Human & Experimental Toxicology

The estimated intestinal absorption after a single administration of ²³⁹NR-nitrate to fasted weanling rats (about 2% of the oral dose) was ten times higher than that of ²³³Pa administered as the chloride. Rats drinking tomato juice, apple juice or tea instead of water had a similar retention to the control group. However, when a small amount of tea was administered immediately before ²³⁹Np, the absorption and retention values were six times lower. When animals received only milk or glucose, the whole body retention of ²³⁹Np and ²³³Pa increased about 20 and 200-300 times, respectively, due mainly to a very high retention in the large intestine. When rats were fed milk plus rat chow, the whole body and gut retention of ²³³Pa was only two and three times higher, respectively; in the other organs less ²³³Pa was found than in control animals. This indicates that the extremely high retention of radionuclides in the gut contents of young rats fed only milk is temporary and disappears when solid food is available.

Blood levels and urinary excretion of triclopyr, the active ingredient in Garlon® herbicides, were followed in six volunteers given single oral doses of 0.1 and 0.5 mg/kg body weight. Five of these volunteers later received dermal applications of Garlon 4 herbicide formulation equivlant to 3.7 mg triclopyr/kg body weight applied to the forearm. Following oral administration blood levels peaked at 2-3 h and declined to undetectable levels within 48 h; more than 80% of. the dose was found as unchanged triclopyr in the urine. A two-compartment pharmacokinetic model was used to describe the time-course of triclopyr clearance; half-lives for the rapid initial and slower terminal phases were 1.3 h and 5.1 h respectively, and were independent of dose. Due to the slow half-life for dermal absorption (t_½ = 16.8 h) the rapid initial elimination phase was obscured and the pharmacokinetics could be simplified by a one-compartment model. An average of 1.37% of the applied dose was recovered in the urine; when corrected for recovery after oral administration this was equivalent to an absorption of 1.65%. Triclopyr is slowly absorbed through skin and is rapidly eliminated. It has very low potential to accumulate in man or to be absorbed through the skin in acutely toxic amounts.

1 Patients who have taken canthaxanthin and beta-carotene to avert phototoxicity have been monitored by electroretinographic testing.

2 Patients took the compounds only during the summer months, but were monitored for more than 1 year to determine if seasonal changes in the ERG were visible.

3 The characteristic refractile retinal crystals reduced during the winter.

4 The scotopic b-wave amplitude increased during the winter, whether evoked by red or blue flashes.

5 No other ERG parameter altered.

6 Changes noted in 3 and 4 above are reversible.

7 A dose/ERG-amplitude response relationship was established, but no correlation between blood level or total cumulative dose and b-wave amplitude could be found.

8 It is suggested that the Müller cells concentrate canthaxanthin and this is the mechanism which affects the ERG.

A study is presented in which eight healthy male non-smoking volunteers ingested a daily amount of 0.5 mg/kg butylated hydroxyanisole (BHA) for 10 consecutive days. Blood samples were taken on days -6 and 0 before and on days 4 and 7 after the first BHA administration for the assessment of standard clinical plasma parameters (L-aspartate aminotransferase, L-alanine-aminotransferase, L-gamma-glutamyltranspeptidase, creatine phosphokinase, lactate dehydrogenase, total protein, albumin, urea, creatinine, Na⁺, and Cl^-). Antipyrine (500 mg p.o.) and paracetamol (500 mg p.o.) were administered before and during BHA administration as test substances to measure phase-I and phase-11 biotransformation capacity. Saliva samples and urine were subsequently collected for the assessment of kinetic parameters (e.g. saliva elimination half-life, saliva clearance, apparent volume of distribution) and urinary excretion of metabolites. Kinetic plasma parameters of BHA itself were determined in plasma samples obtained via a catheter in an arm vein after oral BHA intake on days 0 and 7. Levels of antipyrine, paracetamol, BHA and metabolites in plasma, saliva or urine were quantified by standard or newly developed reversed-phase high-performance liquid chromatography methods. Urinary excretion of Na⁺, K ⁺, and Cl^-, as well as osmolality of urine were measured on three days before and six days during BHA administration.

Generally, no significant differences were detected in the parameters measured, indicating that oral administration of BHA to men for 10 days remains without effects on clinical biochemical parameters and phase-I and phase-II biotransformation capacity. In contrast, urinary excretion of metabolites of BHA was significantly increased on days 3 and 7 vs. the first day of BHA administration. This may result either from an induction or inhibition of BHA-specific phase-I and -II metabolizing enzymes in man, or from a bioaccumulation of BHA and/or its metabolites in the body.

1 Neutrophils play a role in the pathogenesis of ulcerative colitis. Most of the patients with ulcerative colitis are non-smokers.

2 Neutrophil function was examined in healthy males, five smokers and five non-smokers, measuring production of oxygen free radicals by chemiluminescence.

3 The chemiluminescence was examined in the presence of nicotine and its main metabolite cotinine in various concentrations.

4 10 mM nicotine inhibited production of oxygen free radicals (90.2% ± 11.6) compared with controls (P < 0.001), as did the same concentration of cotinine (58.9% ± 34.2), (P < 0.05).

5 1 mM solutions had no effect and 3 mM nicotine was required to achieve 50% inhibition.

6 Smokers and non-smokers did not differ.

7 Since plasma concentrations of nicotine after a cigarette are only between 5 and 15 mM, the observed effects of nicotine and cotinine in much higher pharmacological concentrations in this system are unlikely to be of clinical relevance in ulcerative colitis

Most survivors of paraquat intoxication go on to develop fibrosis of the lung leading to death within a few weeks. The pathogenic effects of paraquat are based on the formation of oxygen free radicals. A cascade reaction occurs at the cell membrane which is damaged and cell integrity is destroyed. Fibroblasts migrate into the damaged region leading to the laying down of collagen and subsequent fibrosis. Currently paraquat intoxication is treated with gastrointestinal lavage, haemoperfusion and haemodialysis with mixed results. Artificial respiration with low percentage of inspired oxygen is instituted in order to decrease the possible release of oxygen radicals. However, in most cases, developing fibrosis prevents this treatment continuing and requires increased concentrations of inspired O₂ and increased ventilation pressure. The combination of increased FiO₂ and barotrauma leads to a vicious circle of parenchymal lung damage.

In this study we present a treatment designed to avoid the development of lung fibrosis using total exclusion of segments of the lung from external ventilation.

Exclusion from external ventilation was performed in animal experiments by instillation of Ethibloc, an amino acid glue, in one main bronchus to create an atelectasis. In different experimental groups this procedure was performed before and after intraperitoneal intoxication with paraquat. Four to twelve days later the experimental animals were sacrified and the ventilated lungs and the atelectatic lungs were compared.

The ventilated lungs showed dose-dependent damage to the alveolar epithelium and gross interstitial oedema. In some cases fibrosis was seen. The atelectatic parts of the lung were not different from the control group. In this study we have shown that total exclusion from ventilation prevents the development of lung fibrosis after paraquat intoxication.

1 In a prospective study of patients hospitalized for deliberate self-poisoning between 1978 and 1987 the number of admissions increased from 303 to 425. The annual incidence increased significantly for both women (P < 0.05) and men (P < 0.01). The mean age decreased significantly in the male group (P < 0.05), but increased in the female group (P < 0.05).

2 The median latency time for patients presenting at the hospital was short; 3.7 h in 1978 and 2.9 h in 1987.

3 There was a significant reduction in the percentage using barbiturates (9% in 1978 and 1% in 1987; P < 0.001) and the use of benzodiazepines increased (18% in 1978 and 32% in 1987; P < 0.05). The percentage of unconscious patients did not change significantly.

4 In 1987 N-acetyl-cysteine was the most frequently used antidote. Physostigmine has almost been abandoned since 1978.

5 Significantly more patients were hypotensive in 1978: 24% vs 11% in 1987; (P < 0.001) and significantly less patients needed treatment in the central intensive care unit (2% in 1987 and 5% in 1978; P < 0.05). Complications were few (8-10%) and the mortality low (approximately 1%) in both years studied.

6 The mean duration of hospitalization in 1978 was 65 h vs 30 h in 1987, (P < 0.001).

Data concerning 15 consecutive cases of single exposures of the skin or eyes during work to paraquat solutions are presented. Urine and serum were analysed for paraquat in all these cases at the laboratory of the Israel Poison Information Center. From these data it is apparent that a single exposure of healthy skin to paraquat solutions caused only local lesions. No systemic effect was detected in these patients.

Capillary gas chromatography with selective nitrogen detection was employed to quantify morphine and 6-monoacetylmorphine in biological fluids and tissues in five deaths attributed to heroin injection overdose. The minimum lethal concentration found was 0.021 μg morphine per ml of blood. In all cases, 6-monoacetylmorphine was identified in urine, confirming heroin abuse.

An unusual case of acute renal failure is reported following accidental cutaneous absorption of phenol and exposure to dichloromethane. Renal function during the onset of the nephrotoxic episode and the subsequent recovery period was monitored using a combination of standard clinical biochemical techniques and high resolution ¹H-NMR urinalysis. The initial urine biochemical patterns (up to 2 weeks following exposure) showed amino aciduria, glycosuria and lactic aciduria consistent with renal cortical necrosis. There followed a period of polyuria revealing a biochemical pattern (succinic aciduria,dimethylaminuria and N,N-dimethylglycinuria) consistent with renal papillary damage. Haemodialysis was required for a period of 3 weeks and the patient was discharged 42 days after admission to hospital when renal function was normal by standard clinical chemistry criteria (urea, potassium, sodium, creatinine, calcium, phosphate, urine glucose and protein). ¹H-NMR spectroscopic urinalysis revealed residual renal biochemical abnormalities consistent with renal papillary damage that were not detected by conventional analytical techniques. One year after the incident the patient is still polyuric, passing up to 3 1 of urine a day.

A 50-year-old man with ischaemic heart disease took 98 tablets of diltiazem 60 mg with alcohol. He developed a junctional bradycardia, hypotension and reduced cardiac function refractory to intravenous calcium gluconate. He survived with temporary cardiac pacing and infusion of dopamine. As much as half the dose was vomited back, but nonetheless the plasma diltiazem concentration reached 6090 μg/l before falling mono-exponentially with a half-life of 8.6 h. Sinus rhythm returned when the plasma concentration of diltiazem was around 750 μg/l. Standard resuscitative procedures sufficed to treat massive diltiazem overdosage.

1 Two thousand, one hundred and seventy-three patients with cancer or chronic infections were treated with coumarin in a clinical trial.

2 0.37% of these patients developed elevated liver enzyme levels during therapy with coumarin.

3 This hepatitis was probably a form of idiosyncratic hepatotoxicity and may have been immune in origin.

Sri Lanka is a developing agricultural country with a high fatality rate due to self-poisoning with very toxic agrochemicals as the main poisoning agents. A prospective study of 97 consecutive admissions following self-poisoning reveals that easy availability of the agrochemicals together with the lack of knowledge regarding their lethality were the main causative factors determining the choice of poisoning agents. Developing community awareness of the lethality of these substances, educating the farmers with regards to proper storage and disposal of agrochemicals together with stricter legislation regarding their sale and distribution may reduce the incidence of self-poisoning due to these agents with a consequent reduction in mortality due to self-poisoning.

Radioactive cerium is a nuclear toxicant. Metallic cerium is used in industry. Aspects of the intracellular metabolism of this element were studied following intraperitoneal injection and aerosol exposure in rat. Two microanalytic methods, an electron microprobe and ionic microanalysis, enabled the sites of incorporation and the process of intracellular concentration of cerium to be determined in the liver, lung, kidney, bone marrow and bone tissue. The very high sensitivity of ionic analysis enabled very low concentrations of cerium to be detected with a spatial resolution of 0.5 μm. Microanalysis by electron microprobe permitted: (i) the lysosomal localization of cerium to be determined; and (ii) the lysosomal coprecipitation of cerium with phosphorus to be demonstrated. Results are discussed in relation to aspects of radiological protection.