally at over 21 mg/kg/day for up to 90 days. Hens treated with EPN developed irreversible ataxia after repeated exposure to as little as 1.3 mg/kg dermally or 5 mg/kg/day orally, while leptophos was neurotoxic at doses of 6-7 mg/kg/day dermally and 10 mg/kg/day orally. Multiple treatments of chlorpyrifos, terbufos, dichlorvos and dimethoate caused death after varying periods of increasing debility; although birds had difficulty walking, they did not display typical symptoms of OPIDN. Fenthion and isofenphos induced drastic weight loss in hens at low levels of treatment; Isofenphos treated hens developed OPIDN, but died soon afterwards. Dichlorvos given at greater than 6 mg/kg/day po or dermally at 1 mg/kg/day produced cholinergic symptoms and most hens died before the end of the treatment period. At lower levels, dichlorvos did not induce overt ataxia. None of the other compounds in this series induced consistent ataxia whether administered orally or dermally. Ethoprop, with an acute oral LD50 near 5 mg/kg and an acute dermal LD50 of approximately 3 mg/kg, was the most toxic compound tested and could not be fully evaluated for its potential to cause OPIDN.     

Toxicological assessment of chlorinated diphenyl ethers in the rat

Chlorinated diphenyl ethers are environmental contaminants that have been found in Great Lakes fish and birds. Because of their presence in the food chain, and potential for human exposure, the present short-term study was conducted to assess their toxicity. Groups of 10 male and 10 female rats were each given by gavage 2,2',4,4'6-pentachlorodiphenyl ether (CDE1), 2,2',4,4',5,6-hexachlorodiphenyl ether (CDE2) or 2,2',3,3',4,6'-hexachlorodiphenyl ether (CDE3) at dose levels of 0.04, 0.4, 4.0 or 40 mg/kg b.w./day for a period of 28 days. The control group received an equivalent volume of corn oil only (0.5 ml/100 g b.w.). Treatment with the three CDE congeners did not result in suppression of growth rate or food consumption. Increased liver weights were seen in the animals of both sexes fed 40 mg/kg CDE2, in males treated with 40 mg/kg CDE1, and in females with 40 mg/kg CDE3. Hepatic microsomal aminopyrine demethylase activity was significantly higher in the male rats administered 40 mg/kg CDE2, and aniline hydroxylase activity was elevated in the females following the same treatment. Serum glucose, calcium, protein and urea nitrogen of CDE1-treated males were higher than the control. Levels of uric acid, potassium and LDH of CDE3-treated females were also elevated. No hematological changes were observed. Histological examination revealed that the liver and thyroid were the target organs affected by CDE treatment but the morphological changes were mild even at the highest dose level. Changes in the liver consisted of nuclear vesiculation and increased cytoplasmic volume. Alterations in the thyroid were characterized by increased epithelial height and follicular collapse. Based on the data presented above, the 3 CDE congeners can only be considered moderately toxic in the rat.     

Low hepatic 7-ethoxyresorufin-O-deethylase (EROD) activity and minor alterations in retinoid and thyroid hormone levels in flounder (Platichthys flesus) exposed to the polychlorinated biphenyl (PCB) mixture, Clophen A50

The effect of the polychlorinated biphenyl (PCB) mixture Clophen A50 on hepatic cytochrome P4501A1 dependent EROD (7-ethoxyresorufin-O-deethylase) activity, plasma thyroid hormone levels and plasma, kidney and liver retinoid concentrations of the euryhaline flatfish flounder (Platichthys flesus) was determined 2 and 10 days after i.p. (intraperitoneal) injection with 20, 100 and 500 mg Clophen A50/kg body weight. No effect of Clophen A50 on total cytochrome P450 content in flounder liver was observed at both time points. A six-fold, dose-dependent, significant increase in EROD activity was found at exposure day 10 in flounder receiving 100 or 500 mg Clophen A50/kg body weight. Plasma retinol concentrations were not altered at both time points after Clophen A50 administration, whereas renal retinol levels showed a minor dose-related increase at day 2 and day 10 of exposure. Significant alterations in hepatic retinoid concentrations were observed, which were not dependent on the dose of PCB administered. In addition Clophen A50 administration did not result in a dose-related alteration of total T4 concentrations in plasma. Total T3 concentrations in plasma were only significantly increased at day 2 after exposure, whereas free T4 concentrations were increased at both time points after Clophen A50 administration. These data indicate that with regard to the parameters investigated and in contrast to other fish species studied, the flounder is not a sensitive species to PCB exposure.     

Temporal induction pattern of hepatic cytochrome P450 1A in thermally acclimated dab (Limanda limanda) treated with 3,3′,4,4′-Tetrachlorobiphenyl (CB77)

Mature male dab (Limanda limanda) acclimated at 10° and 16°C were orally administered a single dose of 0.5 mg/kg 3,3′,4,4′-tetrachlorobiphenyl (CB77). At both temperatures, levels of cytochrome P450 1A (CYP1A) protein and 7-ethoxyresorufin O-deethylase (EROD) activity showed a two to six fold induction 40 days after CB77 treatment compared to control groups. Maximum responses of both EROD activity and CYP1A protein for the warm-acclimated fish were observed at 5 days after treatment. For the cold-acclimated fish a slow, progressive elevation for both EROD activity and CYP1A protein was observed and maximum responses were measured 40 days after treatment. Absolute EROD activity and CYPIA protein levels of fish from both temperatures were equally high at 40 days after treatment. Since in the control groups EROD activity and CYP1A protein levels were higher in the cold-acclimated fish, the magnitude of induction was higher in the warm acclimated ones. The highest concentrations of CB77 in muscle of fish from both temperatures were found at 5 and 10 days after treatment. The liver somatic index (LSI) showed 1.5 fold significantly higher values for the fish acclimated at 10°C.     

Toxicological assessment of chlorinated diphenyl ethers in the rat

Abstract

Chlorinated diphenyl ethers are environmental contaminants that have been found in Great Lakes fish and birds. Because of their presence in the food chain, and potential for human exposure, the present short‐term study was conducted to assess their toxicity. Groups of 10 male and 10 female rats were each given by gavage 2,2’,4,4'6‐pentachlorodiphenyl ether (CDE1), 2,2’,4,4’,5,6‐hexachlorodiphenyl ether (CDE2) or 2,2’,3,3’,4,6'‐hexachlorodiphenyl ether (CDE3) at dose levels of 0.04, 0.4, 4.0 or 40 mg/kg b.w./day for a period of 28 days. The control group received an equivalent volume of corn oil only (0.5 ml/100 g b.w.). Treatment with the three CDE congeners did not result in suppression of growth rate or food consumption. Increased liver weights were seen in the animals of both sexes fed 40 mg/kg CDE2, in males treated with 40 mg/kg CDE1, and in females with 40 mg/kg CDE3. Hepatic microsomal aminopyrine demethylase activity was significantly higher in the male rats administered 40 mg/kg CDE2, and aniline hydroxylase activity was elevated in the females following the same treatment. Serum glucose, calcium, protein and urea nitrogen of CDE1‐treated males were higher than the control. Levels of uric acid, potassium and LDH of CDE3‐treated females were also elevated. No hematological changes were observed. Histological examination revealed that the liver and thyroid were the target organs affected by CDE treatment but the morphological changes were mild even at the highest dose level. Changes in the liver consisted of nuclear vesiculation and increased cytoplasmic volume. Alterations in the thyroid were characterized by increased epithelial height and follicular collapse. Based on the data presented above, the 3 CDE congeners can only be considered moderately toxic in the rat.     

Effect of nonylphenol on steroidogenesis of rat Leydig cells

Nonylphenol is the primary final biodegradation product of nonylphenol polyethoxylate (NPE), a non-ionic surfactant that is frequently incorporated into pesticide and detergent formulation. Recent researchers have hypothesized that environmental/ occupational exposure to nonylphenol poses adverse effects on reproductive system of humans and wildlife species. During our study, in vivo and in vitro experiments were performed to examine the effect of nonylphenol on testosterone biosynthesis of rat Leydig cells. In experiment in vivo, serum testosterone (T) as well as luteinizing hormone (LH) levels were detected after animals had been treated with different doses (0 mg/kg/day, 125 mg/kg/day, and 250 mg/kg/day) of nonylphenol for 50 days by gavage, and the final result revealed that testosterone level dramatically declined at the dose of 250 mg/kg/day, while LH level ascended at the dose of 125 mg/kg/day and 250 mg/kg/day. In experiment in vitro, primary cultured Leydig cells were exposed to nonylphenol for 48 h, including low concentrations (0 mg/L, 0.0011 mg/L, 0.0033 mg/L, 0.0055 mg/L, 0.011 mg/L, 0.022 mg/L) and higher concentrations (0.11 mg/L, 0.55 mg/L, 1.1 mg/L, 1.65 mg/L, 2.2 mg/L, 2.75 mg/L, 3.3 mg/L, 5.5 mg/L). Increase of testosterone levels was observed at low concentrations of nonylphenol while reduction was detected at higher concentrations.     

Toxic and biochemical effects of 3,3',4,4'-tetrachlorobiphenyl (CB-77) and clophen A50 on eider duckling (Somateria mollissima) in a semi-field experiment

In this study the possible toxic and biochemical effects of one intraperitoneal dose of 5 or 50 mg kg(-1) of 3,3',4,4'-tetrachlorobiphenyl (CB-77) or 50 or 200 mg kg(-1) of Clophen A50 (CloA50) on 28-day-old eider ducklings (Somateria mollissima) were investigated. After ten days, no significant differences could be observed in any of the toxic and biochemical parameters studied, apart from ethoxyresorufin (EROD) activity, when comparing group average values of the dosed and control animals. However, significant correlations were observed at day 10 after exposure between the individual internal PCB concentration and body weight gain and beak length growth (negative correlations in the CloA50 groups); relative liver weight and cytochrome P4501A activity (positive correlations in CB-77 and CloA50 groups); plasma thyroid-hormone and hepatic retinoid levels (negative correlations in CB-77 groups); and plasma retinol levels and the ratio plasma retin/hepatic retinyl palmitate (positive correlations in CB-77 groups only). Animal activity was significantly reduced in the group that received 50 mg CB-77 kg(-1). These observations indicate that eider ducks are a sensitive species to PCB toxicity and may be at risk for development of adverse health effects in relatively highly contaminated areas such as the Waddenzee.     

Toxicological assessment of chlorinated diphenyl ethers in the rat, Part II

Chlorinated diphenyl ethers (CDE's) are environmental contaminants that have been found in Great Lakes fish. Because of the paucity of toxicity data and potential for human exposure, the present short-term study was conducted to assess their potential toxic effects. Groups of 10 male and 10 female rats were administered the three CDE congeners (2,2',4,4',5-pentachlorodiphenyl ether (PCDE), 2,2',4,4',5,5'-hexachlorodiphenyl ether (HCDE), 2,2',3,4,4',6,6'-heptachlorodiphenyl ether (HPCDE] in diets at levels of 0.5, 5.0, 50 or 500 ppm for a period of 4 weeks. Decreased food consumption was observed with male and female rats fed the diet containing 500 ppm HPCDE. Treatment with the three isomers at the highest dose level produced an increase in liver weight in both sexes. While administration of PCDE produced an increase in hepatic aminopyrine demethylase activity, HCDE caused a significant increase in aminopyrine demethylase, aniline hydroxylase and ethoxyresorufin de-ethylase activities. HPCDE caused a significant increase in ethoxyresorufin de-ethylase activity. HPCDE at the highest dose level also caused a significant reduction in circulating lymphocytes in male rats. The 3 CDE's produced mild and adaptative histological changes in the liver and thyroid, but only HPCDE elicited mild changes in the thymus, bone marrow, and spleen. The above data indicate that HPCDE is immunosuppressive and that all three CDE isomers are considered to be moderately toxic in rats. The no-observable effects levels appear to be between 5-50 ppm in diet (0.36-3.0 mg/kg b.w.) for the three CDE's.     

Effect of Nonylphenol on Steroidogenesis of Rat Leydig Cells

Nonylphenol is the primary final biodegradation product of nonylphenol polyethoxylate (NPE), a non-ionic surfactant that is frequently incorporated into pesticide and detergent formulation. Recent researchers have hypothesized that environmental/ occupational exposure to nonylphenol poses adverse effects on reproductive system of humans and wildlife species. During our study, in vivo and in vitro experiments were performed to examine the effect of nonylphenol on testosterone biosynthesis of rat Leydig cells. In experiment in vivo, serum testosterone (T) as well as luteinizing hormone (LH) levels were detected after animals had been treated with different doses (0 mg/kg/day, 125 mg/kg/day, and 250 mg/kg/day) of nonylphenol for 50 days by gavage, and the final result revealed that testosterone level dramatically declined at the dose of 250 mg/kg/day, while LH level ascended at the dose of 125 mg/kg/day and 250 mg/kg/day. In experiment in vitro, primary cultured Leydig cells were exposed to nonylphenol for 48 h, including low concentrations (0 mg/L, 0.0011 mg/L, 0.0033 mg/L, 0.0055 mg/L, 0.011 mg/L, 0.022 mg/L) and higher concentrations (0.11 mg/L, 0.55 mg/L, 1.1 mg/L, 1.65 mg/L, 2.2 mg/L, 2.75 mg/L, 3.3 mg/L, 5.5 mg/L). Increase of testosterone levels was observed at low concentrations of nonylphenol while reduction was detected at higher concentrations.     

The subchronic toxicity of acridine in the rat

Abstract

The subchronic toxicity of acridine was investigated in rats following dietary exposure at 0, 1, 10, 100 and 500 ppm for 13 weeks. The growth rate and food consumption were not affected by treatment and no clinical signs of toxicity were observed. There was a slight but significant decrease in spleen weight, both in absolute terms and as a percent of body weight, in the 500 ppm males and a slight increase in absolute thymus weight in the females of the same dose group. Both hepatic ethoxyresorufin O‐deethylase (EROD) and pentoxyresorufin O‐dealkylase (PROD) activities were slightly, but significantly, elevated in females in the 500 ppm dose group. No haematological or other biochemical changes were observed. Females also displayed dose‐related increases in inorganic phosphate and uric acid levels. Treatment‐related histopathological changes were seen in the thyroid, liver and kidney and included hepatic anisokaryosis and vesiculation of nuclei and glomerular adhesions, reticulin sclerosis and nuclear pyknosis in the kidney. Residue data showed a dose‐dependent accumulation of acridine in liver, kidney and adipose with the highest concentration being found in the fat of the 500 ppm dose group. Based on these data, the no observable adverse effect level of acridine was judged to be 100 ppm or 12 mg/kg bw/day.     

The effect of acute administration of the mycotoxin zearalenone to female pigs

Crystalline zearalenone was administered to young female pigs at dose levels of 0, 3.5, 7.5 and 11.5 mg zearalenone/kg body weight. All animals receiving the mycotoxin exhibited vulva vaginitis and had enlarged reproductive tracts, 1 week after dosing. Free zearalenone was found in the blood, feces and urine of dosed animals. The highest zearalenone level detected was 2.61 ng/ml from a pig that received the 7.5 mg/kg dose. After 24 hours, feces collected contained on average upto 308 ng zearalenone per g of dried feces. Zearalenone levels of up to 59 ng/ml, and alpha-zearalenol levels of up to 155 ng/ml urine were found. beta-zearalenol was also detected in the urine.     

The effect of acute administration of the mycotoxin zearalenone to female pigs∗

Abstract

Crystalline zearalenone was administered to young female pigs at dose levels of 0, 3.5, 7.5 and 11.5 mg zearalenone/kg body weight. All animals receiving the mycotoxin exhibited vulva vag‐initis and had enlarged reproductive tracts, 1 week after dosing. Free zearalenone was found in the blood, feces and urine of dosed animals. The highest zearalenone level detected was 2.61 ng/ml from a pig that received the 7.5 mg/kg dose. After 24 hours, feces collected contained on average up to 308 ng zearalenone per g of dried feces. Zearalenone levels of up to 59 ng/ml, and a ‐zearalenol levels of up to 155 ng/ml urine were found. ß ‐zearalenol was also detected in the urine.     

Hepatotoxicity of monobromobenzene and hexabromobenzene: effects of repeated dosage in rats

The aim of the study was to determine whether monobromobenzene (BB) and hexabromobenzene (HBB) administered repeatedly (for 28 days) to female rats resulted in disturbances of heme synthesis. 5-Aminolevulinate dehydratase (ALA-D) and 5-aminolevulinate synthase (ALA-S) activities were slightly changed and the concentration of glutathione increased. The excretion of 5-aminolevulinic acid (ALA-U) in urine after all doses of BB and HBB increased already in the first week. After BB administration, increased excretion of coproporphyrins was detected only at the highest dose. The increased excretion of coproporphyrins following the administration of HBB could be observed already at the lowest dose (15 mg/kg). The excretion of uroporphyrins increased after two higher doses (75 and 375 mg/kg) in the fourth week of exposure. HBB also caused elevation of microsomal P450 level. The data suggest porphyrogenic activity of HBB; whereas in the case of BB we cannot exclude that elevated excretion of ALA-U resulted from kidney impairment.