Abstracts of Current Literature in Toxicology

Banu BS., Danadevi K., Jamil K., Ahuja YR., Rao KV., Ishaq M (Department of Genetics, Osmania University, Hyderabad, Andhra Pradesh, India): In vivo genotoxic effect of arsenic trioxide in mice using comet assay. Toxicology, 162(3), 2001, 171-177. [30 Ref]

Although arsenic has been the subject of toxicological research, acute in vivo genotoxic studies using relevant animals models and uniform methodology are lacking. Hence, the present study aims to study DNA damage caused by arsenic trioxide in mice in in vivo using alkaline single cell gel electrophoresis (Comet) assay. Mice were administered orally 0, 0.13, 0.27, 0.54, 1.08, 2.15, 4.3 and 6.45 mg/kg body weight of arsenic trioxide dissolved in distilled water. The samples of whole blood were collected at 24, 48, 72 h, first and second week post-treatment and the assay was carried out to determine DNA damage as represented by comet tail-length. All the doses induced significant increase in comet tail-length at 24 h post-treatment (P<0.05) showing a clear dose dependent increase from 0.13 to 2.15 mg/kg b.wt. and a dose dependent decrease in higher doses (4.3-6.45 mg/kg b.wt.). At 48 h post-treatment, all the doses showed a significant increase (P<0.05) in comet tail-length when compared to 24 h post-treatment. A gradual decrease in the comet tail-length was observed for all the doses from 72 h post-treatment onwards indicating a gradual repair in DNA damage. This indicates a non-linear dose and time response between DNA damage and different doses of arsenic trioxide at different time-intervals. A significant increase in comet tail-length at all the doses clearly gives evidence that arsenic trioxide cause DNA damage effectively. The study indicates that the alkaline comet assay is a reliable and effective method to detect DNA damage caused by metals.

Campbell A., Hamai D., Bondy SC* (Department of Community and Environmental Medicine, Center for Occupational and Environmental Health, University of California, Irvine, CA 92697-1820, USA): Differential toxicity of aluminum salts in human cell lines of neural origin: implications for neuro-degeneration. Neurotoxicol, 22(1), 2001, 63-71. [28 Ref]

Aluminum is highly oxophilic and its minerals are sually found surrouded by six-oxygen atoms. A role for the metal has been established in dialysis encephalopathy and Al-induced osteomalacia. The metal has been implicated in Alzheimer's disease but the issue is at present controversial. Human cell lines of neural origin were utilized to study the effect of lipophilic aluminum acetylacetonate and non-lipophilic aluminum sulfate on cell proliferation and viability. Although analysis of Al species in the cell culture media demonstrated that there are positively charged Al species present in solutions prepared with both Al salts, only the aluminum acetylacetonate salt caused changes in cell proliferation and viability. Therefore, the lipophilic nature of the organic Al salt is a critical determinant of toxicity. The effect of aluminum acetylacetonate was dose-dependent and time-dependent. Neuroblastoma (SK-N-SH) cells were more susceptible to decreased cell proliferation although the lipophilic Al salt was more toxic to the glioblastoma (T98G) cells. While the toxicity of aluminum acetylacetonate was inhibited in the T98G cells by the addition of phosphate, the same treatment did not reverse cell death in the SK-N-SH cells. Thus, the mechanism of Al toxicity appears to be different in the two cell lines. It is possible that the principal neurotoxic target of the metal is glial and when these cells are in a compromised state, this may secondarily impact the neuronal population and thus eventually lead to neuro-degeneration.

Won YK., Liu J., Olivier K., Zheng Q., Pope CN (College of Veterinary Medicine, Oklahoma State University, 264 McElroy Hall, Stillwater, OK 74078, USA): Age-related effects of chlorpyrifos on acetylcholine release in rat brain. Neurotoxicol, 22(1), 2001, 39-48. [56 Ref]

Chlorpyrifos (CPF) is an organophosphorus insecticide that elicits toxicity through inhibition of acetylcholinesterase (AChE). Young animals are markedly more sensitive than adults to the acute toxicity of CPF. We evaluated acetylcholine (ACh) release and its muscarinic receptor-mediated regulation (i.e. muscarinic autoreceptor function, MAF) during maturation as a possible contributing factor to age-related differences in sensitivity. Cortical and striatal slices were prelabeled with [3H]choline chloride, superfused in the presence or absence of the anticholinesterase physostigmine (PHY, 20 uM) and stimulated twice (S1 and S2} with a high concentration of potassium chloride (20 mM). Depolarization-stimulated ACh release (DSAR) was lowest in neonatal intermediate in juvenile and markedly higher in adult tissues. MAF was not detectable in tissue from neonatal rats but was present in juvenile and adult tissues. ACh release and MAF were studied at 4, 24 and 96 h following oral exposure to CPF (0, 0.5 or 1xLD10). In general, 40-60% and 80-90% maximal AChE inhibition followed exposure to the respective 0.5 and 1xLD10 dosages. DSAR was decreased in neonatal cortex 1 day after LD10 exposure but increased in juvenile striatum 1 day after LD10 treatment. In adults, DSAR was reduced at 4 and 24 h after exposure, but increased 96 h after CPF exposure. In juveniles, MAF was reduced in both brain regions at 24h after 0.5LD10 exposure and at 24 and 96 h after LD10 exposure in cortex. A later reduction in MAF was noted in adult tissues (i.e. only at 96h after LD10 treatment). Together, the results suggest that ACh release dynamics in brain vary markedly during postnatal maturation and that acute CPF exposure can alter ACh release in an age-related manner. The functional status of presynaptic processes regulating neurotransmitter release may contribute to age-related neurotoxicity elicited by high-dose exposure to chlorpyrifos.

Manzo L., Castoldi AF., Coccini T., Prockop LD (Toxicology Division, University of Pavia, Foundation IRCCS, Institute of Pavia, Pavia 27100, Italy): Assessing effects of neurotoxic pollutants by biochemical markers. Environ Res Sec. A, 85(1), 2001, 31-36. [48 Ref]

Nuerotoxins cause biochemical and molecular events which indicate early stage effects in exposed persons well before or well below the induction of overt disease. Monitoring these early events may represent a valid approach to developing markers of neurotoxicity in individuals exposed to environmental chemicals. In neurotoxicology, the use of biochemical markers is more problematic compared to other fields due to the complexity of central nervous system function, the multistage nature of neurotoxic events, and the inaccessibility of target tissue. Neverthless, new biochemical assays have been developed in recent years to assess exposure, subclinical effects, and susceptibility to neurotoxic disorders. This paper reviews novel biomarkers of neurotoxicity and discusses perspectives and limitation of their use in occupational and environmental medicine.

Jelks K., Berger T., Horner C., Miller MG (Department of Environmental Toxicology, University of California Davis, Davis, CA95616, USA): a-Chlorohydrin induced changes in sperm fertilizing ability in the rat: association with diminished sperm ATP levels and motility. Rep Toxicol, 15(1), 2001, 11-20. [37 Ref]

In the present study, a-chlorohydrin (ACH) (5,10,25,50 and 75 mg/kg. po) was administered to rats and the effect on sperm ATP levels, sperm motility, and the ability of sperm to bind and penetrate rat oocytess were determined. Groups of rats were killed 5 days and 3 h following treatment. At both time points, sperm from ACH-treated rats (>- 10 mg/kg) had significantly lower levels of ATP when diluted in media containing glucose. No diminution of ATP was seen in sperm diluted in phosphate-buffered saline (PBS). Computer analysis of sperm motility indicated that straight-line velocity (VSL) was the most sensitive parameter to ACH treatment and was significantly decreased in rat sperm three hours after ACH exposure (25 mg/kg). A clear drop in percent penetration (35% vs, 85% in control) of zona-free rat oocytes by rat sperm of both ACH groups was observed at 10 mg/kg. Higher dose levels produced no significant further decrease in percent penetration. Overall, the fertilizing ability of sperm was highly sensitive to ACH doses that caused minor but significant changes in sperm ATP levels and no significant changes in motility. These data are consistent with the spermatozoan's need for an uncompromised energy supply to maintain its ability to bind and penetrate the oocyte.

Christiani DC., Sharp RR., Collman GW., Suk WA (Occupational Health Program, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA): Applying genomic technologies in environmental health research: Challenges and opportunities. J Occup Environ Med, 43(6), 2001, 526-532. [20 Ref]

Recent discoveries in molecular biology and genetics have made it possible for environmental health researchers to examine how genetic characteristics affect response to environmental exposures. Understanding such gene-environment interactions offers exciting possibilities for the prevention and control of environmentally induced diseases. Despite these potential benefits, the collection and analysis of genetic information in environmental health research presents many of the same ethical, legal, and social (ELSI) challenges found in other types of genetic research. In this article, we describe a number of ELSI challenges in environmental genomic research and the apportunities and responsibilities that accompany this research.

Frumkin H., Letz R., Williams PL., Gerr F., Pierce M., Sanders A., Elon L., Manning CC., Woods JS., Herzberg VS., Mueller P., Taylor BB (Department of Environmental and Occupational Health, Rollins School of Public Health of Emory University, 1518 Clitton Road, Atlanta GA 30322, USA): Health effects of long-term mercury exposure among chlorakali plant workers. Am J Ind Med, 39(1), 2001, 1-18. [80 Ref]

Inorganic mercury is toxic to the nervous system, kidneys, and reproductive system. We studied the health effects of mercury exposure among former employeews of a chloralkali plant that operated from 1955 to 1994 in Georgia. Former plant workers and unexposed workers from nearby employers were studied. Exposure was assessed with a job-exosure matrix based on historical measurements and personal records. Health outcomes were assessed with interviews, physical examinations, neurological and neurobehavioral testing, renal function testing, and urinary porphyrin measurements. Exposure-disease association were assessed with multivariate modeling. Exposed workers reported more symptoms, and tended toward more physical examination abnormalities, than unexposed workers. Exposed workers performed worse than unexposed subjects on some quantitative tests of vibration sense, motor speed and coordination, and tremor, and on one test of cognitive function. Few findings remained significant when exposure was modeled as a continuous variable. Neither renal function nor porphyrin excretion was associated with mercury exposure. Mercury-exposed chloralkali plant workers reported more symptoms than unexposed controls, but no strong associations were demonstrated with neurological or renal function or with porphyrin excretion.

Singh AK., Varma NK., Ahmad I., Sahay N., Singh RP (Central Mining Research Institute, Dhanbad, Bihar, India): Environmental health hazards in coal mines with sapecial reference to radioactivity and its control-A review. Crit Rev Environ Sci technol, 31(1), 2001, 63-77. [17 Ref]

The development of a country depends very much on the advancement of its industrialization. However, as a result of mass scale industrialization, the world's environment is being polluted day by day and endangering the existence of living beings on Earth. This has attracted the attention of environmental engineers, medical practioners, planners, and researchers throughout the world. Attempts are being made to make air, water, and the atmosphere clean and to prevent likely hazards arising out of various industrial activities. In addition, radiation from natural sources is all around us and has been from the advent of time. It is responsible for the radiation exposure of most of the population. Coal miners have small occupational exposures that arise from naturally occurring radioactive substances under ground. The predominant source of natural radiation present in coal mines is radon gas. This article describes the origin of radon, radiological hazard, and an attempt has been made to review the tatus of the problem likely to be caused by the different radioactive elements present in Indian coal and coal ash and allied coal-based industries.

Pande M., Mehta A., Pant BP., Flora SJS (Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474002, India): Combined administration of a chelating agent and an antioxidant in the prevention and treatment of acute lead intoxication in rats. Environ Toxicol Pharmacol, 9(4), 2001, 173-184. [43 Ref]

The administration of chelating agents, meso 2,3-dimercaptosuccinic acid (DMSA, monoisoamyl DMSA (MiADMSA) either individually or in combination with an antioxidant, n-acetylcystein (NAC) in the prevention and treatment of acute lead intoxication in rats, was investigated. The results suggest that concomitant oral supplementation of DMSA with lead was most effective in preventing the inhibition of lead sensitive blood d-aminolevulinic acid dehydratase (ALAD) activity in blood, elevation of zinc protoporphyrin level and the alterations in hepatic reduced and oxidized glutathione (GSH and GSSG) contents. A number of other biochemical variables eitehr remained insensitve to lead exposure or responded moderately to chelation treatment. Combined administrations of NAC plus DMSA was most effective when given during lead exposure to post exposure, followed by DMSA and MiADMSA alone or NAC plus MiADMSA treatment, in reducing the accumulation of lead in blood and liver. Administration of NAC alone was only mildy effective in preventing lead absorption in the blood and tissues. The results suggest that combined administration of DMSA and NAC could be a more effective treatment protocol for acute lead toxicity, keeping in view its beneficial effect on oxidative injury.

Abu-Qare AW., Abou-Donia MB (Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA): Simultaneous determination of chlorpyrifos, permethrin, and their metabolites in rat plasma and urine by high-performance liquid chromatography. J Anal Toxicol, 25(4), 2001, 275-279, 19 Ref.

A high-performance liquid chromato-graphic  (HPLC) method was developed for the separation and quantification of the insecticide chlorpyrifos  (O,O-diethyl-O[3,5,6-trichloro2-pyridinyl]  phosphoro-thioate)  its  metabolites chlorpyrifos-oxon  (O,O-diethyl  O[3,5,6- trichloro-2-pyridinyl] phosphate) and TCP (3,5,6-trichloro2- pyridinol), the insecticide permethrin (3-(2,2-dichlro-ethenyl)-2, 2-dimethyl- cyclopropanecarboxylic  acid  -(3-phenoxyphenyl) methylester),  and two of its metabolites, in phenoxybenzyl alcohol and m-phenoxybenzoic acid, in rat plasma and urine. The method is based on using C18 Sep-Pak cartridges for solid-phase extraction and reversed-phase HPLC. The compounds were separated using a gradient of 1 to 80% acetonitrile in water (pH 3.2) at a flow rate ranging between 1 and 1.5 mL/min in period of 17 min and gradient UV detection ranging between 210 and 280 nm. The retention times ranged from 9.3 to 14.5 min. The limits of detection ranged between 20 and 150 ng/mL, whereas the limits of quantitation were 150-200 ng/mL. The respective average percentage recoveries of chlorpyrifos, chlor-pyrifos-oxon, TCP, permethrin, m-phenoxybenzyl alcohol, and m-phenoxy-benzoic were 78.66.4, 72.86.8, 84.88.0, 79.28.4, 80.57.2, and 82.37.1 from five spiked plasma samples and 77.58.1, 72.88.3,  79.96.4, 79.18.9,  80.57.6,  and  81.47.8 from urine samples. The relationship between peak areas and concentration was linear for concentrations between 200 and 2000 ng/ml. This method was used to analyze these chemicals and metabolites following dermal administration in rats.



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