Toxicity of fumonisin B1 to B6C3F1 mice: a 14-day gavage study

Fumonisin B1 (FB1) is a fungal toxin produced by members of the genus Fusarium. Ingestion of FB1 causes species-specific neurotoxic, nephrotoxic, hepatotoxic and pulmonary effects. The clinical, haematological and pathological responses of adult male and female B6C3F1 mice to FB1 were assessed following 14 daily gavage doses ranging from 1 to 75 mg FB1/kg body weight/day. There were no consistent sex-related changes. Although all responses were modest, the most notable effects of FB1 were on the liver, bone marrow, adrenals and kidneys. In the liver, hepatocellular single cell necrosis, mitosis and anisokaryosis were observed, accompanied by elevated serum ALT. In the kidneys, minor histopathological changes were confined to female mice, while mild decreases in ion transport and increases in blood urea nitrogen were seen only in males. Small changes in glutathione levels were observed in the kidneys and livers of male mice. Adrenal cortical cell vacuolation was observed at 15 mg FB1/kg and higher in females and from 35 mg FB1/kg in males. Serum cholesterol was elevated in both male and female mice, possibly due to FB1-induced changes in lipid metabolism in the liver and adrenals. Although bone marrow cell numbers were unchanged, increases in vacuolated myeloid cells and lymphocytes were observed in female mice. In general, the degree of changes observed indicate that mice are not as sensitive a model of FB1 toxicity as rats.     

Prenatal fumonisin (FB1) treatment in rats results in minimal maternal or offspring toxicity

To investigate the neurobehavioral and developmental effects of the mycotoxin, FB1, Sprague-Dawley rats were treated with FB1 on gestational days 13-20. In Experiment 1, FB1 was obtained from culture material and pregnant rats were gavaged with 0, 0.8 or 1.6 mg/kg. In Experiment 2, pregnant rats were gavaged with purified FB1 at doses of 0, 1.6 or 9.6 mg/kg. Offspring were evaluated on a battery of behavioral tests as well as measures of whole and regional brain weight. There were no effects on maternal weight gain, reproductive outcomes, or offspring body weight through adulthood in either experiment. Complex maze performance, open field and running wheel activity were not altered by prenatal FB1 treatment. In Experiment 2, acoustic startle response was depressed at two ages during the first or second block of 9 trials in males treated with purified FB1. Females exhibited no such alterations. Play behavior at PND 33, but not PND 26, was increased in males prenatally treated with 9.6 mg/kg relative to those treated with 1.6 mg/kg. There were no substantive treatment effects on regional brain weight. These results suggest that doses of < or = 9.6 mg purified FB1/kg and/or < or = 1.6 mg FB1/kg obtained from culture material cause minimal maternal toxicity and produce few development functional alterations. In addition, potential FB1-related functional alterations were evident only in males providing further support for a mild sex-specific effect for fumonisin.     

Murine cerberus homologue mCer-1: a candidate anterior patterning molecule

The fungal toxin fumonisin B1 (FB1) is a contaminant of corn-based foods and feeds produced by members of the genus Fusarium. Fumonisin B1 toxicity was examined using gavage administration of purified toxin to female Sprague-Dawley rats. For 11 consecutive days each rat received a single dose of FB1 at the following concentrations: control (saline), 1, 5, 15, 35, or 75 mg FB1/kg body weight/d. Significantly depressed body weight and food consumption occurred at 35 and 75 mg FB1/kg/d. By the end of the dosing period there were no significant changes in food consumption. Kidneys and bone marrow were most sensitive to FB1 exposure. Changes in renal morphology were observed from 5 to 75 mg FB1/kg/d, accompanied by transient changes in urine osmolality and urine enzyme levels. Increased cellular vacuolation was the primary change associated with bone-marrow toxicity, starting at doses of 5 mg FB1/kg/d. Hepatotoxicity was indicated by reduced liver weight, elevated serum alanine amonitransferase (ALT), and mild histopathological changes occurring at doses of 15 mg FB1/kg/d and higher. Increased cytoplasmic vacuolation of adrenal cortex cells occurred in rats treated with 15 mg FB1/kg/d and higher, indicating that the adrenals are also potential targets of FB1. Elevated serum cholesterol, which is a consistent response to FB1 was observed at 5 mg FB1/kg/d and higher. Based on responses in this study, gavage is an appropriate substitute for longer feeding studies. Compared to previous work with male rats, gender-related difference in FB1 responses lacked consistency but indicated that males may be marginally more sensitive than female Sprague-Dawley rats.     

Development of a new method for the analysis of sphinganine and sphingosine in urine and tissues

The fumonisins are inhibitors of de novo sphingolipid biosynthesis in vitro and in vivo and thus possibly interfere with the regulation of cell growth, differentiation, and neoplastic transformation. In addition, the ratio of free sphinganine (Sa) to free sphingosine (So) has been proposed as a marker of exposure for animals or humans consuming feed or food contaminated by these toxins. A method to analyze these sphingolipid bases has been proposed [Merrill et al., 1988: Anal Biochem 171:373-381; Riley et al., 1994a: JAOAC 77:533-540] but involves numerous steps and consequently is not ideally suited to the analysis of large numbers of samples, as is often required in epidemiological studies. A new method was therefore developed for the analysis of the Sa/So ratio in tissues as well as human and rat urine. Briefly, the method involves isolation of exfoliated cells from as little as 0.5 ml of rat urine or 2 ml of human urine followed by a rapid and efficient extraction of sphingolipid bases in ethyl acetate, an optimized derivatization step with o-phthaldialdehyde and a high-pressure liquid chromatography separation on a 250 mm x 4.6 mm. 5 microns Kromasil C18 column, with a 4-step phosphate buffer/methanol gradient. Fluorescence was monitored at 340 nm excitation, 455 nm emission, and retention times for So, Sa, and C-20 Sa were about 11, 14, and 22 min, respectively. The method was adapted to tissue analysis by partially digesting approximately 30 mg tissue with trypsin to permit isolation of a cell pellet before extraction of the sphingolipids as described above. The method was applied to the analysis of So and Sa in urines and tissues of fumonisin B1 (FB1) treated and untreated male BDIV rats. The Sa/So ratio in urine of untreated rats varied from 0.1 to 0.7, and for treated rats (between 1-5 mg FB1/kg body weight daily by gavage), the ratio was between 1.2-10. In kidney, the ratio was 0.1 in control rats and varied from 4 to 10.3 in treated rats. In human urine, measurements could easily be made in 2 ml of urine in females, but in males much larger volumes were required due to the low levels of sphingolipid bases.     

Study on the developmental toxicity of orally administered isobutylidenediurea in rats

Developmental toxicity of isobutylidenediurea (IBDU) was determined by oral administration to Wistar rats. The substance was administered as an aqueous suspension to 22-24 pregnant rats per group by gavage in daily doses of 100, 400 and 1000 mg/kg body weight from day 6 post-coitum (p.c.) to day 15 p.c. The control group received the vehicle only (0.5% aqueous carboxymethyl cellulose solution). There were no substance-related effects in the dams concerning food consumption, body weight, body weight gain, uterine weights and clinical or autopsy observations even at the highest dose of 1000 mg/kg body weight/day. The reproduction data revealed no biologically relevant differences between the control and treated groups. The incidence and type of the foetal external, soft tissue and skeletal findings, which were classified as malformations, variations and/or retardations observed in the treated foetuses were similar to the concurrent and/or historical control data. Thus, under the conditions of this study, no signs of maternal toxicity or embryo/foetotoxicity were induced by IBDU and the no-observable-adverse-effect level on the maternal and developing organism was 1000 mg/kg body weight/day.     

Evaluation of the developmental toxicity of methacrylonitrile in Sprague-Dawley rats and New Zealand white rabbits

Timed-pregnant Sprague-Dawley (CD) outbred rats and New Zealand White rabbits were dosed by gavage with methacrylonitrile (MACR) in distilled water during major organogenesis. Rats were dosed on Gestational Days (GD) 6 through 15 (0, 5, 25, or 50 mg MACR/kg/day) and rabbits on GD 6 through 19 (0, 1, 3, or 5 mg MACR/kg/day). Maternal clinical status was monitored daily during treatment. At termination (GD 20, rats; GD 30, rabbits), confirmed-pregnant females (25-26 per group, rats; 17-22 per group, rabbits) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In rats, no treatment-related maternal clinical signs or mortality were observed, nor was there any adverse effect on maternal body weight or food or water consumption. At necropsy, absolute, relative, and adjusted maternal liver weight was increased at the mid- and high-dose groups, an effect that may be indicative of induction of hepatic enzymes rather than toxicity. In the absence of any indication of maternal toxicity, the no-observed-adverse-effect level (NOAEL) for maternal toxicity in this study was >/=50 mg MACR/kg/day. The NOAEL for developmental toxicity in rats was also >/=50 mg MACR/kg/day. There was no effect of treatment on postimplantation loss, mean fetal body weight per litter, or morphological development. In rabbits, maternal mortality and clinical signs were not dose related. Maternal food consumption, body weight, and liver weight were not adversely affected by treatment. Thus, the maternal NOAEL was >/=5 mg MACR/kg/day. Maternal toxicity, including death, was observed >/=7.5 mg/kg/day in preliminary studies. The developmental NOAEL was also >/=5 mg MACR/kg/day. There was no adverse effect of treatment on postimplantation loss or fetal body weight. A significant decrease in the percentage male fetuses per litter was observed, although there was no effect on total live litter size, suggesting that the reduction in the ratio of live male fetuses in the high-dose group was not biologically significant. MACR had no adverse effect on morphological development. In summary, oral administration of MACR to rats and rabbits during organogenesis, at doses that did not cause persistent maternal toxicity (50 mg MACR/kg/day, rats; 5 mg MACR/kg/day, rabbits), also did not cause any adverse developmental effects.     

Developmental toxicity evaluation of isopropanol by gavage in rats and rabbits

Timed-pregnant CD (Sprague-Dawley) rats, 25/group, were dosed orally with aqueous isopropanol (IPA; CAS No. 67-63-0) solutions at 0, 400, 800, or 1200 mg/kg/day, once daily on Gestational Days (GD) 6 through 15 at a dosing volume of 5 ml/kg. Artificially inseminated New Zealand white rabbits, 15/group, were dosed orally with IPA at 0, 120, 240, or 480 mg/kg/day once daily on GD 6 through 18 at 2 ml/kg. Maternal body weights, clinical observations, and food consumption were recorded throughout gestation for both species. At scheduled euthanization for both species (GD 20, rats; GD 30, rabbits), fetuses were weighed, sexed, and examined for external, visceral (including craniofacial) and skeletal alterations. For both species, the pregnancy rate was high and equivalent across all groups; no dams or does aborted, delivered early, or were removed from study. In rats, two dams (8%) died at 1200 mg/kg/day and one dam (4%) died at 800 mg/kg/day. Maternal body weights and weight gain were equivalent across all groups, except for statistically significantly reduced gestational weight gain (GD 0-20; 89.9% of control value), associated with statistically significantly reduced gravid uterine weight at 1200 mg/kg/day (89.2% of control value). There were no treatment-related clinical signs or effects on maternal food consumption. All gestational parameters evaluated were equivalent across groups, including pre- and postimplantation loss, fetal sex ratios, and litter size. Twenty-two to 25 litters were examined per group. Fetal body weights per litter were statistically significantly reduced at the two highest doses (97.3 (n.s.), 94.7, and 94.3% of controls at 800 mg/kg/day and 92.1, 91.9, and 95.4% of controls at 1200 mg/kg/day for all fetuses and males and females separately). No evidence of increased teratogenicity was observed at any dose tested in rats. In rabbits, four does (26.7%) died at 480 mg/kg/day. Maternal body weights were statistically significantly reduced during treatment (GD 6-18) at 480 mg/kg/day (45.4% of control value) with a nonsignificant reduction in gestational weight change (GD 0-30; 77.3% of control value) at this dose. Profound clinical signs of toxicity and statistically significantly reduced maternal food consumption were observed at 480 mg/kg/day. All gestational parameters were equivalent across all doses administered. Thirteen to 15 litters were evaluated per group except for the 480 mg/kg/day group with 11 litters (due to maternal deaths). There were no treatment-related effects on pre- or postimplantation loss, fetal sex ratio, litter size, or fetal body weight/litter. Moreover, no evidence was found of increased teratogenicity at any dose tested in rabbits. Therefore, IPA was not teratogenic to CD rats or to NZW rabbits. The NOAELS for both maternal and developmental toxicity were 400 mg/kg/day in rats, and were 240 and 480 mg/kg/day, respectively, in rabbits.     

The selective estrogen receptor modulator, raloxifene: a segment II/III delivery study in rats

Raloxifene is a nonsteroidal, selective estrogen receptor modulator developed by Eli Lilly and Company as a therapeutic agent for postmenopausal osteoporosis. Raloxifene was administered orally by gavage at doses of 0, 0.1, 1, or 10 mg/kg/d to female CD rats (25/group) on Gestation Day 6 (GD 6) through Postpartum Day 20 (PD 20). Females were allowed to deliver and maintain their progeny until PD 21. All dead pups and pups culled on PD 1 were given internal and external examinations. One pup/sex/litter was assigned to each of the following assessment groups: 1) the primary pair for the F1 generation study, in which survival, growth, development, behavior, indicators of sexual maturation, and reproductive performance were evaluated; 2) terminal necropsy evaluations at PD 21; 3) terminal necropsy evaluations at 60 d of age; and 4) assessments of immune function at 5 to 6 weeks of age. At termination on PD 21, 60, or approximately 140, a necropsy was performed; crown rump and tibia lengths were measured; pituitary weights were taken; and a portion of the anterior pituitary was retained for growth hormone, luteinizing hormone, and prolactin content determinations (control and 10-mg/kg groups only). The remainder of the pituitary and reproductive tissues were retained for histologic evaluations. Dose-related depressions in maternal body weight and food consumption occurred during gestation. Mean gestation length was increased at 1 and 10 mg/kg. Delayed, extended, and/or disrupted parturition occurred in dams given 10 mg/kg, which resulted in a high incidence of maternal morbidity and/or death, increased numbers of dead pups, and the survival of only 66% of live pups to PD 21. Progeny body weights were not decreased at birth, but were depressed progressively in a dose-related manner during the 3-week lactation period. Negative geotaxis and incisor eruption were apparently accelerated in the 1- and 10-mg/kg groups, but eye opening was delayed at 10 mg/kg. Postweaning activity levels, auditory startle, and passive avoidance performance were not affected in the raloxifene groups. Dose-related decreases in spleen cellularity and thymus weights occurred in both sexes, but immune system function, as measured by splenic natural killer cell activity and antibody response to sheep red blood cells, was not affected. Postweaning body weights and growth parameters, as well as pituitary hormone content, were affected in both an age- and sex-specific manner. Preputial separation was not affected, but vaginal patency occurred ca 2 d earlier than controls in females from the 10-mg/kg group. Estrous cycles of the F1 females were not affected during the first two weeks after vaginal opening, but were disrupted at 12 to 14 weeks of age in the 10-mg/kg group. These females showed poorer mating and fertility indices, and litter size was reduced in the two females that were pregnant. Histologically, reproductive organs were not affected in males at any age or in females at PD 21. At PD 60, vaginal mucification occurred in females from the 0.1- and 1-mg/kg groups. At PD 140, the only finding was a high rate of uterine hypoplasia in the 10-mg/kg group, and this finding occurred in the absence of any concomitant ovarian or vaginal changes. These reproductive and developmental findings are consistent with estrogen antagonist activity of raloxifene.     

Prospective randomised trial of two dose levels of megestrol acetate in the management of anorexia-cachexia syndrome in patients with metastatic cancer

Two doses of megestrol acetate (MA) have been prospectively compared in a random fashion as treatment for cancer-related anorexia-cachexia syndrome (ACS) in 122 patients with progressive soft tissue sarcoma, colorectal, lung, head and neck and renal cancer resistant to systemic chemotherapy. After 30 days of MA, 55% of patients receiving MA at 160 mg day-1 reported an increase in appetite, 27% of patients no variation and 18% complained of a decrease in appetite. Patients treated with MA at 320 mg day-1 reported an increase in appetite in 68% of cases, a stabilisation in 20% of cases and a decrease in 12%. Although an increase in appetite was more frequently observed in patients receiving MA at 320 mg day-1, however this difference was not statistically significant (P = 0.305). After 30 days of MA, 31% of patients treated with MA at 160 mg day-1 showed an increase in body weight, 25% a stabilisation and 44% a decrease. In the group of patients treated with MA at 320 mg day-1, 45% reported an increase in body weight, 16% no change and 23% weight loss. Although there was a trend favouring the higher dose of MA, overall analysis however failed to detect any statistically significant difference between the two treatment arms (P = 0.242). Twenty-seven patients pretreated with 160 mg day-1 and 23 patients treated with 320 mg day-1 received further therapy with MA at the dose of 320 and 480 mg day-1 respectively. In the group of 22 patients treated with 320 mg day-1 four (18%) reported an increase in body weight, eight (36%) an improvement in appetite, but none had an increase in performance status. Among the 20 evaluable patients treated with 480 mg day-1, two (10%) had an increase in body weight, four (20%) an improvement in appetite, but none reported an increase in performance status. No difference in median survival was detected between the two arms. Toxicity was mild and predictable. In conclusion, the data achieved in the present study confirm the clinical safety and effectiveness of oral MA in the management of ACS in patients with advanced cancer resistant to systemic chemotherapy. Moreover, data concerning the dose escalation of MA dosage in unresponsive patients suggest that a step by step increase in MA dosage could be the best way of administering MA for the management of ACS and that the increase of MA dosage over 480 mg day-1 will probably be useless in the vast majority of cases. Data on body weight suggest that after 2 weeks' therapy MA could be stopped or its dosage tailored to patients' needs since the majority of patients respond after only 15 days of MA.     

Translactational induction of CYP4A expression in 10.5-day neonatal rats by the hypolipidemic drug clofibrate

Lactating mothers of 7.5-day neonatal rats were injected intraperitoneally with 500 mg kg-1 clofibrate for 3 consecutive days at 24-hour intervals; 24 hours after the final injection, the maternal cytochrome P450 4A (CYP4A) mRNA levels had risen 14- and 2.5-fold above the constitutive levels of expression seen in the liver and kidney, respectively. Lactational transfer of clofibrate to the suckling 10.5-day litter was demonstrated by the 15- and 5-fold elevation observed in the neonatal hepatic and renal CYP4A mRNAs, respectively, following suckling from drug-induced mothers. A significant decrease in the relative liver weights of these neonatal pups was seen following clofibrate exposure via maternal milk, in total contrast to the normally observed increase in liver/body weight ratios of rats treated with clofibrate. Western blot analysis using a polyclonal goat anti-rat CYP4A1 antibody also demonstrated a rise in the CYP4A protein levels in both the mothers and their litters following maternal clofibrate treatment.     

Individual and combined effects of fumonisin B1 present in Fusarium moniliforme culture material and diacetoxyscirpenol or ochratoxin A in turkey poults

The individual and combined effects of feeding diets containing 300 mg fumonisin B1 (FB1), and 4 mg diacetoxyscirpenol (DAS) or 3 mg ochratoxin A (OA) were evaluated in two experiments using female turkey poults (Nicholas Large Whites) from day of hatch to 3 wk of age. When compared with controls, body weight gains were reduced 30% (Study 1) and 24% (Study 2) by FB1, 30% by DAS, 8% by OA, 46% by the FB1 and DAS combination, and 37% by the FB1 and OA combination. The efficiency of feed utilization was adversely affected by all treatments except FB1 in Experiment 2. Relative weights of the liver were significantly increased by all treatments except the DAS treatment. Serum concentrations of cholesterol were decreased and activities of aspartate aminotransferase and lactate dehydrogenase were increased and several hematological values were altered in poults fed FB1 alone and in combination with either DAS or OA. Results indicate additive or less than additive toxicity, but not toxic synergy, when poults are fed diets containing 300 mg FB1, and 4 mg DAS or 3 mg OA/kg of diet. The likelihood of encountering FB1, DAS, or OA at these concentrations in finished feed is small. However, under field conditions, other stress factors could alter the impact of these mycotoxins on the health and performance of poultry.     

Expression of calcium-binding protein regucalcin mRNA in fetal rat liver is stimulated by calcium administration

The expression of hepatic calcium-binding protein regucalcin mRNA in fetal rats was investigated. The alteration in regucalcin mRNA levels was analyzed by Northern blotting using liver regucalcin cDNA (0.9 kb with complete open reading frame). Hepatic regucalcin mRNA levels were progressively increased with fetal development; the mRNA was clearly expressed at 15 and 21 days of pregnancy but only slightly at the 8 days. Meanwhile, beta-actin mRNA levels in the fetal liver were remarkable at 8 and 15 days of pregnancy. The fetal liver regucalcin mRNA levels at 15 days of pregnancy were significantly decreased by overnight-fasting of maternal rats. The oral administration of calcium chloride (50 mg Ca/100 g body weight) to maternal rats at 15 days of pregnancy caused a remarkable elevation (about 2 fold) of regucalcin mRNA levels in the fetal liver; this increase was seen 60 and 180 min after the calcium administration. After birth, regucalcin mRNA was increasingly expressed in the livers of newborn and weanling rats, while hepatic beta-actin mRNA expression was not appreciably altered with increasing ages. These findings demonstrate that the expression of hepatic regucalcin mRNA is increased with fetal development, and that the gene expression may be stimulated by the ingestion of dietary calcium.     

Developmental toxicity evaluation of ethylene glycol by gavage in New Zealand white rabbits

Artificially inseminated New Zealand white (NZW) rabbits were administered ethylene glycol (EG) by gavage on Gestational Days (GD) 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day, with 23-24 inseminated animals per group. Clinical signs were recorded and water consumption was measured daily; does were weighed on GD 0, 6-19, 25, and 30. At necropsy (GD 30), maternal liver, kidney, and gravid uterine weights were recorded. Histopathologic examination was performed on kidneys from 10 does/dose and for all unscheduled deaths. Ovarian corpora lutea were counted and uterine implantation sites (total sites, resorptions, dead and live fetuses) were recorded. All live fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations and variations. EG resulted in profound maternal toxicity at 2000 mg/kg/day (42% mortality; three early deliveries and one spontaneous abortion) associated with renal pathology and unaccompanied by any other indicators of maternal toxicity. Renal lesions at 2000 mg/kg/day involved the cortical renal tubules and included intraluminal oxalate crystals, epithelial necrosis, and tubular dilatation and degeneration. No dose-related maternal toxicity occurred at 100-1000 mg/kg/day. There was no indication of developmental toxicity at any dose tested, including no effects on pre- or postimplantation loss, number of fetuses, fetal body weight, or sex ratio (% male fetuses) per litter, and no evidence of teratogenicity. The "no observable adverse effect level" (NOAEL) for maternal toxicity was therefore 1000 mg/kg/day and the NOAEL for developmental toxicity was at least 2000 mg/kg/day in this study. The sensitivity of NZW rabbits relative to that of Sprague-Dawley rats and Swiss mice for maternal and developmental toxicity from gavage administration of EG during organogenesis can be determined for maternal toxicity: rabbits > mice > rats, and for developmental toxicity, mice > rats > rabbits.     

Dietary fumonisins disrupt sphingolipid metabolism in mink and increase the free sphinganine to sphingosine ratio in urine but not in hair

This study was conducted to investigate the effects of dietary Fusarium moniliforme culture material (M-1325) containing known concentrations of fumonisins B1, B2 and B3 on sphingolipids in urine and hair of mink (Mustela vison) for use as potential, non-invasive biomarkers of exposure to fumonisins in this species. Feeding mink diets containing 86, 22, and 7 ppm or 200, 42, and 12 ppm of fumonisins B1, B2 and B3, respectively, yielded marked increases in urinary free sphinganine (Sa) and free sphingosine (So) concentrations, and free Sa/free So ratios (2 to 11-fold) within 7 d, compared to controls. Free Sa and free So concentrations and Sa/So ratios in hair samples from mink fed the control or high dose fumonisin diets for 100 days were similar and were not apparently altered by exposure to these mycotoxins. These results suggest that Sa/So ratios in urine, but not in hair of mink can serve as an early indicator of exposure to fumonisins in this species.     

Influence of fumonisin B1, present in Fusarium moniliforme culture material, and T-2 toxin on turkey poults

Diets containing 300 mg fumonisin B1 (FB1)/kg of feed and 5 mg T-2 toxin/kg of feed singly or in combination were fed to female turkey poults (Nicholas Large White) from day of hatch to 21 d of age. When compared with controls, 21-d body weight gains were reduced 21% by FB1, 26% by T-2, and 47% by the combination. the efficiency of feed utilization was adversely affected by FB1 and the combination of FB1 and T-2. Relative weights (grams/100 g BW) of the liver and gizzard were increased in poults fed the FB1 and the combination diets; whereas, the relative weight of the pancreas was increased in all treated groups. All poults were scored for oral lesions using a scale of 1 to 4 (1 = no visible lesions, 4 = severe lesions). Oral lesions were present in all poults fed the T-2 diet (average score of 3.29) or the combination diet (average score of 3.54). Serum concentration of cholesterol was decreased and lactate dehydrogenase activity was increased in poults fed the FB1 and combination diets. The activity of aspartate aminotransferase and the values for red blood cells, hemoglobin, and hematocrit were increased only in poults fed the combination diet. Inorganic phosphorus concentration was decreased only in poults fed the combination diet. The increased toxicity in poults fed the combination diet for most variables can best be described as additive, although some variables not altered by FB1 or T-2 singly were significantly affected by the combination, indicating that the combination may pose a potentially greater problem to the turkey industry than either of the mycotoxins individually.     

Effect of chronic maternal methadone exposure on perinatal development

The effect of perinatal exposure to methadone on body growth and brain development was studied in rat. Female Sprague-Dawley albino rats received daily intraperitoneal injections of 5 mg/kg dl-methadone-HCl during gestation and lactation. Body weights were reduced in drug-treated mothers during gestation and the first 2 weeks of lactation. No differences in gestation time, litter size, or infant mortality were recorded, however methadone-treated offspring grew more slowly than controls. Weight deficits persisted in rats observed 5-1/2 weeks after cessationof drug exposure (group 1) and in animals continuing to receive daily interperitoneal injections of 5 mg/kg (group 2). From birth to day 21, brain weight and length, cerebral width and cerebellar weight and width were generally smaller in methadone-exposed rats. Brain measurements of group 1 and group 2 animals on day 60 revealed a reduction in brain and cerebellar weights and cerebral and cerebellar widths from control values. Brain:body weight and cerebellum:brain weight ratios were similar to controls. Analysis of these results indicates that maternal methadone treatment retards the growth of young rats and affects brain development.     

Postnatal patterns of fatty acids in brain of progeny from vitamin B-6 deficient rats before and after pyridoxine supplementation

The influence of deficient and adequate maternal intakes of pyridoxine on lipid profiles in brains of progeny at 5, 10, 15, 25 and 50 days of age was studied. The effects of supplementing deficient dams at two different times with pyridoxine on the brain development of progeny were also examined. Three groups of weanling, female rats were fed diets deficient in pyridoxine (1.2 mg pyridoxine-HC1/kg diet) and another group received a control diet (30.0 mg pyridoxine-HC1/kg diet). One deficient group and the control group were fed their diets throughout growth, gestation and lactation. Two groups of dams were fed the deficient diet through growth, gestation and until 5 or 10 days postpartum when pyridoxine was supplemented by feeding the control diet. Body and brain weights were significantly lower in 15, 25 and 50 day-old progeny of deficient dams and deficient dams supplemented at 10 days postpartum. Cerebroside content at 15 days and ganglioside content at 15 and 25 days were significantly lower in brains of pups from unsupplemented deficient dams and deficient dams supplemented at 10 days postpartum. The postnatal development of cerebroside and ganglioside levels in brain was delayed or retarded in brain of pups from unsupplemented deficient dams. Supplementation of dams fed a low level of pyridoxine (1.2 mg/kg diet) with the vitamin beginning at 5 days postpartum reversed all observed effects of the low vitamin intake on brain lipids in progeny.     

Risk of myocardial infarction, angina and stroke in users of oral contraceptives: an updated analysis of a cohort study

BACKGROUND: Ropivacaine has shown less systemic toxicity than bupivacaine, and comparatively low muscle-blocking properties could constitute another advantage when used epidurally for obstetric pain relief. We aimed primarily to compare maternal and foetal drug disposition following continuous epidural infusion of ropivacaine or bupivacaine. METHODS: Twenty-four full-term, nulliparous women were randomized to continuous epidural infusion (10 ml/h) of ropivacaine 2.5 mg/ml or bupivacaine 2.5 mg/ml for labour pain relief in a double-blind, parallel-group design. Maternal blood samples were collected up to 24 h after the end of infusion as well as taken from the umbilical cord at the time of delivery. Sensory and motor block as well as analgesia were assessed. All the women were monitored by cardiotocography and neonatal assessment was performed. RESULTS: The sensory block was adequate for both drugs. Higher plasma levels (total and free) were seen with ropivacaine, although the infusion with bupivacaine continued on average for about 2 hours longer. However, the ratios between maternal and umbilical blood concentrations were similar for both drugs. Normal neonatal Apgar and neonatal adaptive capacity scores (NACS) were found in both groups. CONCLUSION: A continuous epidural infusion of 25 mg/h ropivacaine or bupivacaine both produced good labour pain relief. Higher total and free plasma concentrations were seen for ropivacaine. The ratios between maternal and umbilical plasma levels were similar for both drugs.     

Albendazole as a fasciolicide in experimentally infected sheep

The new drug albendazole (methyl [5-(propylthio)-1H-benzimidazol-2-yl]carbamate) was tested in 90 sheep experimentally infected with Fasciola hepatica. Dose rates of 10, 15, and 20 mg/kg of body weight were active against adult flukes, with efficacies of 98, 95, and 100% respectively. The drug was less active against immature F hepatica at 3 weeks after sheep were inoculated. The drug given at dose rates of 20, 30, 40, and 50 mg/kg had efficacies 24, 47, 63, and 76%. Flukes were not found at posttreatment hour 48 in bile ducts of sheep given a dose of 20 mg/kg. Evidence of drug toxicity was not seen.