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REFERENCE LINKING PLATFORM OF KOREA S&T JOURNALS
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Journal DOI :
The Korean Society of Toxicology
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Volume & Issues
Volume 6, Issue 2 - Dec 1990
Volume 6, Issue 1 - Jun 1990
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BEHAVIORAL TERATOGENICITY OF METHAMPHETAMINE
Chin, Kang ; Cho, Dae-Hyun ; Cho, Tae-Soon ;
Toxicological Research, volume 6, issue 2, 1990, Pages 121~130
Pregnant Wister rats were given daily subcutaneous administrations of methamphetamine (MAPT; varying doses ranging from 1.0 to 4.5mg/kg) from days 7 to20 of gestation and teratogenic effects have been determined. The teratogenic effects inducible with orally administered caffeine (90mg/kg/day)for the same durations were used as the positive controls. MAPT doses greater than 2.0 mg/kg have suppressed the rate of maternal weight gain. Some of the offsprings (F1) of the prenatal MAPT treated groups had decreased growth rate and delayed development of physical characters and functional reflexes. The male offsprings of the MAPT treated groups had significant decreases in their spontaneous motor activity but had enhanced conditioned avoidance responses. However, the mating performances of these offsprings were not affected. These results indicated that prenatal exposure of MAPT may induce some behavioral teratogenicity in rats.
SELECTIVE TOXICITY OF CHRONIC LEAD INGESTION TO CENTRAL CATECHOLAMINERGIC NERVOUS SYSTEM IN RATS
Ryu, Jong-Hoon ; Cheong, Jae-Hoon ; Chin, Kang ; Ko, Kwang-Ho ;
Toxicological Research, volume 6, issue 2, 1990, Pages 131~142
The selective toxicity of lead was tested in central catecholaminergic nervous system of postnatally lead exposed rats. Three groups of animals were prepared; 1) rats exposed to low dose of lead (0.05%PbAc); 2) rats exposed to high dose of lead(0.2%PbAc); 3) age-matched normal control rats. At2, 4, 6 and 8 weeks of age brain and body weight gain, and lead concentrations in brain tissues were measured. At the same ages tyrosine hydroxylase and Na-K ATPase activities were measured in the 4 brain areas of each animal. Body weight gain was decreased after 6 weeks of age in rats exposed to high dose of lead. Concentrations of lead in whole brain tissues were increased from 0.37 to 0.83 (ng/mg wet tissue) in these animals. in lead exposed rats, tyrosine hydroxylase activities were higher but Na-K ATPase activities were lower than those of age-matched control animals. Brain areas where tyrosine hydroxylase activities were detected without concomitant changes of Na-K ATPase activities were pons-medulla (2 weeks of age) and telencephalon (6 weeks of age) in rats exposed to low dose of lead, and those in rats exposed to high dose of lead were midbrain (4 and 6 weeks of age). These data indicate that catecholaminergic nervous system in the brain areas described above could selectively be affected by lead.
A STUDY ON POTENTIAL PROTECTIVE ACTIVITIES OF GLUTATHIONE AND CHLORPROMAZINE AGAINST OXYGEN TOXICITY
Lim, Hyun-Sul ; Yun, Dork-Ro ;
Toxicological Research, volume 6, issue 2, 1990, Pages 143~157
Effective measure to prevent oxygen toxicity is greatly required as there increase chances to be exposed to high oxygen pressure, for example, space travel, deep sea diving and hyperbaric oxygen therapy. In the present study, in an attempt to evaluate glutathione and chlorpromazine as protective agents against oxygen toxicity, effects of the agents were tested on various toxicities (death rate, convulsion rate, time to convulsion, increase in weight of lung and brain and pathological changes in the organs) observed in rats exposed to 5 Absolute Atmosphere (ATA) of 100% oxygen for 120 minute. Glutathione reduced mortality rate and convulsion rate and also markedly suppressed the increase in lung and brain weight. The pathological changes observed in these organs were ameliorated by administration of glutathione. Chlorpromazine also reduced mortality rate but its effects appeared to be limited mainly to pulmonary toxicities. Thus glutathione seems to be more effective than chlorpromazine as a protective agent. The results obtained may support that oxygen toxicity is mediated by oxygen free radicals.
HEALTH RISKS POSED BY MYCOTOXINS IN FOODS
Hsieh, D.P.H. ;
Toxicological Research, volume 6, issue 2, 1990, Pages 159~166
The ability of many toxigenic fungi to invade and develop in a wide variety of raw ingredients of human diet renders human exposure to mycotoxing very difficult to avoid. Most of the energy-rich commodities, such as cereal grains, oil seeds, tree nuts, and dehydrated fruits, are susceptible to mycotoxin contamination. Mycotoxins therefare have been recognized as an important class of hazardous substances in the human food chain. Although human exposure to mycotoxins is largely through ingestion, inhalation and skin contact may also be significant under conditions other than consumption of foods. Human ingestion of mycotoxins is due to consumption of contaminated dietary ingredients and the edible tissues and products of domestic animals that have been exposed to mycotoxins in moldy feed. Large scale acute human mycotoxicoses, such as ergotism in France, alimentary toxic aleukia in Russia, yellow rice syndrome in Japan, endemic nephropathy in Balkan countries, and acute aflatoxin poisonings in India and Taiwan, have been well documented, indicating that mycotoxicosis is a global problem. In some incidents, hundreds of victims were killed and many more became seriously ill. The mycotoxins that have been implicated in the etiology of these human diseases include aflatoxins, citreoviridin, cyclopiazonic acid, ergot alkaloids, moniliformin, ochratoxin A, trichothecenes, tenuazonic acid, and zearalenone. Among these, aflatoxins have been also implicated in the etiology of human primary liver cancer in those high-incidence countries in Africa and southeast Asia. It is well recognized that cause-effect relationship between mycotoxins and human diseases is very difficult to establish, especially for the cancer connection. Careful risk assessment must be performed to determine whether a mycotoxin indeed warrants costly regulatory actions.
MODULATION OF TOXICITY AND CARCINOGENESIS BY CALORIC RESTRICTION
Allaben, William T. ; Chou, Ming W. ; Pegram, Rex A. ; Leakey, Julian ; Feuers, Ritchie J. ; Duffy, Peter H. ; Turturro, Angelo ; Hart, Ronald W. ;
Toxicological Research, volume 6, issue 2, 1990, Pages 167~182
Dietary restriction (caloric restriction) is the only intervention which has been reliably shown to extend the maximum life span of warm-blooded animals and delay the many phenomena associated with aging. It is also one of the most effective modulators of toxicity, especially cancer endpoints. In spite of the known modulator effects of caloric restriction, the biological mechanisms responsible for these effects had not been in vestigated until recently. The National Center for Toxicological Research (NCTR), in a collaborative effort with the National Institute of Aging (NIA), initiated a project whereby nine (9) combinations of rodent species/strains and diets were fed both restricted and ad libitum. The NIA's initiative was to identify biomarkers of aging whereas NCTR's initiative was to identify the biological effects associated with the profound effects caloric restriction has in protecting against both spontaneous (age-related) and chemically-induced toxic endpoints. Independent of sex or species, caloric restriction has similar effects on body temperature, oxygen consumption and
production. Caloric restriction also decreased lipid glycolysis and metabolism in rats and mice, which suggest decreased production of metabolites which could lead to fatty acid epoxide formation. The age-associated loss of ciradian regulation of intermediate enzymes is also significantly reduced. Moreover, caloric restriction reduced the age-associated feminization of sexually dimorphic liver isozymes, increased several glucocorticoid responsive isozymes, elevated glucagon/insulin ratios, produced less microsomal superoxide and enhanced the capacity for utilzing detoxicating metabolic pathways. Calorically restricted rats have less than half the number of aflatoxin (
)-DNA adducts than ad libitum animals and urinary excretion of
was increased significantly. Finally, DNA repair mechanisms are enhanced and oncogene expression is decreased in calorically restricted animals.
THE CARCINOGENIC POTENTIAL OF CADMIUM ARSENIC AND SELENIUM AND THE ASSOCIATED PUBLIC HEALTH AND REGULATORY IMPLICATIONS
Fan, Anna M. ;
Toxicological Research, volume 6, issue 2, 1990, Pages 183~190
NEUROTOXICITY OF TRIMETHYLTIN IN HIPPOCAMPUS: A HYPEREXCITATORY TOXICITY
Chang, Louis W. ;
Toxicological Research, volume 6, issue 2, 1990, Pages 191~204
Trimethyltin (TMT) induced lesions in the rat hippocampal formation was reviewed. Adult rats were treated with a single dose of 6.0 mg TMT/kg b.w. and were sacrificed between 3-60 days following exposure. On the hippocampal formation, the granule cells of fascia dentata showed early changes which subsided considerably at a later time when the destruction of the pyramidal neurons of the Ammon's horn became increasingly pronounced with time, leading to severe destruction of the structure. It is interesting to note that there was an inverse relationship of pathological involvement between the f.d. granule cells and the Ammon's horn neurons; i.e., when there was a large sparing of the granule cells. there was an extensive damage to the Ammon's horn and vice versa. This inverse relationship was also true between the
neurons and the
neurons in the Ammon's horn. Progressive zinc loss, as demonstrated by Timm's method, on the Mossy fibers was also observed. Similar Mossy fiber zinc depletion has been demonstrated in electrical stimulatory excitation condition of the perforant path to the hippocampus. Depletion of corticosterone, an inhibitor to the hippocampal neurons, by means of adrenalectomy will exaggerate the TMT induced hippocampal lesion. Neonatal study revealed that a unique degenerative pattern of the Ammon's horn could be established in accordance with exposure to TMT at specific maturation periods of the fippocampal formation: increasing destruction of the Ammon's horn with increasing synaptogenesis between the f.d. granule cells and the Ammon's horn neurons. Thus it is apparent that the damage of the Ammon's horn, upon exposure to TMT, may depend on the integrity and functional state of the f.d. granule cells. A hyperexcitory scheme and mechanism as the toxicity basis of TMT in the hippocampal formation is proposed and discussed.
BIOLOGICALLY-BASED DOSE-RESPONSE MODEL FOR NEUROTOXICITY RISK ASSESSMENT
Slikker, William Jr. ; Gaylor, David W. ;
Toxicological Research, volume 6, issue 2, 1990, Pages 205~213
The regulation of neurotoxicants has usually been based upon setting reference doses by dividing a no observed adverse effect level (NOAEL) by uncertainty factors that theoretically account for interspecies and intraspecies extraploation of experimental results in animals to humans. Recently, we have proposed a four-step alternative procedure which provides quantitative estimates of risk as a function of dose. The first step is to establish a mathematical relationship between a biological effect or biomarker and the dose of chemical administered. The second step is to determine the distribution (variability) of individual measurements of biological effects or their biomarkers about the dose response curve. The third step is to define an adverse or abnormal level of a biological effect or biomarker in an untreated population. The fourth and final step is to combine the information from the first three steps to estimate the risk (proportion of individuals exceeding on adverse or abnormal level of a biological effect or biomarker) as a function of dose. The primary purpose of this report is to enhance the certainty of the first step of this procedure by improving our understanding of the relationship between a biomarker and dose of administered chemical. Several factors which need to be considered include: 1) the pharmacokinetics of the parent chemical, 2) the target tissue concentrations of the parent chemical or its bioactivated proximate toxicant, 3) the uptake kinetics of the parent chemical or metabolite into the target cell(s) and/or membrane interactions, and 4) the interaction of the chemical or metabolite with presumed receptor site(s). Because these theoretical factors each contain a saturable step due to definitive amounts of required enzyme, reuptake or receptor site(s), a nonlinear, saturable dose-response curve would be predicted. In order to exemplify this process, effects of the neurotoxicant, methlenedioxymethamphetamine (MDMA), were reviewed and analyzed. Our results and those of others indicate that: 1) peak concentrations of MDMA and metabolites are ochieved in rat brain by 30 min and are negligible by 24 hr, 2) a metabolite of MDMA is probably responsible for its neurotoxic effects, and 3) pretreatment with monoamine uptake blockers prevents MDMA neurotoxicity. When data generated from rats administerde MDMA were plotted as bilolgical effect (decreases in hippocampal serotonin concentrations) versus dose, a saturation curve best described the observed relationship. These results support the hypothesis that at least one saturable step is involved in MDMA neurotoxicity. We conclude that the mathematical relationship between biological effect and dose of MDMA, the first step of our quantitative neurotoxicity risk assessment procedure, should reflect this biological model information generated from the whole of the dose-response curve.
U.S. AIR FORCE BASIC RESEARCH IN BIOENVIRONMENTAL HAZARDS
Cerveny, T.Jan ;
Toxicological Research, volume 6, issue 2, 1990, Pages 215~219