Immunogenicity of a DNA vaccine against herpes B virus in mice and rhesus macaques.

Herpes B virus (Cercopithecine herpesvirus 1) is endemic in captive macaque populations and poses a serious threat to humans who work with macaques or their tissues. A vaccine that could prevent or limit B virus infection in macaques would lessen occupational risk. To that end, a DNA vaccine plasmid expressing the B virus glycoprotein B (gB) was constructed and tested for immunogenicity in mice and macaques. Intramuscular (IM) or intradermal (ID) immunization in mice elicited antibodies to gB that were relatively stable over time and predominately of the IgG2a isotype. Five juvenile macaques were immunized by either IM+ID (n=2) or IM (n=3) routes, with two booster immunizations at 10 and 30 weeks. All five animals developed antibodies to B virus gB, with detectable neutralizing activity in the IM+ID immunized animals. These results demonstrated that DNA immunization can be used to generate an immune response against a B virus glycoprotein in uninfected macaques.

1,3-Butadiene induces cancer in experimental animals at all concentrations from 6.25 to 8000 parts per million.

1,3-Butadiene, a chemical produced in large volumes, induces cancer in many organs in rats (at 1000 and 8000 ppm) and mice (at 6.25 to 1250 ppm); however, the sites of tumour induction (seven in rats and nine in mice) and the magnitudes of response differ between the two species. Particularly noteworthy in the studies of mice exposed by inhalation were the early, extensive induction of malignant lymphomas, the induction of uncommon haemangiosarcomas of the heart and the development of malignant lung tumours at 6.25 ppm, the lowest concentration ever used in a long-term carcinogenicity study of this gas. In order to account for the impact of early mortality on the expression of late development of tumours, survival-adjusted tumour rates were computed for mice exposed to butadiene at 6.25-625 ppm. The results provide a more accurate characterization of concentration-dependent responses for butadiene-induced cancers. Stop-exposure studies revealed that the atmospheric concentration of butadiene was a greater contributing factor to the development of lymphomas than was duration of exposure. The studies in mice show a good correspondence with the reported associations between occupational exposure to butadiene and excess mortality from lymphatic and haematopoietic cancers; mice are thus a better experimental surrogate for humans. Although further work is needed to improve our understanding of the mechanisms of tumour induction by butadiene, pursuit of that research must not delay reduction of human exposure to this carcinogenic chemical.

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.

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)

Chemical toxicity and chemical carcinogenesis. Is there a causal connection? A comparative morphological evaluation of 1500 experiments.

Chemicals cause toxic and carcinogenic effects as well as beneficial and other adverse effects in animals and in humans. The purpose of this paper is to assess whether there is a direct, uniform causal relationship between toxicity and carcinogenicity. Within this context, specific issues receive attention: the influence of exposure concentrations on carcinogenesis; kidney cancer and alpha 2 mu-globulin; urinary calculi and tumours; and cell turnover or proliferation and cancer. The data used to evaluate histopathological site-specific correspondence between these two end-points comes from 130 studies of chemical carcinogenesis designed and conducted by the US National Toxicology Program (NTP). Nearly 1500 sex-species-exposure group experiments were evaluated for morphological evidence of toxicity and/or carcinogenicity, for dose-response relationships, and for site-specific correlations of toxicity and carcinogenicity. The major conclusions are that chemicals evaluated for long-term toxicity and carcinogenicity in experimental animals can be divided into three categories: (1) those that cause organ toxicity without cancer, (2) those that cause site-specific cancer with no associated toxicity and (3) those that cause toxicity and cancer in the same organ. Examples are given to illustrate each category. On the basis of this comparative analysis, in the great majority of cases the available data do not support a correlation between chemically induced toxicity and carcinogenicity. Moreover, until considerably more scientific knowledge about molecular mechanisms of carcinogenesis becomes available and accepted, attempts to use findings on toxicity to modify the risk assessment process will be fraught with uncertainty and might even have a negative impact on public health.

Toxicology and carcinogenesis studies of two grades of pentachlorophenol in B6C3F1 mice.

Toxicology and carcinogenesis studies of pentachlorophenol (penta), a biocide used primarily as a wood preservative, were conducted by feeding diets containing a technical-grade composite or Dowicide EC-7 (a commercial grade with lower levels of contaminants) to groups of B6C3F1 mice. Based primarily on liver lesions (hepatocellular necrosis, degeneration, and cytomegaly) observed in 6-month studies, diets containing 100 or 200 ppm technical-grade pentachlorophenol or 100, 200, or 600 ppm EC-7 were fed to groups of 50 male and 50 female mice for 2 years. Control groups consisted of 35 animals. For the most part, mean body weights of mice exposed to technical-grade penta were comparable to those of controls. During the second year, the 600-ppm EC-7 female mice averaged 85% of the control body weights. Feed consumption by exposed mice was similar to that by controls. The average daily doses of penta were approximately 0, 17-18, 35, or 114-118 (EC-7) mg/kg. Survival of mice did not appear to be significantly affected by exposure to either technical penta or EC-7 at the doses used in these studies; survival of the control male mice (technical-grade) was comparatively low. Compound-related neoplasms were observed in three organs/systems: liver, adrenal gland medulla, and vascular endothelium. Dose-related increases of hepatocellular adenomas and of carcinomas were observed in male and female mice exposed to both technical penta and EC-7, although the increase was less marked in females exposed to technical penta. Pheochromocytomas of the adrenal gland in exposed male mice were significantly greater than those in controls for both technical penta and EC-7. These neoplasms were also increased in female mice exposed to EC-7 but not to technical penta. Hemangiosarcomas in the spleen and/or liver were increased in female mice that received technical penta and EC-7. The results of these studies show that both technical penta and Dowicide EC-7 are carcinogenic for mice, causing neoplasms in multiple organs/systems. In addition, the results suggest that the carcinogenic responses were due almost exclusively to penta itself, with possibly a minimal potentiating influence by the contaminants in the induction of liver neoplasms in male mice.

Comparative toxicity and carcinogenicity studies of tetracycline and oxytetracycline in rats and mice.

Two-year toxicity and carcinogenicity studies of oxytetracycline hydrochloride and tetracycline hydrochloride, two structurally similar and widely used antibiotics, were performed in F344/N rats and B6C3F1 mice. Rats and mice were continuously exposed via their diet to the following levels of antibiotic: oxytetracycline HCl--rats 0, 25,000, or 50,000 ppm; mice 0,6,300, or 12,500 ppm; tetracycline HCl--rats and mice 0, 12,500, or 25,000 ppm. On a milligram per kilogram of body weight basis these exposures represent doses that are 20 to 140 times daily human therapeutic doses. Dose-related increased survival was noted among oxytetracycline-treated male rats and tetracycline-treated female rats and male mice, while treatment-related reduced body weight gain occurred in oxytetracycline- and tetracycline-treated mice. Microscopic changes included fatty metamorphosis and focal cellular change in livers of oxytetracycline-treated male rats and basophilic cytoplasmic and clear cell change in livers of tetracycline-treated male rats. The only neoplastic changes were a marginally increased trend in pheochromocytoma of the adrenal medulla (equivocal evidence only) among oxytetracycline-exposed male rats (12/50 controls, 19/50 low dose, 24/50 high dose) and an increased incidence of pituitary adenoma or adenocarcinoma among high-dose oxytetracycline-treated female rats (20/50 controls, 32/50 high dose). Although oxytetracycline and tetracycline appeared to increase the incidence of pituitary hyperplasia in high-dose male and female rats, respectively, the total incidence of proliferative changes (hyperplasia, adenoma, and adenocarcinoma) was not affected by antibiotic exposure. The results from these studies therefore support the notion that neither antibiotic is carcinogenic in rodents. There were several negative trends suggesting possible protective effects by both these tetracycline analogs against certain spontaneous neoplastic and non-neoplastic changes.

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.

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.

Long-term carcinogenesis studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin and hexachlorodibenzo-p-dioxins.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 1,2,3,6,7,8- and 1,2,3,7,8,9-hexachlorodibenzo-p-dioxins (HCDDs) are among the most toxic and carcinogenic of "man-made" chemicals. These "dioxins," as well as many of the other polychlorinated dibenzodioxins (PCDDs) and dibenzofuran (PCDFs) derivatives, are chlorinated aromatic compounds which are chemically stable, insoluble in water, and highly soluble in fats and oils. TCDD acts as a complete carcinogen in several species, causing both common and uncommon tumors at multiple sites. It is a highly potent chemical carcinogen in chronic animal studies, producing carcinogenic effects in laboratory animals with doses as low as 0.001 micrograms/kg/day. In rats, TCDD induces neoplasms in the lung, oral/nasal cavities, thyroid and adrenal glands, and liver. In mice, TCDD induces neoplasms in the liver and subcutaneous tissue, thyroid gland, and thymic lymphomas. In hamsters, it induces squamous cell carcinomas of the facial skin. Tumors of the integumentary system are reported after oral (mice and rats), intraperitoneal (hamsters), and dermal (mice) administration. A mixture of HCDDS (defined as the mixture of the 1,2,3,6,7,8- and 1,2,3,7,8,9 isomers used in the NTP experiments) are potent liver carcinogens in mice and rats. Pharmacokinetic studies in laboratory animals indicate that 50-90% of dietary TCDD is absorbed. It concentrates in adipose tissue and the liver. In mammals, the TCDD present in the liver is slowly redistributed and stored in fatty tissue. Elimination of TCDD occurs via excretion of metabolites in the bile and urine and passively through the gut wall. Metabolism is slow: the biological half-life of TCDD varies from weeks (rodents) to years (humans), and is strongly dependent upon the rate of TCDD metabolism. Many of the toxic effects of TCDD, including teratogenicity, may arise by receptor-mediated mechanisms. The induction of cytochrome P-448 and related enzymes by TCDD occurs by such a mechanism, and is related to the binding of TCDD to the Ah receptor. The specific mechanism(s) by which TCDD exerts its carcinogenic effects is unclear: receptor-binding may be part of the story. The role of the Ah receptor has been indicated in a skin promotion assay. The evidence for mutagenicity is inconclusive. TCDD did not induce lethal mutations, chromosomal aberrations, micronuclei or sister chromatid exchanges in rodents treated in vivo, nor was it mutagenic to bacteria, but it did enhance transformation of mouse C3H 10T1/2 cells by N-methyl-N'-nitro-N-nitrosoguanidine and was mutagenic to mouse lymphoma cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Carcinogenicity of ochratoxin A in experimental animals.

The carcinogenicity of ochratoxin A, a naturally occurring mycotoxin of the fungal genera Aspergillus and Penicillium, was evaluated in three strains of mice and in one strain of rats. The kidney, and in particular the tubular epithelial cells, was the major target organ for ochratoxin A-induced lesions. In male ddY and DDD mice, atypical hyperplasia, cystadenomas and carcinomas of the renal tubular cells were induced, as were neoplastic nodules and hepatocyte tumours of the liver. In B6C3F1 mice, tubular-cell adenomas and carcinomas of the kidneys were induced in male mice, and the incidences of hepatocellular adenomas and carcinomas were increased in male and female mice. In male and female F344 rats, ochratoxin A induced nonneoplastic (degeneration, karyomegaly, proliferation, cytoplasmic alteration, hyperplasia) and neoplastic effects (adenomas, and carcinomas with metastases) in the kidneys; the incidence of fibroadenomas of the mammary glands was also increased in female rats. Other studies on ochratoxin A were considered inadequate for evaluating the presence or absence of a carcinogenic effect; however, these are mentioned and referenced below. The collective experimental findings, together with accumulating evidence in humans, forecast further toxic and carcinogenic effects in humans exposed to ochratoxin A, mainly via foodstuffs.

The carcinogenic activity of commercial grade toluene diisocyanate in rats and mice in relation to the metabolism of the 2,4- and 2,6-TDI isomers.

Groups of 50 F344/N rats of each sex and 50 B6C3F1 mice of each sex were gavaged with corn oil or a mixture of toluene diisocyanate (TDI) in corn oil for 5 days per week for 105 or 106 weeks. Female rats and mice were given doses of 60 or 120 mg/kg body weight, while male rats received 30 or 60 mg/kg, and male mice received 120 or 240 mg/kg. The TDI reacted with the moisture in the corn oil vehicle resulting in doses that were 10% to 23% below the target dose concentrations. The chemical product used was commercial grade TDI, which was an 80%-20% mixture of the 2,4- and 2,6-isomers. Chemical disposition and metabolism studies were conducted with each of the radiolabelled TDI isomers in male rats. Absorption of both of the TDI isomers occurred, with the highest concentrations found in the stomach, cecum, large intestine, and bladder. Excretion occurred via the feces and urine. The major metabolic products from the metabolism of 2,4-TDI were shown to be identical with those from the metabolism of the carcinogen, 2,4-diaminotoluene, whereas the metabolism of the 2,6-TDI isomer yielded one major product, identified as 2,6-bis(acetylamino)toluene. Greater than 10% depression in body weight gain occurred in all dosed groups of rats throughout most of the study. The major non-neoplastic lesions that were observed in both sexes of the TDI-exposed rats were dose-related increases in acute broncho-pneumonia, characterized as chemical pneumonitis, with incidences as high as 50%. In mice mean body weight gain was depressed in dosed male and in high dose females. The principle non-neoplastic lesion in mice that was attributed to chemical treatment was cytomegaly of the kidney tubular epithelium in males. Survival in all groups of dosed rats was significantly lower than in controls. A dose-dependent pattern of mortality did not commence until 70 weeks of exposure, demonstrating that toluene diisocyanate elicited a cumulative toxic response. There was also significantly lower survival in high dose male, but not female mice, by comparison to controls. Despite the reduction of power and sensitivity in the rat studies caused by early mortality, statistically significant increases in tumor incidences were observed in many different target organs. TDI was carcinogenic in F344/N rats, causing subcutaneous fibromas and fibrosarcomas in males and females, pancreatic acinar cell adenomas in males, and pancreatic islet cell adenomas, neoplastic nodules of the liver, and mammary gland tumors in females.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

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.

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)

Occurrence and relevance of chemically induced benign neoplasms in long-term carcinogenicity studies.

Recent carcinogenicity studies conducted and evaluated by the National Toxicology Program/National Institute of Environmental Health Sciences were examined to determine the frequency of chemically increased incidences of neoplasia. Many of the chemicals originally selected for study were chosen because of an a priori suggestion that they might be carcinogens. Of the 143 chemical studies evaluated, usually involving male and female rats and mice, 42 (29%) did not induce any neoplasms, 20 (14%) gave marginal or equivocal neoplastic responses, and 81 (57%) showed positive neoplastic responses in one or more of the 524 species-gender experiments. Of these 81 positive studies, 60 (74%) were considered positive based on malignant neoplasia, 16 (20%) were positive due primarily to benign neoplasia, but had supporting evidence of malignant neoplasia in the same organ/tissue, and 5 (6%) were positive based only on benign neoplasia. These five chemicals are a) allyl isothiocyanate (transitional cell papillomas of the urinary bladder in male rats), b) 2-amino-4-nitrophenol (tubular cell adenomas of the kidney in male rats), c) asbestos intermediate range chrysotile (adenomatous polyps of the large intestine in male rats), d) decabromodiphenyl oxide (neoplastic nodules of the liver in male and female rats), and e) nitrofurazone (fibroadenomas of the mammary gland in female rats and benign mixed tumors and granulosa cell tumors of the ovary in female mice). For all but one of these lesions (mammary gland), the occurrence in historic controls is low. Thus, only 5 of the 143 chemicals studied (3.5%) induced benign neoplasia alone, and those observed benign neoplasms are known to progress to malignancy. Accordingly, we consider chemically induced benign neoplasia to be an important indicator of a chemical's carcinogenic potential in rodents, and believe it should continue to be made an integral part of the overall weight-of-the-evidence evaluation process for identifying potential human health hazards.

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.

Sources of variability in rodent carcinogenicity studies.

A number of factors may influence tumor rates in rodent carcinogenicity studies, including the animal room environment, genetic differences, food consumption/weight gain, survival/age of the animals, identification of gross lesions, pathology sampling procedures and preparation of the histology slides, and histopathologic diagnosis. The relative importance of these factors is evaluated, making use of laboratory animal carcinogenicity data from the National Toxicology Program and from other sources. An investigator must be aware of these potentially confounding factors, so that appropriate measures can be taken to reduce or eliminate their impact on the interpretation of study results. Certain potential sources of within-study variability can be controlled by appropriate experimental design and by proper conduct according to standard operating procedures. The effect of certain factors influencing tumor prevalence may be magnified when variability from study to study is considered, and thus it may be difficult to formulate a biologically meaningful statistical analysis that uses historical control data in a formal testing framework.

Does central nervous system toxicity occur in transplant patients with hypocholesterolemia receiving cyclosporine?

A syndrome of severe central nervous system toxicity (confusion, cortical blindness, quadriplegia, seizures, and coma) associated with cyclosporine therapy and a low serum cholesterol level in patients with liver transplants has been described. We present a case history of a patient who demonstrated several similar features after heart-lung transplantation. Possible cyclosporine neurotoxicity should be considered in any patients with hypocholesterolemia receiving this drug.