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Biomedical subjects

J K Haseman

Publications and source records attributed to J K Haseman.

At least 55 records · Page 3Linked to original sources
PubMed1996

Evaluation of false positive and false negative outcomes in NTP long-term rodent carcinogenicity studies.

The decision-making process used by the National Toxicology Program (NTP) in its evaluation of long-term rodent carcinogenicity studies was investigated to determine whether or not this procedure resulted in an excessive number of false positive or false negative outcomes. All site-specific tumor incidences that were found to be significantly (p < 0.05) increased either by a trend test or by pairwise comparisons of each dosed group against the controls in 218 NTP 2-year studies with Fischer 344 rats and/or B6C3F1 mice were tabulated and compared to the number of statistically significant tumor increases expected to occur by chance. Our evaluation suggests that false positive rates are fairly low in NTP long-term studies. Assessing false negative rates is more difficult because of the limited sensitivity of the bioassay for detecting subtle carcinogenic effects. Moreover, reduced body weights frequently occur in dosed animals, and the positive correlation between the incidences of certain site-specific tumors and body weight may mask the detection of carcinogenic effects. Despite these difficulties, our analysis did identify one tumor showing evidence of false negative outcomes: interstitial cell tumors of the testis in male Fischer 344 (F344) rats. This tumor showed considerably more significant (p < 0.05) increased incidences than expected by chance, yet none were considered to be chemically-related. However, the biological significance of interstitial cell tumor increases in F344 rats is uncertain because of the high background rate of neoplasia (> 90%) for this target site.

Animals↗
PubMed1995

1,2,3-Trichloropropane: a multisite carcinogen in rats and mice.

1,2,3-Trichloropropane was evaluated in 2-year toxicology and carcinogenesis studies by the National Toxicology Program. The selection of this chemical for study was based on the potential for human exposure, its positive in vitro genotoxicity, and the carcinogenicity of structurally related chemicals. During the 2-year study 1,2,3-trichloropropane was administered in corn oil by gavage 5 days per week; groups of 60 F344/N rats received 0, 3, 10, or 30 mg/kg, while groups of 60 B6C3F1 mice received 0,6,20, or 60 mg/kg. Because of reduced survival associated with the development of chemical-related neoplasms, rats that received 30 mg/kg were terminated at 65 weeks (females) or 76 weeks (males). Similarly, mice that received 60 mg/kg were terminated at 73 weeks (females) or 79 weeks (males), while groups of mice that received 20 mg/kg were terminated at 88 weeks. 1,2,3-Trichloropropane induced benign and/or malignant neoplasms at multiple sites in both rats and mice; this included increased incidences of benign and malignant neoplasms of the squamous epithelium of the oral mucosa and forestomach of male and female rats, benign neoplasms of the kidney and pancreas and benign or malignant neoplasms of the preputial gland in male rats, malignant neoplasms of the mammary gland, and benign or malignant neoplasms of the clitoral gland in female rats. In mice, 1,2,3-trichloropropane induced a low incidence of malignant neoplasms of the oral mucosa in females, high incidences of benign and malignant neoplasms of the forestomach in males and females, benign neoplasms of the liver and harderian gland of males and females, and uterine neoplasms in females.

Animals↗
PubMed1995

Toxicity and carcinogenicity of 2,3-dibromo-1-propanol in F344/N rats and B6C3F1 mice.

2,3-Dibromo-1-propanol is a metabolite of the flame retardant tris(2,3-dibromopropyl) phosphate, previously shown to be a mutagen and carcinogen in experimental animals. Toxicology and carcinogenesis studies of 2,3-dibromo-1-propanol were conducted by applying the chemical in 95% ethanol to the interscapular skin of male and female F344/N rats and B6C3F1 mice 5 days a week for 13 weeks in the prechronic study and 48-55 weeks (rats) or 36-42 weeks (mice) in the carcinogenicity study. In the 13-week study, 10 rats and 10 mice of each sex received doses of 0, 44, 88, 177, 375, or 750 mg/kg. Deaths associated with chemical application occurred only in the high-dose (750 mg/kg) male mice. Chemical-related lesions were seen in the kidney of male rats, liver of female rats, and liver and lung of both sexes of mice. Based on the toxicity observed in the 13-week study, 50 rats of each sex received doses of 0, 188, or 375 mg/kg and 50 mice of each sex received 0, 88, or 177 mg/kg in the carcinogenicity study. The planned 2-year study was terminated early because of reduced survival of rats related to chemical-induced neoplasia and because of the appearance of antibodies to lymphocytic choriomeningitis virus in sentinel mice. Nearly all dosed rats had malignant neoplasms at one or more sites, while only one control male and one control female had malignant neoplasms. In rats, neoplasms induced by 2,3-dibromo-1-propanol occurred in the skin, nasal mucosa, Zymbal's gland, oral mucosa, esophagus, forestomach, intestines, liver, kidney, mammary gland (females), clitoral gland (females), spleen (males), and mesothelium (males). In mice, chemical-induced neoplasms occurred in the skin, forestomach, liver (males), and lung (males).

1-Propanol↗
PubMed1995

Chronic nephropathy and renal carcinogenicity of o-benzyl-p-chlorophenol in F344/N rats and B6C3F1 mice.

o-Benzyl-p-chlorophenol, an aryl halide biocide, was evaluated in male and female F344/N rats and B6C3F1 mice in a series of subchronic and 2-year toxicity and carcinogenicity studies. Kidney was the primary target of toxicity in the 13-week gavage studies in rats and mice, with increased nephropathy noted as low as 240 mg/kg in male rats. Considering the nephropathy to be doselimiting, the chronic (2-year) study was conducted at lower doses (male rats: 30, 60, or 120 mg/kg; female rats: 60, 120, or 240 mg/kg; male and female mice: 120, 240, or 480 mg/kg; in corn oil; n = 50/group). Survival and body weights of dosed rats were similar to controls in the 2-year study. Survival of high-dose male and female mice, and body weights of all dosed male and mid- and high-dose female mice, were lower than controls. The incidence and severity of nephropathy increased with dose and length of treatment in both rats and mice. There was an increased incidence of renal tubule adenomas or carcinomas in both the mid- and high-dose male mice. Despite similar evidence of nephropathy, however, there were no increased incidences of neoplasms in female mice or in male or female rats. This study suggests therefore that while nephrotoxicity may have been a necessary component, factors other than the marked nephrotoxicity of o-benzyl-p-chlorophenol were critical to the development of renal carcinogenesis induced in only male mice.

Adenoma↗
PubMed1995

Data analysis: statistical analysis and use of historical control data.

Survival-adjusted methods for the statistical analysis of tumor data from long-term rodent carcinogenicity studies are described. Although most of these methods require knowledge of whether individual tumors are "fatal" or "incidental," such determinations may be difficult. Several methods for dealing with this and with other data analysis issues are discussed. Historical control tumor data may be useful in the interpretation of rodent carcinogenicity studies, particularly for rare tumors and for borderline effects. Although statistical methods are available for using historical control data in a formal testing framework, the primary difficulty is establishing a database that is truly comparable to the study under evaluation with respect to those factors known to influence tumor occurrence. Major sources of variability in tumor incidence include the animal room environment, dietary factors/body weight, gross necropsy and slide preparation procedures, and histopathology diagnosis. The National Toxicology Program's use of historical control data is briefly described and illustrated.

Adrenal Cortex Neoplasms↗
PubMed1995

Incorporation of bromodeoxyuridine (BrdU) in the bronchiolar-alveolar regions of the lungs following two inhalation exposures to chrysotile asbestos in strain A/J mice.

We have been studying early fibroproliferative events in the lungs of rodents exposed to aerosols of asbestos fibers. In the experiments presented here, incorporation of bromodeoxyuridine (BrdU) in the bronchiolar/alveolar (B/A) regions of the lungs in mice was assessed following two consecutive exposures to chrysotile asbestos. Six to 8-week-old male strain A/J mice, a strain with a high spontaneous incidence of B/A tumors, were exposed to inhaled asbestos fibers for two consecutive days (3 hours/day). A group of mice was also given an intraperitoneal injection of urethane, a known lung carcinogen in A/J mice, 48 h after initial inhalation exposure to asbestos. The groups of mice exposed to asbestos had significantly (p <0.05) increased incorporation of BrdU in the nuclei of epithelial and interstitial cells in the B/A regions of the lung at 48 h, 72 h, and 2 weeks after initial exposure. By 1 month, the labeling indices in mice exposed to asbestos were not statistically significantly different from the controls; however, in the regions of the first alveolar duct bifurcations (ALDB), the primary site of initial asbestos deposition, there continued to be detectable labeling of the epithelial and interstitial cells. Because of considerable variability from duct to duct, there were no statistically significant differences between the asbestos-exposed mice and control groups at 3 months. We conclude that in A/J mice the initial proliferative response observed in the B/A regions of the lung after two 3-h inhalation exposures to asbestos is significantly prolonged through 2 weeks post-exposure. In addition, there was measurable labeling above control values in the epithelial and interstitial cells of the first alveolar duct bifurcations up to 3 months after exposure. Urethane had no apparent effect on the incorporation of BrdU into any cells of the B/A regions of the lung when administered after inhalation exposure to asbestos. Furthermore, although the A/J strain is highly susceptible to lung tumor formation, the unexposed control A/J mice showed no spontaneous increases in cell proliferation.

Administration, Inhalation↗
PubMed1994

The relationship between use of the maximum tolerated dose and study sensitivity for detecting rodent carcinogenicity.

The relationship between maximum tolerated dose (MTD) and study sensitivity for detecting rodent carcinogenicity was evaluated for 216 chemicals found to be carcinogens in laboratory animal studies conducted by the National Cancer Institute (NCI) and the National Toxicology Program (NTP). Approximately two-thirds of these rodent carcinogens would have been detected even without the top dose (estimated MTD), but in many of these studies, some site-specific carcinogenic effects would have been missed. Among the remaining one-third of the rodent carcinogens that required the top dose for statistical significance, approximately 80% had numerically elevated rates of the same site-specific tumors at lower doses as well. Only 13 of the NCI/NTP rodent carcinogens had increased tumor rates limited to the top dose for all sites of carcinogenicity. Alternatively, of the 838 site-specific carcinogenic effects observed in the NCI/NTP studies, 447 (53%) would have been detected even without the top dose. Of the remaining effects, 75% (294/391) showed numerically elevated site-specific tumor rates at lower doses. Our evaluation indicates that most carcinogenic effects observed at the top dose in rodent studies are also present (with reduced incidence that might or might not be statistically significant) at the lower doses typically employed (1/2MTD, 1/4MTD).

Animals↗
PubMed1994

Effect of individual housing and other experimental design factors on tumor incidence in B6C3F1 mice.

The effects of individual housing and other experimental design factors on body weight, survival, and tumor incidence in 72 control groups of B6C3F1 mice were evaluated. Individually housed males showed a greatly reduced incidence of dermal/subcutaneous tumors and an improved survival relative to group-housed animals. However, there were significant body weight increases in individually housed males and females and an associated marked increase in liver tumor incidence in both sexes and a lesser increase in lung neoplasms in males. Body weights of mice as young as 19 weeks of age were predictive of subsequent liver tumor incidence. There were no major differences in tumor rates among the various types of control groups, and differences in tumor rates among laboratories were not significant for most tumors. Differences among animal suppliers may have contributed to the time-related decreased incidence of malignant lymphoma observed in control mice, particularly in females. Comparisons with earlier control tumor rates suggest that there has been little change in tumor incidence for control groups having approximately equivalent body weights. However, control groups with heavier animals have shown a striking increase in the incidence of liver tumors. The National Toxicology Program recently returned to its earlier practice of group-housing female mice, and this should reduce the incidence of liver tumors in this sex-species group. However, if measures are not taken to reduce body weights, male mice (which continue to be individually housed because of fighting problems among group-housed animals) will likely continue to show a high incidence of liver tumors and possibly also lung neoplasms.

Animals↗
PubMed1994

Carcinogenicity studies of oxazepam in mice.

Oxazepam is a benzodiazepine widely used as a sedative-hypnotic and antianxiety drug. In chronic studies, groups of 60 male and 60 female Swiss-Webster (SW) or B6C3F1 mice received oxazepam in feed at concentrations of 0,2500, or 5000 ppm. Additional groups of 60 male and female B6C3F1 mice received 125 ppm in feed to allow for study of mice with serum concentrations of oxazepam similar to those achieved in humans taking a therapeutic dose. At 57 weeks, treatment-related mortality of exposed SW mice caused the study to be terminated. Enhanced systemic amyloidosis contributing to heart failure was considered the principal cause of death. Hepatocellular adenomas and carcinomas were increased in exposed SW mice. Survival of B6C3F1 mice receiving 2500 and 5000 ppm oxazepam was also lower than that of controls. Early deaths were due to increased incidences of hepatoblastoma and hepatocellular carcinoma, and nearly all mice receiving 2500 or 5000 ppm developed hepatocellular neoplasia. An increase in follicular cell hyperplasia of the thyroid gland occurred in all exposed groups of B6C3F1 mice, and thyroid gland follicular cell adenoma was increased in exposed females. Further studies of the capacity of oxazepam to induce liver cell mitogenesis and an evaluation of the frequency of activated H- and K-ras oncogenes in the liver tumors of B6C3F1 mice has shown that many of the neoplastic and nonneoplastic responses of mice to oxazepam resemble those observed with phenobarbital.

Animals↗
PubMed1993

Correlations between chemically related site-specific carcinogenic effects in long-term studies in rats and mice.

We examined a database of 379 long-term carcinogenicity studies in rats and mice to evaluate sex and species correlations in site-specific carcinogenic responses. Within a species, most target sites showed a strong correlation between males and females. For example, chemicals producing forestomach or liver tumors in males were likely to produce these same types of tumors in females. There was also a significant correlation between species for certain site-specific carcinogenic effects, most notably tumors of the forestomach, liver, and thyroid gland. In contrast, adrenal pheochromocytoma, preputial/clitoral gland neoplasms, and lung tumors showed no significant interspecies correlation. Many chemicals produced a syndrome of carcinogenic effects involving tumors of the skin, Zymbal gland, preputial/clitoral gland, mammary gland, and/or oral cavity. Regarding different target sites, there appeared to be a correlation between thyroid and liver tumors both within and between species. Further, all chemicals producing mesotheliomas in male rats also produced mammary gland neoplasms in female rats. In contrast, kidney and urinary bladder tumors showed no significant association with any other tumor type in rats or mice. If a chemical produced a site-specific carcinogenic effect in female rats or mice, there was approximately a 65% probability that the chemical would also be carcinogenic at that same site in males. The interspecies correlation was somewhat lower: approximately 36% of the site-specific carcinogenic effects observed in one species (rats or mice) were also observed in the other species.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Comparative carcinogenicity of 5,5-diphenylhydantoin with or without perinatal exposure in rats and mice.

Chronic toxicity and carcinogenicity studies of 5,5-diphenylhydantoin (DPH), were conducted in F344/N rats and B6C3F1 mice of each sex. The major objective of the study was to determine if incorporating exposure to DPH during the perinatal period, in addition to conventional exposure of animals for 2 years, enhances the sensitivity of the bioassay to identify the carcinogenic potential of chemical. The studies were designed to determine the toxic and carcinogenic effects of dietary DPH in rats and mice receiving; (1) the perinatal administration including exposure of maternal animals prior to breeding, through gestation, lactation, weaning, and continued dietary exposure of offspring to the age of 8 weeks followed by control diet for 2 years, (2) exposure for 2 years beginning at the age of 8 weeks, and (3) of combined perinatal/adult exposure to DPH (perinatal exposure to 8 weeks of age followed by the adult exposure for 2 years). During the perinatal period, rats were exposed to DPH at dose levels ranging from 63 to 630 ppm and adult exposure concentrations ranged from 240 to 2400 ppm in diet. In the mice, the perinatal exposure ranged from 21 to 210 ppm in both males and females. In the adult exposure portion of the mouse studies, the dietary levels ranged from 30 to 300 ppm in males and 60 to 600 ppm in females. A total of eight dose groups (including controls) were used with 60 animals in each group. The only effect of perinatal exposure alone on tumor rate was a marginal increase in the incidence of hepatocellular neoplasms in female mice. The adult exposure to DPH significantly increased the incidence of hepatocellular neoplasms in female mice. There were also marginal increases in the incidence of liver tumors in male rats exposed to high DPH dietary concentrations during the adult-only regimen. Combined perinatal and adult dietary exposure to 5,5-diphenylhydantoin confirmed the findings for the increased incidences of hepatocellular neoplasms in male rats and female mice, although combined exposure did not enhance these effects. However, in male mice, perinatal and adult exposure resulted in an increase in the incidence of hepatocellular neoplasms that was not seen when dietary exposure was limited to the adult period only.

Adenoma, Liver Cell↗
PubMed1993

Comparative carcinogenicity of polybrominated biphenyls with or without perinatal exposure in rats and mice.

Chronic toxicity and carcinogenicity studies of a polybrominated biphenyl mixture (PBB) were conducted in F344/N rats and B6C3F1 mice of each sex. The major objective of the study was to determine if exposure to PBB during the perinatal period, in addition to conventional exposure of animals for 2 years, enhances the sensitivity of the bioassay to identify the carcinogenic potential of this chemical. The studies were designed to determine the toxic and carcinogenic effects of dietary PBB in rats and mice receiving (i) perinatal exposure up to 8 weeks of age followed by control diet for 2 years, (ii) exposure for 2 years beginning at the age of 8 weeks, and (iii) combined perinatal/adult exposure to PBB (perinatal exposure to 8 weeks of age followed by adult exposure for 2 years). During the perinatal period, rats were exposed to PBB at dose levels ranging from 1 to 10 ppm and adult exposure concentrations ranged from 3 to 30 ppm in the diet. In the mice, the dose levels ranged from 3 to 30 ppm in both perinatal and adult exposure portions of the chronic studies. A total of eight dose groups (including controls) were used with 60 animals in each group. Liver was the major target organ of PBB toxicity. Perinatal exposure alone (through dietary administration of 10 ppm PBB to the dams) had no effect on the incidences of neoplasms in female F344/N rats, but in male rats, perinatal exposure was associated with a marginally increased incidence of hepatocellular adenomas that may have been related to chemical administration. In male and female B6C3F1 mice, perinatal exposure to 30 ppm PBB resulted in significantly increased incidences of hepatocellular neoplasms. In adult-only dietary exposure studies, PBB was carcinogenic in male and female F344/N rats and male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Combined perinatal and adult dietary exposure to PBB confirmed the findings of the adult-only exposures for the increased incidences of hepatocellular neoplasms in rats and mice. In male rats, there were no enhancing effects of combined perinatal and adult exposure. However, perinatal exposure enhanced the susceptibility of female rats receiving adult exposure of 10 or 30 ppm to the induction of liver neoplasms. For male and female rats, a combined analysis of the incidences of leukemia in the adult-only, perinatal-only, and combined perinatal and adult exposure groups revealed an apparent association between increasing incidences of mononuclear cell leukemia and exposure to PBB.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed1993

Influence of corn oil and diet on body weight, survival, and tumor incidences in F344/N rats.

Amount and type of fat and energy density of diets may influence tumor incidences. The purpose of this report is to summarize the influence of corn oil gavage and different nonpurified diets on spontaneous tumor incidences in 64 diet and 59 corn oil gavage control groups in two-year studies involving approximately 6,100 control Fischer 344 rats of each sex. The maximum mean body weight attained during the course of the study, survival at 106 weeks of age, and spontaneous tumor incidences of groups fed different nonpurified diets with or without corn oil gavage were summarized and evaluated for differences. Male rats fed NIH-07 open-formula diet with or without corn oil gavage had significantly higher body weight, lower survival, and higher incidence of pancreatic acinar cell tumors than rats fed commercial proprietary diets with or without corn oil gavage. Female rats fed NIH-07 diet with or without corn oil gavage had significantly higher body weights and pancreatic tumor incidences than groups fed commercial diets. Time-related trends could account for other apparent differences in tumor incidences between the groups fed commercial and NIH-07 diets. Corn oil gavage significantly increased the body weight and pancreatic tumor incidences but decreased the incidence of leukemia, a lethal tumor, which resulted in higher survival in male rats. Corn oil gavage significantly lowered the body weight and anterior pituitary tumor incidence in female rats. The pancreatic acinar cell tumor incidence appears to be due to a combination of fat intake and body weight.

Animals↗
PubMed1992

Comparative carcinogenicity of ethylene thiourea with or without perinatal exposure in rats and mice.

Chronic toxicity and carcinogenicity studies of ethylene thiourea (ETU), 97% pure, were conducted in F344/N rats and B6C3F1 mice of each sex. The major objective of the study was to determine if incorporation of perinatal exposure, in addition to the conventional exposure of young adult animals for 2 years, enhances the sensitivity of the bioassay in identification of the carcinogenic potential of chemicals when compared to the conventional exposure of animals to a chemical for 2 years, usually beginning at the age of 6-8 weeks. The studies were designed to determine (1) the toxic and carcinogenic effects of dietary ETU in rats and mice receiving perinatal exposure up to 8 weeks of age followed by control diet for 2 years, (2) the effects of ETU in rats and mice receiving exposure for 2 years beginning at the age of 8 weeks, and (3) the effects of combined perinatal/adult exposure to ETU (perinatal exposure to 8 weeks of age followed by the adult exposure for 2 years). During the perinatal period, rats were exposed to dietary ETU concentrations ranging from 9 to 90 ppm and adult exposure concentrations ranged from 25 to 250 ppm. In the mice, the perinatal exposure concentrations of ETU in the diet ranged from 33 to 330 ppm, and in the adults the concentrations were 100 to 1000 ppm. A total of eight exposure groups (including controls) were used with 60 animals in each group. Ten animals from each group were killed at Month 9 of the study for interim evaluation. The thyroid gland in rats and mice and the liver in mice were identified as target organs of ETU toxicity at the 9-month interim evaluation. The perinatal only exposure to ETU was not carcinogenic in rats or mice, while adult or perinatal/adult combination exposures to ETU were carcinogenic both in rats and in mice. The thyroid gland was the major site of ETU carcinogenicity both in rats and in mice. The liver and pituitary glands were other major sites of ETU carcinogenicity in mice. The carcinogenic effects of ETU were generally similar by adult and perinatal/adult combination protocols except that the incidences of thyroid tumors were slightly higher in the rats receiving the perinatal/adult combination of ETU exposure in the diet.

Animals↗
PubMed1992

An examination of the association between maximum-tolerated dose and carcinogenicity in 326 long-term studies in rats and mice.

The association between rodent carcinogenicity and maximum-tolerated dose (MTD) was evaluated in 326 long-term carcinogenicity studies in mice and rats. Others investigating this association have focused primarily on positive studies, but our investigation considered all experimental outcomes. We found that chemicals with low MTDs were somewhat more likely to be rodent carcinogens than chemicals with high MTDs, but this association was limited primarily to gavage studies. Overall, the MTD was not a reliable predictor of whether or not a chemical would be a rodent carcinogen. Our investigation confirms that comparisons of carcinogenic potencies based only on positive studies may result in artifactually elevated estimates of the underlying association between chemical toxicity and rodent carcinogenicity and thus may also inflate the estimated interspecies correlation in carcinogenic response. Nevertheless, the results of our study are consistent with the frequently cited 75% concordance in carcinogenicity outcome between rats and mice. This concordance is quite high, particularly since 80% is approximately the maximum level of observable interspecies concordance achievable for a set of chemicals with relatively low carcinogenic potency, because of the variability in observed tumor responses that can induce false negative or false positive outcomes in either of the two species. Thus, the underlying qualitative interspecies correlation in carcinogenic response between rats and mice may be greater than is commonly recognized.

Animals↗
PubMed1992

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)

Administration, Oral↗
PubMed1992

Liver carcinogenesis by methyl carbamate in F344 rats and not in B6C3F1 mice.

Short-term and long-term carcinogenicity of methyl carbamate (MCB) was evaluated in F344 rats and B6C3F1 mice. In experiments lasting 6, 12, and 18 months, MCB was given in water by gavage to groups of 10 male and 10 female rats at 0 or 400 mg/kg body weight, 5 days per week, and to similar groups of mice at 0 or 1,000 mg/kg. At 6 months, MCB induced atypical mitoses, cytologic alterations, cytomegaly, pigmentation, necrosis, and neoplastic nodules of the liver in rats. At 12 and 18 months, carcinomas of the liver were induced by MCB in 80-90% of male rats and in 60-80% of female rats. None was observed in control rats or in mice. In the 2-year studies, MCB was given to groups of 50 male and 50 female rats at 0, 100, or 200 mg/kg and to similar groups of mice at 0, 500, or 1,000 mg/kg, 5 days/week. Chronic focal inflammation, cytologic alteration, hyperplasia, and neoplastic nodules and carcinomas (200 mg/kg groups only) of the liver were induced by MCB in rats. Liver tumor incidence data for combined experiments in rats were: males--5% in controls, 0% in 100 mg/kg group, 14% in 200 mg/kg group, and 77% in 400 mg/kg group; females--5% in controls, 0% in controls, 0% in 100 mg/kg group, 12% in 200 mg/kg group, and 63% in 400 mg/kg group. MCB was not shown to be carcinogenic in mice.

Animals↗