Jan Willems

Cholinesterase reactivation in organophosphorus poisoned patients depends on the plasma concentrations of the oxime pralidoxime methylsulphate and of the organophosphate.

We measured in nine patients, poisoned by organophosphorus agents (ethyl parathion, ethyl and methyl parathion, dimethoate, or brompphos), erythrocyte and serum cholinesterase activities, and plasma concentrations of the organophosphorus agent. These patients were treated with pralidoxime methylsulphate (ContrathionR), administered as a bolus injection of 4.42 mg.kg−1 followed by a continuous infusion of 2.14 mg.kg−1/h, a dose regimen calculated to obtain the presumed “therapeutic” plasma level of 4 mg.l−1, or by a multiple of this infusion rate. Oxime plasma concentrations were also measured. The organophosphorus agent was still detectable in some patients after several days or weeks. In the patients with ethyl and methyl parathion poisoning, enzyme reactivation could be obtained in some at oxime concentrations as low as 2.88 mg.l−1; in others, however, oxime concentrations as high as 14.6 mg.l−1 remained without effect. The therapeutic effect of the oxime seemed to depend on the plasma concentrations of ethyl and methyl parathion, enzyme reactivation being absent as long as these concentrations remained above 30 μg.l−1. The bromophos poisoning was rather mild, cholinesterases were moderately inhibited and increased under oxime therapy. The omethoate inhibited enzyme could not be reactivated.

Review and Meta-analysis of Risk Estimates for Prostate Cancer in Pesticide Manufacturing Workers

PurposeThe purpose of the present paper is to review cohort studies that examined the occurrence of prostate cancer in pesticide manufacturing workers in order to undertake a qualitative and quantitative evaluation of the risk as well as to assess the level of epidemiological evidence for each class of chemical compounds.MethodsFollowing a systematic literature search, relative risk (RR) estimates for prostate cancer were extracted from 18 studies published between 1984 and 2004. All studies were summarised and evaluated for homogeneity and publication bias. As no significant heterogeneity was detected, combined RR estimators were calculated using a fixed effect model. Meta-analyses were performed both on the whole set of data and for each chemical class separately.ResultsThe meta-rate ratio estimate for all studies was 1.28 [95% confidence interval (CI) 1.05–1.58]. After stratification by specific chemical class, consistent increases in the risk of prostate cancer were found in all groups but statistical significance was found only for accidental or non-accidental exposure to phenoxy herbicides contaminated with dioxins and furans. There was no obvious indication of publication bias.ConclusionThe overall meta-analysis provides additional quantitative evidence consistent with prior reviews focusing on other groups exposed to pesticides (farmers, pesticide applicators). The results again point to occupational exposure to pesticides as a possible risk factor for prostate cancer but the question of causality remains unanswered. Epidemiological evidence did not allow identifying a specific pesticide or chemical class that would be responsible for the increased risk but the strongest evidence comes from workers exposed to phenoxy herbicides possibly in relation with dioxin and/or furan contamination.

Occupation related pesticide exposure and cancer of the prostate: a meta-analysis

Aims: To summarise recent literature on the risk of prostate cancer in pesticide related occupations, to calculate the meta-rate ratio, and to compare it to data from meta-analyses previously published. Methods: A meta-analysis of 22 epidemiological studies, published between 1995 and 2001, was conducted in order to pool their rate ratio estimates. Studies were summarised and evaluated for homogeneity and publication bias. Results: The meta-rate ratio estimate, based on 25 estimators of relative risk from 22 studies, was 1.13 (95% CI 1.04 to 1.22). Significant heterogeneity of rate ratios existed among the different studies. Therefore, a stratified analysis was carried out. Major sources of heterogeneity identified were geographic location, study design, and healthy worker effect. Overall, pooled risk estimates for studies derived from Europe were lower than those derived from the USA/Canada. A significant increase in rate ratio was observed for the occupation category of pesticide applicators, whereas no significant increase was observed for farmers. There was no evidence of publication bias. Conclusion: This increased meta-rate ratio for prostate cancer in different pesticide related occupations, including farmers, is very similar to three, previously published, meta-rate ratios for prostate cancer in farmers calculated from studies published before 1995. Although the underlying data do not identify pesticide exposure as an independent cause for prostate cancer, the fact that an increased meta-rate ratio is again obtained points to occupational exposure to pesticides as a possible factor. Future epidemiological studies should focus, as far as possible, on reliable methods to estimate actual exposure.

Emetic and antiemetic effects of opioids in the dog

The emetic and antiemetic effects of opioid agonists were studied in awake dogs. The mu-agonists morphine, fentanyl and methadone, in sedative doses, prevented the emetic response to apomorphine and copper sulphate; only morphine induced emesis, at doses lower than those required to prevent emesis. The delta-agonist [D-Ala2,Met5]enkephalinamide (DALA) and [Leu5]enkephalin induced emesis in some of the dogs studied but had no antiemetic activity. The kappa-agonists bremazocine and ethylketocyclazocine (EKC) did not induce emesis but, at sedative doses, prevented the emetic response to apomorphine. The emetic effect of DALA was antagonized by naloxone in some dogs; the antiemetic effect of morphine, bremazocine and EKC was blocked by both naloxone and MR 2266. The non-opioid sedatives diazepam, phenobarbital and xylazine, administered in sedative doses, did not prevent apomorphine-induced emesis. Our results suggest that a delta-receptor is involved in the emetic effect and a mu- and/or or kappa-receptor in the antiemetic effect of opioids.

PLASMA CONCENTRATIONS OF PRALIDOXIME METHYLSULPHATE IN ORGANOPHOSPHORUS POISONED PATIENTS

Using pharmacokinetic data from healthy human volunteers in a bicompartmental pharmacokinetic model, a repeated dose scheme for pralidoxime methylsulphate (Contrathion®) was developed producing plasma levels remaining above the assumed “therapeutic concentration” of 4 mg·1−1. Using the same data, it was found that a concentration of 4 mg · 1−1 could also be obtained by a loading dose of 4.42 mg · kg−1 followed by a maintenance dose of 2.14 mg · kg−1 · h−1. In order to study the pharmacokinetic behaviour of pralidoxime in poisoned patients, this continuous infusion scheme was then applied in nine cases of organophosphorus poisoning (agents: ethyl parathion, ethyl and methyl parathion, dimethoate and bromophos), and the pralidoxime plasma levels were determined. The mean plasma levels obtained in the various patients varied between 2.12 and 9 mg·1−1. Pharmacokinetic data were calculated, giving a total body clearance of 0.57±0.271· kg−1· h−1 (mean ± SD), an elimination half-life of 3.44±0.90 h, and a volume of distribution of 2.77±1.451 ·kg−1.

Gastric relaxation and vomiting by apomorphine, morphine and fentanyl in the conscious dog

Apomorphine (0.03 mg . kg-1 s.c.) and morphine (0.5 mg . kg-1 s.c.) produced gastric relaxation and vomiting in the conscious dog. Domperidone (0.1-1 mg . kg-1 i.v.), haloperidol (0.1 mg . kg-1 i.v.) and pimozide (0.025 mg . kg-1 i.v.) selectively blocked the gastric relaxation as well as the vomiting caused by apomorphine. Naloxone (0.07 mg . kg-1 i.v.) selectively blocked the gastric relaxation and the vomiting caused by morphine; after naloxone, morphine produced a delayed gastric relaxation in 2 experiments out of 7. These results suggest that for gastric relaxation as well as for vomiting, apomorphine and morphine act on different receptors. Fentanyl elicited marked gastric relaxation, blocked by naloxone, but did not elicit vomiting. After fentanyl, morphine and apomorphine no longer produced gastric relaxation and vomiting. This observation shows that the known blocking effect of fentanyl at the vomiting center does not affect its gastric relaxing effect.

Toxicokinetics of methyl parathion and parathion in the dog after intravenous and oral administration

Methyl parathion (20 mg · kg−1 intravenously and orally) and parathion (5 mg · kg−1 intravenously and 10 mg · kg−1 orally) were given to non-anesthetized dogs and the serum concentrations were followed in function of time. For both substances a low bioavailability after oral administration was found.In other dogs radioactivity was followed in urine after oral and after intravenous administration of labeled methyl parathion or parathion. The results suggest a good gastro-intestinal absorption of the substances.In anesthetized dogs which were given methyl parathion or parathion intravenously, high hepatic extraction ratios were found, suggesting that the low systemic availability after oral administration can be explained by an important hepatic first-pass extraction.Binding of methyl parathion and parathion to dog serum, to human serum and to a solution of human albumin was determined with equilibrium dialysis. In both species a high binding (>90%) was found for both substances and there was no concentration-dependency in the concentration range used (0.2–30 μg · ml−1). In man and in dog the serum protein binding of parathion was about 5% higher than that of methyl parathion.

Fish consumption is a safe solution to increase the intake of long-chain n-3 fatty acids

OBJECTIVES Dietary intake of long-chain (LC) n-3 PUFA in developed countries is low compared with recommendations. Fish is naturally rich in LC n-3 PUFA, but is also a dietary source of heavy metals and organic pollutants. We investigated whether the recommendation for LC n-3 PUFA could be reached through fish consumption, without exceeding the provisional tolerable weekly intake of methylmercury (MeHg) and the tolerable weekly intake (TWI) of dioxin-like compounds. Also, the contribution of margarines enriched with LC n-3 PUFA was assessed. DESIGN Published nutrient and contaminant data were used in a probabilistic model to calculate the simultaneous nutrient and contaminant intake for different fish consumption scenarios. RESULTS The Belgian recommendation for EPA + DHA (0.3% of total energy intake) can be reached by consuming fatty fish a minimum of twice a week, or by varying between lean and fatty fish a minimum of three times a week. At this fish consumption level, MeHg intake is not an issue of toxicological concern. The intake of dioxin-like compounds approximates the TWI when consuming fatty fish more than twice a week, this being a potential toxicological risk because other food items also contribute to the weekly intake of dioxin-like compounds. Use of margarine enriched with LC n-3 PUFA can help to increase LC n-3 intake, on average by 159 mg/d. CONCLUSIONS Combination of regular fish consumption (twice a week) with important contribution of fatty fish species, in combination with regular consumption of margarine enriched with EPA + DHA, can be advised to achieve the recommendation for LC n-3 intake.

Probabilistic intake assessment and body burden estimation of dioxin-like substances in background conditions and during a short food contamination episode.

The objective was to perform a dioxin body burden estimate based on a probabilistic intake assessment of PCDDs, PCDFs and dioxin-like PCBs because of the so-called 1999 ‘Belgian dioxin incident’. Monte Carlo simulation techniques were used to combine detailed 7-day food intake data on the individual level from a sample of 14–18-year-old adolescents with ‘background’ and ‘incident-related’ food contamination data. In background conditions, 3% of the adolescents had an intake <1 pg TEQ kg-1 bw day-1, while 85% had <4 pg TEQ kg-1 bw day-1. Milk and other dairy products were the basic source of dioxin-like contaminants, while fish constituted the main source at the higher percentiles of intake. During the dioxin incident, the estimated median dioxin intake showed a moderate increase. At the 99th percentile, the highest intake level, and the 95% upper bound uncertainty level, peak body burden—23.73 ng TEQ kg-1 bw—remained below body burdens that in the experimental animal or in man are accompanied by a population-based observable increase in the incidence of adverse effects. The 1999 Belgian dioxin incident most likely did not affect public health in Belgium in a measurable way, although exceptions remain possible on the individual level.

In vitro study of the inhibitory effects of dopamine on the rat gastric fundus

SummaryThe influence of dopamine was studied on strips of the rat stomach fundus, contracted either by electrical stimulation (1 Hz) or by methacholine.Dopamine (3 · 10−5 M), like noradrenaline (3 · 10−7 M), inhibited the electrically induced contraction more than the methacholine-induced contraction. The inhibition by dopamine of the response to electrical stimulation was partially antagonized by phentolamine but less so by propranolol; the opposite was true for the inhibition by dopamine of the methacholine-induced contraction. Domperidone and four other dopamine antagonists slightly changed the inhibitory effect of dopamine, but had a similar influence on the inhibition caused by noradrenaline.The presence of cocaine as well as reserpine pretreatment reduced markedly the inhibitory effect of dopamine on the response to electrical stimulation. To further characterize the α-receptors on the cholinergic neurons, experiments were performed in the presence of cocaine, hydrocortisone and propranolol. Dopamine, noradrenaline, clonidine and phenylephrine concentration-dependently inhibited the contraction induced by electrical stimulation, clonidine being more potent than phenylephrine. However, the inhibitory effect of dopamine on the response to transmural stimulation was equally blocked by rauwolscine and by prazosin, as were the inhibitions caused by noradrenaline and clonidine.Our findings indicate that the inhibitory effect of dopamine in the rat stomach fundus can be explained by interaction with prejunctional β-receptors on the smooth muscle cells and prejunctional α-receptors on the intramural cholinergic neurons. No arguments for the existence of specific dopamine receptors were found. The inhibition by dopamine is largely indirect, through uptake in sympathetic nerve endings and liberation of endogenous noradrenaline. The results obtained with α-agonists and-antagonists suggest that the α-receptors on the intramural cholinergic neurons combine the characteristics of both subtypes of α-receptors, or that the receptor population consists of a mixture of α1-and α2.