bluuebunny/crossref_metadata_2025 huggingface dataset:
Toxicity Studies on the Radioprotective Agent WR-2721 in CDF1 Mice and Beagle Dogs
Authors: Palmer Thomas E. , Glaza Steven M. , Dickie Bruce C. , Weltman Robert H. , Greenspun Katherine S.
Published: September 2009

WR-2721, S-2-(3-aminopropylamino)ethylphosphorothioic acid, is used extensively to protect normal cells during the irradiation of neoplastic cells. Dose levels for human radiotherapy are based on results obtained from laboratory animal lethality and toxicity studies. WR-2721 was administered intravenously to CDF1 mice and beagle dogs. Single dose lethality studies in mice showed the average 1/10 of the lethal dose, the median lethal dose and 9/10 the lethal dose to be 508 (1523 mg/m2), 589 (1766 mg/m2), and 682 mg/kg (2047 mg/m2), respectively. The lethal dose for female mice was lower than that for males. The 1/10 lethal dose in mice was slightly toxic to dogs; 1/10 of that dose was nontoxic. The lethal dose for dogs (6000 mg/m2) was higher than that for mice (2000 mg/m2). Clinical signs of toxicosis in the single-dose mouse toxicity study were evident in the 1st week following treatment and declined during the recovery period; signs of toxicosis were transient in dogs. Acute drug-induced pathologic changes included elevated BUN and SGOT levels, lymphoid necrosis, and renal tubular degeneration in mice. These changes were evident in the 1st week following treatment, but had dissipated by study termination. Generalized vascular changes (congestion, hemorrhage, and edema) and renal tubular degeneration occurred in treated dogs that had died or were killed moribund 7 days postinjection. These findings indicate sex-dependent and interspecies variation in the toxicity of WR-2721 with acute, but reversible, pathologic changes.
Factors Influencing Laboratory Animal Spontaneous Tumor Profiles
Authors: Hardisty Jerry F.
Published: September 2009

In chemical carcinogenicity and drug-safety testing, a cacinogen is defined as an agent that when administered by an appropriate route causes an increased incidence of tumors in experimental animals as compared to unexposed control animals. Although a carcinogen may cause the appearance of tumors in organs where tumors do not usually occur in a given strain, the usual response is to increase the types of tumors seen spontaneously and to shorten the period of latency. The use of cacinogenesis experiments for research and safety assessment requires properly designed and well-conducted experiments and a knowledge of background data and variations in tumor incidences of control animals. Many factors can influence the reported incidences of spontaneous tumors. These include species, strain, sex, age, and source of the experimental test animal; study duration; extent of the pathology examination; dietary and environmental conditions; qualifications and experience of the study pathologist; diagnostic criteria and nomenclature conventions; and quality assurance and review procedures. This paper discusses several factors which may influence the incidence of tumors in control and test animals, and provides examples to illustrate the potential for these factors to affect the data.
The Value and Significance of Life Span and Scheduled Termination Data in Long-term Toxicity and Carcinogenesis Studies
Authors: Solleveld Henk A. , Mcconnell Ernest E.
Published: September 2009

Consideration is given to the age association of lesions, the duration of long-term toxicity and carcinogenesis studies, and to the value and significance of including scheduled termination in such long-term studies. There is now enough evidence that age and cancer are associated. It is argued that the increase in incidence of lesions with age has such disadvantages that extension of the duration of the long-term toxicity and carcinogenicity study beyond 2 years is not warranted in most cases. Incorporation of scheduled termination in long-term studies gives more insight into the biologic behavior of toxic lesions and cancer and may enable one to make a distinction between “incidental” and “fatal” lesions. This distinction may be important for the statistical evaluation of data from chemical carcinogenesis studies.
Species, Sex, and Tissue Specificity in Toxicologic and Proliferative Responses
Authors: Alden Carl L.
Published: September 2009

Responsible regulatory decisions regarding the fate of new chemicals require careful evaluation of a host of health, economic, and social factors, in addition to a thorough evaluation of potential risks. In risk assessment, laboratory animals are used as human surrogates in testing for potential chemical effects since mammals are anatomically, physiologically, and biochemically similar and, in most cases, have similar responses to exogenous chemical, biologic, and physical agents (with differences in response usually quantitative rather than qualitative). Unfortunately for the sake of proper extrapolation to humans, qualitative differences do occur, resulting in species, sex, and/or tissue specificity in toxicologic/proliferative responses. Since the toxicologic pathologist is trained in comparative medicine he/she must play a primary role in recognizing and demonstrating specificities in tissue alteration of laboratory animals by new chemicals of potential importance to society. A model exemplifying the recognition and demonstration of species, sex, and tissue specificity of test substance response will be described. In this model a presumably unique alteration of male rat kidney occurred in response to a specific class of test substances. The decision tree in establishing specificity, as well as the nature of the test substances, will be described.
Skin Irritation Testing in Rabbits Complicated by Dermal Mucormycosis
Authors: Morgan Ronald L. , Castles Thomas R. , Zwicker Gary M. , Taylor Dee O. N.
Published: September 2009

Two insecticide formulations were evaluated for skin irritation using albino rabbits (Stauffland-White strain). While the active ingredient alone produced only mild skin irritation, corn grit formulation produced severe skin irritation. Corn grit from three sources (A, B, and C) was similarly evaluated for skin irritation and at 24 hr, all samples produced erythema and edema of both the abraded and nonabraded test sites. Eschar was observed in 72 hr in about half of the rabbits and persisted through termination on the 7th day. Histologic examination of skin specimens revealed that all three corn grit samples produced epidermatitis. In addition, rabbits exposed to corn grit from two sources (A and B), developed moderate focal to severe diffuse suppurative necrotizing folliculitis and dermatitis. Large tubular branching nonseptate hyphae compatible with the Mucorales species were seen in hair follicle micropustules of rabbits treated with corn grit from sources A and B. Mycologic culture techniques applied to corn grit from each source revealed a potential pathogen in the genus Rhizopus isolated from samples from sources A and C but not B. The skin irritation test involved application of test material covered with gauze to both abraded and nonabraded skin. Rubber damming was placed over the gauze and secured with tape. After 24-hr exposure all bandaging and visible test material were removed. Skin irritation was evaluated immediately after removal and then periodically until termination at 7 days.
The Effect of Exsanguination on Organ Weight of Rats
Authors: Sullivan David J.
Published: September 2009

In three experiments, rats were anesthetized and killed by exsanguination or were killed by an overdose of anesthetic and not exsanguinated. The second group of rats in each experiment mimicked rats found dead on toxicology studies. Liver and kidney weights of rats killed by exsanguination were statistically significantly lower than those of rats not exsanguinated both in terms of gross organ weight and of percentage of body weight. The results of these experiments indicate that organ weight data of rats killed by exsanguination should be segregated from those of rats found dead. In fact, because of uncontrollable variables, organs of rats found dead should not be weighed.
A Pilot Study in Adult Rhesus Monkeys (M. mulatta) Treated with Aroclor 1254 for Two Years
Authors: Tryphonas Leander , Arnold Douglas L. , Zawidzka Zofia , Mes Jos , Charbonneau Sylvia , Wong James
Published: September 2009

Aroclor 1254, at a dose level of 280 μg/kg body weight equivalent to 200 μg/kg/day, was given 5 days per week to rhesus monkeys over a 27 to 28 month period. Terminal clinical signs of varying severity included fingernail detachment, exuberant nail beds, weight loss, stomatitis and normocytic anemia. At necropsy the bone marrow was hypocellular with increased M:E ratio and cytoplasmic vacuoles in crythroid precursor cells. Histopathologic lesions included dilatation of the tarsal gland ducts, atrophy or absence of splenic and lymphonodal germinal centers, bone marrow depletion, gingival erosion and ulceration, moderate mucinous hypertrophic gastropathy with cystic dilatation of occasional gastric glands, hepatocellular enlargement and necrosis, hypertrophy of biliary duct epithelium, hyperplasia of biliary ducts, hypertrophy of the gall bladder epithelium, and an equivocal increase in the number of lysosomes in thyroid follicular epithelial cells. PCB tissue concentrations were lowest in brain and highest in blood. The results suggest that severe potentially fatal PCB toxicity can develop in rhesus monkeys following ingestion of Aroclor 1254 at 200 μg/kg/day for a period of 27 months or longer.
Spontaneous Renal Disease in Dogs
Authors: Robertson John L.
Published: September 2009

Renal disease is common in dogs. The incidence of significant renal disease increases with age. Many disease processes are subtle and subacute, and so many are not detected until they result in chronic renal failure. The causes of many renal diseases are not known but one must suspect immune-mediated damage in some.
Age-Related Variations in Renal Structure and Function in Sprague-Dawley Rats
Authors: Owen Roger A. , Heywood Ralph
Published: September 2009

Data from 500 male and 500 female Sprague-Dawley rats used as controls in studies performed at Huntingdon Research Centre to assess the safety of drugs were sampled at 17, 30, 56, 82, or 108 weeks of age. Plasma urea nitrogen levels remained constant, except in aged males. Aging caused increased proteinuria and decreased urinary concentrating ability, in addition to increased size, weight, and degree of cortical scarring of kidneys. Chronic progressive nephropathy, first seen histopathologically at 30 weeks of age, accounted for these changes and ultimately affected 81% of male and 44% of female rats. One-fifth of two-year-old male rats had diffuse parenchymal damage and a small number also had secondary hyperparathyroidism. Other notable changes included basophilic (often colloid-filled) cortical tubules, mononuclear cell infiltrations, parenchymal and pelvic mineralization, urothelial hyperplasia, and pyelonephritis. Miscellaneous low incidence findings included one lipomatous tumour and generalized lymphosarcoma.
Spontaneous Renal Lesions in Five Rat Strains
Authors: Solleveld Henk A. , Boorman Gary A.
Published: September 2009

A survey of non-neoplastic and neoplastic renal lesions found in 5 rat strains, namely, ACI (August x Copenhagen Irish), A22807 (August), F344 (Fischer), M520 (Marshall), and OM (Osbome-Mendel) is given. The results from this survey indicate that the OM, M520, and ACI rat strains have major disadvantages for their use in long-term toxicology and carcinogenesis studies. Male OM rats had a high incidence of renovascular lesions which consisted of necrotizing arteritis or arteriolitis and intimal thickening of small arteries, and resembled renal lesions described in hypertensive rats and human patients. Predominant renal lesions in the M520 and ACI rat strains included extensive calculus formation at the pyramido-pelvic junction, which was of ten associated with proliferative pelvic transitional cell lesions and hydronephrosis. The ACI rat strain also had unilateral congenital renal agenesis in about 12% of the animals of either sex. Based on the spectrum of renal lesions observed in the 2 remaining rat strains, namely A28807 and F344, it is difficult to determine which one of the two should be preferred for long-term studies. The A28807 rat strain had less severe chronic renal disease than the F344 but had a higher incidence of pelvic transitional cell hyperplasia. The ultimate choice should be based on the spectrum, incidence, and severity of extra-renal lesions.
Autoimmune Disease Induced by Oral Administration of Mercuric Chloride in Brown-Norway Rats
Authors: Knoflach Peter , Albini Boris , Weiser Milton M.
Published: September 2009

Only few reports are available on the consequences of chronic oral administration of low doses of mercuric chloride (HgCl2). Forty Brown-Norway rats received 150 μg HgCl2/100 g body weight 3 times a week by gavage or by i.m. injection with 100 μg twice per week. After 2 weeks of oral HgCl2 administration, the rats lost weight and hair. Phases of proteinuria were observed in weeks 5–8 and then continuously from week 12 until the end of the experiment at week 39. Antibodies binding to renal, intestinal, and vascular basement membrane developed after 2 weeks; circulating immune complexes were detectable in increasing titers starting at week 3. There were linear deposits of IgG, IgM, and IgA in the glomerular basement membrane and tubular basement membrane, and along the intestinal basement membrane. After week 11, the first granular immune deposits were observed in renal and intestinal basement membranes. Light microscopy showed thickening of glomerular basement membrane, mesangial matrix, and tubular basement membrane. In addition, interstitial nephritis was observed in some animals. Interestingly, kidney involvement was as severe in the orally as the i.m.-treated animals.
Nephrotoxicity of Hexachlorobutadiene and Its Glutathione-Derived Conjugates
Authors: Ishmael John , Lock Edward A.
Published: September 2009

The nephrotoxicity of hexachloro-1,3-butadiene (HCBD), its glutathione conjugate (HCBD-GSH), cysteine conjugate (HCBD-CYS), and its N-acetyl cysteine conjugate (HCBD-NAC) were compared in male and female Alderley Park rats. Rats, six to eight weeks of age, were given a single intra-peritoneal injection of HCBD or its conjugates and killed 24 hours later. Nephrotoxicity was assessed by histological examination and plasma urea. All three glutathione-derived conjugates produced an elevation of plasma urea and proximal renal tubular necrosis with a similar localization in the pars recta as seen with HCBD. All the conjugates were more nephrotoxic than HCBD itself. HCBD was about four times more toxic to female rats than males. This sex difference was also shown by all the HCBD metabolites.
Cell-Cell Interaction and Carcinogenesis
Authors: Yamasaki Hiroshi
Published: September 2009

Before carcinogenic stimuli are introduced, a potentially cancerous cell functions normally; growth is controlled and the cell exists in complete harmony with that of surrounding cells in a given tissue. During the process of multi-stage carcinogenesis, such harmony is destroyed and a presumptive initiated cell accomplishes a clonal expansion, neglecting the growth pattern of surrounding normal cells. Recent results from our own laboratory and others strongly suggest that blocked gap-junctional intercellular communication is an important determinant during the process of tumor promotion.
Glutathione Synthesis in Normal Liver and in Yoshida AH-130 Hepatoma
Authors: Biocca Maria E. , Canuto Rosa A. , Muzio Giuliana , Rossi Maria A. , Dianzani Mario U.
Published: September 2009

The amount of reduced glutathione in transplantable hepatomas and in a primary DEN-induced hepatoma is lower than in normal liver. In all tumors examined, the glutathione decrease is not due to an increase of oxidized glutathione. In this paper the in vitro activities of two enzymes involved in glutathione synthesis, γ-glutamylcysteine synthetase and glutathione synthetase, are studied in normal adult rat liver, in regenerating rat liver and in highly anaplastic Yoshida AH-130 hepatoma cells. The activity of these enzymes was determined in the postmicrosomal supernatant fraction as nmoles of [U-14C]-glutamate incorporated into product per mg of soluble protein. In Yoshida AH-130 hepatoma, the γ-glutamylcysteine synthetase and glutathione synthetase activities are lower in respect to normal liver. This is in agreement with the low glutathione content observed in the hepatoma cells. On the other hand, in regenerating liver, there are minimal differences in comparison with normal liver.
In Vitro Models for Studying the Molecular Biology of Carcinogenesis
Authors: DiPaolo Joseph A. , Burkhardt Anne , Doniger Jay , Pirisi Lucia , Popescu Nicholas C. , Yasumoto Shigeru
Published: September 2009

Although carcinogens cause various similar deleterious effects on rodent and human cells, only rodent cells can convert to malignancy in a quantitative, predictable fashion. Therefore, the control mechanisms involving indefinite proliferation and tumorigenicity are different. Human cell lines may exhibit normal or aneuploid chromosome constitutions with numerical or structural alterations frequently involving proto-oncogene loci, but fail to produce progressively growing tumors in nude mice. A new approach for obtaining human cells susceptible to malignant transformation by chemical or physical carcinogens is to use DNA from a cancer associated virus. Transfection of human papilloma virus (HPV) DNA associated with genital cancer can extend life-span of human cells; post-X-irradiated cells grow in agar suspension. Southern blot analysis of extracted DNA indicates that HPV sequences persist. Similar results are obtained with human fibroblast and epithelial cells.
Regulatory Aspects of Cholesterol Metabolism in Cells with Different Degrees of Replication
Authors: Rao Kalipatnapu N.
Published: September 2009

This study explored cholesterol biosynthesis and its possible involvement in cell proliferation and cancer development. Normal proliferating cells and cancer cells were used to study the regulation of the cholesterol biosynthetic pathway. Evidence is presented that shows a positive correlation between the activity of the HMP pathway, DNA synthesis, and cholesterol biosynthesis; this evidence also shows a negative correlation between circulating cholesterol levels and/or cholesterol influx from serum to rates of cell proliferation. It is suggested that since cell proliferation is a prerequisite for the development of cancer, altering the HMP pathway, circulating cholesterol levels, and cholesterol influx from serum alters rates of cell proliferation and development of cancer.
Comparative Studies on Protein Turnover Regulations in Tumor Cells and Host Tissues: Development and Analysis of an Experimental Model
Authors: Tessitore Luciana , Bonelli Gabriella , Isidoro Ciro , Kazakova Olga V. , Baccino Francesco M.
Published: September 2009

The protein mass of cells and tissues is determined by the relative rates of protein synthesis (PS) and degradation (PD). A convergent modulation of both PS and PD is operated by many cell types to regulate protein accumulation and thus growth. Transformed and neoplastic cells may show markedly defective PD regulations. Yet even highly-deviated cells such as those of the transplantable Yoshida ascites hepatoma AH-130 cease growth when attaining a conspicuous population size, by operating a combined reduction of PS and acceleration of PD. As in normal cells, PD acceleration is effected through an activation of the acidic-vacuolar (lysosomal) mechanism. AH-130 tumor-bearing rats develop a markedly negative nitrogen balance early after transplantation. Tumor growth involves pronounced perturbations in host body and tissue protein metabolism. Apparently, these changes occur mostly at the level of PD rather than PS, at least in liver and skeletal muscle (gastrocnemius). These observations indicate that either tumor and host cells sense different signals for PD regulations or their thresholds for the same signals are poised differently. This model seems most suitable for further studies to elucidate which signals and mechanisms are involved in these protein metabolic perturbations and possibly, to develop the rationale for adequate corrective strategies.
Endogenous Formaldehyde Does Not Produce Detectable DNA-Protein Crosslinks in Rat Liver
Authors: Lutz Werner K.
Published: September 2009

Formaldehyde is an electrophilic molecule able to crosslink DNA and protein. It has been found to induce tumors in the nasal epithelium in rodents. The safety margin between the maximum tolerated FA concentration in the work place and the concentration found to be tumorigenic in animal studies is very small. Because FA is produced endogenously as a result of a variety of oxidative demethylations, the assessment of the tumor risk from exogenous FA exposure has to be related quantitatively to the level of DNA-protein crosslinks induced by endogenous FA generation. It is reported here that the high level of endogenous FA formed in the liver after a large dose of methanol or of aminopyrine did not lead to any observable increase in DNA-protein crosslinks. Using positive and negative control data from in vitro incubations of liver homogenate with FA or methanol it is estimated that the endogenous level of DNA damage in the liver must be more than three orders of magnitude below the damage observed at tumorigenic concentrations for the rat nose. The fact that FA is formed endogenously cannot, therefore, be used to claim that exogenous FA merely leads to a negligible increase in DNA damage.
Possible Model of Liver Carcinogenesis Using Inhibitors of NAD+ ADP Ribosyl Transferase in Rats
Authors: Konishi Yoichi , Takahashi Sehchi , Nakae Dai , Uchida Kazuhiko , Tsutsumi Masahiro , Shiraiwa Kazumi , Denda Ayumi
Published: September 2009

The response of cellular NAD+ metabolism to DEN and/or ABA and the carcinogenesis of the liver initiated by DEN and ABA were studied in rats. The liver NAD+ level was depleted by an ip injection of 20 mg or 200 mg/kg body weight of DEN. ABA, administered ip at a dose of 600 mg/kg simultaneously with or 4 hours after DEN, prevented the depletion of NAD+ by DEN. These biochemical findings correlated with the changes of conspicuous intranuclear immunofluorescence of poly(ADP-ribose), which were studied by immunohistochemistry. When initiated by 20 mg/kg body weight DEN and 600 mg/kg ABA and then processed to selection pressure, the liver was found to be capable of developing hepatocellular carcinomas with or without PB promotion. These results suggest that the inhibition of poly(ADP-ribosylation) might lead to irreversible initiation of liver carcinogenesis by DEN in rats.
HMP-Shunt and Cholesterol Metabolism in Experimental Models Involving Normal and Preneoplastic Liver Growth
Authors: Columbano Amedeo , Dessì Sandra , Ledda-Columbano Giovanna Maria , Chiodino Caterina , Coni Pierpaolo , Pani Paolo , Rao Kalipatnapu N.
Published: September 2009

Previous studies from our laboratories have shown a stimulation of HMP-shunt, cholesterol metabolism and DNA synthesis during cell proliferation. In order to understand the co-ordinated regulation of these pathways during cell growth, the above metabolic pathways were studied in: 1) liver regeneration after partial hepatectomy, 2) lead-induced liver hyperplasia, 3) liver cell proliferation induced by insulin in streptozotocin-diabetic rats, 4) liver cell proliferation in fasted rats after refeeding and, 5) hepatocyte nodules induced by a selection procedure. The results indeed indicate that changes in HMP-shunt and cholesterol metabolism occur at a very early stage during the process of normal as well as preneoplastic cell growth. The coordinated regulation between cell growth and changes in these metabolic pathways needs further study.
Immunochemical Studies of Microsomal Membranes of Rat Preneoplastic and Neoplastic Hepatocytes
Authors: Ogawa Katsuhiro , Narasaki Masanobu , Mori Michio
Published: September 2009

Heterogenous rabbit antisera were prepared against microsomal proteins of hyperplastic hepatic nodules (HPN) induced by chemicals, and were utilized to assess the antigenic differences of microsomal polypeptides within a normal liver, HPN, and hepatocellular carcinomas (HCC), utilizing immunodetection of antigens separated electrophoretically and transferred to nitrocellulose. Although most antigens were common to all microsomes, differences (increase or decrease) were noted in some polypeptides not only between the normal liver and HPN, but also between HPN and HCC. On the other hand, monoclonal antibodies against epoxide hydrolase (EH), which was initially found as the PN antigen, reacted to a single polypeptide with a molecular weight of 49,000 in all the microsomes. These results suggested that there is little molecular modification of EH during hepatic carcinogenesis.
Preliminary Results of a Geographic Correlation Study on G6PD Deficiency and Cancer
Authors: Cocco Pierluigi , Manca Pierina , Dessì Sandra
Published: September 2009

Checking the resident 1,868 males found to be G6PD deficient out of 15,964 examined, we observed the percentage of G6PD deficiency in male population largely varying among the various Sardinian towns ranging from 1 to over 50%. As preliminary analysis, in 24 towns out of 39 in which the sample was sufficiently suggestive of their whole resident male population, we calculated Standardized Mortality Rates (SMR) for all cancers and linear regression between SMRs and frequency of G6PD deficiency in the same towns. Previous observations suggested the hypothesis of a negative correlation between frequency of G6PD deficiency and incidence of cancer, as we found in the preliminary analysis of this study. The results are not sufficient either to accept or to refuse this hypothesis.
Complementarity Between Two Rat Liver Tumor Promoters
Authors: Laconi Ezio , Vasudevan Shanthi , Rao Prema M. , Rajalakshmi Srinivasan , Sarma Dittakavi S. R.
Published: September 2009

A delay in the exposure of initiated rats to orotic acid (OA) beyond a specific time frame results in a progressive loss of promotional effect in liver carcinogenesis. The current study was designed to ascertain whether the loss of promotional effect could be counteracted by pre-exposing the initiated animals to other rat liver promoting regimens such as a diet deficient in choline (CD). Male Fischer 344 rats (150 g) were initiated with diethylnitrosamine (200 mg/kg, ip); 1 week later they were given either a CD diet or a CD diet supplemented with choline for 5 weeks. Animals from these two groups were then fed either a 1% OA diet or the basal diet for another 20 weeks. The results indicated that the loss of OAs promotion efficacy from delaying the start of the promoting regimen can be counteracted by pre-exposing the initiated rats to a CD diet. Thus in rats exposed to OA from the first week of initiation, 7% of the liver developed as nodular areas, whereas only 0.8% of liver was nodular when OA feeding was delayed by 5 weeks. This loss was abolished when initiated rats were fed a CD diet for 5 weeks prior to feeding OA for 20 weeks. These results suggest that in a rat liver tumor promotion model, two tumor promoters, OA and CD, show some degree of complementarity when given sequentially.
Utilization of the Quantitative Component of the Information Obtained from Short Term Tests
Authors: Parodi Silvio , Boero Paolo , Taningher Maurizio , Storace Paola , Santi Leonardo
Published: September 2009

We are referring in this paper to traditional tests of genotoxicity that are essentially detecting properties correlated with the initiating activity of chemical and physical agents. In classical initiation-promotion experiments, promotion is changing dramatically tumor frequency, but a better correlation between initiation and tumor frequency may exist when carcinogenesis experiments in rodents utilize only an initiator agent. End points, metabolism and target organs of short term test may be not optimal in respect to the real initiation process. In conclusion, we have to expect a very high level of statistical noise in the correlation between short term tests and carcinogenicity in rodents. Correlations of this type are not unique in science. For instance, the input data for weather forecasting and the real weather are of ten related with a high level of statistical noise. But this is not considered a good reason for throwing away the quantitative component of the input information. Similarly, in this context the utilization of the quantitative component of the information improves in a moderate, but not negligible way the predictive value of the information of fered from short term tests, especially when they are used in a battery. In this review we discuss the possibility that, when studying correlations between genotoxicity tests and carcinogenicity in rodents, a quantitative approach could replace with important advantages the qualitative approach generally adopted up to the present time. The qualitative approach appeared as a more modest but realistic approach to the complexities of these correlation studies. What we suggest is that a quantitative approach mathematically not less correct than the qualitative approach is feasible. More precise and useful information for risk assessment evaluations can be obtained.
The Complementary Role of Primary Prevention, Early Detection, and Therapy in Our Fight Against Cancer
Authors: Santi Leonardo , Bruzzi Paolo A. , Parodi Silvio
Published: September 2009

Public health strategies for cancer control are determined by the epidemiological, clinical and biological characteristic of each cancer. Primary prevention is most easily implemented in cancers due to one or few factors. Secondary prevention is best suited for frequent cancers with a long preclinical, detectable phase. Therapy has to be relied upon in rare cancers of unknown etiology. A critical evaluation of the accomplishments of these three approaches shows that the potential role in cancer control of early detection and treatment is severely hampered by the high social and human costs, that are only partially counterbalanced by the limited effectiveness. As a consequence, primary prevention should be regarded as the key approach to cancer control, and efforts should be concentrated on studies concerning cancer etiology and on the implementation of preventive measures.
Three Stage Carcinogenesis in Mouse Skin—Recent Results and Present Status of an Advanced Model System of Chemical Carcinogenesis
Authors: Hecker Erich
Published: September 2009

In the three stage model of carcinogenesis in mouse skin, to a certain compartment of normal cells new and adverse biological properties are imposed by the initiator DMBA yielding ‘potential tumor cells,’ or ‘initiated cells.’ These initiated cells exhibit a selective advantage of growth over surrounding normal cells if exposed to DTE promoters. The new properties may result from a genomic mutation associated with an increase of density, affinity or cooperativity of certain membrane receptors as compared to normal cells. Complete promoters, such as TPA, but not incomplete promoters such as RPA may impose a second additional genomic or epigenomic insult onto initiated cells (‘conversion'). As a consequence, initiated cells become ready to respond to unspecific mitogenic stimuli (‘propagation'), as provided by hyperplasiogenic agents. The initiation/promotion model of mouse skin presents new and attractive possibilities to apply the oncogene approach for further in-depth analysis of the molecular mechanisms of its stages. It remains to be seen to what extent molecular events demonstrated causative for the stages in the mouse skin model are applicable also to stages in multistage models of chemical carcinogenesis operational in other target tissues.
Collaborative Multidisciplinary Approach to Investigation of Chemical-Induced Contact Dermatitis
Authors: Ruben Zadok
Published: September 2009

Immune-mediated contact dermatitis induced by chemicals is a complex biologic process, the pathogenesis of which is not completely understood. Some immuno-dermatotoxins also induce direct dermatotoxicity. This pathogenic complexity presents a serious problem if one wishes to screen chemicals for dermatotoxic effect and investigate their pathogenic mechanism. Rapid toxicologic assays such as the mouse ear swelling test are excellent for detecting chemicals that cause contact dermatitis, but are limited for pathogenic investigations. Morphologic pathology is important for determining which pathologic reactions are involved, but is a relatively crude method for investigating immunobiologic mechanisms. Immunobiologic studies are being used for mechanistic investigations, but the relevance of many measured end points to assessment of immunotoxicity is still unclear. A collaborative multidisciplinary approach involving investigators conducting rapid toxicologic screen tests, morphologic pathology and immunobiology studies is proposed as a solution. This approach is based on complementary integration of the disciplines, and considers the advantages and limitations of each specialty.
Extrahepatic Lesions Induced by Acetaminophen in the Mouse
Authors: Placke Michael E. , Wyand D. Stuart , Cohen Steven D.
Published: September 2009

Acetaminophen in acute overdose is primarily recognized as potentially hepatotoxic with few descriptions of extrahepatic lesions other than nephrotoxicity. Fasted adult, male mice, both standard and germ-free, were given acetaminophen orally and killed at selected times, from 30 minutes to 48 hours after treatment. In addition to the expected hepatic effects after 600 mg acetaminophen/kg, degenerative and necrotic changes were found in four non-hepatic tissues. Nephrosis developed 2 to 4 hours after treatment and paralleled the course of hepatic damage. Necrosis of bronchiolar epithelium in the absence of inflammation was evident 4 to 6 hours after acetaminophen administration as was onset of testicular changes. Spermatidic degeneration with early development of spermatidic multinucleated giant cells were characteristic features. Areas of lymphoid necrosis were also visible in splenic follicles and Peyer's patches 18 to 24 hours after treatment. These observations have demonstrated that other tissues in addition to liver and kidney are damaged by acetaminophen toxicity and should be considered in cases of acetaminophen overdosage.
Induction of Uterine Leiomyomas in Mice by Medroxalol and Prevention by Propranolol
Authors: Gibson John P. , Sells Donald M. , Cheng Hsien C. , Yuh Lianng
Published: September 2009

Medroxalol hydrochloride is an antihypertensive agent with β1adrenergic cardiac blocking properties, and β2and some α1vasodilating activity. In previous carcinogenicity studies medroxalol was shown to induce leiomyomas of the uterus in CD-I mice but not in Long Evans rats. In addition, there was a significant increase in endometrial stromal sarcomas in mice receiving the lowest dose of medroxalol; however, the*** lack of a dose response made the relationship to treatment questionable. Because of these findings, additional 18-month drug diet studies were conducted in 3 parallel segments using female CD-1 mice to determine the effects of: 1) an expanded range of doses, 2) various durations of dosing, and 3) the effect of the β-blocker, propranolol, on leiomyoma induction. These studies confirmed the fact that chronic dietary treatment with medroxalol can lead to an increased incidence of leiomyomas in the mouse uterus, but failed to demonstrate any relationship between endometrial stromal sarcomas and medroxalol administration. A linear trend occurred in the incidence of leiomyomas and of smooth muscle hypertrophy/hyperplasia, a possible precursor to leiomyoma. Both findings were notably increased at 250 mg/kg/day or more. Doses of 50 mg/kg/day or less were considered no effect levels. At 500 mg/kg/day a treatment period of 12 months or more was required before a noticeable increase in leiomyomas occurred in mice examined after 18 months. The β-blocker, propranolol, prevented this increase in leiomyomas, and led to the conclusion that the β2agonist activity of medroxalol was involved in their induction. Propranolol did not block the spontaneous occurrence of these tumors.
Primary Cardiac Hemangiosarcomas Induced by 1,3-Butadiene in B6C3F1 Hybrid Mice
Authors: Solleveld Henk A. , Miller Rodney A. , Banas Deborah A. , Boorman Gary A.
Published: September 2009

Proliferative vascular lesions of the heart were found in mice exposed chronically to 1,3-butadiene by inhalation with an overall incidence of 30% in males and 43% in females. Based on histological criteria, the lesions were subclassified as endothelial hyperplasia with an incidence of 7% in males and 13% in females and hemangiosarcoma with an incidence of 23% and 30%, respectively. A dose-relationship for both lesions was observed in females, but not in males. The absence of a dose response in males was most likely due to the lower survival rate for high-dose animals (14%) when compared to the lower-dose animals (22%). Endothelial hyperplasia was characterized by widened vascular spaces lined by a single layer of plump endothelial cells. When cellular pleomorphism and piling up of endothelial nuclei were observed the lesion was diagnosed as hemangiosarcoma. Ultrastructural examination of hemangiosarcomas revealed lumen formation, intercellular junctions and cytoplasmic filaments. Pinocytotic vesicles which are 1 of the characteristics of endothelial cells could not be identified with certainty. Weibel-Palade bodies were not detected in the neoplastic endothelium. Metastatic lesions were observed in liver, lung and kidney. To date, 1,3-butadiene is the only carcinogen reported that induces proliferative vascular lesions in the heart of mice.
Morphologic Considerations in the Interpretation of Gastrointestinal Disorders
Authors: Van Kruiningen Herbert J.
Published: September 2009

Misinterpretations of gastrointestinal alterations can be reduced or eliminated by avoiding sampling/labeling errors, reducing artifact, and gaining familiarity with normal variations for the species under study. The errant thrust of the gastroscopic biopsy forceps can yield mucosa resembling atrophic gastritis; ileal villi taken for jejunal erroneously lead to consideration of sprue-like disorder. Reduction of the postmortem delay prior to fixation is critical for avoiding artifact. Villous epithelial cells separate from basement membrane within 5 to 10 minutes. Flushing saline, water, or fixative through unopened intestine causes intolerable damage to epithelium and villi. The thin-walled intestines of small laboratory species may be fixed unopened, but without dissection gross lesions are overlooked. Osmolarity of the fixative is important for preserving normal shapes of villi. Smooth muscle of the muscularis and villi of the dog contracts vigorously after euthanasia and immediate fixation. Optimum preservation may be had by applying iso-osmolar neutral buffered fixatives to intestinal segments which have been opened, stretched slightly, and pinned to cardboard or styrofoam. The villous height: crypt depth ratios vary among species and among intestinal segments. Shapes vary as well, ileal villi of many species appearing short and Christmas-tree- or thumb-shaped. Dilated lacteals occur occasionally in normal villi. The goblet cell population increases aborally, while the lymphocytic-plasmacytic population of the core increases with age. Eosinophils are a normal component in several species; globule leukocytes are common in others. Mast cells of the villi will be overlooked unless tissues are fixed in Carnoy's solution and stained with Astra or Alcian blue. Solitary lymphoid follicles, jejunal Peyer's patches, ileal Peyer's patches, and colonic lymphoid areas must each be evaluated with an understanding of the dome epithelium, B-cell germinal centers, T-cell zones, and surrounding lymphatic sinusoids.
Gastrointestinal Hormones and the Quantitation of Spontaneous Duodenal Motor Activity
Authors: Tansy Martin F. , Kendall Frank M.
Published: September 2009

This is a survey of the results of recent investigations on gastrointestinal (GI) peptide hormones. In addition to the classical GI hormones (secretin, gastrin, and cholecystokinin-pancreozymin (CCK-PZ)), there are at least nine other peptides whose structures and GI effects are known. These include vasoactive intestinal polypeptide (VIP), gastric inhibitory polypeptide (GIP), motilin, pancreatic polypeptide (PP), substance P, neurotensin, somatostatin, enkephalins, and a bombesin-like gastrin-releasing peptide. It is now obvious that the traditional distinctions between hormones, neurotransmitters, and paracrines are rapidly becoming obsolete, as the actions and interactions of these substances within the complex motor system of the GI tract are gradually revealed. The study of perturbed states and toxic effects on the motor function of the small intestine is complicated by the integration of the activity of the small intestine with the activities of the body as a whole. A contemporary approach for evaluating intestinal contractile activity is described that uses computer assistance to measure the intercontractile interval (ICI). This technique may prove useful in assessing the effects of toxicological agents on spontaneous intestinal motor activity in vitro when the agents are delivered to the target sites by physiological mechanisms, in contrast to adding them to the tissue bath.
From Cysteamine to MPTP: Structure-Activity Studies with Duodenal Ulcerogens
Authors: Szabo Sandor , Cho Chi Hin
Published: September 2009

Cysteamine is the first chemical identified that induces acute and chronic duodenal ulcers in rodents. Structure-activity studies with cysteamine, propionitrile and their derivatives, as well as with analogues of toluene, revealed numerous alkyl and aryl duodenal ulcerogens. Among these, one of the most interesting from an etiologic and pathogenetic point of view is the dopaminergic neurotoxin MPTP, which shows structural similarities with toluene. The chemically-induced duodenal ulcers are similar and localized on the anterior and posterior wall of the duodenal bulb. Both cysteamine and MPTP affect endogenous dopamine; MPTP is especially potent in depleting central dopamine and inducing lesions in the substantia nigra. MPTP given in high doses induces Parkinson's disease-like syndrome and gastric ulcers. Cysteamine and propionitrile also cause dyskinesia in large and multiple doses. The motility disorders and duodenal ulcers are abolished by dopamine agonists. Cysteamine and MPTP have been known to increase and decrease gastric acid secretion, respectively. However, both compounds induced duodenal dysmotility, decreased bicarbonate production, and reduced its delivery from distal to proximal duodenum. These factors decrease acid neutralization in the duodenal bulb and contribute to duodenal ulceration. Thus, studies with animal models may reveal endogenous mediators and specific receptors which might be involved in the pathogenesis of duodenal ulceration. Specific structure-activity studies in toxicology may lead to new insights in the pathogenesis and pharmacology of a poorly understood human disorder such as duodenal ulceration.
The Effects of Steroids Upon the Gastrointestinal Tract
Authors: Black Hugh E.
Published: September 2009

The steroid hormones and bile acids are important to digestive tract structure and function. Glucocorticoids administered during pregnancy have been shown to induce cleft palate in the of fspring in several species. Postnatally, a significant rise in corticosterone during week 3 in the rat coincides with profound morphological and biochemical changes in the small intestine toward the adult state. Exogenous glucocorticoids given suckling rats leads to precocious development of these changes. In the adult, glucocorticoids increase brush border enzyme levels, while adrenal insufficiency decreases mucosal weight, enzyme activity, and absorptive functions. Water and sodium absorption and potassium excretion are enhanced in both small and large intestine. The jejunum, through its sense of food, provides the entraining signal that governs corticosterone rhythm. In the stomach, high doses of glucocorticoids inhibit prostaglandin biosynthesis, thereby inhibiting the gastric alkaline response and producing severe gastric lesions. However, in man, peptic ulcer disease is not clearly associated with glucocorticoid therapy. Exacerbation of subclinical intestinal infections and perforative lesions have been observed in both animals and man given glucocorticoids. The female sex hormone estrogen, when given to rats, stimulates intestinal enzyme levels and facilitates absorption. Progesterone inhibits both circular and longitudinal smooth muscle contractile activity. Virtually the entire pool of bile acids is found in the enterohepatic circulation. The dihydroxy secondary bile acids, regardless of their conjugation states, are physiologically and morphologically more damaging to mucosal cell membranes than are the trihydroxy primary bile acids.
Morphologic Stomach Findings in Rats and Mice Treated with the H2 Receptor Antagonists, ICI 125,211 and ICI 162,846
Authors: Streett C. Spencer , Robertson John L. , Crissman James W.
Published: September 2009

The gross and histopathologic findings seen in the stomachs of rats and mice treated with 2 different H2 receptor antagonists are presented. Studies with the first drug, ICI 125,211, elicited dysplasia/carcinoma lesions in 17 of 828 treated rats with 12 of the 17 lesions occurring in the pyloric region of the stomach. No tumors occurred in mice on study for 18 months. Studies conducted with another drug candidate, ICI 162,846, produced neuroendocrine carcinomas in the stomach of rats and mice. Twenty-five rats out of 312 treated male and female rats had neuroendocrine carcinomas in the gastric fundus with a higher tumor incidence in females. In a 24-month mouse study with ICI 162,846, 45 of 300 treated mice developed neuroendocrine carcinomas in the gastric fundus with a higher incidence in males.
Spontaneous Tumors in Aging (C57BL/6N X C3H/HeN)F1 (B6C3F1) Mice
Authors: Tamano Seiko , Hagiwara Akihiro , Shibata Masa-Aki , Kurata Yasushi , Fukushima Shoji , Ito Nobuyuki
Published: September 2009

Spontaneous tumors in untreated (C57BL/6N x C3H/HeN)F1 (B6C3F1) mice used as controls in carcinogenicity tests were recorded. In both sexes, the development of spontaneous tumors was age-related. In 244 male mice, the most common tumors were hyperplastic nodules of the liver, hepatocellular carcinomas, malignant lymphomas/leukemias, lung adenomas, and adenocarcinomas. In 246 female mice, the most common tumors were malignant lymphomas/leukemias, pituitary adenomas, neoplastic nodules of the liver, hepatocellular carcinomas, and lung adenomas. Hepatocellular carcinomas metastasized in 20.3% of the animals with these tumors. Few other tumors except malignant lymphomas and leukemias metastasized. Various tumors of other organs and/or tissues were found at low incidences.