Behavioural effects in female rats of postnatal exposure to sub-toxic doses of polychlorinated biphenyl congener 153.

Polychlorinated biphenyls (PCBs) are widespread environmental contaminants that are also present in human tissues and breast milk. Behavioural disturbances have been reported in both children and animals exposed perinatally to PCBs. The present study assessed the behavioural consequences in female rats of postnatal exposure to the di-ortho-substituted 2,2',4,4',5,5'-hexachlorobiphenyl (IUPAC no. 153), which is one of the PCB congeners most frequently detected in human milk. The different groups of mothers were dosed via gavage with 5 mg/kg bodyweight of PCB 153 in corn oil or 5 ml/kg bodyweight corn oil vehicle every second day from day 3 to day 13 after delivery. The exposure did not affect the bodyweight of the dams nor the physical development of the pups. Operant behavioural testing of the female offspring by two different schedules of reinforcement was performed. First, the animals were tested by a multiple schedule with two components: fixed interval (FI) and extinction (EXT), which has proved sensitive in revealing changes in activity level. There were no statistically significant differences in frequency or interresponse times of lever pressing between the PCB-exposed female rats and the controls. These results were in contrast to a previous, analogous study where PCB 153 produced an increased frequency of lever presses during the FI in male rats, indicating a sex-specific behavioural effect of PCB 153. The female offspring was also tested by a conjunctive schedule with two components: variable interval (VI) and differential reinforcement of low rate (DRL). This schedule revealed slower acquisition of time discrimination in the PCB 153-exposed females as compared with the controls. The VI-DRL results showed that PCB 153 may also produce long-lasting behavioural effects in female rats following postnatal exposure through the mother's milk.

Behavioural hyperactivity in rats following postnatal exposure to sub-toxic doses of polychlorinated biphenyl congeners 153 and 126.

Rats were exposed through mother's milk either to the di-ortho-substituted polychlorinated biphenyl (PCB) congener 2,2',4,4',5,5'-CB (IUPAC no. 153) or to the non-ortho-substituted PCB congener 3,3',4,4',5-CB (IUPAC no. 126). The different groups of mothers were dosed via gavage with corn oil vehicle, 5 mg/kg b.w. of PCB 153 or 2 microg/kg b.w. of PCB 126 every second day from day 3 to 13 after delivery. The exposure did not affect the body weight (b.w.) of the dams or the physical development of the pups. A two-component schedule of reinforcement was used to study behavioural effects of the PCB exposures in male offspring. One component was operating when the house light was turned on. Then a reinforcer, a drop of water, was delivered every 2-min. This component is called a 2-min fixed interval (FI) schedule of reinforcement. The other component was in effect when the house light was turned off. Then no reinforcer was ever delivered. This is called an extinction (EXT) component. It was shown that the PCB-exposed offspring were hyperactive as they had an increased frequency of lever presses. In addition, the PCB 153-exposed male pups showed a behavioural pattern similar to that observed in spontaneously hypertensive rats (SHR), an animal model of attention-deficit hyperactivity disorder (ADHD). This behaviour is characterized by 'burst' of lever presses with short interresponse times (IRT) just before the next reinforcer is given. These results show that both PCBs 153 and 126 may produce significant neurotoxic effects following postnatal exposure through mother's milk.

In vitro reproductive toxicity of polychlorinated biphenyl congeners 153 and 126.

This study was conducted to investigate the applicability of an in vitro technique for maturation, fertilization, cleavage, and growth to blastocysts of bovine oocytes to investigate reproductive toxicologic effects. During maturation, the oocytes were exposed to the di-ortho-substituted PCB congener 2,2',4,4',5,5'-CB (PCB 153) in the three concentrations 0.84 ng/mL, 8.4 ng/mL, and 84 ng/mL or to the non-ortho-substituted PCB congener 3,3'4,4',5-CB (PCB 126) in the three concentrations 1.006 pg/mL, 10.06 pg/mL, and 100.6 pg/mL and compared with control groups. PCB 153 had no effect on maturation but resulted in a reduced proportion of oocytes that cleaved at the highest concentration. There were no differences in blastocyst development among groups. PCB 126 resulted in a reduction in maturation percentage at the highest concentration and in blastocyst development at all concentrations. These results demonstrated adverse effects of PCB congeners on bovine oocytes and showed that this system can be used to evaluate toxic effects on oocytes and preimplantation-stage embryos.

Assessment of environmental pollution by PCBs, DDT and its metabolites using human milk of mothers in Zimbabwe.

The milk samples were collected from mothers who had lived in the area for at least 5 years, healthy and breast feeding their first, second or third child. Of the 175 mothers' milk samples analysed, the organochlorine pesticide residues were detected in the following order of frequency: pp-DDE, 100%, pp-DDT 98%; and sum PCB, 53%. Of all the seven areas analysed the Kariba area and the highest mean level of sum DDT--25,259 ng/g milk fat and the lowest mean level of sum DDT of 1607 ng/G milk fat was found in Esigodini which is a rural area. The major DDT metabolite was pp-DDE. The ratio of pp-DDT/pp-DDE was highest in Kariba (0.6) suggesting recent pollution by DDT in that area. The results show that the vector control programmes (extensive pesticide spraying of disease-carrying pests, such as mosquitoes and tsetse flies), agricultural activities and dietary habits were the main contributing factors towards the high levels of pesticides in most of the areas. Kadoma area had the highest mean level of sum-PCB (60 ng/g milk fat).

Effects of feeding deoxynivalenol-contaminated oats on reproduction performance in White Leghorn hens.

1. The effect of feeding trichothecene-contaminated diets with graded concentrations of deoxynivalenol ranging from 120 to 4900 micrograms/kg to groups of laying hens was investigated. 2. Food intake, weight gain and egg production were not affected by mycotoxin administration. No significant differences were found between groups. 3. The overall results from the hatching tests did not reveal any significant differences in fertility, hatchability or perinatal mortality, which could be explained by the mycotoxin content in the diets. 4. Body weight at hatching and viability of the chicks were not affected by the mycotoxin concentrations in the diets. 5. The incidence of chick developmental anomalies was increased in the mycotoxin-administered groups compared to controls. Minor malformations were the dominating anomalies and included unwithdrawn yolk sac and delayed ossification. The most frequent major malformations were cloacal atresia and cardiac anomalies.

The effects of naturally deoxynivalenol-contaminated oats on the clinical condition, blood parameters, performance and carcass composition of growing pigs.

A feeding trial with naturally deoxynivalenol (DON)-contaminated oats included in feed mixtures at graded levels was conducted in growing pigs. The DON concentrations were 0, 0.7, 1.7, and 3.5 mg/kg of complete feed mixture given ad libitum to different groups. The data recorded were feed consumption, body weight gain, slaughter weight, biochemical and haematological data including serum immunoglobulin A, clinical condition and post-mortem pathology including histopathology. Significantly decreasing body weight gain throughout the experimental period, decreased slaughter weight and reduced feed utilization efficiency were observed for the group fed a diet containing 3.5 mg/kg of DON. At the same DON concentration, there were increased liver weights and decreased concentrations of serum protein and albumin, and a temporary fall in packed blood cell volume, serum calcium and serum phosphorus. For the groups fed diets containing 1.7 and 3.5 mg/kg of DON, a statistically significant, dose-related decrease in daily feed consumption was observed. No other effects on haematological, biochemical or immunological parameters were recorded. The carcass quality was not affected in any group. It was concluded that significant effects in growing pigs may be observed at a dietary DON concentration of 1.7 mg/kg, originating from naturally contaminated oats included in a diet that was otherwise adequate and contained only minor traces of other mycotoxins.

Effects of diets with graded levels of deoxynivalenol on performance in growing pigs.

Feeding trials were conducted to evaluate the effect of including deoxynivalenol (DON)-contaminated oats to provide approximately 0.5, 1.0, 2.0 and 4.0 mg/kg in the complete diets of growing pigs with initial weight of 25 kg. Performance was recorded as weight gain, feed intake, efficiency of feed utilization and carcass quality. Restricted feeding was compared to ad libitum feeding. For the groups fed diets containing 2 and 4 mg/kg of DON, a dose-related decrease in weight gain was observed during the first 8 weeks on experimental diets. With 4 mg/kg DON there were decreased feed intake, weight gain and efficiency of feed utilization throughout the experiment. No effect was observed in groups fed diets containing 0.5 or 1.0 mg/kg of DON. The carcass quality was not affected in any group.

Plasma concentration of paracetamol and its major metabolites after p.o. dosing with paracetamol or concurrent administration of paracetamol and its N-acetyl-DL-methionine ester in mice.

1. Single doses of paracetamol 400 (PAR 400) and 800 mg/kg (PAR 800), SUR 2647 combination (free paracetamol + paracetamol-N-acetyl-DL-methionate, paracetamol/methionine ratio 2:1) equivalent to PAR 400 (SURc 400) and PAR 800 (SURc 800) were given p.o. to male Bom:NMRI mice. 2. The objective was to compare the plasma concentrations of free paracetamol and the major metabolites paracetamol-sulphate and paracetamol-glucuronide for a 6 hr period after each test drug. 3. There was no significant difference between PAR 400 and SURc 400 with respect to plasma paracetamol, paracetamol-glucuronide and paracetamol-sulphate concentration with the exception of lower plasma paracetamol concentration (P less than 0.03) at 3 hr following PAR 400. 4. There was no significant difference between PAR 800 and SURc 800 with respect to plasma paracetamol, paracetamol-glucuronide and paracetamol-sulphate concentrations with the exception of lower plasma paracetamol-glucuronide concentration (P less than 0.03) at 4 hr after dosing following SURc 800. 5. Combining free paracetamol and its methionine ester does not seem to alter the pattern of plasma paracetamol, paracetamol-glucuronide and paracetamol-sulphate compared to equal doses of free paracetamol alone after p.o. administration of toxic doses to male Bom:NMRI mice.

Behavioural method to detect marginal neurotoxic effects of ivermectin in DA/Orl rats.

Ivermectin (22, 23-dihydroavermectin B 1) in subtoxic doses was administered subcutaneously to young adult DA rats. Prior to treatment the rats had been trained in a visual discrimination learning programme until their response pattern was stable. The behavioural response data were recorded during continued discrimination testing following the Ivermectin injection and compared with those of a control group. The results showed that the Ivermectin injection reduced the total number of lever presses and reinforcement collections. Further the treatment caused an increase in the total number of erroneous responses.

The disposition of ivermectin in Atlantic salmon (Salmo salar).

The disposition of tritium-labelled ivermectin (22,23 di-3H-avermectin, B1a) in Atlantic salmon was studied by whole-body autoradiography, liquid scintillation counting, and thin-layer chromatography. Ivermectin was slowly absorbed, the highest concentrations being found in lipid-containing organs. High concentrations were also found in the central nervous system, indicating that the blood-brain barrier in salmon is poorly developed compared to mammals. The excretion of the drug was very slow. The total amount of radioactivity in blood, muscle, liver and kidney diminished by only 35% from day 4 to day 28 after administration. Excretion was mainly by the biliary route, and enterohepatic circulation of the drug was apparent. The drug was mainly excreted in the unchanged form. Distribution to the central nervous system, and the prolonged excretion period, makes the drug unsuitable for the control of parasitic infestations in salmon.

A study on melanin affinity of 14C-trimethoprim in male Mol:WIST and Mol:PVG rats.

Hooded (Mol:PVG) and albino (Mol:WIST) rats were used to study the distribution pattern of 14C-trimethoprim by whole body autoradiography. Accumulation of radioactivity was demonstrated in the uveal tract of the eye and the pigmented parts of the skin in the hooded rats. No radioactivity was present in the corresponding tissues in the albino rats. This difference in the distribution pattern was interpreted to reflect binding to melanin of 14C-trimethoprim and/or its metabolites.

The absorption and distribution of 14C-bacitracin in rainbow trout (Salmo gairdneri) after a single oral dose, as observed by whole body autoradiography.

This study was performed to investigate the absorption, distribution and elimination of orally given radiolabelled bacitracin methylene disalicylate (BMD) in rainbow trout kept in salt water. The level of radioactivity in skeletal muscle tissue remained low, but stable throughout the experiment, while radioactivity in bile and liver tissue increased for about 48 hr, before decreasing. There was a trapping of BMD and/or its metabolites in excretory kidney tissue, where the amount of radioactivity continued to increase when radioactive material was being removed from other tissues. The maximum concentration found in excretory kidney tissue was about 7 times as high as the maximum concentration found in the liver. Even though there is no appreciable absorption of BMD from the gastrointestinal tract in homoiotherms, we found the absorption in rainbow trout to be significant.

Organophosphate poisoning of Atlantic salmon in connection with treatment against salmon lice.

Three incidents with high mortality in Atlantic salmon after trichlorfon treatment against salmon lice are described. All 3 incidents occurred at water temperatures of 12 degrees C or higher. The mean brain acetylcholinesterase (AChE) activity of dead fish was less than 20% of normal activity, while survivors showed mean activities of 22-61% of normal levels. Dichlorvos residues in muscular and liver tissues ranged from nondetectable levels to 0.2 micrograms/g tissue. The strongest inhibition of brain AChE was found in association with the highest dichlorvos residues. Substantial AChE-inhibition was, however, also found in samples in which dichlorvos residues could not be detected. AChE-determination was found to be more reliable than residue analysis for the diagnosis of organophosphate poisoning in salmon.

In vivo studies on toxic effects of concurrent administration of paracetamol and its N-acetyl-DL-methionine ester (SUR 2647 combination).

1. Single p.o. doses of paracetamol 400 and 800 mg/kg or SUR 2647 combination (free paracetamol + paracetamol-N-acetyl-DL-methionate, paracetamol/methionine ratio 2:1) equivalent to paracetamol 400 and 800 mg/kg were given to Bom:NMRI mice. Vehicle treated (1% w/v aqueous methylcellulose) mice were established as a control group. 2. All treatment groups irrespective of medication caused an initial GSH depletion. However, SUR 2647 combination 400 mg/kg caused a much earlier hepatic GSH recovery than paracetamol 400 mg/kg. SUR 2647 combination 800 mg/kg caused a higher hepatic GSH level than paracetamol 800 mg/kg. 3. There was no significant difference in the plasma ALAT level after SUR 2647 combination 400 or 800 mg/kg and the control group. Paracetamol 400 and 800 mg/kg caused significant plasma ALAT elevations compared to the control group. 4. The addition of N-acetyl-DL-methionine esterified to paracetamol, as in the SUR 2647 combination, enhances the hepatic GSH synthesizing capacity in Bom:NMRI mice after experimental overdosage and offers protection of hepatic cell integrity as assessed by plasma ALAT level compared to paracetamol alone.

The influence of atenolol and prazosin on serum lipids and atherosclerosis in minipigs fed a hyperlipidemic diet.

1. The effect of the adrenergic blockers prazosin and atenolol were tested in hypercholesterolemic Göttingen minipigs. 2. After 1 yr there was a significant reduction of plasma triglycerides and total cholesterol in the medicated animals as compared to untreated ones. 3. No significant difference in atherosclerotic lesions was observed.

Distribution and elimination of [14C]octachlorostyrene in cod (Gadus morhua), rainbow trout (Salmo gairdneri, and blue mussel (Mytilus edulis).

Cod (Gadus morhua) and rainbow trout (Salmo gairdneri) were given a single oral dose of 100 microCi/kg b.w. of [14C]octachlorostyrene [( 14C]OCS) in peanut oil. Blue mussel (Mytilus edulis) was exposed to [14C]OCS in water. The distribution and elimination of the compound was studied by liquid scintillation counting and whole-body autoradiography. The highest degree of radioactivity in the cod and rainbow trout was measured in the liver and the visceral fat, respectively. The degree of radioactivity in the brain of cod exceeded that of the rainbow trout by a factor between 2 and 4 at all survival times. In addition to bile excretion of [14C]OCS-derived radioactivity, a possible excretion over the intestinal mucosa was suggested. The rate of elimination was slow in both species, and substantial amounts of radioactivity remained in the tissues 90 d after administration. In the blue mussel, the highest degree of radioactivity was found in the hepatopancreas. Substantial amounts of radioactivity were present in the mussel tissues 60 d after administration.

Time development of distribution and toxicity following single toxic APAP doses in male BOM:NMRI mice.

The time development of the biodistribution and the hepatotoxicity following peroral administration of 14C-acetaminophen (APAP 400 or 800 mg.kg-1; 1 microCi) was characterized in a trial procedure using male Bom:NMRI mice. APAP (400 mg.kg-1) caused a transitory hepatic glutathione (GSH) depletion while APAP 800 mg.kg-1 maximally depleted hepatic GSH throughout the 12 h trial period. A lag time between the initial GSH depletion and the ensuing hepatic necrosis was seen. From 8 h post dosing a decrease of 14C-APAP or its metabolites coincided with recovery of the hepatic GHS level and the regeneration of the hepatic cells caused by APAP 400 mg.kg-1. Hepatic glycogen depletion preceded centrilobular necrosis, and irrespective of APAP dose definite kidney damage was absent. Irrespective of APAP dose the biodistribution of 14C-APAP or its metabolites was predominantly in organs associated with metabolism and excretion. After APAP (800 mg.kg-1) significant amounts of 14C-APAP or its metabolites were present up to 24 h post dosing. The operative status of the hepatic GSH conjugative system has an important influence on the rate of elimination of toxic APAP doses. Hepatic cell necrosis with a possible effect on the circulation may play an important secondary role in the elimination of toxic APAP doses. Factors which may influence the status of the hepatic GSH conjugative system and toxicokinetics of perorally administered APAP doses are discussed.