Human & Experimental Toxicology

1 After overnight fasting, two young male adults each received a single oral dose of 100 Bq ²⁶Al in tap water. Coincidence gamma-ray spectrometry and accelerator mass spectrometry were used to determine the ²⁶Al content of excretion collections and of blood samples.

2 Close to 100% of the intake was recovered in faeces during the first 7 days. Gastro-intestinal uptake, determined by comparing urinary excretion with patterns previously established following intravenous administration of ²⁶Al, averaged 0.22% in the two subjects.

3 Uptake fractions based on comparisons of blood concentration following ingestion and injection were much lower, but were judged to be unreliable. It is concluded that aluminium present in most water supplies is unlikely to contribute as much as 1% of a typical daily uptake of 10 mg from food.

Objective: To estimate the equivalent cadmium levels in renal cortex and in urine, as based on autopsy analysis of subjects not exposed to cadmium occupationally.

Methods: The levels of Cd were determined in renal cortex, liver, urine and urinary bladder of 39 subjects deceased at the age 42+14 years. Flame atomic absorption spectrometry (kidneys, liver) and flameless AAS (urine, bladder) were used.

Results: The urinary cadmium level determined post mortem is strongly correlated with the renal Cd levels. Eliminating cases with high urinary proteins and extrapolating from sets of data with elevated urinary protein concentration to its normal range yielded a value of 1.7 mg/g creatinine as equivalent to the renal level of 50 mg/g w.w.

Conclusions: It seems possible to use monitoring data for cadmium in urine and in renal cortex in a coherent way.

1 We have carried out a prospective study of all adult patients presenting with acute poisoning during one month to the Helsinki University Central Hospital (Meilahti Hospital).

2 Two hundred and twenty-six cases of acute poisoning (113 males and 113 females) presented to the emergency department. Most cases in both men (66%) and women (67%) involved alcohol. As to drugs, psychotropic agents predominated in both men and women. The frequency of patient presentation peaked between 7 p.m. and 9 p.m. and was lowest between 8 a.m. and 10 a.m. In most cases, the delay from ingestion of the poison to presentation was longer than 4h.

3 The clinical status of the patients on arrival was generally good; more than half (55%) of them were fully awake. Serious symptoms (e.g. unconsciousness, insufficient respiration necessitating intubation, aspiration, convulsions or hypotension) occurred in 15% of the presentations. There were no fatalities.

4 One hundred and thirty-five patients (60%) received at least one 50-g dose of activated charcoal. However, charcoal was given in 86% of the cases of drug poisoning. Gastric lavage was performed in 112 cases (50%), and 106 cases (47%) involved both gastric lavage and administration of charcoal. Twenty-one patients received antidotes (flumazenil, calcium gluconate or naloxone) and three patients were hemodialysed.

5 Of the 226 cases, 142 (63%) were managed solely in the emergency department. Of the 84 cases admitted to the hospital, eight had to be managed in the intensive care unit. Almost all patients (94%) were discharged within 24 h.

6 In this survey on 226 consecutive cases of acute poisoning, about two-thirds of the cases involved alcohol, while the most common drugs taken were psychotropic agents. The poisoning was mild in the great majority of the cases. Activated charcoal was generally administered in all but trivial cases of drug poisoning.

Aluminum (Al) toxicity has been mainly investigated in uremic patients although healthy subjects and patients without renal insufficiency are not exempt from its potential deleterious effects. This experimental study aims to elucidate the action of different doses of Al citrate on in vivo erythropoiesis and find out whether the metal exerts a local toxic effect upon the bone marrow late erythroid progenitor cells. The groups in the first experimental series were: C₁ (n=5) controls and T_Al-1 (n=5) rats receiving 1 mmol Al citrate/g body weight/day by gavage. Colony-forming units-erythroid (CFU-E) development was inhibited in the T_Al-1 group, but the median osmotic fragility (MOF) and hematocrit (Ht) values were similar to those of the C₁ group. The groups in the second series were C₂ (n=5) controls and T_Al-2 (n=5) rats receiving Al citrate in drinking water (100 mmol/l). The T_Al-2 group showed decreased Ht, hemoglobin concentration, MOF and red blood-cell life-span values (P50.05), and a marked inhibition of the CFU-E development (P50.01). Serum and bone Al concentrations were increased in both Al-treated groups (P50.01). There was a dose-dependent increase in bone Al levels (P50.01) and a dose-dependent decrease of CFU-E development (P50.05). The CFU-E development was inversely correlated with the bone Al content (r=70.79; P50.05). The results demonstrate that even very low doses of Al citrate impair erythropoiesis in vivo and higher doses exert a deleterious action on both CFU-E and mature erythrocytes. This might show a local effect of Al on CFU-E caused by the bone sensitivity to the metal accumulation.

Aluminum (Al) has no known physiological function and is not considered an essential dietary compound. Nowadays, it is recognized as an element that can produce adverse effects on biological systems. The present study determined Al partitioning in the body compartments of rats that have been orally exposed for 15 weeks. Three experimental groups were studied: Controls (C, n=19), T_Al-1 (n=10) rats receiving daily doses of Al citrate (1.0 mmol/g body weight) by gavage and T_A1-2 (n=13), receiving Al citrate with the drinking water (100 mmol/ l). At the end of the experimental period, the Al contents of organs and sera were determined. Results are expressed as median and range values. Comparing the T_Al-2 rats with the control ones, remarkable Al accumulation could be observed in serum (4.8/2.7 - 16.3 vs 0.4/0.2 - 1.2 mmol/l, P50.001), bone (3.33/1.78 - 4.85 vs 1.00/0.48 - 1.59 mmol/ g, P50.001), kidney (2.33/0.96 - 3.15 vs 0.52/0.22 - 2.07 mmol/g, P50.001), spleen (2.22/0.70 - 4.19 vs 0.27/ 0.11 - 0.36 mmol/g, P50.001) and liver (0.60/0.42 - 0.91 vs 0.24/0.14 - 0.78 mmol/g, P50.01) while brain Al content was not significantly increased. Aluminum levels were raised in the T_Al-1 group only in serum (2.8/1.3 - 10.4 mmol/ g, P50.001), bone (1.85/1.00 - 3.41 mmol/g, P50.001) and kidney (1.74/0.96 - 2.07 mmol/g, P50.01). Bone Al concentration increased in a dose-dependent manner (T_Al-2 vs T_Al-1, P50.001). The results demonstrate different tissue Al accumulation in rats chronically exposed to Al citrate, irrespective of their intact renal function.

1 The oncogenicity of Piperonyl butoxide (PBO) has been studied in the mouse and rat. CD-1 mice were administered PBO in the diet at target doses of 0, 30, 100 and 300 mg/kg/day for 79 weeks and Sprague - Dawley rats 0, 30, 100 and 500 mg/kg/day for 104/105 weeks.

2 At termination of the study in the mouse there was evidence of increased liver weights and an increased incidence of eosinophilic adenomas at 100 and 300 mg/kg/day in males and 300 mg/kg/day in females.

3 In rats there was increased liver weights at 100 and 500 mg/kg/day associated with hepatocyte hypertrophy in both male and female rats. There was no increased incidence of neoplasia at any site. Hyper-trophy and hyperplasia of thyroid follicles was observed at 500 mg/kg/day in both sexes.

4 The observations reflect the expected changes related to the induction of the mixed function oxygenase group of enzymes. In the mouse the increased incidence of eosinophilic adenomas is not considered relevant for human risk evaluation.

1 The influence of three oximes (obidoxime, HI-6 and the new asymmetric bispyridinium oxime BI-6) in combination with atropine on soman-induced cholinergic and stressogenic effects in rats was studied.

2 The oxime BI-6 produced significantly higher reactivation of soman-inhibited blood and diaphragm cholinesterases than obidoxime. On the other hand, its reactivating effect was not so high as the effect of the oxime HI-6.

3 There were not significant differences in the reactivation of soman-inhibited brain acetycholinesterase among all three oximes tested.

4 The influence of the oxime BI-6 on soman-induced stressogenic effects was greater than the antistressogenic effects of HI-6 or obidoxime at 1 h or 3 h following soman poisoning.

5 These findings confirm that the oxime BI-6 has no definite advantages over HI-6 in the antidotal treatment of soman poisoning but BI-6 is significantly more effective in rats than obidoxime, one of the oximes presently in use.

1 Di-(2-ethylhexyl)-phthalate (DEHP) possesses a great industrial value as a plasticizing agent and has become an ubiquitous environmental contaminant. In most species it is rapidly metabolized to mono-(2-ethylhexyl)-phthalate (MEHP) and 2-ethylhexanoic acid (2- EHA). Evaluation of toxicity of DEHP and its primary metabolites has been focussed on reproductive toxicity and hepatocarcinogenic properties. The aim of this study was to determine the nephrotoxic potential of both DEHP metabolites by use of cultured kidney epithelial cells (Opossum kidney cells; OK cells).

2 For this purpose, OK cells were exposed for 3 days to MEHP and 2-EHA at concentrations ranging from 0.1 -500 mmol/L and the toxicity as well as the effects on migratory activity and intracellular cytoskeleton were studied by cell biological, morphological and morpho-metric methods.

3 When compared with corresponding controls, treatment of OK cells with MEHP and 2-EHA, respectively, showed marked differences in cell viability between both DEHP metabolites. MEHP caused a dose-depen-dent decrease in cell viability (ED₅₀ =25 mmol/L) accompanied by a moderate swelling of the cells at concentrations up to 25 mmol/L. MEHP concentrations higher than 25 mmol/L caused a dose-dependent shrinkage of the cells and the occurrence of a high amount of cell debris as a result of cell lysis. 2-EHA did not cause a reduced viability or an altered cell volume. The migratory activity of OK cells was not significantly influenced by both metabolites. Moreover, MEHP toxicity resulted in a largely reduced and altered organization of F-actin (stress fibers), but not of myosin, microtubules and vimentin.

4 The study indicates that cultured epithelial cells can be used as a prescreening system to assess the nephrotoxicity of hazardous substances such as DEHP. As demonstrated in this study, only MEHP, but not 2-EHA, has a marked nephrotoxic effect in vitro.

The toad possesses several toxic substances. Toad toxin poisoning manifests itself primarily with digitalis-like, cardioactive effects which results in bradycardia, varying degrees of atrio-ventricular block, ventricular tachycardia, ventricular fibrillation and sudden death. We report a cluster poisoning in a family who became intoxicated after ingestion of cooked toad soup for a skin problem. The youngest one (15 months old) died of refractory bradydyarrhythmias soon after arriving at our hospital. A second child (20 months old), who survived, arrived in shock with hyperkalemia (potassium 7.3 mEq/ L) and varying degrees of atrio-ventricular block. She was successfully treated with atropine, lidocaine, and cardio-version, and had a transvenous temporary pacemaker implanted for 1 day. The third boy (16 years old) had hyperkalemia (potassium 6.3 mEq/L) and bradycardia. The remaining three adults had only mild symptoms of nausea, vomiting, watery diarrhea and a sensation of numbness over their oral mucosa.

We found that the level of serum potassium had prognostic implications in toad intoxication. Determination of serum potassium level is readily available in almost every hospital and is therefore more convenient to measure than serum digoxin level. We conclude that if hyperkalemia develops, the treatment of toad intoxication must be more aggressive to prevent mortality.

1 In humans morphine is metabolised to morphine-3- glucuronide (M3G) which possess no opioid activity, and morphine-6-glucuronide (M6G) which is a potent opioid receptor agonist that probably contribute to the desired as well as toxic effects of morphine.

2 In order to investigate the possible effect of ranitidine on morphine glucuronidation indicated by clinical studies and later confirmed in vitro, a double blind cross-over study on eight human volunteers administered oral morphine plus ranitidine or placebo was conducted.

3 Urine was collected in fractions for 24 h. Serum and urine samples were prepared by solid phase extraction andmorphine, M3G and M6G were quantified by HPLC.

4 Ranitidine significantly reduced the individual serum M3G/M6G ratio, and tended to increase the serum AUC₍₀ - 90) of morphine. In contrast, ranitidine had no significant effect on the urinary M3G/M6G ratio. The urinary recovery of morphine or morphine glucuronides was unaffected by ranitidine.

5 Possible explanations to the apparent incongruity between the serum and urine data are discussed.