Topical and oral administration of the natural water-soluble antioxidant from spinach reduces the multiplicity of papillomas in the Tg.AC mouse model.

The Tg.AC mouse carrying the v-Ha-ras structural gene is a useful model for the study of chemical carcinogens, especially those acting via non-genotoxic mechanisms. This study evaluated the efficacy of the non-toxic, water-soluble antioxidant from spinach, natural antioxidant (NAO), in reducing skin papilloma induction in female hemizygous Tg.AC mice treated dermally five times over 2.5 weeks with 2.5 microg 12-O-tetradecanoylphorbol-13-acetate (TPA). The TPA-only group was considered as a control; the other two groups received, additionally, NAO topically (2 mg) or orally (100 mg/kg), 5 days/week for 5 weeks. Papilloma counts made macroscopically during the clinical observations showed a significant decrease in multiplicity (P<0.01) in the NAO topically treated group. According to histological criteria, papilloma multiplicity were lower in both topical-NAO and oral-NAO groups, but significantly so only in the oral-NAO mice (P<0.01). The beneficial effect of NAO in the Tg.AC mouse is reported.

Proliferative exocrine pancreatic lesions in rats. The effect of sample size on the incidence of lesions.

Pancreatic tissue from untreated and corn oil gavage control rats in four chronic (2-year) toxicity and carcinogenicity studies was examined microscopically for the presence of acinar hyperplasia, acinar adenoma, and acinar carcinoma. Formalin-fixed pancreatic tissue that had been saved from these rats was then examined for grossly visible lesions; and all additional available pancreatic tissue was embedded, routinely processed, and sectioned at 5-7 microns for histopathological examination. There were no additional gross lesions identified in the review of the residual tissues. However, microscopic examination of this additional tissue resulted in a marked increase in the number of proliferative lesions diagnosed. The incidence of acinar cell adenomas increased from 1/188 (0.5%) to 28/193 (15%) in untreated control male rats and from 8/194 (4%) to 73/195 (37%) in corn oil gavage vehicle control male rats. There were similar increases in hyperplasia in vehicle and untreated male rats, and similar but much less dramatic increases in hyperplasia and adenoma in vehicle and untreated control female rats. The previously reported effect of increased proliferative lesions of the exocrine pancreas of male rats given corn oil vehicle was confirmed. In addition, examination of a larger tissue sample identified a similar but smaller effect of the corn oil vehicle in female F344 rats that had not been detected by routine sampling of the pancreas.

Lung neoplasms in rodents after chronic administration of dimethyl hydrogen phosphite.

Dimethyl hydrogen phosphite (DMHP), an intermediate in the production of insecticides or herbicides, was administered by p.o. gavage for 2 yr to male Fischer 344/N rats and male and female B6C3F1 mice at doses of 0, 100, or 200 mg/kg and to female Fischer 344/N rats at doses of 0, 50 or 100 mg/kg. Dose related toxicity was seen in the lungs of treated male and female rats. The lung lesions were most prevalent in the high dose male rat group which received a dose twice that given to the high dose female rats. Lung lesions included alveolar epithelial hyperplasia, chemically related pneumonia, alveolar-bronchiolar adenoma, alveolar-bronchiolar carcinoma, and squamous cell carcinoma. DMHP also caused neoplastic and nonneoplastic lesions of the forestomach in male rats; a similar but less pronounced effect was observed in female rats. Nonneoplastic lesions associated with administration of DMHP included mineralization of the cerebellum in male rat and focal calcification of the testis in male mice. Under the conditions of this study, there was clear evidence for carcinogenicity for male rats, equivocal evidence for carcinogenicity in female rats, and no evidence for carcinogenicity in either male or female mice. DMHP caused the highest incidence of lung tumors in the male rat of all chemicals studied to date in the National Cancer Institute-National Toxicology Program Carcinogenesis Testing Program.

Proliferative lesions of the exocrine pancreas: relationship to corn oil gavage in the National Toxicology Program.

A microscopic review of pancreata from corn oil vehicle control and untreated control F344/N male rats in thirty-seven 2-year carcinogenesis studies was conducted to determine the extent and strength of the association of proliferative exocrine pancreatic lesions with corn oil gavage. The incidence of focal basophilic cellular change was similar in both untreated and vehicle control groups and was unrelated to corn oil gavage. The overall incidences of focal acinar hyperplasia and acinar adenoma were about five times greater in male rats that received the corn oil than in untreated rats (12.6 and 4.9% vs. 2.6 and 0.9%). This association was not consistent for each study group of vehicle controls. Over one-third (7/20) of the vehicle control groups had incidences of hyperplasia and adenoma no greater than the average rate for untreated male rats. There was no relationship between incidences of proliferative acinar lesions and the animal laboratory, the animal source, and the brand, lot, or peroxide level of the corn oil. The incidences of focal acinar hyperplasia and acinar adenoma were related to maximum mean body weights attained by the groups during the course of the study.

Neoplasms observed in untreated and corn oil gavage control groups of F344/N rats and (C57BL/6N X C3H/HeN)F1 (B6C3F1) mice.

Control data on F344/N rats and (C57BL/6N X C3H/HeN)F1 (B6C3F1) mammary tumor virus-free mice from the National Toxicology Program (NTP) were examined to determine if animals receiving corn oil by gavage showed tumor incidences that differed from those of untreated control animals. Analyses of these data were adjusted for interlaboratory variability, time-related trends, and supplier effects. Two biologically significant effects were found: Male F344/N control rats receiving corn oil by gavage showed a higher (P less than .05) incidence of pancreatic acinar cell adenoma and a lower (P less than .001) incidence of leukemia (primarily mononuclear cell leukemia) than did the corresponding untreated controls. The increased incidences of pancreatic acinar cell adenoma seen in male rats administered corn oil by gavage were associated with elevated body weights observed in these animals relative to untreated controls. Female F344 rats and male and female B6C3F1 mice showed little or no evidence of a difference in tumor incidence between corn oil gavage-treated and untreated controls. A review of nearly 300 carcinogenesis studies done by the National Cancer Institute (NCI) and the NTP revealed that there were no corn oil gavage studies in which increased incidences of pancreatic acinar cell tumors or leukemia in male F344/N rats were the sole evidence of the carcinogenicity of a test chemical. Thus use of corn oil appears to have little impact on the interpretation of NCI-NTP carcinogenicity studies.

Myelotoxicity and macrophage alteration in mice exposed to ochratoxin A.

Six- to seven-week-old female B6C3F1 mice were administered a total of 0, 20, 40, or 80 mg/kg of ochratoxin A (OCT A) ip on alternate days over an 8-day period. Twenty-four hours following the final dose, histopathology, bone marrow, and macrophage parameters were assayed. There was a dramatic dose related decrease in thymic mass with the mean thymus weight of the high dose animals being only 33% of controls. Histologic evidence of nephrotoxicity was minimal and restricted to the inner cortex. Myelotoxicity was present as evidenced by bone marrow hypocellularity, decreased marrow pluripotent stem cells (CFU-S), granulocyte-macrophage progenitors (CFU-GMs), and decreased 59Fe uptake in marrows and spleens of exposed mice. Peritoneal macrophages from sc as well as ip injected mice demonstrated increased phagocytic capacities and increased capacity to inhibit tumor cell growth. These alterations in bone marrow cells and macrophages suggest myelotoxicity is an additional potential hazard of OCT A exposure.

Lesions of the urinary tract produced in Fischer 344 rats and B6C3F1 mice after chronic administration of 11-aminoundecanoic acid.

11-Aminoundecanoic acid, the monomer of nylon 11, was toxic to the urinary tract of both male and female B6C3F1 mice and Fischer 344 rats, when administered in the diet at 7500 or 15 000 ppm for 103-104 weeks. Dose-related effects included a decrease in mean body weight gain and in survival for male rats and for mice of each sex; increased incidence of hyperplasia of the transitional epithelium of the kidney in rats of each sex; increased incidence of calcification of the kidney in the female rats; increased incidence of hyperplasia of the urinary bladder in male rats; and mineralization of the kidney in mice of each sex. Transitional cell carcinomas of the urinary bladder of the male rat occurred with increased frequency in the high-dose group (control, 0/48; low-dose, 0/48; high-dose, 7/49). Additional evidence for carcinogenicity in the male rat was seen in the liver, where an increased frequency of neoplastic nodules was found in the treated animals (controls, 1/50; low-dose, 9/50; high-dose, 8/50). Therefore, under the conditions of these studies, 11-aminoundecanoic acid was carcinogenic for male Fischer 344 rats, inducing transitional cell carcinomas in the urinary bladder and neoplastic nodules in the liver. The test chemical was not demonstrated to be carcinogenic for female Fischer 344 rats or for B6C3F1 mice of either sex.

Methods and approaches for assessing immunotoxicity: an overview.

The goals of the National Toxicology Program as they relate to immunological evaluation in toxicity assessment are discussed. The advantages of immune function assays for defining cellular injury as subtoxic levels following exposure to general or immunocyte specific chemical toxicants are proposed. A comprehensive screening panel of immune function and host resistance assays is presented in the context of an NIEHS approach for immunotoxicity assessment and methods selection. A second panel for defining the mechanism underlying immunological injury was also described. Studies utilizing these methods and approaches are described in companion papers by our group.