ABSTRACT+ AC133 + population was also enriched (sevenfold) in dendritic cell precursors, and the dendritic cells generated were functionally active in a mixed lymphocyte reaction assay. AC133 + cells should be useful in the study of cellular and molecular mechanisms regulating primitive hemopoietic cells.

ABSTRAC~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 twoyear-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. INTRODUC~IONDrug safety assessment depends on distinguishing spontaneous changes and pharmacological responses from toxic reactions. Base-line data are useful for putting anomalies into perspective and interpreting results (22). Age-related renal functional changes and lesions of rats have been reviewed several times (3, 8, 10, 14,28). Chronic progressive nephropathy (3) is of major importance in some strains of laboratory rats, and Sprague-Dawley rats are apparently more prone to develop this condition than are Wistars (30). This paper reports a retrospective survey of data obtained from a large number of laboratory-maintained Sprague-Dawley rats. METHODSData for this survey originated from records of chronic toxicity studies undertaken with SpragueDawley rats (CD strain from Charles River, Manston, UK, Wilmington, USA or St. Aubin-Les-Elbeuf, France) at the Huntingdon Research Centre between 1968 and 1979. Details of the rats used as untreated controls were examined. The rats were barrier maintained and housed in groups of five in suspended metal cages that had wire mesh floors. Room temperature and relative humidity were maintained at 21°C f 2°C and 50% 4 5% respectively. Lighting was controlled to allow 12 hours light (0800 to 2000 hours) and 12 hours dark per day. Except when blood or urine samples were taken, rats received Spillers' Laboratory Small Animal Diet or Spratts' Laboratory Rodent Diet Nos. 1 or 2 and tap water adlibition. Food was withheld overnight prior to obtaining blood from the orbital sinus of rats anesthetised with ether. Water was withdrawn when individual 16-1 8-hour overnight urine samples were obtained from rats placed in metabolism cages fitted with faecal separators. Blood samples were analyzed for plasma urea by routine methods. The volume of overnight urine voided was measured and the pH, specific gravity, and protein concentration were determined. At the end of the experimental periods, the rats were killed by carbon dioxide asphyxiation. A full macroscopic pos...

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Investigation of thyroid glands from 500 male and 500 female Sprague-Dawley rats, at time points of 8, 17, 30, 56, and 108 weeks of toxicity studies conducted at the Huntingdon Research Centre between 1981 and 1984, revealed age-related structural and functional changes that have previously not been well documented. The number of ultimobranchial cysts decreased with age, while area(s) of C-cell hyperplasia appeared with age. Beginning at 56 weeks, some of the thyroid follicles were hyperdistended with colloid, had irregular lumens, and were lined by flattened epithelium. These follicles had clumped, granular, and stratified colloid. Follicular tumors were found in 8% of the males and 6% of the females at 108 weeks. There was an increase in absolute thyroid weights (males from 21.8 +/- 4.0 g to 46.5 +/- 19.05 g, females from 17.2 +/- 4.53 g to 41.7 +/- 26.92 g) and body weights (males from 382.0 +/- 70.6 g to 806.0 +/- 120.7 g, females from 220.0 +/- 21.0 g to 495.0 +/- 127.3 g) with age in both sexes, but the relative thyroid weights were not significantly affected. Negative allometry was observed. With an increase in the age of the rats, there was a decrease in the height of the follicular epithelium and an increase in the internal follicular diameter and the total number of follicles. No prediction for sex could be detected. Serum T3 and T4 concentrations were constant until 56 weeks of age, but at 108 weeks, the values were markedly reduced (in males, serum T3 concentration decreased from 91.60 +/- 13.970 ng/100 ml to 32.90 +/- 10.878 ng/100 ml, and in females, from 90.80 +/- 11.338 ng/100 ml to 48.10 +/- 8.875 ng/100 ml; in males, serum T4 concentration decreased from 5.94 +/- 0.679 microgram/100 ml to 3.04 +/- 0.604 microgram/100 ml, and in females, from 4.59 +/- 0.717 microgram/100 ml to 2.77 +/- 0.786 microgram/100 ml). The data suggest that the thyroid function of Sprague-Dawley rats reduces as the rats age.

SUMMARYThe eye of the rat shows the main characteristics of all mammalian eyes. The cornea is prominent, and is subject to infection and injury. Age changes were detected in the lenses of a high proportion of rats examined, but cataract did not appear to be a feature of aging of rat lenses. The retina of the albino rat is devoid of pigment, and was subject to destruction of the visual cells by the application of bright light. L'oeil du rat montre les caracteristiques principales de tous les yeux des mammiferes. La cornee est saillante et est sujet aux infections et blessures. Dans une grande proportion des lentilles de rats examinees on a trouve des changements d'age, mais les cataractes ne semblaient pas faire partie des changements d'age des lentilles de rat. La retine du rat albino manque de pigment, et les cellules visuelles furent facilement detruites par une forte lumiere.The albino rat is the most commonly used laboratory animal.This paper records a systemic study and describes the spontaneous changes observed in the eyes of a strain of Sprague-Dawley rats.

A workshop was held to critically discuss the need for a non-rodent species and the role of the dog in regulatory toxicity testing of pharmaceuticals; to discuss opportunities to reduce and refine the use of dogs in preclinical toxicology; and to identify a number of specific recommendations which could be feasibly achieved to move the process forward. To facilitate a preliminary evaluation of the contribution of dog studies to the risk assessment process, anonymised, unpublished data were provided from fully evaluated, repeat dose toxicity studies in the rat and dog. Results ofthe International Life Sciences Institute (ILSI) Human Toxicity Project were also presented and discussed. Analysis of the data demonstrated that the dog can provide additional toxicity information, which, in some cases, was shown to be predictive for humans. Discussions indicated that there is potential for achieving a reduction in dog use and several possible approaches were identified. To further the progress of this initiative, there is a need to collate the results of pharmacology, toxicology, and clinical studies to address some of the proposed approaches. One of the outcomes of the workshop will be the establishment of a steering group to co-ordinate data collation for further analysis.

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