Multiple organ carcinogenicity of 1,3-butadiene in B6C3F1 mice after 60 weeks of inhalation exposure.

Groups of 50 male and 50 female B6C3F1 mice were exposed 6 hours per day, 5 days per week, for 60 to 61 weeks to air containing 0, 625, or 1250 parts per million 1,3-butadiene. These concentrations are somewhat below and slightly above the Occupational Safety and Health Administration standard of 1000 parts per million for butadiene. The study was designed for 104-week exposures but had to be ended early due to cancer-related mortality in both sexes at both exposure concentrations. There were early induction and significantly increased incidences of hemangiosarcomas of the heart, malignant lymphomas, alveolar-bronchiolar neoplasms, squamous cell neoplasms of the forestomach in males and females and acinar cell carcinomas of the mammary gland, granulosa cell neoplasms of the ovary, and hepatocellular neoplasms in females. Current workplace standards for exposure to butadiene should be reexamined in view of these findings.

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.

Species correlation in long-term carcinogenicity studies.

Species correlation in neoplastic response was examined for 266 long-term toxicology and carcinogenicity studies. The overall concordance between rats and mice exposed to the same chemical was 74% (198/266). Within a species, the results for males and females were also highly correlated (87% concordance for rats and 89% for mice). Had only male rats and female mice been utilized in these experiments, the same conclusions regarding carcinogenicity would have been reached in 96% of the studies (255/266). The high interspecies correlation shown in these studies supports the view that extrapolation of carcinogenicity outcomes to other species, including humans, is appropriate.

Inhalation of tetranitromethane causes nasal passage irritation and pulmonary carcinogenesis in rodents.

Fischer 344 rats and B6C3F1 mice were exposed for 2 years to vapors of tetranitromethane at concentrations below (0.5 ppm) and slightly above (2 or 5 ppm) the current U.S. recommended occupational exposure limit. Under the conditions of exposure of 6 h/day, 5 days/week, tetranitromethane was found to cause mild irritation and hyperplastic lesions in the nasal passages, but not nasal cavity neoplasms were observed. In contrast, nearly all animals exposed to the higher TNM concentrations, and the majority of animals exposed to the lower concentrations developed alveolar/bronchiolar adenoma or carcinoma; squamous cell neoplasms of the lung also occurred in exposed rats. The extent of the lung tumor response, and the low concentrations of tetranitromethane required for this response, are unprecedented in National Toxicology Program (NTP) studies.

Comparative results of 327 chemical carcinogenicity studies.

The National Cancer Institute (NCI) and the National Toxicology Program (NTP) have carried out a number of laboratory animal carcinogenicity studies and presented the results of these experiments in a series of Technical Reports. This paper tabulates the results of the 327 NCI/NTP studies carried out to date on 308 distinct chemicals, and discusses certain issues relevant to the evaluation of carcinogenicity in these experiments. This compilation of results from NCI/NTP carcinogenicity experiments provides a large database that can be used to study structure-activity correlations, interspecies concordance, and associations between laboratory animal carcinogenicity and other toxicological effects.

Long-term hazards of polychlorinated dibenzodioxins and polychlorinated dibenzofurans.

During January 10-11, 1978 in Lyon, France, a joint National Institute of Environmental Health Sciences/International Agency for Research on Cancer ad hoc Working Group considered and discussed the feasibility of coordinating epidemiological studies on the long-term hazards associated with the chlorinated dibenzo-p-dioxins and chlorinated dibenzofurans (PCDDs and and PCDFs). Nineteen invited scientists from eight countries presented introductory working papers summarizing the most up-to-date and relevant information available from their individual programs. This report represents the collective views and scientific opinions of the Working Group. The greater part of this document comprises epidemiological studies related to episodes of human exposures. The review begins with a brief section concerning possible routes of human exposure, an overview of the pertinent chemical characteristics, and the salient toxicological properties of the structurally similar PCDDs/PCDFs. The Working Group report ends with recommendations for future activities.

An overview of prechronic and chronic toxicity/carcinogenicity experimental study designs and criteria used by the National Toxicology Program.

Since the establishment of the National Toxicology Program (NTP), there have been gradual changes in strategies to evaluate the overall toxicity of chemicals as well as their carcinogenic potential. The spectrum of toxicologic information sought on selected chemicals has been broadened by the multidisciplinary approach to evaluating chemicals. This paper describes the scientific rationale and experimental processes used by NTP in designing studies. Also, an outline of current NTP protocols are given for prechronic and chronic toxicity/carcinogenicity studies.

Inhalation toxicology and carcinogenicity of 1,3-butadiene in B6C3F1 mice following 65 weeks of exposure.

1,3-Butadiene, a large-production volume chemical used mainly in the manufacture of synthetic rubber, was found to induce multiple-organ carcinogenicity in male and female B6C3F1 mice at exposure concentrations (625 and 1250 ppm) equivalent to and below the OSHA standard of 1000 ppm. Since this study was terminated after 60 weeks of exposure because of reduced survival due to fatal tumors, and because dose-response relationships for 1,3-butadiene-induced neoplastic and nonneoplastic lesions were not clearly established, a second long-term inhalation study of 1,3-butadiene in B6C3F1 mice was conducted at lower exposure concentrations, ranging from 6.25 to 625 ppm. Both the histopathological findings from animals dying through week 65 and the results of evaluations of animals exposed for 40 and 65 weeks are presented in this report. Exposure to 1,3-butadiene caused a regenerative anemia at concentrations of 62.5 ppm and higher. Testicular atrophy was induced at 625 ppm, and ovarian atrophy was observed at 20 ppm and higher. During the first 50 weeks of the study, lymphocytic lymphoma was the major cause of death of mice exposed to 625 ppm 1,3-butadiene. Neoplasms of the heart, forestomach, lung, Harderian gland, mammary gland, ovary, and liver were frequently observed in 1,3-butadiene-exposed mice that died between week 40 and week 65 of the study. Studies in which exposure to 1,3-butadiene was stopped after limited periods were also included to assess the relationship between exposure levels and duration of exposures on the outcome of 1,3-butadiene-induced carcinogenicity. In these studies, lymphocytic lymphomas were induced in male mice exposed to 625 ppm 1,3-butadiene for only 13 weeks. The incidence of lymphocytic lymphoma in male mice exposed to 625 ppm 1,3-butadiene for 26 weeks was two times that in mice exposed to 625 ppm for 13 weeks. However, when the exposure concentration was reduced by half to 312 ppm and the exposure duration extended to 52 weeks, the incidence of lymphocytic lymphoma was reduced by 90%. Thus, the multiple of the exposure concentration times the exposure duration did not predict the incidence of lymphocytic lymphoma in mice. The early mortalities resulting from lymphocytic lymphomas in male mice exposed to 625 ppm 1,3-butadiene limited the expression of tumors at other sites. A clearer dose-response for 1,3-butadiene-induced neoplasia should be apparent from experiments in mice exposed to lower concentrations of this chemical for 2 years.

Carcinogenicity testing of phthalate esters and related compounds by the National Toxicology Program and the National Cancer Institute.

Five phthalate ester and related compounds (phthalic anhydride, phthalamide, di(2-ethylhexyl) phthalate, di(2-ethylhexyl) adipate and butyl benzyl phthalate) have been tested for carcinogenic effects in standard lifetime rodent feeding studies. Groups of 50 male and female rats and mice were fed diets containing various concentrations of the test chemicals for 102-106 consecutive weeks. The dietary concentrations were estimated to be maximally tolerated doses and half maximally tolerated doses. All animals that died during the study and all survivors at the end of two years were examined grossly and microscopically for the presence of tumors. The incidences of animals with tumors at a specific anatomic site in the treated groups and the controls were compared statistically. Neither phthalamide nor phthalic anhydride increased tumor incidences in rats or mice. Di(2-ethylhexyl) phthalate increased the incidences of liver tumors in rats and mice of both sexes, while di(2-ethylhexyl) adipate caused liver tumors in male and female mice, only. Butyl benzyl phthalate did not cause tumors in male or female mice, but the incidence of myelomonocytic leukemia in butyl benzyl phthalate-treated female rats was significantly greater than that in the controls. Chemically induced early deaths in the butyl benzyl phthalate-treated male rats precluded an evaluation of carcinogenic potential in this sex. Under the conditions of these tests, di(2-ethylhexyl) adipate was considered to be carcinogenic in both rats and mice and di(2-ethylhexyl) adipate was considered to be carcinogenic in mice. The evidence for carcinogenic effects of butyl benzyl phthalate in female rats was judged to be equivocal because of the variable nature of the incidence of myelomonocytic leukemia in Fischer 344 rats. Phthalamide and phthalic anhydride did not exhibit carcinogenic effects in these studies.

Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.

Toxicology and carcinogenesis studies of benzene (CAS No. 71-43-2; greater than 99.7% pure) were conducted in groups of 60 F344/N rats and 60 B6C3F1 mice of each sex for each of three exposure doses and vehicle controls. These composite studies on benzene were designed and conducted because of large production volume and widespread human exposure, because of the epidemiologic association with leukemia, and because previous experiments were considered inadequate or inconclusive for determining carcinogenicity in laboratory animals. Using the results from 17-week studies, doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten animals in each of the 16 groups were killed at 12 months, and necropsies were performed. Hematologic profiles were performed at 3-month intervals. For the 2-year studies, mean body weights of the top dose groups of male rats and of both sexes of mice were lower than those of the controls. Survivals of the top dose group of rats and mice of each sex were reduced; however, at week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the dosed animals that died before week 103 had neoplasia. Compound-related nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found both for rats and mice. Further, the oral cavity was affected in rats, and the lung, liver, Harderian gland, preputial gland, ovary, and mammary gland were affected in mice. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of benzene in male F344/N rats, female F344/N rats, male B6C3F1 mice, and female B6C3F1 mice. In male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. In female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity.(ABSTRACT TRUNCATED AT 400 WORDS)

Two-year inhalation carcinogenesis studies of methyl methacrylate in rats and mice: inflammation and degeneration of nasal epithelium.

Methyl methacrylate (MMA), a liquid monomer, is used as a chemical intermediate in the manufacture of plexiglass and other acrylic products and as "bone cement" in orthopedic and dental surgery. Toxicology and carcinogenesis inhalation studies of MMA were conducted because of: (1) widespread human exposure; (2) evidence of mutagenicity; and (3) inadequacy of previously conducted long-term oral, dermal, and inhalation studies. Groups of 50 male F344/N rats were exposed to MMA by inhalation at 0, 500, or 1000 ppm, female F344/N rats at 0, 250, or 500 ppm, and male and female B6C3F1 mice at 0, 500, or 1000 ppm, 6 h a day, 5 days a week for 102 weeks. Survival rates of male and female rats and mice exposed to MMA were similar to those of their respective controls. Body weights were reduced in the low and high dose male (3-6% and 5-10%, respectively) and female (5-7% and 8-10%) rats exposed to MMA for more than 80 weeks and in male (7-19% and 6-17%) and female (0-13% and 0-17%) mice for more than 20 weeks. Inhalation exposure of MMA for 102 weeks did not induce any increased incidences of neoplasms in male or female rats or mice. Non-neoplastic lesions in the nasal cavity of MMA-exposed rats and mice were significantly increased and these included inflammation and degeneration of the olfactory epithelium of MMA-exposed male and female rats and inflammation, hyperplasia, cytoplasmic inclusions in the respiratory epithelium, and degeneration of the olfactory epithelium in male and female mice.

Comparative carcinogenicity of two structurally similar phenylenediamine dyes (HC blue no. 1 and HC blue no. 2) in F344/N rats and B6C3F1 mice.

Toxicology and carcinogenesis studies of 2 structurally-related p-phenylenediamines, HC Blue No. 1, and HC Blue No. 2 were conducted by administering each chemical in feed for 103 weeks to both sexes of Fischer 344/N rats and B6C3F1 (C57BL/6N x C3H/HEN) mice. Diets containing 0, 1500, or 3000 ppm HC Blue 1 were fed to male and female rats and male mice; female mice received diets with 0, 3000, or 6000 ppm. Diets containing 0, 5000, or 10,000 ppm HC Blue 2 were fed to male rats and mice and the females received diets containing 0, 10,000 or 20,000 ppm. These concentrations were compatible with long-term growth and survival. The results demonstrated substantial differences in the neoplastic and non-neoplastic lesions caused by these structural analogs. HC Blue 2 caused histocytosis in lungs and hyperostosis of the skull in rats, and splenic hematopoiesis, fibrous osteodystrophy, and hyperostosis of the skull in mice. These non-neoplastic lesions were not observed in rats or mice treated with HC Blue 1. Contrasting, in male and female mice, HC Blue 1 produced dose-related increases in the incidences of both adenomas and carcinomas of the liver. HC Blue 1 produced a marginally positive trend in hepatocellular nodules and carcinomas in male rats and dose-related increases in hyperplasias and neoplasms of the lungs in female rats. In contrast, there was no evidence of carcinogenicity for HC Blue 2 in either sex of rats or mice, despite the fact that it was administered 3-5 times the dose of the HC Blue 1. Since these 2 nitroaromatic compounds differ only in the methyl vs. 2-hydroxyethyl substituent on the secondary amine of ring carbon 4, the great discordance in their carcinogenicity is most probably due to side group-directed alteration in their metabolic profiles.

Benzyl acetate carcinogenicity, metabolism, and disposition in Fischer 344 rats and B6C3F1 mice.

Carcinogenesis studies of benzyl acetate (a fragrance and flavoring agent) were conducted in F344 rats and B6C3F1 mice. The chemical was given in corn oil by gavage once daily, 5 days/week for 103 weeks, to groups of 50 animals of each sex and species. For rats the doses were 0, 250, and 500 mg/kg body weight and for mice the doses were 0, 500, and 1000 mg/kg. Mean body weights of control and dosed rats and mice were not affected adversely by benzyl acetate. The survival of control and low dose female mice was lower than that of the high dose group. A genital tract infection may have contributed to the reduced survival. No other significant difference in survival was observed for dosed rats or mice. Benzyl acetate was absorbed from the gastrointestinal tract of rats and mice, with approximately 90% of the administered dose recovered as various metabolites in the urine within 24 h. The primary metabolite was hippuric acid, with minor amounts of a mercapturic acid, and one or more unidentified metabolites. This capacity for absorption, metabolism, and disposition was unaffected by the amount or number of doses administered. Under the conditions of these studies, benzyl acetate administration was associated with an increased incidence of acinar cell adenoma of the exocrine pancreas in male F344/N rats. No evidence of carcinogenicity was found for female F344/N rats. For male and female B6C3F1 mice there was evidence of carcinogenicity, in that benzyl acetate caused an increased incidence of hepatocellular neoplasms (particularly adenomas) and squamous cell neoplasms of the forestomach.

A review of the genetic toxicology of chlorinated dibenzo-p-dioxins.

Information from both published and unpublished sources considered relevant to the understanding of the genetic toxicology of chlorinated dibenzo-p-dioxins is summarized in this review. Interest in writing this paper was stimulated by the fact that this class of compounds, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has gained notoriety as an extreme environmental and industrial hazard. The potential for human exposure occurs in the work place when dioxins are formed during the synthesis of a number of commercially important compounds such as 2,4,5-trichlorophenoxyacetic acid, hexachlorophene, and pentachlorophenol. Environmental contamination may result from manufacturing processes and from dioxin contaminants in marketed products. Research on dioxins as potential mutagens was initiated because of their structural similarity to acridines, a class of known intercalating agents. To date, only 4 dioxin compounds have been evaluated for mutagenicity: the di-, tetra-, and octa-chlorinated derivatives and the unsubstituted dibenzo-p-dioxin. Since only a few of the many possible structural forms of dioxins have been tested, no definite conclusions can be made about their potential mutagenicity. Furthermore, the positive mutagenicity and cytological effects reported thus far with the few dioxin isomers examined seems to depend on the position of chlorine substitution. The most active form of the molecule is the 2,3,7,8-derivative (TCDD). Data available for assessing the mutagenic potential of TCDD are conflicting and scarce. Differences in testing results reported in these studies could be attributed to solubility problems with the test chemical, treatment protocols, purity of test samples, or toxicity. Because there are conflicting data, additional experiments are needed before the mutagenic potential of TCDD and other dioxins can be determined. Studies exploring the promoting effect of dioxins on the mutagenicity of other compounds are also recommended because experiments have shown TCDD to be an extremely active liver enzyme inducing agent that enhances the mutagenicity of certain polycyclic hydrocarbons such as 3-methylcholanthrene in vitro. The importance of discerning the hazards to human health from dioxin compounds became apparent after an accidental release of TCDD from a chemical plant contaminated the Seveso, Italy area in July 1976. This accident revealed that insufficient data were available to properly evaluate the long-term health risks posed by dioxin compounds. Several research projects were therefore initiated after the Seveso incident; it is hoped that many of the questions concerning the mutagenicity of TCDD and possibly of other dioxin congeners will be answered as a result of this work.

Carcinogenicity of p-chloroaniline in rats and mice.

p-Chloroaniline (PCA), a dye intermediate, was evaluated for potential long-term toxicity and carcinogenicity. Groups of 50 F344/N rats of each sex were given by gavage PCA hydrochloride in deionized water at doses of 0, 2, 6 or 18 mg/kg body weight, 5 days/wk for 103 wk. Groups of 50 male and female B6C3F1 mice of each sex were given 0, 3, 10 or 30 mg/kg on the same schedule. In general, body weights and survival were unaffected by PCA administration. In rats the group given 18 mg/kg had mild haemolytic anaemia and slight increases in methaemoglobin at various times during the study. Fibrosis of the spleen was significantly increased in all PCA-treated groups of male rats and in the 18-mg/kg group of female rats. Sarcomas of the spleen occurred in male rats, their incidence being 0/49, 1/50, 3/50 and 38/50 in control low-, mid- and high-dose groups, respectively. There was a slightly increased incidence of pheochromocytomas of the adrenal gland in both male and female rats. Dosed groups of male mice had increased incidences of hepatocellular adenomas or carcinomas (11/50, 21/49, 20/50 and 21/50 in controls, low- mid- and high-dose groups, respectively). Haemangiosarcomas of the liver or spleen were also increased in the high-dose group (incidences of 4/50, 4/49, 1/50 and 10/50 in controls, low-, mid- and high-dose groups, respectively). In conclusion, PCA was carcinogenic in male rats and male mice.

Toxicity and carcinogenicity of hydroquinone in F344/N rats and B6C3F1 mice.

Toxicology and carcinogenesis studies were conducted by administering hydroquinone (more than 99% pure) by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 wk or 2 yr. 14-day studies were conducted by administering hydroquinone in corn oil to rats at doses ranging from 63 to 1000 mg/kg body weight and to mice at doses ranging from 31 to 500 mg/kg, 5 days/wk. In the 13-wk studies, doses for rats and mice ranged from 25 to 400 mg/kg. At those doses showing some indication of toxicity in the 14-day and 13-wk studies, the central nervous system, forestomach and liver were identified as target organs in both species and renal toxicity was observed in rats. Based on these results, 2-yr studies were conducted by administering 0, 25 or 50 mg hydroquinone/kg in deionized water by gavage to groups of 65 rats of each sex, 5 days/wk. Groups of 65 mice of each sex were given 0, 50 or 100 mg/kg on the same schedule. 10 rats and 10 mice from each group were killed and evaluated after 15 months. Mean body weights of high-dose male rats and high-dose mice were approx. 5-14% lower than those of controls during the second half of the study. No differences in survival were observed between dosed and control groups of rats or mice. Nearly all male rats and most female rats in all vehicle control and exposed groups had nephropathy, which was judged to be more severe in high-dose male rats. Hyperplasia of the renal pelvic transitional epithelium and renal cortical cysts were increased in male rats. Tubular cell hyperplasia of the kidney was seen in two high-dose male rats, and renal tubular adenomas were seen in 4/55 low-dose and 8/55 high-dose male rats; none was seen in vehicle controls or in female rats. Mononuclear cell leukaemia in female rats occurred with increased incidences in the dosed groups (vehicle control, 9/55; low dose, 15/55; high dose, 22/55). Compound-related lesions observed in the liver of high-dose male mice included anisokaryosis, syncytial alteration and basophilic foci. The incidences of hepatocellular neoplasms, primarily adenomas, were increased in dosed female mice (3/55; 16/55; 13/55). Follicular cell hyperplasia of the thyroid gland was increased in dosed mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Toxicity and carcinogenicity of nitrofurazone in F344/N rats and B6C3F1 mice.

Toxicology and carcinogenesis studies were conducted by feeding diets containing nitrofurazone (99% pure) to groups of F344/N rats and B6C3F1 mice for 14 days, 13 wk or 2 yr. In the 14-day studies, in which doses ranged from 630 to 10,000 ppm, nitrofurazone was more toxic to mice than to rats. Accordingly, in the 13-wk studies, doses for rats ranged from 150 to 2500 ppm and for mice from 70 to 1250 ppm. At the higher doses, convulsive seizures and gonadal hypoplasia were observed in both species. Evidence of toxicity in rats also included degenerative arthropathy. For the 2-yr studies, rats were exposed to 0, 310 or 620 ppm nitrofurazone and the survival of male rats given 620 ppm was lower than that of controls (33/50, 30/50 and 20/50 in the control, 310- and 620-ppm groups, respectively). Nitrofurazone administration increased the incidences of mammary gland fibroadenomas in female rats (8/49, 36/50 and 36/50 in the control, 310- and 620-ppm groups, respectively). In male rats it was associated with a marginal increase in sebaceous gland adenomas and trichoepitheliomas of the skin, mesotheliomas of the tunica vaginalis, and tumours of the perputial gland. Nitrofurazone caused testicular degeneration (atrophy of germinal epithelium and aspermatogenesis) in rats, and degeneration of vertebral and knee articular cartilage in rats of both sexes. In mice, dietary concentrations of nitrofurazone for the 2-yr studies were 0, 150 or 310 ppm. In mice of each sex, nitrofurazone administration induced stimulus-sensitive convulsive seizures, primarily during the first year of study. In male mice, there was no evidence of any chemically-related carcinogenic effects, but there was a treatment-related decrease in survival (39/50, 31/50 and 27/50 in the control, 150- and 310-ppm groups, respectively). In female mice nitrofurazone induced ovarian lesions with increased incidences of benign mixed tumours (0/47, 17/50 and 20/50 in control, low- and high-dose groups, respectively) and granulosa cell tumours (1/47, 4/50 and 9/50 in control, low- and high-dose groups, respectively).

Forestomach neoplasms in Fischer F344/N rats and B6C3F1 mice exposed to diglycidyl resorcinol ether--an epoxy resin.

Repeated dose (14 days), subchronic (13 wk) and chronic (2 yr) studies were carried out in succession to evaluate the toxic and carcinogenic effects of diglycidyl resorcinol ether (DGRE), a liquid spray epoxy resin, in F344/N rats and B6C3F1 mice. DGRE in corn oil was administered by gavage for 14 consecutive days in the repeated dose study and 5 days/wk in the subchronic and chronic studies. The mortality rate was increased in rats and mice in the repeated dose and subchronic studies. Hyperkeratosis, basal cell hyperplasia and squamous cell papillomas of the forestomach were observed in a few treated rats and mice in the subchronic study. Based on the results of the subchronic study, F344/N rats and B6CF1 mice (50 males and 50 females/species/dose) were administered DGRE (rats--0, 12, 25 and 50 mg/kg body weight, mice--0, 50 and 100 mg/kg body weight) in corn oil by gavage 5 days/wk for 103 wk. The incidence of neoplastic and non-neoplastic changes of the forestomach was increased in rats and mice in the chronic study. Under the conditions of the study, DGRE is considered to be carcinogenic to F344/N rats and B6C3F1 mice.

No evidence of carcinogenicity of D-mannitol and propyl gallate in F344 rats or B6C3F1 mice.

Chronic toxicity and carcinogenicity studies were conducted on D-mannitol and propyl gallate in F344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were maintained on diets containing either 0, 2.5 or 5.0% D-mannitol or 0, 0.6 or 1.2% propyl gallate for 103 wk. D-Mannitol had no effect on survival or mean body weight of rats and mice, and feed consumption was approximately the same in control and treated groups in each species. Gastric fundal gland dilation occurred at a higher incidence in treated female rats than in controls. A mild nephrosis characterized by focal vacuolization of the renal tubular epithelium was observed in an increased incidence in treated mice. No significant increase in tumour incidence was observed in any of the treated groups in comparison with the corresponding controls. Survival of rats and mice given propyl gallate was similar to that of the controls. Mean body weights were lower in chemically exposed animals, and more so for females. Male rats exposed to propyl gallate showed an increased incidence of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate gland. Tumours of the preputial gland, islet-cell tumours of the pancreas, and phaeochromocytoma of the adrenal gland occurred at a significantly (P less than 0.05) higher incidence in the low-dose male rats. Malignant lymphoma occurred with a positive trend in male mice (control 1/50, low dose 3/49 and high dose 8/50), and the incidence in the high-dose group was significantly (P less than 0.05) higher than in the control group. However, since the incidence in the control group was much less than the historical control rate (36/398 or 9%) in this laboratory, this apparent increase was not considered to be related to propyl gallate administration. Under the conditions of these studies, neither D-mannitol nor propyl gallate was considered to be carcinogenic to F344 rats or B6C3F1 mice of either sex.

An aging model for surface acoustic wave devices.

The authors present a study of the phase-aging kinetics of a 591.2 MHz quartz-crystal surface acoustic wave (SAW) filter intended for application in an undersea telecommunication system. At aging temperatures from 50 to 140 degrees C, a previously established SAW-device aging model describes the time dependence of the phase aging. The results of an investigation of the temperature dependence of the coefficients in this aging model allows the authors to extend the model, capturing both the time and the temperature dependence of the degradation. They then identify and assess the sources of variation, or error, affecting the data and model, estimate the distributions of the errors, and incorporate these error distributions in the extended aging model. This leads to a composite aging model that describes the time and temperature dependence of the complete phase-aging distribution. The authors use this composite model to predict end-of-life phase-aging distributions, demonstrating that the devices exhibit the high level of stability required by the application.