bluuebunny/crossref_metadata_2025 huggingface dataset:
Complications in Neonates With Short Bowel Syndrome and Long‐Term Parenteral Nutrition
Authors: Suita Sachiyo , Masumoto Kouji , Yamanouchi Takeshi , Nagano Miki , Nakamura Masatoshi
Published: September 2009

Background: Because of advances in parenteral nutrition (PN), the prognosis for patients with short bowel syndrome (SBS) has recently shown great improvement. Even infants with a small bowel measuring only 20 cm either with or without an ileocoecal valve can now survive. However, because of the increased periods of PN, severe complications associated with PN have been observed. Patients and Methods: We analyzed 17 patients with SBS treated by long‐term PN to investigate the complications of PN, particularly hepatic dysfunction, micronutrient deficiency, and intoxication. Results: Eleven of 17 patients (64.7%) had hepatic dysfunction, mostly cholestasis. The main causes of hepatic dysfunction were loss of enteral feeding and infections. Regarding the complications of the micronutrients, zinc and copper deficiencies have been observed less often because of trace element supplements. However, manganese deposition, especially in the basal ganglia, was recognized in one patient. Conclusions: We therefore need to pay more attention to these problems when treating this disease in order to improve the overall prognosis significantly. (Journal of Parenteral and Enteral Nutrition 23:S106‐S109, 1999)
Growth Factors and Nutrients in the Short Bowel Syndrome
Authors: Wilmore Douglas W.
Published: September 2009

ABSTR.ACT. Massive intestinal resection often results in long‐term dependence on parenteral nutrition (TPN). In an effort to enhance bowel rehabilitation, the amino acid glutamine, growth hormone and a diet optimized to enhance absorption have been administered to >300 patients with the short bowel syndrome. Initially about 60% of the patients were weaned from TPN and an additional 30% had reduced TPN requirements. At long‐term follow up (2 years) 40% of the group remained off TPN, 40% had reduced TPN requirements, and 20% had the same requirements. This report addresses issues such as the optimization of diet and provides a care map which should enhance the rehabilitation of patients with the short bowel syndrome. (Journal of Parenteral and Enteral Nutrition23:S117‐S120, 1999)
Impediments to the Successful Use of Anabolic Agents in Clinical Care
Authors: Wilmore Douglas W.
Published: September 2009

Growth factors represent one of the next important steps in providing efficient and effective nutrition to catabolic patients. However, several issues will need to be addressed in order to optimize their use. These include the effects of these agents in malnourished patients, the influence of nutritional deficiencies on anabolic effects, the effect of inflammation on growth factor‐stimulated protein synthesis, and concerns with safety and cost. Adequate training of physicians and changes in our present approach in caring for patients may be the greatest obstacles to overcome if full application of this biotechnology to patient care is to be realized. (Journal of Parenteral and Enteral Nutrition23:S210‐S213, 1999)
Cephalothoracopagus in a Mouse Conceptus
Authors: Hemm R. D. , Arslanoglou L. , Pollock J J.
Published: September 2009

Multiple major malformations, characterized as conjoined twins (cephalothoracopagus monosymmetros), occurred as an incidental finding in a single conceptus from a CD-1 mouse dam. The dam had 14 other normal siblings, and the cephalothoracopagus was regarded as a case of incomplete twinning of “spontaneous” origin. Similar cephalothoracopagus twins occur rarely in various species, including man, and are thought to arise from a monozygotic origin. The cephalothoracopagus twin had essentially a single head with some duplicated structures and a duplicated torso which was fused near the umbilical cord. The conceptus had a common umbilical cord emerging from a single placenta and entering the site of ventral attachment. Several components of the axial and appendicular skeleton were duplicated, but the twin had a normal complement of viscera with the exception of a duplicated heart. The initiation of the cephalothoracogagus anomaly is thought to occur between the two-cell stage and gastrulation and would thus antedate the period of drug administration (gestation days 6-15) in mouse teratology studies. Evaluation of the temporal events of embryogenesis is thus critical in vitiatina a potential relationship of the developmental abnormality to administration of a drug.
Naturally Occurring Granular Cell Tumors of the Brain in Rats
Authors: Chen H. C. , Stula E. F.
Published: September 2009

A retrospective study was conducted to determine the incidence of granular cell tumors of the brain in ChR-CD rats, used as controls in two-year toxicity studies conducted at Haskell Laboratory (1971-73). Two (1.6%) such tumors were found in 127 male rats, 13 to 25 months of age. No granular cell tumors of the brain were found in 128 female ChR-CD rats, 13 to 25 months of age. These appear to be the first reported cases of granular cell tumors of the brain in this strain of Sprague-Dawley rat.
The Interfering Effects of Hemolyzed Blood on Rat Serum Chemistry
Authors: Chin Byong Han , Tyler Tipton R. , Kozbelt Sarah J.
Published: September 2009

The influence of Hb on 14 serum constituents was evaluated. Among the 7 enzymes for which analyses were conducted, LD and HBD values were elevated fivefold at the highest Hb concentration of 1500 mg/liter. Hb had less of an effect on the activities of other enzymes, i.e., AST activity was increased by only 30% whereas CK activity was decreased by 10%. Among the 7 nonenzymatic constituents of rat serum studied, a Hb concentration of 1500 mg/liter resulted in a fivefold increase in total bilirubin concentration. Creatinine and glucose values were negatively correlated to Hb concentrations but the dependence was not nearly as great as that with total bilirubin. The remaining serum constituents studied were not affected by Hb concentrations.
Hypoplastic Renal Corpuscles in the Dog
Authors: Yoon Young H. , Santamarina Enrique
Published: September 2009

Hypoplasia of renal corpuscles was studied in 238 dogs ranging in age from 1 to 24 months: 98 purebred beagles, 115 foxhounds and 25 dogs of 10 other breeds. Twenty-six (26.5%) of the beagles had hypoplastic renal corpuscles, comprising approximately 0.3 to 4% of the total number of renal corpuscles counted in each kidney. All beagles which had hypoplastic renal corpuscles appeared to have normal glomerular function as determined by serum creatinine concentration level, and all other histological structures of the kidney appeared normal. Most of the hypoplastic renal corpuscles in these dogs were observed undergoing atrophy, degeneration, necrosis, and occasional calcification. Since these beagles had no noticeable abnormalities in the kidneys and the other organs that might cause secondary atrophy of renal corpuscles, it could be assumed that the small renal corpuscles were the result of true hypoplasia.

Calcification of hypoplastic renal corpuscles was seen in 25 of the dogs of all other breeds studied. Suppurative pneumonia was the most common disease in 16 of the 25 animals which had the calcification. Nine of the 16 animals had pneumonia and canine distemper concurrently and the remaining 7 animals had pneumonia only with no other detectable diseases.

Since the dog is extensively used for research in animal and human kidney diseases and for testing drugs, the finding of hypoplastic renal corpuscles could be a valuable contribution for pathologists and physiologists dealing with studies on kidney function.
Hemangiopericytoma and Other Tumors of Urinary Tract of Guinea Pigs
Authors: Hoch-Ligeti Cornelia , Congdon Charles C. , Deringer Margaret K. , Strandberg John D. , Stewart Harold L.
Published: September 2009

Hemangiopericytoma, transitional cell carcinoma, squamous cell carcinoma and adenosquamous carcinoma developed in the urinary bladder of 6 of 95 guinea pigs of a noninbred stock and 16 of 87 guinea pigs of inbred strains 2 and 13 all gamma or X-ray irradiated. An additional 7 of 66 untreated guinea pigs of the two inbred strains also developed bladder tumors. Twenty-four guinea pigs had multiple tumors of the bladder. In the irradiated animals, the tumors arose significantly earlier but the increase in number of tumor bearing guinea pigs did not reach statistical significance. The tumors extended through the superficial muscularis into the underlying connective tissues and occasionally into lymphatic vessels and veins but none metastasized. Of 29 animals with tumor of the bladder, 21 had papillary proliferation of the renal pelvic mucosa, two papillary transitional carcinoma and one hemangiopericytoma. The EM and light microscopic criteria for the identification of hemangiopericytoma are described.
Lethal and Teratogenic Effects of Lambda—Carrageenan, A Food Additive, On the Development of the Chick Embryo
Authors: Rovasio Roberto A. , Monis Benito
Published: September 2009

Lambda-Carrageenan, a food additive, injected into the yolk sac of fertile chicken eggs had teratogenic and lethal effects on chick embryo development. Anomalies were mainly localized in the cephalic end (exencephaly, abnormal beak, anophtalmy, etc.). All abnormal chicks of the group injected with carrageenan showed two or more anomalies. Growth of newborn chicks in the carrageenan-injected group was significantly diminished until the 4th day of age.
A Microcomputer Based Management Information System for Toxicologic Pathology
Authors: Burkhardt K. J. , Rapp W. R.
Published: September 2009

The system described in this paper is a series of programs for a microcomputer that have been designed to aid in the recording, analysis, and reporting of pathology data. This paper describes the design criteria on which the system is based, its operational characteristics, and the hardware required for the system to operate.
Spongiform Leukoencephalopathy Induced in Mice by Oral Benzidine Administration
Authors: Morgan K. T. , Crowder D. M. , Frith C. H. , Littlefield N. , Coleman G.
Published: September 2009

Small foci of spongy change, often bilaterally symmetric, were observed in the brains of mice exposed to benzidine dihydrochloride. These vacuoles were most frequent in the superior thalamic radiation of the internal capsule. They possibly represent swollen glial cells and intramyelinic vacuoles. No consistent relationship was observed between the presence of vacuoles in the brain and hepatic lesions in these mice, and this change may be attributable to benzidine treatment unrelated to toxic effects of the liver.
Muscular Dystrophy-Like Syndrome in Young Adult Sprague-Dawley Rats Following Neonatal Treatment with 6-Mercaptopurine
Authors: Slaughter L. J. , Alleva F. R. , Haberman B. H. , Balazs T.
Published: September 2009

Ninety-six male and female rats were injected subcutaneously with 2 mg./kg. of 6-mercaptopurine monohydrate (as the free base) daily from 2 to 22 days of age. An equal number of controls received saline. Clinically, 15 of 77 surviving treated rats exhibited paresis of the hindlegs while 44 (including the 15 with paresis) had flattened croups (gluteal area). Grossly, the gluteal, thigh and lumbar vertebral muscles were markedly atrophied and partially replaced by adipose tissue. Microscopically, the muscles of 50 of 66 treated rats consisted of varying sizes and shaped myofibers which were extensively infiltrated by fat cells. Chains of centrally positioned nuclei, foci of necrosis and inflammation were occasionally observed in the affected muscles. Other regions of the musculature and other organ systems of the treated rats were normal. None of the 77 surviving control rats presented clinical signs, gross or microscopic lesions comparable to the treated rats. The observations presented at this meeting were demonstrated and discussed with respect to their correlations with other clinical, gross anatomical, biochemical and histochemical findings.
Endocardial Thickening in the Sprague-Dawley Rat
Authors: Zaidi I. , Sullivan D. J. , Seiden D.
Published: September 2009

Thickening of the endocardium is sometimes observed in rats and other animals as a spontaneous or experimentally induced lesion. However, its nature, pathogenesis, and significance are not well understood.

In this study, 480 Sprague-Dawley CD outbred albino rats between the ages of 6 and 25 months were examined grossly and microscopically. Endocardial thickening was observed in six cases. It was diffuse and was caused by proliforation of fibroblast-like cells, most frequently involving the left ventricle.

Endocardial thickening in Sprague-Dawley rats appears to be primarily due to endomyocardial fibrosis. It may represent repair of damage to subendocardial myocardium occurring spontaneously or as a consequence of exposure to chemicals or other agents.
The Effect of Uniform Exsanguination on Absolute and Relative Organ Weights, and Organ Weight Variation
Authors: Kanerva R. L. , Alden C. L. , Wyder W. E.
Published: September 2009

The effect of uniform exsanguination on absolute and relative organ weights was assessed. The data demonstrate that the simple, rapid, and uniform procedure described for exsanguination of rats prior to necropsy significantly (P < .05) reduces both absolute and relative liver and kidney weights with respect to weights from animals that are not exsanguinated. In addition, liver weight standard deviation relative to controls is significantly (P < .05) reduced, increasing sensitivity of the measurement. Exsanguination also decreases agonal change related variation in macroscopic tissue appearance, enhancing the gross examination.
Phenotypic Properties of Preneoplastic Rat Liver Lesions and Applications to Detection of Carcinogens and Tumor Promoters
Authors: Williams Gary M.
Published: September 2009

A variety of cellular lesions arise during liver carcinogenesis by chemicals in rats. The altered focus is a lesion of hepatocytes that occurs early in hepatocarcinogenesis and appears to give rise to both neoplastic nodules and carcinomas. Foci display numerous phenotypic abnormalities which together with nuclear abnormalities indicate that they are truly a new altered population.

Using histochemical markers, the induction of foci can be measured as a quantitative index of hepatocarcinogenicity of genotoxic carcinogens. In addition, determination of the effect of agents on foci previously induced by genotoxic carcinogens can be used to assess the capacity of chemicals to act as liver tumor promoters.
Response of liver foci in rats to hepatic tumor promoters
Authors: Schulte-Hermann R. , Timmermann-Trosiener I. , Schuppler J.
Published: September 2009

Putative preneoplastic foci (islands) of altered hepatocytes were induced by single doses of initiating hepatocarcinogens and identified by various histochemical and morphological markers. DNA synthesis, measured by 3H-thymidine and autoradiography, as well as mitotic activity were found to be higher in the foci than in normal hepatocytes. Without promotion this proliferative advantage is partially counterbalanced by reversion of altered cells to the normal phenotype and/or increased incidence of cell death by apoptosis, so that the islands show little growth. Prolonged administration of promoters such as phenobarbital, hexachlorocyclohexane etc. resulted in the appearance of more and larger foci, which exhibited steady growth. Island enlargement was due to an upsurge of cell proliferation (in the initial stage only) and to interference of the promoter with phenotypic reversion and/or apoptosis of island cells. Island multiplication during promotion was essentially due to induction of the histochemical marker (γ-GT) in “latent” islands. Promoter withdrawal led to rapid reductions in size and number of foci suggesting that the effect of promoters on the phenotype of island cells is reversible under the conditions employed. Finally we offer the hypothesis that non-mutagenic compounds may produce liver tumors in experimental animals by promotion of “spontaneous” preneoplastic lesions.
Hypolipidemics Carcinogenicity and Extrapolation of Experimental Results for Human Safety Assessments
Authors: de la Iglesia Felix A. , Farber Emmanuel
Published: September 2009

Dyslipoproteinemias represent a group of disorders closely related to alterations of cholesterol and triglycerides. The alterations of these lipids are considered important risk factors in coronary heart disease and indicate the need for clinically effective and safe drugs.

Hypolipidemic agent therapy, however, does not appear without risk since the administration of these agents is by necessity, on a long-term basis. In the conduct of animal safety studies with some hypolipidemics, hyperplastic nodules or tumors developed in the liver of rodents. Data from the literature seem to indicate that the tumor response in rodents varies with the type of hypolipidemic drug administered. This paper summarizes the studies with the new lipid-regulating agent gemfibrozil. Aside from conventional long-term studies in rodents, the ultrastructural aspects of the liver were analyzed in several species and genotoxicity assays and short-term tests for hepatocarcinogenicity were conducted. Thus, it was possible to obtain an overview of these biological phenomena in order to allow for safety extrapolations. The biological behavior of these liver nodules showed that gemfibrozil and clofibrate-induced hepatocytes had not undergone malignant transformation. Further, the phenomenon of peroxisome proliferation, a characteristic event that follows hypolipidemic administration in rodents, was not confirmed in primate or human liver. Peroxisome proliferation has been linked to the process of hepatocarcinogenesis in rodents, although genotoxicity assays were negative and initiation/promotion tests failed to elicit tumors or nodules in a system where hepatocarcinogens manifest their activity.

Thus, hypolipidemics such as gemfibrozil or Clofibrate may possess low tumorigenic potential with low risk due to the lack of correlation between these tests. Nevertheless, these agents are indicated for specific lipoprotein phenotype alteration with the resulting clinical benefits.
Serum and Hepatic Enzyme Activity in Rats Treated with Diethylnitrosamine
Authors: Giuliani Eleanor R. , Zaki F. George , Hall James C.
Published: September 2009

Comparative studies of enzyme activities during the dedifferentiation of hepatic cells and through their development into overt hepatomas are few and contradictory. This study was designed to investigate the histochemical, biochemical and morphologic features of the altered liver cells with particular emphasis on the importance and validity of the histoenzymatic behavior of glucose-6-phosphatase (G6Pase) as a marker for the detection of precancerous hepatic cells. Serum and hepatic levels of G6Pase were analyzed and compared with the histoenzymatic behavior of this enzyme. The use of other enzymes, such as adenosine triphosphatase (ATPase) and gamma glutamyl-transpeptidase (GGT) as histochemical markers for malignancy was also tested. The activities of a variety of enzymes commonly used as diagnostic tools were also evaluated in both the liver homogenates and sera of rats treated with 2 mg diethylnitrosamine (DENA)/kg body weight for 2-28 weeks. Using G6Pase as a histoenzymatic marker, precancerous cells appeared after 4 weeks of exposure to DENA in the form of small islets devoid of G6Pase activity. These G6Pase free cells increased in number forming larger islands and finally appeared as tumor nodules after 28 weeks of treatment. The histoenzymatic behavior of ATPase was identical to that of G6Pase. The precancerous cells, as well as the tumor cells appeared devoid of ATPase activity. The application of GGT as a marker, showed significantly increased activity in the altered liver and tumor cells. Increased serum levels of G6Pase were noted after 10 weeks and were greatly elevated in the late stages of the evolution of the precancerous cells. After 14 weeks of DENA administration, the hepatic G6Pase activity was depressed and greatly diminished as the size and number of these foci increased. In animals bearing hepatomas, the G6Pase levels were markedly decreased in both the sera and liver homogenates and totally lacking in the tumor cells. Data obtained from the evaluation of sera and hepatic activities of acid and alkaline phosphatases, aspartate and alanine aminotransferases, and lactic and isocritic dehydrogenases were inconclusive as compared to G6Pase.
Pathology Requirements for Two-year Rodent Studies II. Alternative Approaches
Authors: McConnell Ernest E.
Published: September 2009

The preceeding paper described the origin and evolution of the pathology portion of carcinogen bioassays conducted under the direction of the National Cancer Institute (NCI) and subsequently by the National Toxicology Program (NTP). Review of 277 studies conducted under the NCI/NTP protocol suggested that the present number of tissues/organs was in excess to what is needed to detect if a given chemical induces cancer in rats and/or mice. In addition, the ability of the previous protocol to detect and define non-neoplastic chemically related lesions may be inadequate. This paper describes alternative pathology protocols and proposes one that will answer the question of a given chemicals' carcinogenic potential while at the same time give superior information on non-neoplastic chemical related pathology. In addition this protocol will reduce the volume of histopathology required in most studies by over 50%.
Statistical Support of the Proposed National Toxicology Program Protocol
Authors: Haseman Joseph K.
Published: September 2009

Statistical issues related to the design, analysis and interpretation of carcinogenicity studies are considered. A proposed modification of the “standard” National Cancer Institute (NCI) design of carcinogenicity studies in rodents is discussed. The primary objective was to obtain a design that maintained the power of the NCI design for detecting carcinogenic effects, while increasing the precision with which the underlying dose-response model could be estimated. “Optimum” three-dose designs are presented and discussed.

Data analysis issues are also considered. Comparisons of tumor incidence should include adjustments for survival differences, and, if possible, cause of death determinations should be made for each individual animal. In some instances historical control data can aid an investigator in the overall evaluation of experimental results. Several important problems are discussed that must be overcome before historical control data can be used in a meaningful way.

One critical issue in the interpretation of tumor incidence data is the issue of false positives. Data from 25 recent long term feeding studies are used to derive a statistical decision rule that closely approximates the scientific judgment process used in these studies. The overall false positive rate associated with this decision rule was found to be no more than 7-8%.
Initiation/Promotion Designs in Carcinogenicity Bioassays
Authors: Hayashi Yuzo
Published: September 2009

Routine carcinogenicity testings have been designed and conducted primarily for providing data to show whether or not the test compounds have a potential of inducing tumors in animals. Therefore, in the case of safety assessment or risk assessment of test compounds in humans, additional data are needed, at times, to learn how intensely the test compound can induce tumors in animals or by which mechanism the test compound can induce tumors in animals. The initiation/promotion experiment is performed as a proceeding for such requests. This paper describes the updating principle and procedures to evaluate initiation effects and promotion effects separately. However, it must be realized that our present knowledge about the initiation/promotion is still limited to some qualitative evidences. Actually, we know very little about mechanistic background and quantitative aspect of the initiation/promotion such as the site or mode of action of promoter action, the organ-specificity of promoter action, or threshold of the initiator action and promoter action. All these problems are necessary to be studied systematically in order that the initiation/promotion design can make a more important contribution to the evaluation of carcinogenicity of chemicals.
Thyroid and Chemical Hepatocarcinogenesis: Further Insights from the Hepatocarcinogen Zami 1305
Authors: Presta Marco , Zavanella Teresa , Mazzocchi Cecilia , Ziliani Silvia , Mazzoleni Giovanna , Calovini Daniela , Braga Marina , Ragnotti Giovanni
Published: September 2009

The β-blocker DL-1-(2-nitro-3-methyl-phenoxy)-3- tert-butylaminopropan-2-ol (ZAMI 1305), oncogenic to the liver of the female but not of the male Wistar rat, was used to investigate some aspects of the relationship between liver and thyroid during chemical hepatocarcinogenesis. Thyroidectomy (TDX) strongly reduces the amount of hepatic DNA damage induced by a single administration of ZAMI 1305 in the female Wistar rat. One week of treatment with triiodothyronine (T3) completely restores the susceptibility of the liver of thyroidectomized animals to the genotoxic activity of the molecule. The amount of hepatic DNA damage in intact females varies with the age of the animal, being maximal in rats of 4-8 weeks of age, when T3serum concentration are also maximal. An increase of relative thyroid weight, coupled with histological hyperplasia of the gland, is observed in female Wistar rats treated for 6 months with ZAMI 1305. Minimal changes of the thyroid are observed in ZAMI 1305-treated male rats. The increase of relative thyroid weight in female rats appears to be related to the severity of preneoplastic and neoplastic liver changes. These findings and several suggestions from the literature lead us to propose a model for the interaction between liver and thyroid during chemical hepatocarcinogenesis.
Acinar Cell Carcinoma of Rat Pancreas: Mechanism of Deregulation of Cholesterol Metabolism
Authors: Rao Kalipatnapu N. , Kottapally Sujatha , Shinozuka Hishashi
Published: September 2009

The mechanism of deregulation of choleserol metabolism was studied in fast and slow growing nude mouse tumors and cancer cells in culture derived from azaserine-induced rat pancreatic acinar cell carcinoma. The tumors showed a loss of feedback control of the de novo synthesis of cholesterol, probably due to a loss of low density lipoprotein (LDL) receptors on plasma membranes or to a defect in the binding and internalization of LDL in the cancer cells. The hexosemonophosphate shunt pathway is stimulated in the cancer cells, presumably because of an increased demand for NADPH in cholesterol synthesis and for ribose phospate in DNA synthesis. The uncontrolled de novo synthesis of cholesterol is one of the factors responsible for the high rate of cell proliferation in the tumors.
Is There More Than One Critical Lesion Relevant for Experimental Liver Carcinogenesis?
Authors: Denda Ayumi , Rao Prema M. , Rajalakshmi Srinivasan , Sarma Dittakavi S.R.
Published: September 2009

The present study was designed to determine whether there is one or more than one critical lesion, induced by a carcinogen, relevant for initiation. The experimental approach consisted of administering a non-necrogenic dose of the carcinogen 1,2-dimethylhydrazine 2HCl (100 mg/kg, i.p.) to male Fischer 344 rats (120-140 g) and completing the initiation process by two different methods: (i) induction of liver cell proliferation by partial hepatectomy, or (ii) creation of hypomethylation in DNA by giving 5-azacytidine, an agent that inhibits DNA methylation. The initiated hepatocytes were assayed as γ-glutamyltransferase positive foci. The rationale for the approach was based on the premise that the two methods used for completing the initiation step might give either the same or a different pattern in the incidence of initiated hepatocytes depending on whether one or more than one lesion was important for initiation, particularly if some of the lesions were allowed to repair before applying the cell proliferative stimulus or administering the 5-azacytidine. The results obtained indicated that 5-azacytidine facilitated the induction of the same number of foci whether given 12 or 96 hours after the carcinogen indicating that the critical lesion involved in this mode of initiation persisted up to at least 96 hours. In contrast, our earlier results showed that there was a reduction in the number of γ-glutamyltransferase positive foci when partial hepatectomy was delayed beyond 24 hours after the carcinogen administration, indicating that the critical lesion involved in this mode of initiation has a half-life of not more than 24 hours. The results of these two sets of experiments taken together indicate that carcinogens induce more than one critical lesion and the importance of the lesion might depend on the mode by which initiation is completed.
The Role of Toxicological Interactions in Chemical Carcinogenesis
Authors: Witschi Hanspeter
Published: September 2009

Toxicological interactions may occur not only when exposure to two or more chemicals is simultaneous, but also when exposures are separated in time. Often the sequence of exposure determines the nature of the toxicological response. This is illustrated with the two hindered phenolic antioxidants, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). Evidence available suggests that in certain tissues exposure to BHT first and then to a carcinogen is without significant consequences, whereas exposure to BHT after a carcinogen may enhance tumor formation. On the other hand, exposure to BHA before carcinogen administration often has a protective effect, whereas exposure to BHA after a carcinogen sometimes protects and sometimes is without any influence. Mechanisms underlying these interactions may be induction of mixed function oxidases, production of cell hyperplasia or other, as yet ill-defined, events such as modification of biological reactivity.
Evidence Against a Role for Disturbed Hepatocellular Calcium Homeostasis in the Fatty liver of Carbon Tetrachloride Hepatotoxicity
Authors: Pencil Scot D. , Brattin William J. , Glende Eric A. , Recknagel Richard O.
Published: September 2009

A consensus does not exist regarding the nature of mechanisms linking the initial events of CCl4 metabolism to emergence of the classical indices of CCl4, liver cell injury. The possibility that a CCl4-dependent disturbance of intra-hepatocellular calcium homeostasis might be a linking mechanism was investigated with isolated hepatocytes in suspension. CCl4-dependent inhibition of very low density lipoprotein secretion was studied. On the basis of kinetic data, dose-response data, and failure of elevated cytosolic calcium levels to inhibit lipid secretion, it was concluded that disturbed intracellular calcium homeostasis probably is not important in CCl4-dependent inhibition of secretion of very low density lipoproteins.
Use of Historical Control Data in Carcinogenicity Studies in Rodents
Authors: Haseman Joseph K. , Huff James , Boorman Gary A.
Published: September 2009

This paper considers the use of historical control data in the evaluation of tumor incidences from carcinogenicity studies in rodents. Although the most appropriate control group for interpretative purposes is always the concurrent control, there are instances in which the use of historical control information can aid an investigator in the overall evaluation of tumor incidence data. One example is rare tumors; another is a tumor that shows a marginally significant result relative to concurrent controls.

However, before historical control data can be used in a formal testing framework, a number of important issues must first be considered. The nomenclature conventions and diagnostic criteria for each study should be identical to insure unambiguous identification of all relevant tumors in the historical control database. Criteria should be established that will aid in determining whether a particular study should be included in the database. This will assure a homogeneous set of studies upon which to base statistical comparisons. Since study-to-study variability in tumor rates may exceed what would be expected by chance alone, these sources of variability should be identified and controlled. Finally, statistical procedures should be employed that adjust for extra-binomial variability.

This paper also summarizes tumor incidence data from untreated Fischer 344 rats and B6C3F1 mice in the National Toxicology Program (NTP) historical control database. All studies in the database are of two years duration, and all neoplasms occurring with a frequency of 0.5% or more are reported.
Phenotyping Cytochromes P450 with Monoclonal Antibodies
Authors: Friedman Fred K. , Park Sang Shin , Fujino Tadahiko , Song Byung-Joon , Robinson Richard C. , West Donna , Radkowsky Allen K. , Miller Haruko , Gelboin Harry V.
Published: September 2009

Monoclonal antibodies (MAbs) to cytochrome P-450 isozymes can be used to phenotype tissues for epitope-specific cytochrome P-450 content. MAbs that inhibit specific cytochrome P-450 dependent drug or carcinogen reactions are useful tools for quantitative measurement of the individual or classes of cytochromes P-450 that catalyze these reactions. This method has been applied successfully to animal as well as human tissues. Radioimmunoassays based on MAbs have been developed and provide a rapid and efficient means for detecting cytochromes P-450 independent of functional enzyme activity. In addition, MAbs coupled to a Sepharose support can be used to immunopurify cytochromes P-450 in a procedure that is more rapid and efficient than conventional purification schemes. MAbs add a new dimension to analyses of cytochrome P-450 multiplicity and will find numerous applications in elucidation of the relationship between cytochrome P-450 phenotype and carcinogen or drug metabolism.
Fluorescence Measurements of DNA-bound Metabolites of Benzo(a)pyrene Derivatives with Different Carcinogenic Effects
Authors: Gräslund Astrid , Jernström Bengt , Undeman Ola , Dock Lennart , Ehrenberg Anders , Astlind Torbjörn
Published: September 2009

(±)- trans-dihydroxy-7,8-dihydrobenzo(a)pyrene (BP-7,8-diol) and 9-hydroxybenzo(a)pyrene (9-OH-BP) were metabolized by rat liver microsomes in the presence of calf thymus DNA, resulting in preferential DNA binding of fluorescent (+)- anti-BP-7,8-diol-9,10-epoxide (BPDE) and 9-OH-BP-4,5-epoxide, respectively. When the DNA is denatured the fluorescence intensities of the bound metabolites change in a characteristic manner. Fluorescence decay measurements show that the intensity changes are due to changes in lifetimes of the excited states. Model substances for the bound metabolites were studied in solvents of different polarity. We found that the fluorescence changes observed after denaturation of the DNA may be explained as solvent polarity effects, so that denaturation forces the bound metabolites from a more hydrophobic environment to a hydrophilic one. Fluorescence depolarization studies as a function of temperature in combination with previous linear dichroism studies show that both BPDE and 9-0H-BP-4,S-epoxide form rigidly associated complexes with native DNA.
Comparison Between Photo-Induction and Microsomal Activation of Polycyclic Hydrocarbons with Different Oncogenic Potency
Authors: Prodi Giorgio , Grilli Sandro , Mazzullo Mario , Colacci Annamaria , Arfellini Giancarlo
Published: September 2009

The binding of five polycyclic aromatic hydrocarbons (PAH) (anthracene (A), benzo(a)anthracene (BA), dibenz(a,h)anthracene (DBA), benzo(a)pyrene (BP) and 7,12-dimethylbenz(a)anthracene (DMBA)) to calf thymus DNA and synthetic polyribonucleotides was studied. Binding was mediated by near-ultraviolet (NUV) irradiation and 3-methylcholanthrene-induced microsomes from rat liver, in order to compare the effectiveness of these two activating systems in forming in vitro intermediates capable of binding covalently to nucleic acids. With NUV irradiation, an interaction among PAH and nucleic acids was obtained regardless of the PAH or the nucleic acid employed. The effectiveness of this activating system was higher (between 1 to 2 orders of magnitude) than that shown by induced microsomes. The enzymatic pathway bioactivated all PAH, except A, to interact with DNA. Therefore, a certain degree of correlation between the extent of DNA binding and oncogenic potency of the chemicals seemed to exist. Polynucleotide labeling was always higher than DNA labeling.
Comparative Responses of Vaginal Mucosa to Chronic Pyrimidinone-induced Irritation
Authors: Gray Jack E. , Weaver Royal N. , Lohrberg Suzanne M. , Larsen Erik R.
Published: September 2009

Intravaginal studies in guinea pigs, Cebus monkeys ( Cebus apella), and beagles were made with an anti-herpes drug, 2-amino-5-bromo-6-phenyl-4(3 H)-pyrimidinone (ABPP). Concentrations of 5 to 40 mg/ml, suspended in saline or polyethylene glycol, were given for periods of 2 1/2 to 90 days. Very little gross evidence of injury was observed. Histologically, the regimens brought about increasing degrees of mononuclear cell infiltrations (histiocytes, lymphocytes, and plasma cells) in the vaginal lamina propria of the respective species. In the Cebus monkey and beagle the nonkeratinized vaginal lining became progressively thinned. The integrity of focal denuded areas was preserved by a process of homogenization in the lamina propria of the Cebus monkey. In contrast, the most severely affected areas in the canine mucosa were covered by what appeared to be a coagulated exudative layer. The effect of 90 days of treatment in the beagle did not noticeably increase the severity of the findings beyond that observed after 30 days. Considerable reversibility of the lesions occurred in guinea pigs held for 1 week and in Cebus monkeys held for 3 weeks posttreatment. Local cell-mediated immunity was believed to be implicit with the mononuclear cell infiltration in the lamina propria of the vagina.
Free Radical Intermediates under Hypoxic Conditions in the Metabolism of Halogenated Carcinogens
Authors: Tomasi Aldo , Albano Emanuele , Bini Anna , Botti Barbara , Slater Trevor F. , Vannini Vanio
Published: September 2009

Many halogenated hydrocarbons are known to have carcinogenic potency, nevertheless, humans may be exposed to such xenobiotics for prolonged periods during industrial occupations. In this study, eight aliphatic haloalkanes, all suspected carcinogens, have been studied with respect to their metabolic activation to free radical intermediates, that may exert toxic effects when produced in vivo. The eight haloalkanes studied here are: carbon tetrachloride, chloroform, 1,2-dibromoethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trich-loroethane, 1,1,2-trichloroethane and 1,1,2,2-tetrachloroethane. Using isolated rat hepatocytes as a model system, and electron spin resonance spectroscopy coupled to the spin trapping technique as a detection technique, it has been possible to demonstrate the formation of free radical derivatives, both under normoxic as well as under hypoxic conditions from carbon tetrachloride, chloroform, 1,1,1-tetrachloroethane and 1,1,2,2-tetrachloroethane. In contrast, free radical production was only detectable under hypoxic conditions when 1,2-dibromoethane, 1,1-dichloroethane, 1,2-dichloroethane and 1,1,2-trichloroethane were added to the hepatocyte suspensions. It is known that some xenobiotics that usually undergo oxidative pathways of metabolism can be metabolized differently when the oxygen concentration is substantially diminished. Evidence have been obtained suggesting that such different types of metabolism may be of relevance in vivo. Possible relationships between free radical production, metabolic activation, covalent binding and carcinogenic potency are discussed.
Streptozotocin-induced Functioning Islet Cell Tumor in the Rat: High Frequency of Induction and Biological Properties of the Tumor Cells
Authors: Masiello Pellegrino , Wollheim Claes B. , Gori Zina , Blondel Benigna , Bergamini Ettore
Published: September 2009

After a long latency, hormone-producing islet cell tumors are induced with high frequency by a single administration of streptozotocin and nicotinamide in the rats. Thus, pancreatic islets must be considered a target tissue for the tumorigenic, as well as diabetogenic, action of streptozotocin. These tumors are well-differentiated and resemble normal islet tissue, both morphologically and functionally, as they are rich in typical β cells and release insulin in response to glucose, both in vivo and in culture. However, some noteworthy differences have been observed in comparison to normal tissue: (a) the release of large amounts of proinsulin after glucose stimulation, (b) the presence of granulated cells of uncertain classification, similar but not identical, to δ cells, and (c) the altered proportion in hormone content, which suggests a different sensitivity of the different islet cell types to the chemically induced transformation.
Chemical Carcinogenesis: Hepatocyte Nodules with a Special Phenotype As a Common Step at the Crossroads
Authors: Farber Emmanuel , Eriksson Lennart C. , Roomi M. Waheed , Cameron Ross G. , Hayes M. Anthony
Published: September 2009

Unlike the great heterogeneity and diversity in the initial interactions of a chemical carcinogen with DNA and in the phenotypes of the late malignant neoplasms, the intermediate steps in liver carcinogenesis, the hepatocyte nodules, are remarkably similar. This commonality is seen in six different models of liver cancer development using carcinogens and promoters of quite different chemical structure and properties. The hepatocytes in the nodules show a similar arrangement and architecture, cytology and cytochemistry, blood supply, biological behavior, and biochemical pattern. These observations, coupled with the program nature of the remodeling of the hepatocyte nodules, strongly suggest that at least some of the earlier steps in carcinogenesis are of a physiological adaptive nature.
Increased Incidence of Hepatic Foci and Nodules in Rats Given One or Two Doses of 1,2-Dibromoethane
Authors: Moslen Mary Treinen
Published: September 2009

Livers of male Sprague-Dawley rats were evaluated for foci and nodules 90 days and 16 months after one or two oral doses of 1,2-dibromoethane (DBE). Rats (190 g) were given the following oral treatments. Controls received corn oil (2.5 ml/kg) at 0 and 24 hr. DBE × 1 received corn oil at 0 hr and 75 mg DBE/kg at 24 hr. DBE × 2 received 75 mg DBE/kg at 0 and 24 hr. All rats underwent a two-thirds partial hepatectomy at 28-29 hr, a one-third partial hepatectomy at 90 days, and were given 0.05% phenobarbital in drinking water for 4 months beginning at 1 yr. DBE was given to the DBE × 2 group twice within 24 hr because the compound is a hepatocyte mitogen. At 90 days, no appreciable changes were evident in any group. At 16 months, the incidence of nodules in the DBE × 2 group (25 of 41) was double that of the DBE × 1 group (12 of 38) ( p < 0.01) and triple that of the control group (6 of 34) ( p < 0,0001). Both the DBE × 1 and the DBE × 2 groups had higher incidences of eosinophilic foci, and also higher numbers, larger sizes, and larger areas of γ-glutamyltranspeptidase-positive foci than the control group. These results demonstrate for the first time that hepatocyte foci and nodules are initiated by limited exposure of animals to DBE.
The Possible Role of Nitrosamines in the Link between Alcohol Consumption and Esophageal Cancer in Man
Authors: Swann Peter F.
Published: September 2009

Ethanol in amounts equivalent to a man drinking a pint of beer has a dramatic effect on the metabolism and distribution of nitrosamines in rats. It prevents the first pass clearance of dimethylnitrosamine and thus exposes the extrahepatic organs to oral doses of this carcinogen. By selectively inhibiting metabolism in liver and kidney, ethanol increases the amount of diethylnitrosamine activated in the esophagus between 1.8- and 4.6-fold. It is suggested that there may be a link between these observations and the increase in human esophageal cancer which is associated with alcohol consumption.
Identification of Chemicals Carcinogenic to Man
Authors: Wilbourn Julian D. , Haroun Lynne , Vainio Harri , Montesano Ruggero
Published: September 2009

Although both the epidemiologic and experimental studies have led to the identification of chemical carcinogens, the limitations in epidemiologic approaches and the need for primary prevention of cancer require a greater reliance on experimental studies. Long-term carcinogenicity studies in experimental animals have been instrumental in identifying chemicals with carcinogenic activity, and, in some cases, the experimental evidence has preceded the epidemiologic evidence (for 4-aminobiphenyl, aflatoxin B1, diethylstilbestrol, melphalan, mustard gas, and vinyl chloride). A better understanding of the multistage process of carcinogenesis and the findings from various short-term tests available more recently may provide a more solid basis for extrapolating experimental findings to man.
Characterization of Dimethylnitrosamineinduced Focal and Nodular Lesions in the Livers of Newborn Mice
Authors: Cater Kathleen C. , Gandolfi A. Jay , Sipes I. Glenn
Published: September 2009

Newborn Swiss-Webster mice were given an intraperitoneal injection of 25 μg of dimethylnitrosamine. At weaning they began receiving 0.05% phenobarbital in the drinking water to promote the lesions for the term of the study. Preneoplastic foci and hyperplastic nodules were identified histologically by two markers, resistance to exogenous iron accumulation and an increase in γ-glutamyltranspeptidase activity. AT 8, 12, and 16 weeks of age, livers of affected male mice exhibited 12, 18, and 12 iron-resistant foci/cm2 and 13, 9, and 9 γ-glutamyltranspeptidase-positive foci/cm2, respectively (average for median right and right anterior sublobes). Iron-resistant nodules were first observed at 8 weeks; however, γ-glutamyltranspeptidase-positive nodules were not noted until 12 weeks. In animals that received dimethylnitrosamine but were not placed on phenobarbital, there was an average of 5 foci/cm2 (iron-resistant or γ-glutamyltranspeptidase-positive) at 12 weeks while no nodules were noted. This model could provide a practical short-term in vivo tool for the detection of early sequential cellular alterations produced by initiators, inhibitors, and promoters of carcinogenesis.
Neoplasia Induced in Male Rats Fed Lead Acetate, Ethyl Urea, and Sodium Nitrite
Authors: Koller Loren D. , Kerkvliet Nancy I. , Exon Jerry H.
Published: September 2009

Sprague-Dawley rats were exposed to 0, 26, or 2600 ppm lead as lead acetate in drinking water for 76 weeks. At 28 weeks of lead exposure, a portion of each group was exposed simultaneously to 6.36 g/kg ethyl urea (EU) and 2.0 g/kg sodium nitrite (NaNO2) for a duration of 20 weeks, and then continued an additional 28 weeks on standard diet free of EU and NaNO2. The animals were observed for incidence, latency, and distribution of tumors. Rats exposed to 2600 ppm lead alone had 81% renal tumors, while rats given 2600 ppm lead in combination with EU/NaNO2 had a 50% incidence. Renal tumors did not occur in the EU/NaNO2 only or EU/NaNO2-26 ppm lead groups. The major tumor type found in EU/NaNO2-exposed rats was lymphosarcoma. ***Lead did not appear to be syncarcinogenic to the activity of ethylnitrosourea, the carcinogen formed by oral exposure to EU and NaNO2. The lead-induced renal neoplasms were histologically similar to those which occur spontaneously in man and, therefore, may serve as an animal model to study human disease.