Title: Toxicology and Applied Pharmacology

Title: Toxicology and Applied Pharmacology

ISO Abbreviated Title: Toxicol. Appl. Pharmacol.

JCR Abbreviated Title: Toxicol Appl Pharm

ISSN: 0041-008X

Issues/Year: 24

Journal Country/Territory: United States

Language: English

Publisher: Academic Press Inc

Publisher Address: 525 B St, Ste 1900, San Diego, CA 92101-4495

Subject Categories:

Pharmacology & Pharmacy: Impact Factor 3.148, 48/193 (2005)

Toxicology: Impact Factor 3.148, 9/75 (2005)

? Cantilena, L.R. and Klaassen, C.D. (1982), Decreased effectiveness of chelation-therapy with time after acute cadmium poisoning. Toxicology and Applied Pharmacology, 63 (2), 173-180.

Full Text: Tox App Pha63, 173.pdf

Abstract: The effect of increasing the time interval between cadmium (Cd) exposure and chelation therapy was studied in male Swiss Webster mice. The following chelating agents were administered ip at 0, 2, 12, 36, and 72 hr after giving radioactive Cd (1 mg Cd/kg, iv): diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), and 2,3-dimercaptosuccinic acid (DMSA). Daily elimination of Cd into urine and feces was determined for 5 days after which time the mice were killed, and the concentration of Cd was determined in various organs. In most of the tissues examined, including kidney and liver, only administration of chelators immediately after Cd significantly reduced tissue Cd concentrations. The mice treated immediately after Cd administration excreted between 50 and 75% of the Cd into urine in the first 24 hr compared to 0.1% excreted by controls. Treatment at later times (2 to 72 hr) significantly increased Cd excretion but the magnitude of the effect was far less than that seen in mice treated immediately after Cd. In a separate group of mice, the time course for the induction of metallothionein synthesis was determined by administering 1 mg Cd/kg iv at various times before death. Metallothionein concentration increased within 2 hr after Cd administration and reached a maximum within 8 hr. The results show that the length of time before initiating chelation therapy for Cd poisoning greatly influences the effectiveness of the therapy. Hepatic metallothionein may be responsible for this phenomenon.

van Barneveld, A.A. and van den Hamer, C.J. (1985), Influence of Ca and Mg on the uptake and deposition of Pb and Cd in mice. Toxicology and Applied Pharmacology, 79 (1), 1-10.

Full Text: T\Tox App Pha79, 1.pdf

Abstract: The influence of high but not extreme concentrations of Ca and Mg (25 µmol/ml) on the apparent absorption and retention of 203Pb and 115mCd from water was investigated in mice. Ca reduced the absorption of Pb from an intubated solution by 62% and the absorption of Cd by 22%, but these effects were not significant. Mg showed no effect on Pb and Cd absorption. The retention of ip-injected Pb and Cd was not influenced by addition of Ca or Mg to the drinking water. Feeding of a Ca-deprived diet for 2 weeks prior to dosage stimulated the absorption of Pb from water by more than 100% (p less than 0.01) and the absorption of Cd from water by 17% (p less than 0.05). Feeding of a Ca-supplemented diet did not influence the absorption of Pb or Cd, but fecal Cd excretion seemed to be reduced. Feeding of Mg-deprived or Mg-supplemented diets did not show any effect on Pb and Cd metabolism. These results give supporting evidence that in soft water regions the uptake of Pb from the drinking water could be increased because of the absence of Ca in the drinking water, particularly when dietary Ca intake is low. This relationship between drinking water hardness and absorption of Pb could be important in view of general public health.

Hobara, T., Kobayashi, H., Kawamoto, T., Iwamoto, S. and Sakai, T. (1987), Intestinal absorption of trichloroethylene in dogs. Toxicology and Applied Pharmacology, 91 (2), 256-265.

Full Text: T\Tox App Pha91, 256.pdf

Abstract: In order to examine the intestinal absorption of trichloroethylene (TRI), we developed the intestinal circulation system of dogs and administered TRI solution at three concentrations (0.1, 0.25 and 0.5%) to the three parts of the intestinal tract (jejunum, ileum, and colon) of the operated dogs. We measured TRI and its metabolites, free-trichloroethanol, trichloroacetic acid, and conjugated trichloroethanol, in serum or blood, urine, bile and circulating solutions. The absorption rates of TRI from the intestine were 50-70% of the administered volume of TRI 2 hr after administration in all groups, and all parts of intestine readily absorbed TRI. Moreover, there were no significant differences in the absorption rates of TRI and water between the jejunum and ileum, and ileum and colon, respectively. The excretion rates of TRI and its metabolites in urine and bile were very low (0.1-0.4%) compared with the volume of absorbed TRI from the intestine 2 hr after administration in all groups. The high degree of absorption of TRI should be considered when threshold limits for TRI in the drinking water, the surface water, and the ground water are established.

? Moser, R., Oberley, T.D., Daggett, D.A., Friedman, A.L., Johnson, J.A. and Siegel, F.L. (1995), Effects of lead administration on developing rat-kidney. I. Glutathione-s-transferase isoenzymes. Toxicology and Applied Pharmacology, 131 (1), 85-93.

Full Text: 1995\Tox App Pha131, 85.pdf

Abstract: The effects of acute and chronic exposure to lead on glutathione S-transferase (GST) isoforms were determined in developing kidney in the rat. The ontogeny of glutathione S-transferase isoforms was characterized as were the effects of depletion of dietary calcium on glutathione S-transferase isoform profiles in control and lead-treated rats, In the acute exposure experiments, rats of 14 and 50 days of age received three daily injections of lead acetate (114 mg/kg) and in the chronic exposure studies, rats received lead acetate at doses ranging from 50 to 500 ppm in their drinking water. Lead acetate administration in these chronic studies began 1 day after conception. Acute and chronic lead exposure had similar effects, causing increases in all but one glutathione S-transferase isoform (Yb-3); these increases were markedly exacerbated by dietary calcium depletion, In all lead paradigms, GST subunits Yb-1 and Yp showed the largest increases-greater than 25-fold in rats fed a low-calcium diet, GST subunit Yb-3 showed small increases in the 14-day acute lead and the 4 week low-calcium animals and did not increase in other groups. Lead-related increases in GSTs were partially reversed by transferring animals previously receiving lead to lead-free water for a 4-week period. Kidneys of rats fed the low-calcium diet did not have detectable GST Yk, but in rats on this low-calcium diet that received 500 ppm lead; this GST isoform was found at levels comparable to those in control rats fed lab chow. (C) 1995 Academic Press. Inc.

Keywords: Intranuclear Inclusion-Bodies, Dietary Calcium, Liver, Expression, Induction, Binding, Nephrotoxicity, Resistance, Pressure, Subunits

? Oberley, T.D., Friedman, A.L., Moser, R. and Siegel, F.L. (1995), Effects of lead administration on developing rat-kidney. II. Functional, morphologic, and immunohistochemical studies. Toxicology and Applied Pharmacology, 131 (1), 94-107.

Full Text: 1995\Tox App Pha131, 94.pdf

Abstract: The effects of chronic lead administration on renal function and cytoarchitecture and on the immunohistochemical localization of glutathione S-transferase (GST) isoenzymes were determined. Pregnant rats were given 250 ppm lead acetate in drinking water from conception until weaning and mothers and pups received 500 ppm of lead acetate from weaning until termination at either 3 or 7 weeks of age, Light and electron microscopic studies after 3 weeks of lead administration showed tubular injury with frequent mitoses noted in proximal tubular cells and, after 7 weeks of treatment, interstitial fibrosis, characteristic intranuclear inclusions, and tubular injury characterized by both nuclear and cytoplasmic pleomorphism. Rats treated with lead for 7 weeks showed significantly lower body weights and creatinine clearances than age-matched control animals, Immunohistochemical studies of glutathione transferase subunits in control rats showed unique isoform localization in each segment of the nephron; treatment with lead caused large increases in immunoreactive protein of Yc, Yk, Yb-1, and Yp GST subunits in proximal tubules, No increases in the antioxidant enzymes copper-zinc superoxide dismutase, catalase, and glutathione peroxidase were found in lead-treated rats, but there was a diffuse lead-related increase in immunoreactive protein for manganese superoxide dismutase throughout the renal cortex. Our results demonstrate large lead-induced increases of specific isoforms of glutathione S-transferase in specific kidney cell types and show that these increases preceded irreversible renal damage. (C) 1995 Academic Press, Inc.

Keywords: Glutathione-S-Transferase, Manganese Superoxide-Dismutase, Syrian-Hamster Tissues, Antioxidant Enzymes, Catalytic Activity, Messenger-RNAs, Cell-Nucleus, Nephropathy, Localization, Isoenzymes

? Ronis, M.J.J., Badger, T.M., Shema, S.J., Roberson, P.K. and Shaikh, F. (1996), Reproductive toxicity and growth effects in rats exposed to lead at different periods during development. Toxicology and Applied Pharmacology, 136 (2), 361-371.

Full Text: 1996\Tox App Pha136, 361.pdf

Abstract: The reproductive toxicity and growth effects of developmental lead exposure were assessed using a rat model in which 0.6% (w/ v) lead acetate was administered in the drinking water ad libitum. Three series of experiments were conducted in which lead exposure was initiated beginning in utero, prepubertally, or postpubertally. Lead effects were measured on reproductive physiology and endocrinology, sexually dimorphic hepatic testosterone hydroxylation, and growth rates in both male and female animals. In male animals secondary sex organ weights were significantly decreased only in animals exposed prepubertally. In addition, serum testosterone levels were significantly suppressed, most severely in animals exposed from in utero (in the in utero group). Little effect was observed in adult female rats. However, in female animals exposed prepubertally, delayed vaginal opening and disrupted estrus cycling was observed, More severe reproductive disruption was accompanied by suppression of circulating estradiol in the in utero group. Effects on circulating sex steroids were accompanied by variable effects on circulating luteinizing hormone (LH) levels, pituitary LH, and pituitary LH beta mRNA, suggesting a dual site of lead action: (a) at the level of the hypothalamic pituitary unit, and (b) directly at the level of gonadal steroid biosynthesis. Prepubertal growth in both sexes was suppressed 25% in the in utero group. However, pubertal growth rates were significantly suppressed only in male animals and postpubertal growth was not significantly different from controls in any of the experiments, despite continued exposure to high lead levels in the drinking water. In addition, at age 85 days, male-specific hepatic hydroxylation of testosterone at positions 2 alpha and 16 alpha, which is catalyzed by a cytochrome P450 isozyme CYP 2C11, itself regulated by sexually dimorphic growth hormone secretion, was unaffected. This suggests that the growth effects of lead are possibly due to a delay in the development of sex-specific pituitary growth hormone secretion patterns rather than a persistent developmental defect. Thus, the reproductive and growth effects of lead are complex and sex-dependent, and appear to involve multiple sites on the hypothalamic- pituitary gonadal axis. (C) 1996 academic Press, Inc.

Keywords: Blood Lead, Stimulating Hormone, Weanling Rats, Pituitary, Pregnancy, Children, Ethanol, Mice, Axis, Age

Kulp, K.S., Vulliet, P.R. (1996), Mimosine blocks cell cycle progression by chelating iron in asynchronous human breast cancer cells. Toxicology and Applied Pharmacology, 139 (2), 356-364.

Full Text: T\Tox App Pha139, 356.pdf

Abstract: Mimosine is a toxic nonprotein amino acid that is a major constituent of the tropical legumes Leucaena and Mimosa. Mimosine has been shown to cause acute and chronic toxicosis in livestock fed from forage containing these plants. Recently, mimosine has been demonstrated to reversibly block cell cycle progression in mammalian cells in culture. In this study, we compared the effects of mimosine to desferrioxamine (DFO), a well-characterized iron chelator, and found that both chemicals similarly altered cell cycle progression in MDA-MB-453 human breast cancer cells. Mimosine (400 µM) and DFO (150 µM) both reduced DNA synthesis by greater than 90% of control within 4 hr of treatment, and suppressed total proline-directed protein kinase activity to less than 10% of control after 16 hr treatment. These effects were antagonized by the addition of iron as ferrous sulfate (250 µM), which is bound to transferrin and imported into the cell via transferrin receptor endocytosis, or as hemin (100 µM), which passes through the cell membrane and releases iron into the cytosol. After 24 hr treatment with the chelators, a large portion of the available transferrin receptors moved to the cell surface, indicating that the cells were iron-starved. Our data demonstrate that mimosine, through iron chelation, blocks cell cycle progression in MDA-MB-453 human breast cancer cells. (C) 1996 Academic Press, Inc.

Keywords: Mammalian Ribonucleotide Reductase, Chinese-Hamster Cells, Plant Amino-Acid, Protein-Kinase, DNA-Synthesis, S-Phase, Transferrin Receptors, Diphosphate Reductase, Tumor-Cells, G1 Phase

Zheng, W., Shen, H., Blaner, W.S., Zhao, Q., Ren, X. and Graziano, J.H. (1996), Chronic lead exposure alters transthyretin concentration in rat cerebrospinal fluid: The role of the choroid plexus. Toxicology and Applied Pharmacology, 139 (2), 445-450.

Full Text: T\Tox App Pha139, 445.pdf

Abstract: The choroid plexus, which is responsible for the maintenance of the biochemical milieu of the cerebrospinal fluid (CSF), avidly sequesters Pb. In order to test the hypothesis that chronic Pb exposure may impair choroid plexus function, male weanling Sprague-Dawley rats were exposed to Pb in drinking water at doses of 0, 50, or 250 micrograms Pb/ml (as Pb acetate) for 30, 60, or 90 days. The function of the choroid plexus was assessed as reflected by CSF concentrations of transthyretin (TTR, a major CSF protein manufactured by brain choroid plexus) and CSF essential metal ions (Ca²⁺, Mg²⁺, K⁺, and Na⁺). TTR concentrations were determined by radioimmunoassay using a monospecific rabbit anti-rat TTR polyclonal antibody, and CSF metal ions analyzed by flame atomic absorption spectrophotometry. Two-way ANOVA of CSF TTR concentrations revealed highly significant dose (p < 0.0001), time (p < 0.0223), and dose-by-time effects (p < 0.0379). Moreover, the percentage of reduction of CSF TTR was directly correlated with Pb concentrations in the choroid plexus (r = 0.703, p < 0.05). Pb exposure significantly increased CSF concentrations of Mg²⁺, but did not markedly altered CSF concentrations of Ca²⁺, K⁺, and Na⁺. Histopathologic examination under the light microscope did not show distinct alterations of plexus structure in Pb-treated rats. Since TTR is responsible for transport of thyroid hormones to the developing brain, we postulate that the depression of choroid plexus TTR production (and/or secretion) by Pb may impair brain development in young animals by depriving the CNS of thyroid hormones.

Wilson, A.K. and Bhattacharyya, M.H. (1997), Effects of cadmium on bone: A in vitro model for the early response. Toxicology and Applied Pharmacology, 145 (1), 68-73.

Full Text: T\Tox App Pha145, 68.pdf

Abstract: Cadmium (Cd) exposure induces bone resorption in vitro and in vivo that can lead to low bone mass and increased incidence of fracture. We have developed an animal model for following the early skeletal response to Cd. A low-calcium (but not calcium-deficient) diet is used to increase gastrointestinal absorption of calcium so that the endogenous fecal calcium excretion is essentially the total fecal calcium excretion. The bone response is followed by quantitation of stable fecal calcium and does not require a radioactive label. After mice were adjusted to a low-calcium diet, Cd was administered by a single gavage and fecal calcium was monitored to determine the magnitude of the calcium release from bone. Fecal calcium excretion (µg Ca/hr; mean±SE) remained at the background level for 8 hr (13.6±1.8, n = 18) but increased during the 8-to 24-hr and 24-to 56-hr collection periods (43.8±6.8, n = 12; 50.75±3.7, n = 6, respectively). The bone response was transient and dropped to nearly background levels during the 56-to 104-hr collection period. Blood calcium levels were normal throughout the time course. Bone resorption occurred at Cd levels of 7.9±0.7 µg/liter blood (mean±SE, n = 6), which is in the range of occupational exposure levels. The transient nature of the bone response contrasted to the slow but continuing rise observed in blood Cd levels. These results suggest that a threshold level of Cd is required for a bone response but that chronic levels of Cd in blood do not necessarily indicate the occurrence of continuous active bone resorption. This model can be used to probe early gene changes (prior to the bone response) that may be occurring in response to Cd exposure. (C) 1997 Academic Press.

Keywords: Calcium-Deficient Diet, Occupational Exposure, Resorption, Mice, Rat, Osteopetrosis, Macrophage, Metabolism, Culture, Workers

Zhao, Q., Slavkovich, V. and Zheng, W. (1998), Lead exposure promotes translocation of protein kinase C activities in rat choroid plexus in vitro, but not in vivo. Toxicology and Applied Pharmacology, 149 (1), 99-106.

Full Text: T\Tox App Pha149, 99.pdf

Abstract: Lead (Pb) exposure reportedly modulates PKC activity in brain endothelial preparations, which may underlie Pb-induced damage at the blood-brain barrier. Our previous work indicates that Pb accumulates in the choroid plexus and causes dysfunction of this blood-cerebrospinal fluid (CSF) barrier. The present studies were undertaken to test the hypothesis that Pb in the choroid plexus may alter PKC activity and thus affect the functions of the blood-CSF barrier. When choroidal epithelial cells in a primary culture were exposed to Pb (10 microM in culture medium), the membrane-bound PKC activity increased by 5.2-fold, while the cytosolic PKC activities decreased, an indication of the induction of PKC translocation by Pb. The effect of Pb on cellular PKC was concentration dependent in the range of 0.1-10 microM. We further evaluated PKC activity of the choroid plexus in rats chronically exposed to Pb in the drinking water (control, 50 or 250 micrograms Pb/ml) for 30, 60, or 90 days. Two-way analysis of variance revealed a significant age-related decline of PKC activities in both cytosol and membrane of the choroid plexus. However, Pb treatment did not alter plexus PKC activities. In addition, we found that short-term, acute Pb exposure in rats did not significantly change PKC activities nor did it affect the expression of PKC isoenzymes in the choroid plexus. Our results suggest that Pb exposure may promote the translocation of PKC from cytosol to membrane in rat blood-CSF barrier in vitro, but not in vivo.

? Costa, M. (2003), Potential hazards of hexavalent chromate in our drinking water. Toxicology and Applied Pharmacology, 188 (1), 1-5.

Full Text: 2003\Tox App Pha188, 1.pdf

Abstract: A consideration of the consequences of human exposure to hexavalent Cr in the drinking water has been compiled. Since there is an absence of adequate human data on this subject the problem has been analyzed not only from human and animal studies but also from a mechanistic point of view. This treatise has been inspired by recent reviews and speculations that suggest that we may safely drink hexavalent Cr in great excess of the current EPA and states drinking water standards of 50-100 ppb. (C) 2003 Elsevier Science (USA). All rights reserved.

Keywords: Chromium, Cancer, Cellular Uptake, Reduction, In-Vitro, Chromium Picolinate, Gene-Expression, Strand Breaks, DNA, Cells, Carcinogenesis, Ingestion, Toxicity, Glutathione