Check out our New Publishers' Select for Free Articles

Archives of Toxicology (v.72, #2)

The influence of calcium content in diet on cumulation and toxicity of cadmium in the organism Review by Malgorzata M. Brzóska; Janina Moniuszko-Jakoniuk (pp. 63-73).

Voluminous literature data show that great interdependence exists between the nutrition status of the organism and the degree of accumulation and toxicity of heavy metals. In this work, the connection between dietary calcium and cadmium toxicity is discussed from the toxicological point of view. Cadmium is one of the most dangerous occupational and environmental poisons. The intake of diet containing an inappropriate amount of calcium causes increased absorption of cadmium from the gastrointestinal tract and increased accumulation of this metal in the organism, finally leading to enhancement of cadmium toxic action. The large intake of calcium protects against absorption, cumulation and toxicity of this heavy metal. Interactions between calcium and cadmium may take place at different stages of their metabolism (absorption, distribution in the organism, elimination) and cadmium may interfere with the biological functions of Ca²⁺ ions.

Keywords: Key words Calcium; Cadmium; Absorption; Cumulation; Toxicity

Effects of photoisomers of cyclodiene insecticides on liver and microsomal cytochrome P450 in rats by M. A. Q. Khan; L. V. Jovanovich; L. T. Martin; S. Y. Qadri; A. A. Podowski (pp. 74-83).

Threshold dosages of the photoisomers of cyclodiene insecticides, namely photochlordane, photodieldrin, and photoheptachlor, for the induction of hepatic microsomal cytochrome P450 (P450) and liver hypertrophy in male rats were at least one-quarter of those reported for corresponding parent cyclodienes. Maximum increase in total P450 concentration (30%) and demethylases activities (100%) was always respectively one-third or one-tenth of that reported for parent cyclodienes. The P450 isozymic form induced by photoheptachlor resembled that induced by pentobarbital (P4502B1) in its substrate specificity, spectral characteristics, and electrophoretic mobility. The induction of P450 was initially followed by hepatic hypertrophy. However, higher dosages of photoisomers caused wasting and lowered both the liver weight and the activity of aniline hydroxylase while those of mirex and endrin, which also caused wasting and lowered aniline hydroxylase activity, continued causing further hepatic hypertrophy.

Keywords: Key words Cyclodiene photoisomers; Liver weight; Cytochrome P450 induction

Nerve agent poisoning in primates: antilethal, anti-epileptic and neuroprotective effects of GK-11 by G. Lallement; Didier Clarençon; Catherine Masqueliez; Dominique Baubichon; Monique Galonnier; Marie-France Burckhart; Michel Peoc’h; Jean Claude Mestries (pp. 84-92).

Organophosphorus nerve agents are still in use today in warfare and as terrorism compounds. Classical emergency treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, recent experiments with primates have demonstrated that such treatment, even when administered immediately after organophosphate exposure, does not rapidly restore normal electroencephalographic (EEG) activity and fails to totally prevent neuronal brain damage. The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the available emergency therapy against organophosphate poisoning. GK-11 was injected at a dose of 0.1 mg/kg (i.v) after a 45-min latency period to heavily intoxicated (8 LD₅₀) primates. Just after intoxication, man-equivalent doses of one autoinjector containing atropine/pralidoxime/diazepam were administered. The effects of GK-11 were examined on survival, EEG activity, signs of toxicity, recovery after challenge and central nervous system histology. The present data demonstrate that treatment with GK-11 prevents the mortality observed after early administration of classical emergency medication alone. EEG recordings and clinical observations also revealed that GK-11 prevented soman-induced seizures and motor convulsions. EEG analysis within the classical frequency bands (beta, theta, alpha, delta) demonstrated that central activity was totally restored to normal after GK-11 treatment, but remained profoundly altered in animals receiving atropine/pralidoxime/diazepam alone. GK-11 also markedly accelerated clinical recovery of soman-challenged primates. Lastly, this drug totally prevented the neuropathology observed 3 weeks after soman exposure in animals treated with classical emergency treatment alone. GK-11 represents a promising adjuvant therapy to the currently available emergency polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication.

Keywords: Key words Organophosphate poisoning; Seizures; Neuropathology; Gacyclidine; Primates

Repeated low doses of O-(2-chloro-2,3,3 trifluorocyclobutyl) O-ethyl S-propyl phosphorothioate (KBR-2822) do not cause neuropathy in hens by M. Jokanovic; A. Moretto; M. Lotti (pp. 93-96).

Certain esterase inhibitors such as O-(2-chlo-ro-2,3,3-trifluorocyclobutyl) O-ethyl S-propyl phosphorothioate (KBR-2822) and phenylmethanesulfonyl fluoride (PMSF) cause exacerbation (promotion) of toxic and traumatic axonopathies. Although these chemicals are capable of inhibiting neuropathy target esterase (NTE), which is the target for organophosphate induced delayed neuropathy, the target for promotion is unlikely to be NTE. Experiments were aimed to ascertain if neuropathy is caused by repeated dosing with a promoter not causing NTE inhibition and in the absence of deliberate injury to axons. Hens were treated with KBR-2822 (0.2 or 0.4 mg/kg per day) by gavage for 90 days and observed for clinical signs up to 21–23 days after treatment when histopathological examination was carried out. NTE and acetylcholinesterase (AChE) were measured at intervals and mean percentages of inhibition at steady state of inhibition/resynthesis (on day 20) were as follows: mean inhibition NTE was ≤8% in the 0.2 mg/kg group and between 15 and 18% in the 0.4 mg/kg group in brain, spinal cord and peripheral nerve; mean AChE inhibition in brain was 31 and 57% in the two experimental groups, respectively. Controls treated with paraoxon (not neuropathic or a promoter and given at 0.05 mg/kg per day by gavage) showed 45% mean AChE inhibition and no NTE inhibition. Neither clinical nor morphological signs of neuropathy were observed in any group. To ascertain whether sub-clinical lesions were produced by the repeated treatment with KBR-2822, hens were given KBR-2822 (0.2 mg/kg per day) for 21 days by gavage followed by PMSF (120 mg/kg s.c. 24 h after the last dose of KBR-2822). A control group of hens was treated with the neuropathic DFP (0.03 mg/kg s.c. daily for 21 days causing 40–50% NTE inhibition) followed by PMSF (120 mg/kg s.c.). After PMSF, the KBR-2822 treated hens did not develop neuropathy whereas DFP treated hens did. Lack of neuropathy after repeated treatment with KBR-2822 indicates that a continuous promoting `pressure' on hen axons is harmless in the absence of a concurrent biochemical or neurotoxic injury.

Keywords: Key words Neuropathy; Promotion; Organophosphate-induced delayed polyneuropathy (OPIDP); Neuropathy target esterase (NTE)

Hepatotoxicity of brominated benzenes: relationship between chemical structure and hepatotoxic effects in acute intoxication of mice by Jadwiga A. Szymańska (pp. 97-103).

Brominated benzenes appear in the environment and human tissues. Their detection in the environment may be as a result of their usage, e.g. hexabromobenzene (HBB), and as products of HBB degradation or metabolism. The aim of this study was to compare liver impairment in acute intoxication of mice with bromobenzene (BB), 1,2,4-tribromobenzene (1,2, 4-triBB), 1,3,5-tribromobenzene (1,3,5-triBB), 1,2,4,5-tetrabromobenzene (1,2,4,5-tetraBB) and hexabromobenzene (HBB). The data for these compounds were compared with the data obtained for dibromobenzenes (1,2-dBB, 1,3-dBB, 1,4-dBB). Male Balbc mice were administered the investigated compounds in single, intraperitoneal doses equal to 20–90% of the approximate lethal dose (ALD). Acute toxicity of bromobenzenes decreases with the increase of the number of bromine atoms in the molecule. All examined compounds decreased the liver glutathione (GSH) level in a short time following administration. Later in the experiment, GSH either returned to control values or the concentration increased. Changes in alanine aminotransferase (ALT) activity in mice serum depended on the type of compound and the time of observation. BB, 1,2-dBB, 1,3-dBB and 1,2,4-triBB caused statistically significant increases (30- to 120-fold) in ALT activity. For the remaining compounds these changes were not significant being two- to threefold. Histopathological examination demonstrated that BB, 1,2-dBB, 1,3-dBB and 1,2,4-triBB resulted in coagulative or haemorrhagic necrosis in the liver central lobular zone. All investigated compounds resulted in the increase of gamma-glutamyltransferase activity in serum and malondialdehyde concentration in liver. Octanol water partition coefficient (expressed as log P) and molecular volume (log V) were calculated for all examined compounds. With the increase of lipophilicity and molecule size, the ability of the examined compounds to decrease the level of GSH in mice liver and increase ALT activity in the serum diminishes.

Keywords: Key words Brominated benzenes; Hepatotoxicity; Mice

Urinary biomarkers monitoring for experimental fluoride nephrotoxicity by Kan Usuda; Koichi Kono; Tomotaro Dote; Kimio Nishiura; Kaori Miyata; Hiroyuki Nishiura; Masashi Shimahara; Katsuichi Sugimoto (pp. 104-109).

An excess of sodium fluoride (135 mg F/kg body weight) was given in a single oral dose to male Wistar rats. Effects were investigated of fluoride-induced acute kidney intoxication on the time-dependent variations of urine volume. Also, of urinary fluoride ion (F⁻), α-glutathione-S-transferase (α-GST), N-acetyl-β-d-glucosaminidase (NAG), and creatinine (CR) concentrations. Fluoride administration strongly affects these urinary biochemical indices. Of the several biomarkers studied, α-GST is particularly useful as marker of S3 proximal tubule damage. We found that α-GST shows the strongest and more durable changes as a result of the large dose of F⁻ given to the experimental animals. Our results suggest that the toxic effect of F⁻ on the kidney may be more pronounced in the proximal tubule than the glomeruli region, and that the disorder of the proximal tubule is more serious in the S3 segment than S1 or S2 segment. α-GST proved to be a useful marker for the early detection and long-term observation of proximal renal tubular injury resulting from F⁻ intoxication. The animal model should help to establish guidelines for the treatment of industrial workers suffering from acute renal failure resulting from accidental exposure to fluoride.

Keywords: Key words Fluoride; Acute renal failure; α-Glutathione-S-transferase; N-acetyl-β-d-; glucosaminidase; Creatinine

Intestinal absorption of aluminium: effect of sodium and calcium by G. B. van der Voet; F. A. de Wolff (pp. 110-114).

Aluminium (Al) is recognized as a toxin in patients with deficient renal function. Moreover, Al may play a role in some neurodegenerative diseases. It is hypothesized that more than one intestinal absorption mechanism exists for Al, related to various intraluminal chemical species, and that Al shares intestinal transport routes for essential inorganic substances due to similarities in their chemical speciation characteristics. The purpose of the present investigation was to study the ef-fects of ionic Na (0–120 mmol/l) and Ca (0–10 mmol/l), alone and in combination, on the intestinal absorption of ionic Al (20 and 30 mmol/l). A previously standardized method of perfusion of rat small intestine was used, combined with serial blood sampling. Mucosal uptake and systemic appearance of Al in the blood were monitored during 1 h perfusion, together with Na and Ca; the metals were given as the chloride. The intestinal absorption of Na and Ca was taking place according to previously reported mechanisms. A one-sided negative interaction was shown to exist between Ca and Al resp. Al and Na during both mucosal uptake and systemic appearance; Ca interacts negatively with Na during systemic appearance, but enhances mucosal uptake of Na. It may be speculated that Al mimicks Ca in its Na-dependent intestinal passage.

Keywords: Key words Aluminium; Sodium; Calcium; Intestinal absorption; Transport mechanism

Ultrastructural changes in motor endplates of the lumbrical muscles of rats induced by a microsomal Ca2+ ATPase inhibitor, 2,5-di(tert-butyl)-1,4-hydroquinone by Kunitoshi Mitsumori; Takayoshi Imazawa; Hiroshi Onodera; Michihito Takahashi; Satoshi Kitajima; Tohru Inoue; Yuji Kurokawa (pp. 115-118).

Female Wistar rats were treated orally for 5 days with 80 mg/kg body weight of 2,5-di(tert-butyl)-1,4-hydroquinone (DTBHQ), a microsomal Ca²⁺ ATPase inhibitor. Motor endplates of the lumbrical muscles were examined by light and electron microscopy. There was a decrease in body weight in the treated rats from the first day after administration, and toxic signs appeared after the third day, such as adoption of a prone position, salivation, lacrymation, and an abnormal gait and/or muscle weakness. No remarkable macroscopic or light microscopic changes were noted in the lumbrical muscles as well as other peripheral nerves of hind legs of the treated rats killed 1 day after the last DTBHQ treatment. Ultrastructurally, neurotoxicity characterized by loss of synaptic vesicles and mitochondria in the motor endplates, and by destruction of the motor terminals was detected in the lumbrical muscles of the treated rats. These results strongly indicate that DTBHQ targets the motor endplates in the rat lumbrical muscles and suggest that the resultant damage is responsible for the appearance of neurological signs, such as an abnormal gait and loss of muscle control.

Keywords: Key words 2; 5-di(tert-butyl)-1; 4-Hydroquinone; Ca2+ ATPase inhibitor; Neurotoxicity; Ultrastructure; Motor endplate

S-p -Toluylmercapturic acid in the urine of workers exposed to toluene: a new biomarker for toluene exposure by J. Angerer; M. Schildbach; A. Krämer (pp. 119-123).

A mercapturic acid attached to the aromatic ring of toluene was for the first time detected in human urine as a metabolite of toluene. Since the metabolism of toluene is usually considered to take place at the side-chain, this gives, besides the biosynthesis of cresols, a further hint of a metabolic conversion of the aromatic system. We examined a group of 33 workers occupationally exposed to toluene, determining the concentrations of toluene in ambient air and in whole blood, o-cresol and hippuric acid in urine and p-toluylmercapturic acid (p-TMA) in urine. All blood and urine samples were collected post-shift. The renal excretion of S-p-toluylmercapturic acid showed highly significant correlations with established parameters of a biological monitoring of toluene. The median ambient air concentration was 63 ppm, ranging from 13 to 151 ppm, the median concentration of toluene in whole blood was 804 μg/l, corresponding to median urinary concentrations for o-cresol of 2.3 mg/l, hippuric acid of 2.3 g/l and p-TMA of 20.4 μg/l. p-TMA was not detectable in urine samples of a control group of 10 non-exposed persons. Both the German Biological Tolerance Values (BAT-values) for toluene in blood (1000 μg/l) and o-cresol in urine (3 mg/l) correspond to a mean p-TMA elimination of ∼50 g/l, and thus are in agreement with each other. According to our results p-TMA reflects internal toluene exposure diagnostically sensitive and specifical. With the developed analytical procedure we determined a median benzylmercapturic acid (BMA) concentration of 190 μg/l in the urine samples of the toluene exposed persons. We also determined a median BMA concentration of 30 μg/l in the control samples of non-exposed persons. However, these results are preliminary and require further confirmation as the reliability of the method was determined only for p-TMA.

Keywords: Key words Biological monitoring; Mercapturic acids; Toluene metabolism; S-p-Toluylmercapturic acid; o-Cresol

Sections

Personal tools

Archives of Toxicology (v.72, #2)

Sections

Personal tools

Local resources

Archives of Toxicology (v.72, #2)