Absolute Kidney Weights Research Articles

Comparative chronic toxicity and carcinogenicity of acrylonitrile by drinking water and oral intubation to Spartan® Sprague–Dawley rats

Comparative chronic toxicity and carcinogenicity of acrylonitrile by drinking water and oral intubation to Spartan® Sprague–Dawley rats

Chronic toxicity and oncogenicity study with glutaraldehyde dosed in the drinking water of Fischer 344 rats

Glutaraldehyde (GA) has a wide spectrum of industrial, scientific and biomedical applications. Its potential to produce chronic toxic and/or oncogenic effects was investigated in Fischer 344 rats (100/sex/group) given GA in drinking water for a maximum of 104 weeks. GA concentrations were 0 (control), 50,250 and 1000 ppm, resulting in average daily GA consumptions, respectively, of 0, 4, 17 and 64 mg/kg for males and 0, 6, 25 and 86 mg/kg for females. Interim euthanasia (10/sex/group) was performed at 52 and 78 weeks. Parameters evaluated were clinical signs, body weight, food and water consumption, hematology, serum chemistry, urinalysis, organ weights, gross and microscopic pathology. There were no treatment-related effects on mortality. Absolute body weights and body weight gains of the 250 and 1000 ppm males and females were reduced over the study in a dosage-related manner. Food and water consumption by the 250 and 1000 ppm groups were decreased in a statistically significant dose-related manner over the study, and mean water consumption by the 50 ppm animals was slightly reduced but not with statistical significance. The 250 and 1000 ppm groups had a dose-related decrease in urine volume with increased osmolality, and pH was slightly reduced. Absolute kidney weights were increased in the 250 and 1000 ppm groups at the 52 and 78 week sacrifices, and decreased at 104 weeks. Relative kidney weights were increased at all sacrifice times for the 1000 ppm group, at 52 weeks for the 250 ppm group, and at 72 weeks for the 50 ppm group. The urinalysis and renal weight changes are compatible with a physiological compensatory adaptation to reduced water consumption. Gross and histological evidence for gastric irritation was observed principally in the 1000 ppm rats euthanized at 104 weeks and in animals that died during the study. Bone marrow hyperplasia and renal tubular pigmentation, seen in rats that died and the 104 week euthanasia animals, may have been secondary to a low grade hemolytic anemia in animals with large granular lymphocytic leukemia (LGLL). The only neoplasm that showed a statistically significant increase was LGLL, which occurred at a high incidence in both sexes and all groups, including the controls, for both animals that died and at the 104 week euthanasia. A few instances of LGLL were observed at 78 weeks. The overall incidence of LGLL in the spleen for the 0, 50, 250 and 1000 ppm groups was, respectively, 43, 51, 40 and 46% for males, and 24, 41, 41 and 53% for females. Statistical analyses indicated that the severity of LGLL was associated with the higher dosages of GA in female, but not male, rats. Due to the background and variable incidence of LGLL in the Fischer 344 rat, the finding of a statistical significance only for female rats, and because, there was no clear dose-response relationship, the biological significance of the LGLL findings is unclear. There is the possibility that the significance was a statistical artifact due to the low incidence of LGLL in the female control animals as a result of biological variability within the study. It is also considered to be possible that the chronic dosage of GA in the drinking water resulted in a modification of one or more of the factors responsible for the expression of this common and spontaneously occurring neoplasm in the Fischer 344 rat.

ROLE OF THE ARYL HYDROCARBON RECEPTOR IN THE DEVELOPMENT OF CONTROL AND 2,3,7,8-TETRACHLORODIBENZO-p-DIOXIN-EXPOSED MALE MICE

Experiments were conducted to determine the role of the aryl hydrocarbon receptor (AhR) in the development of control and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-exposed C57Bl/6 male mice. Male and female mice heterozygous for the AhR (Ahr +/-) were mated, and pregnant females were dosed orally on gestation day 13 with corn oil vehicle or TCDD (5 µg/kg). Pups were necropsied on postnatal day (PND) 21, 35, and 90. Comparison of vehicle-exposed wild-type (Ahr +/+) pups with vehicle-exposed AhR knockout (AhRKO; Ahr -/-) pups confirmed and extended previous reports that development of the liver, heart, spleen, thymus, and kidney is affected by absence of the AhR. Lung, submandibular gland, testis, and epididymis weights were also affected, indicating that the AhR plays a role in normal development of these organs as well. The presence or absence of the AhR had no effect on the incidence of hydronephrosis, daily sperm production, or cauda epididymal sperm numbers in vehicle-exposed mice. TCDD caused numerous effects in wild-type mice that were absent in AhRKO mice; specifically, hydronephrosis, increases in relative liver and heart weight, decreases in absolute heart and lung weight, and decreases in absolute and relative thymus, submandibular gland, epididymis, and testis weight. In several cases, TCDD produced one effect in wild-type mice (reductions in body weight and absolute thymus, submandibular gland, and epididymis weight on PND 21; and reductions in absolute and relative submandibular gland and absolute testis weight on PND 35) but caused the opposite effect in AhRKO mice. In yet other cases (reduced relative spleen weight on PND 21 and reductions in absolute and relative thymus weight on PND 35), TCDD produced similar effects in wild-type and AhRKO mice. There were also cases in which TCDD significantly affected AhRKO mice without significantly altering the same endpoint in wild-type mice; absolute liver, lung, and kidney weight were increased and relative submandibular gland weight was decreased on PND 21; relative heart weight was reduced and absolute lung weight increased on PND 35; and relative liver weight was decreased on PND 90. Although many effects of TCDD required the presence of the AhR, these results provide evidence either for multiple forms of the AhR in mice (one or more of which are still present in AhRKO mice), or for AhR-independent effects of low-level TCDD exposure.

90-Day Subchronic Toxicity Study in Rats and Mice Fed N-Methylpyrrolidone (NMP) Including Neurotoxicity Evaluation in Rats

ABSTRACTNinety-day feeding studies were conducted to evaluate the repeated dose toxicity of NMP, a widely used industrial solvent, in Crl:CD®BR rats and B6C3F1 mice. Groups of 20 to 26 male and female rats each were fed either 0, 3,000, 7,500, or 18,000 ppm NMP for 90 days. Groups of 10 male and female mice were fed either 0, 1,000, 2,500, or 7,500 ppm NMP for 28 or 90 days. In vivo parameters, hematology and clinical chemistry parameters, ophthalmologic examinations, functional and histopathologic neurologic parameters (rats only), and complete pathology evaluations were conducted after 90 days.Decreases in mean body weights, reflecting decreases in food consumption and efficiency were observed in male and female rats fed either 7,500 or 18,000 ppm NMP. A change in urine coloration was observed at 3,000 ppm and above in both males and females. This was considered to be evidence of systemic availability since it was not associated with any functional or pathological changes. Of 36 neurobehavioral parameters investigated, male rats in the 7,500 and 18,000 ppm groups showed an increase in foot splay, and 18,000 ppm males had a higher incidence of low arousal and slight palpebral closure suggestive of a sedative effect. Absolute and relative liver weights were increased in 18,000 ppm females which were associated with an increased incidence of centrilobular hepatocellular hypertrophy and were considered to be an adaptive/physiological response. Absolute and relative kidney weights were increased in 18,000 ppm males and females, however, there were no pathological or functional changes associated with the increases.In mice, there were no effects on body weight or food consumption. As observed in rats, mice fed 2,500 or 7,500 ppm exhibited a change in urine coloration which was not associated with morphological changes in the kidney. In 2,500 and/or 7,500 ppm mice, changes in cholesterol, triglycerides, calcium, and alkaline phosphatase occurred at 28 days but not 90 days. These changes are thus assessed as being of minor toxicological relevance. Liver weights were elevated in males fed 2,500 or 7,500 ppm and centrilobular hypertrophy was seen in both sexes fed 7,500 ppm. These changes may be regarded as an adaptation process but are clearly related to NMP exposure. Other toxicological endpoints examined were unaffected by NMP.The NOAEL was 3,000 ppm for both sexes of rats based on body weight effects and changes in 3 neurobehavioral parameters (males only) at higher feeding levels. In mice, the NOAEL was 1,000 ppm based on liver responses to higher concentrations.

TOXICITY EVALUATION OF PETROLEUM BLENDING STREAMS: INHALATION SUBCHRONIC TOXICITY/NEUROTOXICITY STUDY OF A LIGHT ALKYLATE NAPHTHA DISTILLATE IN RATS

A 13-wk inhalation study was conducted with Sprague-Dawley CD rats ( 12/sex/ group) were exposed by inhalation for 13 weeks to a light alkylate naphtha distillate (LAND-2, C-C ; average molecular weight 89.2) at actual average concentrations of 0 (room 4 10 air), 668, 2220, or 6646 ppm, 6 h/d, 5 d/wk; 12 additional rats/sex in the control and high dose groups were held after final exposure for a 4-wk recovery period. The highest exposure concentration was 75% of the lower explosive limit. Standard parameters of subchronic toxicity were measured throughout the study; at necropsy, organs were weighed and tissues processed for microscopic evaluation. Neurotoxicity evaluations consisted of motor activity (MA) and a functional operational battery (FOB) measured pretest, during 5, 9, and 14 wk of the study, and after the 4-wk recovery period. Wholebody perfusion and microscopic examination of selected organs and nervous tissue from the control and high dose rats were conducted at the end of exposure. No testrelated mortality or effects on physical signs, body weight, or food consumption were observed. Statistically significant increases in absolute and relative kidney weights in high-exposure males correlated with microscopically observed hyaline droplet formation and renal nephropathy, effects in male rats that are not toxicologically significant for humans. Increased liver weights in both sexes at the highest dose had no microscopic correlate and appeared reversible after the 4-wk recovery period. Exposure to LAND-2 at any dose did not produce neurotoxicity measured by MA, FOB, or neuropathology. The no-observed-effects level (NOEL) for LAND-2 was 2220 ppm for subchronic toxicity and 6646 ppm for neurotoxicity.

Subchronic Oral Toxicity Studies with Erythritol in Mice and Rats

Erythritol is a sugar alcohol (polyol) with potential applications as a low-calorie, bulk sweetener. Ingested erythritol is efficiently absorbed and excreted unchanged via the urine since it is not metabolized systemically by the animal or human body. Erythritol was administered to four groups of 10 male and 10 female Swiss CD-1 mice and four groups of 15 male Wistar Crl:(WI) WU BR rats at dietary levels of 0, 5, 10, or 20% for 90 days. A fifth group of rats received a diet containing 20% erythritol on a time-restricted basis (6 hr/day), and a sixth group received a diet containing 20% mannitol for comparison. There were no treatment-related mortalities in either mice or rats. Soft stools and occasional diarrhea were observed in rats fed diets with 20% erythritol or mannitol but not in mice. Body weights were slightly yet significantly reduced in rats fed 20% erythritol or mannitol and in male mice of the 20% dose group. Erythritol intake in the high-dose group was approximately 12 g/kg body wt in rats and 44 and 45 g/kg body wt in male and female mice, respectively. Hematological and clinicochemical examinations of blood and plasma did not reveal any treatment-related effects. Urine output increased with increasing erythritol dose. In male and female mice of the 20% erythritol group, the creatinine-normalized urinary excretion of protein, K-glutamyltransferase (GGT), and electrolytes (Na+, K+, Ca2+, Pi, citrate) was significantly increased while urinaryN-acetylglucosaminidase (NAG) remained unchanged. At the 10% level, significantly increased urinary protein (both sexes) and GGT (males only) excretion were seen. In rats, the creatinine-normalized urinary excretion of GGT, NAG, and some electrolytes (Na+, K+, and Ca2+) was increased in some erythritol groups but a clear dose–response relationship was evident only for calcium. On termination of the study, cecal enlargement was seen in rats of the 10 and 20% dose groups and in mice of the 20% dose group. Increased relative and absolute kidney weights were observed in both sexes of mice in the 20% erythritol group, in male mice of the 5 and 10% groups, and in rats of the 10 and 20% erythritol groups. Histopathological examination did not reveal any treatment-related abnormalities in either mice or rats. In conclusion, the ingestion of erythritol for 90 days at dietary levels of up to 20% did not produce signs of toxicity in mice or rats. In particular, the morphological integrity of the kidneys was not adversely affected by the treatment in either species. The increases in urinary excretion of protein, GGT, NAG, and electrolytes were considered to result from extensive osmotic diuresis and a potential overload of the renal excretory system at the high dose levels employed.

Two-Year Inhalation Toxicity Study in Rats with Hydrochlorofluorocarbon 123

Two-Year Inhalation Toxicity Study in Rats with Hydrochlorofluorocarbon 123. Malley, L. A., Carakostas, M., Hansen, J. F., Rusch, G. M., Kelly, D. P., and Trochimowicz, H. J. (1995). Fundam. Appl. Toxicol. 25, 101-114. The potential chronic toxicity and oncogenicity of hydrochlorofluorocarbon 123 (HCFC-123) was evaluated by exposing male and female rats to 0, 300, 1000, or 5000 ppm HCFC-123 for 6 hr/day, 5 days/week, for 2 years. Clinical pathology was evaluated at 6, 12, 18, and 24 months. An interim termination and measurements of hepatic cell proliferation and beta-oxidation activity were conducted at 12 months. The terminal euthanization occurred at 24 months. Males and females exposed to 5000 ppm and females exposed to 300 or 1000 ppm had lower body weights and body weight gains. Serum triglyceride and glucose concentrations were significantly decreased at all exposure concentrations in both sexes. Serum cholesterol was also lower in 300, 1000, and 5000 ppm females and in 5000 ppm males. Alterations in serum protein concentrations occurred at 300, 1000, and 5000 ppm. Survival was higher in 1000 and 5000 ppm males and females. At 24 months, increased relative liver weight occurred in 5000 ppm males, and decreased absolute kidney weight occurred in 5000 ppm males and in 1000 and 5000 ppm females. Benign hepatocellular adenomas were increased in 5000 ppm males and in all test groups of females. Hepatic cholangiofibromas were also increased in 5000 ppm females. Pancreatic acinar cell adenomas were increased in all test groups of males, and acinar cell hyperplasia was increased in the 1000 and 5000 ppm males and females. Benign testicular interstitial adenomas and focal interstitial cell hyperplasia were also increased in all male test groups compared to controls. Diffuse retinal atrophy was increased in all male and female test groups, but it was considered to be an indirect compound-related effect. Hepatic beta-oxidation activity (peroxisome proliferation) was higher in 300, 1000 and 5000 ppm males and 1000 and 5000 ppm females. Compound-related differences in the rate of hepatic cell proliferation were not observed at any exposure concentration. Decreased incidences of a variety of age-related lesions occurred at 1000 and 5000 ppm.

Acute and 2-Week Aerosol Inhalation Studies on 970 and 1700 Molecular Weight Ethylene Oxide/Propylene Oxide (EO/PO) Polymers

Prior aerosol inhalation studies on heavier molecular weight members of this series of ethylene oxide/propylene oxide (EO/PO) polymers have demonstrated that the lung is the primary target organ in rats. These studies extended the toxicological data on the lower molecular weight (MW) members (970 and 1700) of this series. In the present group of studies, the 4-hr acute LC50 value (95% confidence limits) for the 970 MW polymer (U-260) was determined to be 4770 (4260–5350) mg/m3 for the combined sexes of Sprague-Dawley rats. A previous study had determined the LC50 value for the 1700 MW polymer (U-660) to be 4670 (4090–5320) mg/m3 in Wistar rats. Repeated exposure studies were also conducted on both polymers, in which Fischer 344 rats were exposed for 6 hr/day, 5 days/week, for 9 exposures. For U-660, repeated exposure to mean concentrations of 504, 982, or 2460 mg/m3 produced total mortality at 2460 mg/m3, while signs of ocular and nasal irritation, respiratory difficulties, and reduced body weight (BW) and/or BW gain occurred in the 504 and 982 mg/m3 groups. Many of the hematological, serum chemistry, and urinalysis parameters were abnormal for the 504 and 982 mg/m3 groups when compared to controls. Absolute and relative lung weights were increased for the 504 and 982 mg/m3 groups. Of the organs evaluated, only the lung had histopathological lesions, including interstitial pneumonitis, bron-chioalveolar cell hyperplasia, and intra-alveolar macrophage infiltrates. The severity of the lesions was concentration-related. In a subsequent U-660 study with exposure concentrations of 5, 51, 98, and 492 mg/m3, effects observed at 492 mg/m3 were consistent with those observed in the previous U-660 study at 504 mg/m3. The most notable effects of lower concentrations included increases in absolute and relative lung weight observed for male rats of the 51, 98, and 492 mg/m3 groups and female rats of the 98 and 492 mg/m3 groups, as well as increases in absolute and/or relative kidney weights noted for females for the 98 and 492 mg/m3 groups. Additionally, histological evaluation indicated an increased incidence or alveolar histiocytosis for male animals exposed to 51 mg/m3 or higher concentrations of U-660. However, the injury to the lung that resulted from exposure to 492 mg/m3 U-660 completely resolved during a 6-week recovery period. For U-260, repeated exposure to mean concentrations of 5, 52, or 512 mg/m3 produced decreased BW gain in the 52 and 512 mg/m3 groups and increased absolute kidney weights in the 512 mg/m3 group. There were no histopathological lesions in the kidneys or lungs. Thus, despite the similar LC50 value for these compounds, data for the 1700 MW polymer (U-660) indicate that the toxicity is cumulative, while data for the 970 MW polymer (U-260) indicate that, in contrast to other higher MW members of this series, pulmonary toxicity is not produced in rats during a 2-week exposure to concentrations up to 512 mg/m3. Further, a clear no-observed-effect concentration of 5 mg/m3 was established for both U-660 and U-260.

A 4-week subcutaneous toxicity study of recombinant human interferon alpha A (LBD-007) in Sprague-Dawley rats.

Recombinant human interferon alpha A (code name: LBD-007) was subcutaneously administered to both sexes of Sprague-Dawley rats at the doses of 0, 6, 12 and 24 x 10(6) IU/kg of body weight five days per week for 4 weeks to evaluate the subchronic toxicity. 20 to 50% of rats except the male control group showed minimal to mild, focal to multifocal renal mineralization. Whether renal mineralization is related to the test substance is not elucidated. Male rats dosed at 24 x 10(6) IU/kg showed the decrease of the absolute kidney weights and the increase of the brain relative weights. Female rats dosed at 24 x 10(6) IU/kg showed the increase of the absolute and relative ovary weights, and the decreases of specific gravity, bilirubin and urobilinogen in urine. However, no drug-related changes were noted in clinical findings, body weights, food consumption, water consumption, hematology, blood clinical chemistry and necropsy findings. Based on the results it is concluded that the estimated subcutaneous non-toxic dose of the recombinant human interferon alpha A (LBD-007) in rats is (6 approximately 12) x 10(6) IU/kg.

Safety evaluation of benzophenone

Benzophenone (FEMA No. 2134; CAS No. 119-61-9) was administered in the diet to rats at target dose levels of 20 mg/kg body weight/day for 90 days and 100 or 500 mg/kg/day for 28 days. Body weights and food consumption were measured weekly; haematology, clinical chemistry and urinalysis values were obtained at 4 wk and at the end of the study. Gross and microscopic pathological examinations were conducted and organ weights were recorded. Treatment-related changes occurred in erythrocyte count, haemoglobin, haematocrit, bilirubin, total protein and albumin at the mid- and high-dose levels, although all changes did not occur in both groups in both sexes. There were indications of increased absolute and relative liver and kidney weights in the mid- and high-dose groups, but this was not statistically consistent for absolute kidney weights. Histopathology of the liver in the mid- and high-dose groups showed hepatocellular enlargement with an associated clumping of cytoplasmic basophilic material around the central vein. A no-effect level was demonstrated at 20 mg/kg/day for 90 days of administration. This would be equivalent to an intake of 1200 mg/day for a 60-kg human. On the basis of the calculated Possible Average Daily Intake of 0.33 mg/day, a safety factor of > 3600 is demonstrated. The safety factor based on the more realistic per capita consumption of 0.32 μg/day would be approximately 3.7 million.

Inhalation toxicity study of formamide in rats

Formamide is a widely used solvent for the manufacture and processing of plastics, and the possibility for inhalation exposure exists for workers. To assess the toxicity of repeated inhalation of sublethal concentrations of formamide, three groups of 10 male Crl:CD BR rats each were exposed nose-only for 6 hr/day, 5 days/week for 2 weeks to design concentrations of 100, 500, or 1500 ppm of formamide vapor in air. A control group of 10 male rats was exposed simultaneously to air only. At the end of the exposure period, blood and urine samples were collected for clinical analyses, and 5 rats per group were killed for pathologic examination. The remaining 5 rats per group were retained for a 14-day postexposure observation (recovery) period and then subjected to the same clinical and pathologic examinations. Male rats exposed to 1500 ppm had significantly depressed body weights and body weight gains during the exposure and recovery periods compared to controls. Clinical pathologic examinations revealed that decreased platelet and/or lymphocyte counts were observed in rats exposed to 500 or 1500 ppm of formamide. Pathologic examinations revealed compound-related microscopic changes in the kidnevs of rats exposed to 1500 ppm formamide. Minimal to severe necrosis and regeneration of renal tubular epithelial cells were observed principally in the outer stripe of the outer medulla and in cortical medullary rays. Based upon the hematologic and clinical chemical parameters measured, the no-observed-effect exposure concentration for repeated inhalation of formamide was considered to be 100 ppm, under the conditions of this study. The findings of treatment-related microscopic lesions in the kidneys as well as increases in mean absolute kidney weights and kidney-to-body weight ratios reflect the target organ toxicity.

Inhalation Toxicity Study of Formamide in Rats

Formamide is a widely used solvent for the manufacture and processing of plastics, and the possibility for inhalation exposure exists for workers. To assess the toxicity of repeated inhalation of sublethal concentrations of formamide, three groups of 10 male Crl:CD BR rats each were exposed nose-only for 6 hr/day, 5 days/week for 2 weeks to design concentrations of 100, 500, or 1500 ppm of formamide vapor in air. A control group of 10 male rats was exposed simultaneously to air only. At the end of the exposure period, blood and urine samples were collected for clinical analyses, and 5 rats per group were killed for pathologic examination. The remaining 5 rats per group were retained for a 14-day postexposure observation (recovery) period and then subjected to the same clinical and pathologic examinations. Male rats exposed to 1500 ppm had significantly depressed body weights and body weight gains during the exposure and recovery periods compared to controls. Clinical pathologic examinations revealed that decreased platelet and/or lymphocyte counts were observed in rats exposed to 500 or 1500 ppm of formamide. Pathologic examinations revealed compound-related microscopic changes in the kidneys of rats exposed to 1500 ppm formamide. Minimal to severe necrosis and regeneration of renal tubular epithelial cells were observed principally in the outer stripe of the outer medulla and in cortical medullary rays. Based upon the hematologic and clinical chemical parameters measured, the no-observed-effect exposure concentration for repeated inhalation of formamide was considered to be 100 ppm, under the conditions of this study. The findings of treatment-related microscopic lesions in the kidneys as well as increases in mean absolute kidney weights and kidney-to-body weight ratios reflect the target organ toxicity.

Hyalin Droplet Nephrosis in Male Fischer-344 Rats Following Inhalation of Diisobutyl Ketone

Four groups, each consisting of 10 male and 10 female Fischer-344 rats, were exposed 6 h/day, 5 days/week, for 9 days to diisobutyl ketone (DIBK) vapor at concentrations of 905, 300, 98, or 0 (control) ppm. An additional 10 rats/sex were assigned to the 905 and 0 ppm groups and allowed two weeks recovery prior to sacrifice. Rats exposed to 905 ppm had mild ocular irritation (lacrimation) and evidence of kidney toxicity, manifested as: 1) an increase in absolute and relative (as a percentage of body weight) kidney weights, 2) an increase in urine volume (and water intake) with a concomitant decrease in urine osmolality (males only), and 3) an increase in severity of hyalin droplet nephrosis in the proximal tubules (males only). Absolute and relative liver weights were also increased in both male and female rats of the 905 and 300 ppm groups. These effects either disappeared or lessened in severity following the 2-week recovery period. Male rats exposed to 300 ppm had similar renal alterations to the males of the 905 ppm group, although the alterations were fewer in number and smaller in magnitude. Kidney weights and renal histology of the males of the 98 ppm group were similar to the control male rats, although an increase in urine volume with a decrease in urine osmolality was observed. The kidney findings in this study were not surprising because of the chemical relationship of DIBK with other aliphatic ketones (e.g., methyl isobutyl ketone, methyl isoamyl ketone) which, after repeated inhalation exposure, cause hyalin droplet nephropathy in male rats. The significance of this male rat nephrosis with regard to human exposure is unknown.

Renal innervation is not required for compensatory renal growth in the rat.

The purpose of this study was to determine whether renal innervation is required for compensatory growth of the remaining kidney following unilateral nephrectomy. In the first study, young (6-week-old) rats were divided into 4 groups and the following surgical procedures were performed. Group 1 animals had their left and right kidneys removed and weighed to provide a measure of control weight prior to compensatory growth. Group 2 and 3 animals underwent right nephrectomy, followed by left kidney denervation (Group 2) or sham denervation (Group 3). Animals from Group 4 were subjected to right sham nephrectomy and sham denervation of the left kidneys. Three weeks later, animals from Groups 2, 3 and 4 were sacrificed and left kidneys were weighed. Relative to control kidney weight (Group 1), left kidney weight increased over 3 weeks by 92% when both kidneys were present (Group 4), representing normal renal growth. Animals with prior nephrectomy but intact renal innervation (Group 3) demonstrated an additional increase in kidney weight of 74% over the same interval, representing compensatory growth. Prior denervation of the left kidney (Group 2) had no effect on the degree of compensatory growth whether expressed in absolute kidney weight or relative to body weight. A second study was performed to determine whether renal innervation influences the initial state of compensatory growth when measured at an earlier time after unilateral nephrectomy. One week after right nephrectomy, left kidney weight was similar in animals with sham left renal denervation (1.08 +/- 0.04 g) when compared to animals with left renal denervation (1.06 +/- 0.02 g). Thus, for a least young rats, renal innervation is not required for full compensatory renal growth following unilateral nephrectomy.

Evaluation of the toxicity and carcinogenicity of hair dyes in Swiss mice.

The chronic toxicologic and carcinogenic potential of two oxidative and twelve non-oxidative hair dyes has been evaluated. The dyes were skin painted up to 3 times weekly on groups of 60 male and 60 female Eppley Swiss mice. Treatments were carried out for 20 months followed by terminal sacrifice. Nine months after treatments were initiated an intermediate sacrifice of ten mice per sex per group was carried out. Body weights and survival differed little between appropriate male and female treatment and control groups. Differences between treated and control groups in absolute and relative liver and kidney weights and in hematological and urinary values were not considered to be indicative of toxicologic effects. Microscopic examinations of the skin revealed occasional hyperplasia, necrosis, ulceration and other lesions not significantly increased by dye treatment. Chronic inflammation of the skin was observed in the control and treated mice and was significantly increased by one non-oxidative dye. The predominant tumors diagnosed were liver hemangioma, lung adenoma and malignant lymphoma. There was a statistically significant increase in the incidence of malignant lymphoma in female mice in 3 treated groups when compared to control group 2, but the differences were not significant when these groups were compared to control group 1. In addition the values in these 3 groups were within the range of control values for this tumor in female mice in the Eppley colony. No other tumors occurred at significantly increased frequencies in treated mice. We conclude that toxicological and carcinogenic effects were not clearly induced by the hair dye formulations.

The Effect of Uniform Exsanguination on Absolute and Relative Organ Weights, and Organ Weight Variation

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.

Multigeneration feeding studies in mice for safety evaluation of the microalga, Scenedesmus acutus. I. Biological and haematological data

Seven generations of mice of both sexes were given a diet containing 20% drum-dried alga, for 80 wk. The alga ( Scenedesmus acutus, strain 276-3a) containing 50% protein, was substituted for some of the protein-rich constituents of the basic diet. The body weight, feed efficiency, reproductive capacity, life-span, organ weights, haematology and blood chemistry of the test animals were compared with those of controls. Body weights were increased by the algal diet by 10% over the controls, litter size was decreased by 11%, mean birth weights of pups increased by 4% and survival of female mice was increased by 48%. In older females, the liver-to-body weight ratio increased by 15%, absolute spleen weight increased by 19% and absolute kidney weight increased by 13%. There were no other significant differences between the test animals and the controls. Some of these differences may have been caused by the altered feed composition rather than the algal supplement specifically. The increased feed intake of the test group may also have contributed to the differences.

Effect Upon the Kidney of Feeding Large Amounts of Amino Acids for a Short Period of Time

It has been claimed by many investigators that high protein diets produce renal injury. Newburgh and Curtis have shown that the type and degree of injury is dependent on the nature and amount of the protein and the duration of feeding. In an earlier study Newburgh and Marsh had definite renal injury in 24 to 48 hours following the intravenous injection of certain amino acids. During the course of an investigation on the metabolism of creatine a series of animals became available for histological study of the effects of large quantities of ingested amino acids for short periods of time. A total of 81 rats, weighing between 40 and 60 gm. have been examined, 48 were fed amino acids, 10 other nitrogenous substances, and 6 were normal. All food except water was removed from the cage at night and the next morning 1 gm. of the substance to be fed was mixed with Sherman's diet B (consisting of whole wheat flour two-thirds, whole milk powder one-third, NaCl and CaCO3, each, to the extent of 1% of the wheat flour) and placed in the cage. Twenty-four hours later the animals were sacrificed by a blow on the head. The kidneys were weighed, sectioned saggitally, fixed in Zenker's solution, embedded in paraffin and stained with hematoxylin and eosin. Two animals were fed phenylalanine, 5 glutamic acid, 6 tyrosine, 5 glycine, 3 alanine, 11 arginine, 3 aspartic acid, 1 leucin, 6 cystine, and 3 histidine. In the second group 7 were fed creatine and 3 glycocyamine. The absolute kidney weight and the kidney weight body weight ratio show no differences in the several groups. Sections were examined with concealed key numbers and later with knowledge of the source of each specimen.