Efficacy of paracetamol-esterified methionine versus cysteine or methionine on paracetamol-induced hepatic GSH depletion and plasma ALAT level in mice.

The effect of paracetamol-N-acetyl-DL-methionate (PAM) in preventing paracetamol-induced hepatic glutathione (GSH) depletion and hepatic cell damage assessed by plasma ALAT level, was compared to those of concomitantly administered paracetamol and N-acetyl-L-cysteine (NAC) or N-acetyl-DL-methionine (NAM) and paracetamol 400 mg/kg (P) alone. PAM, NAM and NAC reduced hepatic GSH depletion compared to P. The concomitant administration of GSH precursors in either form apparently maintained hepatic cell integrity as evaluated by plasma ALAT compared to predose and 16 hr control measurements. No statistically significant difference between PAM, NAM and NAC was observed. In group P a statistically significant, but transitory, rise in plasma ALAT level following dosage was seen. NAC was more effective than PAM and NAM in the prevention of GSH depletion 1 hr after dosing but was less effective in promoting de novo GSH synthesis towards 16 hr. There was no statistically significant difference between PAM and NAM with respect to effect on GSH depletion or hepatic cell integrity. PAM and NAM increased the GSH level significantly above control level 16 hr after dosing. PAM is rapidly cleaved to paracetamol and methionine following dosage as shown by the observed plasma paracetamol level. PAM compares favourably in hepatoprophylactic effect, to concomitant administration of equimolar doses of free N-acetyl-DL-methionine added to the paracetamol formulation.

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.

Acute toxicity studies with quinuronium sulfate in laboratory animals and sheep.

The acute toxicity of quinuronium was investigated by measurements of lethal doses (LD50) in mice and rats, cholinesterase activity in vivo in whole blood, and protection from anticholinesterase activity by atropinisation in sheep and rabbits. The LD50s in mice injected i.p. and s.c. were 4.80 and 5.40 mg/kg and in rats 6.3 and 6.5 mg/kg for i.p. and s.c. routes, respectively. Signs of salivation, defecation, anorexia and muscular spasms were observed in sheep. In rabbits anorexia and depression only were observed. There was species variation in normal cholinesterase activity, rabbits being low in activity. Quinuronium inhibited cholinesterase activity from 10 min to 24 h after treatment in sheep by 24% of the normal baseline values. The enzyme activity returned to normal at 48 h. Atropinisation partially protected against anticholinesterase activity in sheep; cholinesterase activity was inhibited by only 14% of the normal baseline values 10 min to 2 h after treatment. This study indicates that quinuronium is highly toxic and that rabbits are moderately resistant.

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).

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.

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.

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.

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.