Title: Toxicologic Pathology

Title: Toxicology

ISO Abbreviated Title: Toxicology

JCR Abbreviated Title: Toxicology

ISSN: 0300-483X

Issues/Year: 18

Journal Country/Territory: Netherlands

Language: English

Publisher: Elsevier Sci Ireland Ltd

Publisher Address: Customer Relations Manager, Bay 15, Shannon Industrial Estate Co, Clare, IR

Subject Categories:

Pharmacology & Pharmacy: Impact Factor 2.584, 58/193 (2005)

Toxicology: Impact Factor 2.584, 13/75 (2005)

Yang, R.S. and Rauckman, E.J. (1987), Toxicological studies of chemical mixtures of environmental concern at the National Toxicology Program: Health effects of groundwater contaminants. Toxicology, 47 (1-2), 15-34.

Full Text: T\Toxicology47, 15.pdf

Abstract: In cooperation with the Agency for Toxic Substances and Disease Registry, the National Toxicology Program is participating in a Public Health Service activity related to the Comprehensive Environmental Response, Compensation and Liability Act (Superfund Act) by conducting toxicology studies on chemicals found in high-priority hazardous waste sites and for which adequate toxicological data are not available. As part of this effort, a project on the toxicology of chemical mixtures of groundwater contaminants was initiated. The first study, centered on the health effects of groundwater contaminants, is at the contractual stage. Nineteen organic and six inorganic chemicals, selected from more than 1000 known groundwater contaminants, will be given in drinking water to Fischer 344 rats and B6C3F1 mice for 3 or 6 months. Controls and five dose levels, based on average concentrations (i.e., baseline level) of individual component chemicals, or 0.1-, 10-, or 1000-fold of the baseline level, will be used. Toxicological end points include mortality, clinical signs, water and food consumption, body and organ weights, clinical pathology analytes (e.g., hematology, clinical chemistry, and urinalysis), gross and histopathology, neurobehavioral tests, sperm morphology and vaginal cytology evaluations (SMVCE), and cytogenetics. This paper summarizes the rationale behind our experimental design and the factors one must consider when designing studies of complex chemical mixtures.

Liimatainen, A., Müller, D., Vartiainen, T., Jahn, F., Kleeberg, U., Klinger, W. and Hänninen, O. (1988), Chlorinated drinking water is mutagenic and causes 3-methylcholanthrene type induction of hepatic monooxygenase. Toxicology, 51 (2-3), 281-289.

Full Text: T\Toxicology51, 281.pdf

Abstract: Acid/neutral fractions of 4 chlorinated drinking water samples were tested for mutagenicity in the Ames’ test and injected intraperitoneally to 10-and 20-day-old Wistar rats at doses of 200 and 100 liters of water/kg body weight. Cytochrome P-450 mediated enzyme activities of ethylmorphine-N-demethylase (EMND), 7-ethoxycoumarin-O-deethylase (ECOD), 7-ethoxyresorufin-O-deethylase (EROD) and 7-pentoxyresorufin-O-dealkylase (PEROD) were determined in the 9000 g supernatant fraction of liver homogenate. EROD was introduced by the concentrates. The induction was related to the mutagenic activity. About 4-fold increase in activity was observed with the most mutagenic sample. PEROD was also slightly enhanced. EMND and ECOD activities were not affected by the lower dose, but the higher dose caused inhibition of 30-40%. Although the extracts were not toxic to bacteria, they were unexpectedly toxic to rats. It is concluded that the samples contained 3-methylcholanthrene (3-MC) type inducer (s).

Penn, A., Lu, M.X. and Parkes, J.L. (1990), Ingestion of chlorinated water has no effect upon indicators of cardiovascular disease in pigeons. Toxicology, 63 (3), 301-313.

Full Text: T\Toxicology63, 301.pdf

Abstract: Cardiovascular disease (CVD) accounts for nearly half the deaths, yearly, in the United States. The arterio (athero) sclerotic plaque is the principal lesion of CVD. The White Carneau (WC) pigeon is an animal model that has been employed extensively for studying CVD. Cholesterol (CHOL) feeding aggravates atherosclerosis in WC pigeons greater than 2 years old. In, (1986), two reports appeared from a single laboratory claiming a direct effect of drinking chlorinated (Cl) water upon lipid levels and plaque development in young (less than 1 year) WC pigeons. These are the only reports of such direct effects, to date. Three months’ exposure to 2 ppm or 15 ppm Cl in the drinking water, resulted in increased circulating CHOL levels in young male WC pigeons fed a normocholesterolemic (NC) diet in which Ca²⁺ levels were reduced. In addition, at both Cl concentrations there was a significant increase in plaque size, compared to controls. Pigeons in the 2 ppm group also exhibited elevated low density lipoprotein (LDL) levels after 3 months on the NC diet. These findings, if extrapolated to man, could have considerable public health consequences, since nearly 200 million people in the United States drink Cl water. We have carried out a similar set of studies but with strikingly different results. We used the same suppliers of pigeons and feed as did the authors of the 1986 reports and followed their approach where possible. Six month-old male WC pigeons drank water with 2 ppm or 15 ppm Cl (pH 8.5) and ate a NC diet with Ca²⁺ reduced to 80% of normal. At both 1 and 3 months, body weight, CHOL, triglyceride and LDL levels were unaffected by drinking Cl water. There was also no effect of Cl water on plaque size after 3 months. Thus, we found no evidence that drinking chlorinated water has any effect upon circulating lipid levels or upon the development of arteriosclerotic plaques, in this animal model.

Siracusa, G., Bastone, A., Sbraccia, M., Settimi, L., Mallozzi, C., Monaco, E. and Frontali N. (1992), Effects of 2,5-hexanedione on the ovary and fertility. An experimental study in mice. Toxicology, 75 (1), 39-50.

Full Text: T\Toxicology75, 39.pdf

Abstract: Sixty-day-old virgin female Swiss CD1 mice were treated with 1.5% 2, 5-hexanedione in their drinking water; control mice received tap water; duration of treatment was either 4 or 6 weeks. Under these conditions the treated mice did not show any clinical symptoms although electromyography revealed some signs of polyneuropathy. Protein and DNA content per mg of ovarian tissue in treated mice were not significantly different from controls. Histological examination of ovarian sections at the light microscope level showed no significant alterations after exposure. A morphometric study revealed a statistically significant reduction in the number of growing oocytes after 6 weeks of treatment. For fertility studies three groups of 15 female mice each were treated for 0, 4 or 6 weeks as above and then permanently housed with untreated proven breeder male mice (one male per female); cages were checked daily for newly born mice. All litters appeared normal by gross examination. During the first 14 weeks of continuous mating the mean litter size (number of newborns per litter) remained about 11.4 in all groups; this number subsequently began to decrease. Control and 4-week treatment regression curves did not differ statistically, while the slope of the 6-week line was significantly steeper, indicating a faster decrease in litter size over time and a shortening of fertile life in the latter group of treated females.

? Adonaylo, V.N. and Oteiza, P.I. (1999), Lead intoxication: Antioxidant defenses and oxidative damage in rat brain. Toxicology, 135 (2-3), 77-85.

Full Text: 1999\Toxicology135, 77.pdf

Abstract: Oxidative damage associated with the presence of lead (Pb) in the brain has been proposed as one possible mechanism involved in Pb toxicity. To investigate this hypothesis, we examined the long-term effects of Pb²⁺ on parameters of oxidative stress in the brain from rats chronically exposed to the metal (1 g Pb acetate/l drinking water). After 8 weeks of treatment, Pb²⁺-intoxicated rats (blood Pb concentration > 100 g/dl) showed lower body weight, and lower hematocrit and 5-aminolevulinic acid dehydratase activity as compared to controls. The content of brain 2-thiobarbituric acid-reactive substances (TBARS), an indicator of lipid oxidation, was significantly (P < 0.05) higher in the Pb²⁺-intoxicated animals than in controls. Higher activities of the antioxidant enzymes glutathione reductase and glutathione peroxidase, and a lower (44%) level of ubiquinol 10 were found in the brain of the Pb²⁺-treated rats, compared to controls. A negative correlation between brain ubiquinol 9 (r(2) = 0.79), 10 (r(2) = 0.84) and blood Pb concentration was observed. Brain alpha-tocopherol levels, superoxide dismutase activity and parameters of oxidative damage to proteins were similar between control and Pb²⁺-treated rats. The present results indicate that chronic Pb²⁺ intoxication induces an oxidative stress situation in rat brain. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Antioxidants, Free Radicals, Lead Intoxication, Neurotoxicity, Lipid-Peroxidation, Toxicity, Cells, Acid, Erythrocytes, Exposure, Binding, Stress, Liver

? Choi, D.W., Kim, J.H., Cho, S.Y., Kim, D.H. and Chang, S.Y. (2002), Regulation and quality control of herbal drugs in Korea. Toxicology, 181-182, 581-586.

Full Text: T\Toxicology181-182, 581.pdf

Abstract: Korea has a great diversity in resources of medicinal plants. The traditional herbal medicines and their preparations have been widely used in Korea as well as in China and Japan for thousands of years. One of the characteristics of Korean herbal medicine preparations is that all the herbal medicines are incorporated into an extractor at the same time and extracted with boiling water during the decoction process. In this process, a variety of interactions between the active components of several herbal medicines may occur. This is the main reason why quality control of oriental herbal drug is more difficult than that of western herbal drug. In this paper, we would like to present an overview of the characteristics of regulation and quality control of herbal medicines in Korea.

Keywords: Korean Herbal Medicine, Quality Control, Decoction

Notes: highly cited

? Waisberg, M., Joseph, P., Hale, B. and Beyersmann, D. (2003), Molecular and cellular mechanisms of cadmium carcinogenesis. Toxicology, 192 (2-3), 95-117.

Full Text: 2003\Toxicology192, 95.pdf

Abstract: Cadmium is a heavy metal, which is widely used in industry, affecting human health through occupational and environmental exposure. In mammals, it exerts multiple toxic effects and has been classified as a human carcinogen by the International Agency for Research on Cancer. Cadmium affects cell proliferation, differentiation, apoptosis and other cellular activities. Cd²⁺ does not catalyze Fenton-type reactions because it does not accept or donate electrons under physiological conditions, and it is only weakly genotoxic. Hence, indirect mechanisms are implicated in the carcinogenicity of cadmium. In this review multiple mechanisms are discussed, such as modulation of gene expression and signal transduction, interference with enzymes of the cellular antioxidant system and generation of reactive oxygen species (ROS), inhibition of DNA repair and DNA methylation, role in apoptosis and disruption of E-cadherin-mediated cell-cell adhesion. Cadmium affects both gene transcription and translation. The major mechanisms of gene induction by cadmium known so far are modulation of cellular signal transduction pathways by enhancement of protein phosphorylation and activation of transcription and translation factors. Cadmium interferes with antioxidant defense mechanisms and stimulates the production of reactive oxygen species, which may act as signaling molecules in the induction of gene expression and apoptosis. The inhibition of DNA repair processes by cadmium represents a mechanism by which cadmium enhances the genotoxicity of other agents and may contribute to the tumor initiation by this metal. The disruption of E-cadherin-mediated cell-cell adhesion by cadmium probably further stimulates the development of tumors. It becomes clear that there exist multiple mechanisms which contribute to the carcinogenicity of cadmium, although the relative weights of these contributions are difficult to estimate. (C) 2003 Elsevier Ireland Ltd. All fights reserved.

Keywords: Cadmium, Oxidative Stress, Cancer, DNA Repair, Gene Regulation, Reactive Oxygen Species, E-Cadherin, Apoptosis, Alveolar Epithelial-Cells, Metallothionein Gene-Expression, Protein-Kinase-C, Zinc-Finger Proteins, Upstream Stimulatory Factor, Human Promonocytic Cells, Proximal Tubule Cells, Heme Oxygenase Gene, Heat-Shock Element, Rat L6 Myoblasts