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Archives of Toxicology (v.69, #8)

Review of the toxicology of beclomethasone dipropionate by S. E. Libretto (pp. 509-525).

This paper reviews the published toxicity of beclomethasone dipropionate (BDP). BDP is a synthetic glucocorticosteroid which has a powerful local anti-inflammatory effect but little systemic action. It has been developed for both dermatological and inhaled applications. LD₅₀ values and other acute studies indicated low toxicity. Findings published for repeat dose and reproductive toxicity studies embraced the known range of metabolic and physiological effects of glucocorticoids. For repeat dose studies, these included reduction in body weight gains, cushingoid syndrome in dogs, reductions in the numbers of lymphocytes and the weights of the tissues connected with the immune system, and hepatic glycogen deposition and fatty liver changes. In reproductive studies, there was an increase in the prevalence of cleft palate in mice and rabbits and in the number of dead foetuses, and ossification was retarded. Despite the route of administration, there was a general similarity of effects within and between species. All observations were characteristic of synthetic glucocorticoids and related to the intrinsic effects of these drugs.

Keywords: Beclomethasone dipropionate; Toxicology review; Glucocorticosteroid; Corticosteroid; Steroid

2-Butoxyethanol autoprotection is due to resiliance of newly formed erythrocytes to hemolysis by Digavalli V. Sivarao; Harihara M. Mehendale (pp. 526-532).

Pretreatment with a low dose of a toxic chemical protecting the animals from a subsequently administered lethal dose of the same chemical is called autoprotection. Autoprotection by model hepatotoxicants has been recently shown to be due to augmentation of cell division and tissue repair as well as an inherent resiliance of newly divided cells. The present studies were designed to investigate if an autoprotection model could be established in an extrahepatic tissue. The second objective was to test the hypothesis that inherent resiliance of newly divided cells is a major contributing mechanism for autoprotection. Female Sprague-Dawley rats (200–250 g) received a single administration of a moderately toxic but nonlethal dose (500 mg/kg, p.o.) 7 days prior to the administration of an LD₉₀ dose (1500 mg/kg, p.o.) of the same compound. All rats receiving the initial protective dose are able to survive the lethal dose of butoxyethanol, in contrast to the death of those receiving the lethal dose alone. Following the administration of butoxyethanol, the hematocrit decreased from the normal 45% to 18% and by day 7, recovered to normal levels. Following the lethal challenge, hematocrit decreased to 13% in the naive rats, while decreasing only to 27% in rats receiving the protective dose, permitting animal survival. Administration of pyrazole to inhibit metabolism of butoxyethanol to butoxyacetic acid abolished autoprotection. A time-course study, wherein the time intervening between the protective and lethal dose of butoxyethanol was increased, indicated that 100% autoprotection observed at 7 days wanes to a mere 12% by day 21, suggesting that ageing of the newly formed cells results in loss of their resiliance to hemolysis. This was also confirmed by in vitro studies. To test the hypothesis that new blood cells that replace the hemolyzed cells form the basis of autoprotection, rats were bled and allowed to recover prior to challenge with a lethal dose of butoxyethanol. Bled/recovered rats demonstrated an 87% survival. In vitro incubation experiments revealed that the red blood cells from the bled/recovered rats were resilient to a 10-fold range of butoxyacetic acid concentration compared to cells from control rats. This work has led to the establishment of 2-butoxyethanol autoprotection model in an extrahepatic tissue. The mechanism of this autoprotection seems to be the inherent resiliance of newly formed red blood cells that replace the cells lost due to hemolysis caused by the protective dose.

Keywords: Autoprotection; Bled/recovered; 2-Butoxyacetic acid; 2-Butoxyethanol; Ethylene glycol monobutyl ether; Hematocrit; Hematopoiesis; Hematotoxicity; Packed cell volume; Pyrazole; Red blood cells; Resiliance

Effect of inhibitors and substrates on methyl mercury uptake by rat erythrocytes by Guang Wu (pp. 533-539).

Methyl mercury (MeHg) uptake by isolated erythrocytes from rats was studied at 20°C. Inhibitors and substrates were used to test which transport system was involved in MeHg uptake. Ouabain and ATP were used to test the active transport system. Glycine was used to test system Gly. dl-Methionine was used to test system L. Cysteine was used to test the cysteine-facilitated transport system. The effects of Ca²⁺, Mg²⁺ and Na⁺ on MeHg uptake have been examined. MeHgCl and 4,4′-diisothiocyano-2,2′-stilbenedisulfonic acid (DIDS) were used to test Cl⁻ ion transport system. d-Glucose and cytochalasin B were used to test the facilitated diffusive d-Glucose transport system. Colchicine and vinblastine were used to test the microtubule system. Probenecid was used to test the organic acid transport system. Valinomycin was used to test the effect of the membrane potential on MeHg uptake. The results showed that MeHg uptake at 20°C might be involved in the following transport systems: 1) an active transport system; 2) a cysteine-facilitated transport system; 3) a Cl⁻ ion transport system; 4) a facilitated diffusive d-glucose transport system; 5) an organic acid transport system. The transport systems for MeHg uptake were sensitive to the membrane potential.

Keywords: Methyl mercury; Erythrocytes; Uptake; Transport system; Inhibitors

Benzo(a)pyrenediolepoxide-hemoglobin adducts and 3-hydroxy-benzo(a)pyrene urinary excretion profiles in rats subchronically exposed to benzo(a)pyrene by Michèle Bouchard; Claude Viau (pp. 540-546).

The time profiles of benzo(a)pyrenediolepoxide (BaPDE)-hemoglobin (Hb) adduct formation and 3-hydroxybenzo(a)pyrene (3-OHBaP) urinary excretion were studied in male Sprague-Dawley rats exposed to daily benzo(a)pyrene (BaP) intraperitoneal doses of 1.25, 6.25, and 31.25 μmol/kg administered Tuesday to Friday for 4 consecutive weeks. Blood was withdrawn weekly, on Tuesdays, prior to dosing. Twenty-four-hour urine samples were collected on Mondays (following 72 h without treatment) and Thursdays. Analytes were quantified by high performance liquid chromatography (HPLC)/fluorescence. Exposure to BaP resulted in the accumulation of BaPDE-Hb adducts, reaching an average of 1.2±0.3, 8.3±1.9, and 38.2±6.1 pmol/g Hb for the 1.25, 6.25, and 31.25 μmol/kg per day doses after 4 weeks of treatment. The expected saw tooth excretion profile of 3-OHBaP was observed, with peaks on Thursdays and troughs on Mondays, and showed a progressive rise on both Mondays and Thursdays. Increase in Monday values with time suggested a possible increase in BaP body burden during exposure. To verify this aspect further, the urinary excretion kinetic of 3-OHBaP following acute intraperitoneal dosing (31.25 μmol/kg) was determined. Urine samples were collected at frequent timed intervals for up to 164 h post-dosing. Two-step elimination was observed, the second step having a half-life of 25 h, presumably linked to the slow release of BaP accumulated in fatty tissues upon repeated treatment. Therefore, it seems that 1) BaPDE-Hb adducts are good indicators of repeated exposure, 2) the difference between pre- and post-exposure 3-OHBaP urinary excretion gives a measure of recent exposure, and 3) excretion levels of this latter metabolite after a non-exposure period of sufficient duration, to allow elimination of the bulk BaP from the last dose, could reflect BaP body burden.

Keywords: Benzo(a)pyrene; Hemoglobin adducts; Urinary metabolites; Time profiles

Comparative toxicity of four chlorinated dibenzo-p-dioxins (CDDs) and their mixture by Karl K. Rozman; Bernhard U. Stahl; Laszlo Kerecsen; Antonius Kettrup (pp. 547-551).

Groups of male Sprague-Dawley rats were administered orally the following chlorinated dibenzo-p-dioxins (CDDs) in corn oil/acetone (95/5; v/v): 30–60 μg/kg 2,3,7,8-tetrachlorodibenzo-dioxin (tetra-CDD), 160–270 μg/kg 1,2,3,7,8-pentachlorodibenzo-p-dioxins (penta-CDD), 630–1249 μg/kg 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (hexa-CDD) and 5000–8000 μg/kg 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (hepta-CDD) or a mixture of the four homologues such that each was present in the mixture at one quarter of its dose as a single compound. Animals were killed at 2 and 8 days after dosing. Livers were immediately removed, and aliquots frozen in liquid nitrogen. Storage occurred at −80°C until further use. About 0.2 g of each lyophilized rat liver was extracted, the extract purified by column chromatography and analyzed by GC/MS for CDD content. Results obtained suggest that the absorption of CDDs after oral administration decreases in the order of tetra-CDD≥penta-CDD>hexa-CDD>hepta-CDD, indicating that the dose was an incomplete surrogate of exposure in parts I–III of this publication series (Stahl et al. 1992; Weber et al. 1992a,b). Moreover, data also support the notion that the pharmacokinetics of CDD mixtures at high doses are somewhat different from those expected based on single compound exposures. Our findings suggest that the intrinsic relative potency in terms of toxic equivalents (TEQ) of the higher chlorinated homologues is slightly greater (about a factor of 2) than suggested by Stahl et al. (1992), because of reduced absorption, whereas the contribution to total potency of the lower chlorinated homologues in mixtures is slightly higher (about a factor of 2) because of increased relative liver concentrations. This later finding appears to be due to altered pharmacokinetics of mixtures of CDDs, probably originating in changes of partial solubility of the lower chlorinated homologues in fat under conditions of near saturation.

Keywords: Chlorinated dibenzo-p-dioxins; Liver; Rats; Toxicity

Foodstuffs and human blood contamination by the mycotoxin ochratoxin A: correlation with chronic interstitial nephropathy in Tunisia by K. Maaroufi; A. Achour; A. M. Betbeder; M. Hammami; F. Ellouz; E. E. Creppy; H. Bacha (pp. 552-558).

Ochratoxin A (OTA) has been detected in high amounts in human blood samples collected in nephrology departments in Tunisia from nephropathy patients under dialysis, especially those categorised as having a chronic interstitial nephropathy of unknown aetiology. These represent 12–26.1% of all chronic renal failure patients. To clarify the situation, food and blood samples were collected from nephropathy patients and controls, (with no familial case of nephropathy). The OTA assay showed very different scales of OTA food and blood contamination from 0.1 to 16.6 μg/kg and 0.1–2.3 ng/ml, respectively, in controls and healthy individuals and 0.3–46 830 μg/kg for food and 0.7–1136 ng/ml for blood in nephropathy patients. The disease seems related to OTA blood levels and food contaminations, since the control group was significantly different from the nephropathy group (p<0.005) for both food and blood ochratoxin A contamination. Combined with data published already, the results emphasize the likely endemic aspect of this OTA-related nephropathy occurring in Tunisia and possibly in other countries of northern Africa. This nephropathy is very similar to Balkan endemic nephropathy.

Keywords: Ochratoxin A; Food and blood contamination; Chronic interstitial nephropathy; Tunisia; Endemic nephropathy

A direct involvement of the central nervous system in hypophagia and inhibition of respiratory rate in rats after treatment with O,O,S-trimethyl phosphorothioate by Kosei Ohtaka; Naoto Hamade; Yutaka Yamazaki; Masahiro Suzuki; Akio Koizumi (pp. 559-564).

O,O,S-Trimethyl phosphorothioate (OOS-TMP) is known to induce unique symptoms, which are characterized by hypophagia, progressive weight loss, and hypothermia. To determine whether there is the possibility of a causal relationship between these toxic symptoms and a direct action of OOS-TMP on the central nervous system, we investigated the development of these symptoms in Fischer 344 female rats after oral or intracerebral treatment with OOS-TMP. Oral administration of OOS-TMP at 20 mg/kg induced marked hypophagia, progressive weight loss and hypothermia. Moreover, inhibition of respiratory rate was observed immediately after treatment. It lasts during the entire experimental period. Profound hypothermia below 34°C was observed more frequently in the rats, which became hypercapnic (PaCO₂≥50 mmHg). In contrast, administration of OOS-TMP at 20 mg/kg (as much as the oral dose) into the cerebral lateral ventricle succeeded in inducing hypophagia, progressive weight loss and lowered respiratory rates. On the other hand, by this route of administration, OOS-TMP at 20 mg/kg failed to induce hypothermia, hypercapnia and lung injury. The present results suggest that hypophagia and inhibitions of respiratory rate are attributable to the direct action of OOS-TMP on the central nervous system, while other symptoms are associated with lung injury.

Keywords: OOS-TMP; Intracerebroventricular injection; Inhibition of respiratory rate; Fischer 344 rats; Toxicity

Production, characterization and application of monoclonal antibodies against the organophosphorus nerve agent Vx by Yun-xiang Ci; Yong-xin Zhou; Zhen-quan Guo; Kang -Tai Rong; Wen-bao Chang (pp. 565-567).

Two monoclonal antibodies (Vx-BB8 and Vx-EA11) to the chemical warfare agent Vx were produced and characterized. A competitive inhibition enzyme immunoassay was developed to detect Vx concentrations as low as 3.7×10⁻⁷–3.7×10⁻⁶ mol/l in biological samples. Vx-BB8 400 μg given intravenously immediately before 1×LD₉₅ Vx or 400 μg Vx-BB8 intraperitoneally 1.5 h−3 days before 1×LD₉₅ Vx could protect all the tested mice from death.

Keywords: Monoclonal antibodies; Competitive inhibition enzyme immunoassay; Vx; Detection

Bioaccumulation of water soluble aluminium chloride in the hippocampus after transdermal uptake in mice by Rachid Anane; Michelle Bonini; Jean -Marie Grafeille; Edmond Ekué Creppy (pp. 568-571).

Normally, only very small amounts of ingested aluminium are absorbed and accumulated. Despite the percutaneous absorption of many drugs and chemicals, the skin has not been considered as a possible site at which aluminium could enter the body. Application of low aqueous concentrations of aluminium chloride (AlCl₃, 6H₂O) (0.025–0.1 μg/cm²) to healthy shaved Swiss mouse skin for 130 days led to a significant increase in urine, serum and whole brain aluminium, especially in the hippocampus, compared to control animals. This percutaneous uptake and accumulation of aluminium in the brain was greater than that caused by dietary exposure to 2.3 μg per day in feed and water. In vitro studies demonstrated the passage of aluminium through viable mouse skin. This study shows for the first time that aluminium is absorbed through the skin of mice in vivo and this contributes to a greater body burden than does oral uptake.

Keywords: Aluminium chloride (AlCl₃, 6H₂O); Transcutaneous absorption; Bioaccumulation; Hippocampus; Mouse

Low serum concentration of all-trans and 13-cis retinoic acids in patients treated with phenytoin, carbamazepine and valproate by G. Fex; K. Larsson; A. Andersson; M. Berggren-Söderlund (pp. 572-574).

All-trans retinoic acid deficiency resulting from ethanol’s interference with the synthesis of all-trans retinoic acid from retinol was recently suggested to cause the malformations of the fetal alcohol syndrome. Phenytoin, carbamazepine and valproate, might be teratogenic because they lower the concentration of all-trans retinoic acid in serum, by inducing the enzyme systems in the liver responsible for the metabolism of the all-trans retinoic acid, or by other mechanisms. Here we show, that in patients given therapeutic doses of phenytoin, carbamazepine and valproate, serum all-trans and 13-cis retinoic acid concentrations are indeed significantly lowered. We propose that drugs with this ability should be considered as potential teratogens.

Keywords: Retinoic acid; Phenytoin; Carbamazepin; Valproate; Teratogenicity

Use of dantrolene in experimental scorpion envenomation by Androctonus Australis Hector by R. Guieu; C. Kopeyan; F. Sampieri; C. Devaux; G. Bechis; H. Rochat (pp. 575-577).

Hyperthermia and profuse perspiration are rarely absent in severe cases of scorpion envenomation. Based on these observations, the aim of this study was to determine the therapeutic effects of dantrolene, on experimental poisoning by the venom of Androctonus australis hector. Dantrolene is a directly acting muscle relaxant which lowers the body temperature in malignant hyperthermia. The results indicate that the early use of this drug raises the LD₅₀ in experimentally poisoned mice. If these results are transposable to humans, dantrolene could be a useful therapeutic adjuvant.

Keywords: Dantrolene; Scorpion envenomation; Hyperthermia

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Archives of Toxicology (v.69, #8)