Human & Experimental Toxicology

Passive smoking is defined as an involuntary exposure to a combined but diluted cigarette sidestream smoke (SS, gas and particle phases that are evolved fromthe smoldering end ofacigarettewhilethesmokerisnotpuffing) andthe exhaled smoke from smokers. SS contains numerous cytotoxic substances such as polycyclic aromatic hydrocarbons (PAHs), aromatic amines, nitrosamines, heavy metals, poisonous gases, pesticide residues, and radioactive elements in quantities much higher than those found from the cigarette mainstream smoke (MS) which is puffed by smokers. Passive smoking is found to be the cause of death from cancers and cardiac disease. Furthermore, it damagingly involves reproductive organs, the nervous system, genetic materials, and is particularly hazardous to mother and child during pregnancy and to those with a history of asthma, chronic infections, induced or earned immune deficiency, or predisposed susceptibility.

Trichothecenes are mycotoxins produced by various species of fungi, which can occur on various agricultural products. Among these compounds, T-2 toxin, HT-2 toxin, diacetoxyscirpenol (DAS) and deoxynivalenol (DON) are the most naturally encountered and the most potent trichothecenes. Consumption of trichothecene contaminated foods by farm animals and humans leads to mycotoxicosis. Trichothecenes are known to induce haematological disorders such as neutropenia, aplastic anemia and thrombocytopenia in humans and animals. Four trichothecenes, T-2 toxin, HT-2 toxin, DAS and DON have been tested on human platelet progenitors (CFU-MK) using a culture model of CFU-MK optimized for toxicological studies. Trichothecenes cause, at low concentrations, cytotoxic effects in megakaryocyte progenitors, which could induce thrombocytopenia. Sensitivity of human CFU-MK is compared to respective sensitivities of human red blood cell progenitors (BFU-E) and white blood cell progenitors (CF-U-GM) that were described in previous works.

A primary culture of baboon proximal tubule cells (bPTC) was prepared and characterised using LLC-PK₁ cells of proximal tubule origin and MDCK cells of distal tubule origin, as positive and negative references, respectively. The proximal tubular origin of the bPTC was determined by morphological studies, immunoperoxidase staining and the expression of proximal tubule markers alkaline phosphatase and gammaglutamyltransferase.

The hypothesis that paraquat (PQ) is transported by the bPTC was investigated. The cytotoxic threshold for PQ in these cells was determined and compared to the LLC-PK₁ and MDCK cells. Furthermore, this study investigated the transport of the monovalent cation tetraethyl ammonium (TEA) and the polyvalent cation cimetidine in the bPTC and demonstrated their effect on the cellular uptake of PQ. The cytotoxic threshold of PQ in the bPTC, determined by cellular viability studies using the method of Trypan blue exclusion, is 0.05 mM at 2 h incubation. The LC₅₀ after 24 his 76, 61 and 455 pM for the bPTC, LLC-PK₁ and MDCK cells, respectively. This indicates that proximal tubule cells are more susceptible to PQ toxicity compared to distal tubule cells, which is consistent with clinical PQ toxicity where renal damage is found predominantly in the proximal renal tubules.

The cations PQ and cimetidine were actively transported by the bPTC. The uptake of PQ (0.05 mM) commenced after 15 min whereas cimetidine (0.5 mM) uptake was evident after 2 min. Furthermore, cimetidine was shown to compete with PQ for uptake in the bPTC. Coincubating PQ (0.05 mM) and cimetidine (0.5 mM) for 60 min resulted in an approximate 50% decrease in PQ uptake.

The cation TEA was not transported by the bPTC suggesting either a genetic mutation or complete absence of the transporter for TEA in the cells. The results suggest that PQ may be transported by the same cation transporter as cimetidine and not TEA, indicating PQ uptake in the bPTC to be via a polyvalent organic cation transporter.

Progressive renal dysfunction in 5/6 nephrectomized (NX) rats can be physiologically divided into three stages, coinciding with morphological stages, after definition of physiological parameters for identification of stage. Now, for the establishment of a toxicity screening approach using 5/6 NX rats, our concept, “Differential toxicity synchronized with renal dysfunction process could be identified using 5/6 NX rats” was examined by dosing gentamicin. Firstly, electrophoretic fractional changes of urinary proteins during gentamicin treatment were clarified with determination of amino acid sequences and the three differential features were proven, revealing the unpredictable depression of urinary albumin with progression of the stages in NX rats. Secondly, marked elevation of urinary lactate dehydrogenase (LDH) and glucose (GLU) was evident, indicating the intensified hypoxic conditions and glycolysis in tubular cells synchronized with increased tubular damage. Thirdly, these transit metabolic changes were proven as intensive cause for the advancement of renal dysfunction by the reduction of FR_{electrolytes and water} at the end of each dosing period. These results indicate that toxicity studies of newly developed drugs using 5/6 NX rats have potentiality prior to clinical dosing to the patients.

An open compartmental model for describing aluminium biokinetics is presented with a central compartment consisting of transferrinand citrate-bound aluminium in blood plasma and interstitial fluid, and three peripheral compartments for organs, muscles and bones and the gastro-intestinal tract. The rate constants describing the transport of aluminium are normalized to an estimated plasma volume and do not depend on the size of the individual. Effects due to changes in compartmental sizes or to transport characteristics are described. The model is applied to biokinetics studies of a volunteer after i.v. administration and of Sprague-Dawley rats with different iron status and with nephrectomization after p.o. administration of 2⁶Al.

We report a case of fatal weeverfish sting. An 18-yearold man was stung on the left leg by a weeverfish, which he was attempting to capture while snorkelling off the coast of Majorca (Spain). The man felt intense pain, but managed to swim to his boat where he lost consciousness after boarding rapidly. An hour later, when examined by a doctor, the subject was found to be in cardiorespiratory arrest. Reanimation manoeuvres were unsuccessful. The most import post-mortem findings were in the skin and lungs. A puncture wound, which traversed the greater saphenous vein and was covered by an intense haemorrhagic infiltrate, was observed in the skin. The lungs showed haemorrhagic alveolar oedema.