Incidence Of Hepatocellular Adenomas Research Articles

Assessment of chronic toxicity and carcinogenicity in rats of Wingstay®100, a rubber antioxidant/antiozonant

The chronic toxicity and carcinogenicity of Wingstay 100 (W 100), a rubber antioxidant/antiozonant, were studied in Fischer 344 (F 344) rats in two chronic studies. Earlier genetic studies indicated that the product had weak activity in a bacterial mutation assay, but lacked activity in chromosomal aberration assays. In an one year study, both genders of F 344 rats were exposed to 53, 310 or 1900 ppm in NIH-07 diet for 52 weeks, and sacrifices were made at 38, 52 and 64 weeks. No test substance related deaths occurred, although the high dose of 1900 ppm caused a decrease in body weight gain and food consumption in both genders. Red blood cell mean corpuscular volume was significantly increased at 38 weeks, accompanied by a significant decrease in mean corpuscular hemoglobin concentration. At 52 weeks, the red blood cell count and hemoglobin values were also significantly decreased in high dose animals of both genders. Total bilirubin and cholesterol were increased in high dose animals of 38 and 52-week sacrifices. During the 3 month recovery, hematology parameters, bilirubin and cholesterol returned to control values. Total protein was reduced in high dose animals of both genders, throughout the entire exposure and recovery periods. W 100 also produced increases in relative liver, spleen, heart and kidney weights in high dose animals. Both genders of all W 100 groups exhibited significant increases in urothelial cell proliferation (measured by PCNA) and adaptive hyperplasia. No regenerative hyperplasia, preneoplasia, or neoplasia were present. There was microscopic evidence of extramedullary erythropoiesis in the spleen and liver of high dose animals in both genders, otherwise no other pertinent microscopic finding was evident. In parallel, an accelerated bioassay (ABA) was conducted, which is a mechanistic initiation/promotion carcinogenicity study designed to assess tumor induction and promotion potential of a test substance in major organs of carcinogenesis. The present study was conducted in male F 344 rats for 38 weeks. The target sites chosen for the ABA were liver and urinary bladder and the dose for W 100 was 1900 ppm previously established to be a toxic dose. The liver tumor initiator was diethylnitrosamine (DEN), and the urinary bladder initiator was N-butyl N-(4-hydroxybutyl) nitrosamine (BBN). The initiators were administered during the first 14 weeks followed by the promoters. The promoters, phenobarbital (PB) for the liver and nitrilotriacetate (NTA) for the urinary bladder, were administered during the last 24 weeks of the study after the test substance. The study had 11 test groups including a negative control. The critical comparisons for initiating activity were conducted between groups 3 (PB) and 6 (W 100 + PB) for the liver and groups 8 (NTA) and 11 (W 100 + NTA) for the urinary bladder. The critical comparisons for promoting activity were conducted between groups 2 (DEN) and 5 (DEN + W 100) for the liver and groups 7 (BBN) and 10 (BBN + W 100) for the urinary bladder. There were 26 and 38-week sacrifices. In this study, most body weight reductions were due to DEN. At 26 weeks, significant increases in liver weights were present in all PB-exposed groups. Significant increases in renal weights occurred in all NTA, BBN and DEN groups. A similar organ weight pattern was present at 38 weeks. At 26 weeks, there were hepatocellular (33%) and urothelial (67%) tumors present in positive control groups (DEN/DEN + PB/BBN/BBN + NTA). In contrast, in the DEN + W 100 (5) and the BBN + W 100 (10) groups no tumors were present indicating absence of promotion. In addition, no tumors were present in groups 6 (W 100 + PB) or 11 (W 100 + NTA) indicating absence of initiation. At 38 weeks, the incidences of hepatocellular adenomas and carcinomas in positive control group (DEN) was 44%. The incidence of urothelial adenomas and carcinomas was 67% in group 7 (BBN). In contrast, groups 5 (DEN + W 100) or group 10 (BBN + W 100) had

Enhancement by indole-3-carbinol of liver and thyroid gland neoplastic development in a rat medium-term multiorgan carcinogenesis model.

The modification potential of indole-3-carbinol (I3C), a naturally occurring compound found in cruciferous vegetables, on neoplastic development was assessed using a rat medium-term multiorgan carcinogenesis model. One-hundred male Sprague-Dawley (SD) rats were randomly divided into three groups and sequentially treated with diethylnitrosamine (DEN; 100 mg/kg b.w., a single i.p.), N-methyl-N-nitrosourea (MNU; 20 mg/kg b.w., four times i.p., at days 5, 8, 11 and 14), and dihydroxy-di-N-propyl-nitrosamine (DHPN; 0.1% in the drinking water during weeks 1 and 3) (DMD treatment; groups 1 and 2) or the vehicles alone (group 3) in the first 3-week initiation period. Animals of groups 1 and 3 were then given diet containing 0.25% I3C from week 4 until week 24, followed by a return to basal diet for 28 weeks, and subgroups were killed at weeks 24 and 52. I3C caused significant increases in both number (no./cm2) and area (mm2/cm2) of glutathione S-transferase placental form (GST-P)-positive liver cell foci assessed at week 24 of the experiment (P<0.01, 0.001). The incidence of hepatocellular adenomas in the DMD and I3C group at week 52 showed a tendency for elevation as compared to the DMD alone group, but this was not statistically significant. The thyroid gland tumour incidences in the DMD and I3C groups were significantly increased compared with the DMD alone group values at week 52 (P<0.01). In conclusion, I3C enhanced liver and thyroid gland neoplastic development when given during the promotion stage in the present rat medium-term multiorgan carcinogenesis model.

Hepatotumorigenicity and peroxisome proliferation induced by the hypolipidemic CI-924 in a two-year study in male and female B6C3F1 mice.

The hepatic tumorigenicity of CI-924 (5,5'-(1,1'-biphenyl)-2,5-diylbis(oxy)(2,2-dimethylpentanoic acid)), a hypolipidemic agent, was evaluated in 50 B6C3F1 mice/sex/dose given drug in the diet at 0, 5, 25, and 75 mg/kg/day for 2 yr. Peroxisomal and drugmetabolizing enzyme determinations, as well as ultrastructural evaluations, were conducted in subsets of these same groups, because drugs of this class cause peroxisome proliferation and hepatic tumors in rodents. CI-924 elicited dose-dependent increases in the incidence of hepatocellular adenomas and carcinomas in both sexes that were statistically significant at 75 mg/kg. Stereologic evaluation revealed significant increases in hepatocellular peroxisome volume ratio, due to increased numbers of peroxisomes, in females at all doses and males at 75 mg/kg. Peroxisomal enzyme activity measurements revealed no change in catalase, but dose-dependent increases in carnitine acetyltransferase and cyanide-insensitive beta-oxidation in both sexes. Peroxisome proliferation, determined biochemically or ultrastructurally, was twice as great in females compared to males. Total cytochrome P-450 was increased in both sexes given 75 mg/kg. There were dose-dependent decreases in glutathione S-transferase in males and increased glutathione peroxidase in both sexes at 25 and 75 mg/kg. In conclusion, this study demonstrated that while CI-924 induced hepatic tumors in male and female B6C3F1 mice the associated peroxisome proliferation, while moderate in females, was only weak in the males after 2 yr of exposure.

Histopathological Evaluation of Spontaneous Hepatocellular Tumors in B6C3F1 Hybrid Mice.

A retrospective evaluation of spontaneous hepatocellular tumors in B6C3F, mice of 9 two-year and 4 seventy eight-week carcinogenicity studies was conducted. The incidences of hepatocellular adenomas and carcinomas (HCCs) in males were significantly higher than those in females in both series, and development of less-well-differentiated carcinomas with metastases was clearly linked to aging. PCNA positive indices of well-differentiated HCCs were significantly higher than those of hepatocyte foci, hepatocellular adenomas, and moderately differentiated HCCs. This parameter was useful for the definition of foci and adenomas because in these cases the PCNA positive cells demonstrated a uniform distribution pattern. The number of AgNOR dots tended to increase in accordance with the progression of hepatocarcinogenesis, with bizarre-irregularly shaped forms found in the nuclei of moderately differentiated HCC cells. This parameter therefore appears to be useful for evaluation of the degree of malignancy in hepatocellular carcinomas. While no c-H-ras protein expression could be detected in 9 cases of well-differentiated HCCs examined in the present study, 18 to 50% of preneoplastic lesions (foci) and neoplastic lesions including adenoma, carcinoma within adenoma, and moderately differentiated HCC. The present study showed that assessment of the atypical grade in HCC is paramount for evaluation of malignancy, requiring appropriate methods for objective diagnosis.

Transplacental carcinogenesis by cisplatin in F344/NCr rats: promotion of kidney tumors by postnatal administration of sodium barbital.

Transplacental carcinogenic effects of cis-dichlorodiammineplatinum (cis-DDP) in F344 rats were investigated. Pregnant F344 rats were given a single i.p. administration of either cis-DDP (5 mg/kg body wt; group 1) or saline only (group 2) on Day 18 of gestation. Offspring of groups 1 and 2 were randomly and equally divided into two subgroups: 1a, 1b and 2a, 2b, respectively. Beginning at 4 weeks of age, offspring in groups 1b and 2b received 500 ppm of sodium barbital (NaBB) in diet, while those in groups 1a and 2a received normal diet. The experiment was terminated at 79 weeks of age. A low incidence (2/19; 10.5%) of male offspring exposed to transplacental cis-DDP (group 1a) developed renal cell adenomas. Postnatal administration of NaBB significantly enhanced this incidence (10/22; p < 0.01) in cis-DDP-initiated offspring. Also, multiple kidney tumors were more common in group 1b than any other group and three animals in this group developed frank renal cell carcinomas. cis-DDP, administered transplacentally, was a complete carcinogen for rat liver as the incidence of hepatocellular adenomas was significantly higher in offspring exposed transplacentally to cis-DDP than in those exposed to saline (20/82 vs 3/75; p < 0.05). NaBB, a known promoter of hepatocellular carcinogenesis in adult rats initiated with N-nitrosodiethylamine, failed to promote liver carcinogenesis initiated by transplacental cis-DDP. Tumors of the central nervous system (3/82; gliomas) and peripheral nervous system (2/82; schwannomas) were found only in offspring exposed transplacentally to cis-DDP. Thus, cis-DDP, administered transplacentally, was a strong initiator of renal cell tumors and a complete carcinogen for multiple organs in rat offspring.

Dose and time dependence of the cellular phenotype in rat hepatic preneoplasia and neoplasia induced in stop experiments by oral exposure to N-nitrosomorpholine.

The dose and time dependence of the cellular phenotype in preneoplastic and neoplastic liver lesions was evaluated quantitatively in groups of male Sprague-Dawley rats exposed for 7 weeks to 0, 12 and 24 mg/kg body wt of N-nitrosomorpholine (NNM) and studied at different time points up to 80 weeks after withdrawal of NNM (stop model). NNM-treated rats showed a dose- and time-dependent increase in the total number and volume of preneoplastic foci of altered hepatocytes (FAH) and in the incidence of hepatocellular adenomas (HCA) and carcinomas (HCC) at both dose levels, compared with the untreated controls. After stopping treatment with 12 mg/kg body wt, the well-known sequence of cellular changes leading from glycogenotic clear and clear/acidophilic cell foci to mixed and diffusely basophilic cell populations poor in glycogen was found. In contrast, at the higher NNM dose level (24 mg/kg) predominantly mixed and diffusely basophilic cell foci appeared immediately after cessation of treatment, but their number rapidly declined up to 13 weeks after withdrawal. At the same time, there was a reciprocal increase in the number of the less altered clear/acidophilic cell foci, indicating an early reversion-linked phenotypic instability of FAH. However, in spite of this reversion higher numbers of mixed and diffusely basophilic cell foci were retained after treatment with 24 compared to 12 mg/kg of NNM at all time points studied, and there was even a slow additional increase in the number of these types of FAH 20 weeks after withdrawal of NNM. At both dose levels, the volume fraction of the persistent mixed cell foci correlated positively with the incidence of HCA and HCC, suggesting that this phenotype of FAH represents a direct precursor of the neoplastic lesions. Tigroid cell foci, which appeared most frequently after treatment with the lower dose of NNM, were not integrated into the predominant sequence of cellular changes leading to HCC, but they may represent an intermediate stage in a side lineage of this sequence, endowed with the potential to progress at least to HCA. Our results show that reversion-linked phenotypic instability of FAH occurs mainly after high dose treatment, possibly resulting from rapid adaptive cellular responses to the primary carcinogenic lesion(s) which may be fixed by genetic or epigenetic mechanisms. In contrast, progression-linked phenotypic instability of FAH is a slow process developing in a dose- and time-dependent manner at all dose levels leading to hepatic neoplasia.

Dose and time dependence of the cellular phenotype in rat hepatic preneoplasia and neoplasia induced by single oral exposures to N-nitrosomorpholine.

The dose and time dependence of the cellular phenotype in preneoplastic and neoplastic liver lesions was studied quantitatively in groups of male Sprague-Dawley rats exposed to single oral doses of 0, 200 and 320 mg/kg body wt of N-nitrosomorpholine (NNM) and killed at different time points between 7 and 80 weeks. Compared with the untreated controls, NNM-treated rats showed a dose- and time-dependent increase in the total number and volume of preneoplastic foci of altered hepatocytes (FAH) and in the incidence of hepatocellular adenomas (HCA). In controls, two major phenotypes of FAH were found in low numbers, namely clear and combined clear/acidophilic cell foci which both store excessive amounts of glycogen. The increase in the total number and volume of FAH by single doses of NNM was associated with changes in their cellular phenotype. Clear cell foci were more frequent in the lower dose group than in the higher dose group throughout the observation period. With the exception of the first 15 weeks, combined clear/acidophilic cell foci represented the most frequent phenotype at both dose levels and all time points studied. In contrast, mixed cell foci, which were completely lacking in controls, showed a high relative frequency after a single NNM dose of 320 mg/kg body wt throughout the observation period, but emerged at later time points and in lower numbers when the lower single dose was given. At both dose levels, mixed-cell foci represented the largest phenotype of FAH; their volume fraction correlated positively with the incidence of HCA, indicating a direct precursor-product relationship between these lesions. The size class distribution and temporal appearance of the different phenotypes of FAH and of the adenomas suggest a progression-linked phenotypic instability of the altered cellular phenotypes, resulting in a predominant sequence of cellular changes which leads from glycogenotic clear and acidophilic cell foci to mixed and basophilic cell populations, the latter being poor in glycogen. In addition to these types of FAH, tigroid cell foci, which were very rare in controls, developed in significantly greater numbers after single-dose treatment with NNM at both dose levels. This type of focus may either represent a side lineage of the predominant lineage or an intermediate stage in an alternative lineage of hepatocellular changes, but in any case has the potential to give rise to HCA.

Dose and time dependence of the cellular phenotype in rat hepatic preneoplasia and neoplasia induced by continuous oral exposure to N-nitrosomorpholine.

The dose and time dependence of the cellular phenotype in preneoplastic and neoplastic liver lesions was evaluated quantitatively in groups of male Sprague-Dawley rats continuously exposed to 0, 6, 12 and 24 mg/kg body wt of N-nitrosomorpholine (NNM) and studied at different time points up to 80, 50, 37 and 20 weeks respectively. Continuous oral administration of NNM resulted in a dose- and time-dependent increase in the total number and volume of preneoplastic foci of altered hepatocytes (FAH) and in the incidence of hepatocellular adenomas (HCA) and carcinomas (HCC) at all dose levels studied. In contrast to earlier stop experiments with 24 mg NNM/kg body wt, there was no reversion-linked phenotypic instability but a rapid progression of FAH of the mixed cell type to a high incidence of hepatocyte nodules and HCC after continuous treatment with NNM at this dose level. At the two lower dose levels of NNM (12 and 6 mg/kg) the well-known sequence of cellular changes leading from glycogenotic (clear, combined clear/acidophilic and acidophilic) to mixed and diffusely basophilic cell populations, in which HCC prevailed. A considerable part of the glycogenotic foci contained exclusively acidophilic cells, and HCA consisting of a mixture of acidophilic and basophilic cells were the most common benign tumour type in these groups. At the end of the observation period there was also a high incidence (> 50%) of HCC at both dose levels, indicating the potential of persistent nodules (HCA) containing acidophilic cells to progress to HCC. FAH and HCA exhibiting a tigroid cell pattern appeared only at the two lower dose levels, but for this type of HCA it remained open whether it may progress to HCC. From a comparison of the different dosing regimens of NNM studied in this and previous experiments we conclude that the rapid, potentially reversible shift from glycogenotic to mixed cell populations at the highest dose level of continuously applied NNM (24 mg/kg) and the high proportion of pure acidophilic glycogen storage foci observed after continuous administration of NNM at the two lower dose levels (6 and 12 mg/kg) represent different phenotypic expressions of promoting effects exerted by the ongoing influence of the carcinogen on FAH initiated by the same compound. The metabolic and molecular changes underlying these 'initiating' and 'promoting' effects of NNM seem to differ in terms of quantity rather than quality.

2-year Toxicity Study of Doxylamine Succinate in the Fischer 344 Rat

Doxylamine succinate, a commonly used antihistamine, was administered as an admixture in the feed to groups of male and female Fischer 344 rats at dose levels of 0, 500, 1000, and 2000 parts per million (ppm) (based on free amine) for 65 weeks (9 per group) or two years (48 per group). There were no significant treatment-related differences in survival in either sex. Compared to controls, final body weights of rats in the 2000 ppm group were reduced 8.4% and 22.8% in males and females, respectively. Treatment-related, non-neoplastic lesions were found primarily in the liver and parotid salivary gland. Liver lesions consisted of fatty change and degeneration in both sexes; hyperplasia (resulting from degeneration due to leukemia) and atypical cells in males; and hypertrophy, chronic inflammation, and mixed cell foci in females. Both sexes exhibited a treatment-related increase in cytoplasmic alteration in the salivary glands. Liver neoplasms were found only in the highest dose group of male rats. The trend test was significant (p ≤ 0.05) for increased incidence of hepatocellular adenoma and carcinoma with increasing doses of doxylamine, but the increased incidence of either lesion in the high dose group was not significant compared to that in controls. However, when animals with carcinoma or adenoma were combined, the trend test remained significant (p ≤ 0.01), and the incidence of the highest dose group was significantly increased (p ≤ 0.05) over that in controls. No treatment-related increase in neoplasms was found in females, but doxylamine produced a marked dose-related decrease in mammary fibroadenomas. Although not statistically significant, a very rare pineal gland tumor was found in 1 male and 1 female rat in the 2000 ppm group.

Inhibition by wine of tumorigenesis induced by ethyl carbamate (urethane) in mice

Groups of 18–21 male weanling C3H mice were given, as drinking fluid, tap-water, 12% ethanol solution, one of two commercial white mines, or red wine, ad lib. for 41 wk. Ethyl carbamate intakes of 0, 10 or 20 mg/kg body weight. After 41 wk the cumulative survival of the mice given 20 mg ethyl carbamate/kg in water was depressed compared with the mice drinking wines or ethanol solution with this ethyl carbamate level. Both ethanol and wine treatments reduced the incidence of lung Clara-cell adenomas in mice given 10 mg ethyl carbamate/kg and reduced the frequency (number of specific tumours/number of tumour-bearing mice) of both Clara-cell adenomas in mice given 10 mg ethyl carbamte/kg and of alveolar adenomas in mice given 20 mg ethyl carbamate/kg. Wine treatments also reduced the frequency of hepatocellular adenomas compared with those of other treatment groups, and no hepatocellular carcinomas developed in any of the groups given wine, even with the 20-mg/kg ethyl carbamate dose. The incidence of hepatocellular adenomas in the groups given 10 mg ethyl carbamate/kg was, as shown by chi-square analysis, significantly reduced by the ethanol and wine treatments. The mean weight gains of mice on all the wine treatments were lower than those of water-treated mice and this may have been a factor in tumour inhibition; however, it is also possible that wine components other than ethanol may play a role in the inhibition of tumour development.

CARCINOGENICITY STUDY OF TRIS (2-CHLOROETHYL) PHOSPHATE IN ddY MICE

Groups of 50 male and 50 female ddY mice were fed commercial diet containing 0, 0.012, 0.06, 0.3, and 1.5% tris (2-chloroethyl) phosphate (TCEP) for 18 months. In both sexes fed 1.5% TCEP, body weight gain was apparently suppressed and mortality rates were clearly higher compared to other groups. After histopathological examination, the incidences of renal cell carcinomas and adenomas were significantly increased in males fed 1.5% TCEP. The incidences of hepatocellular adenomas were significantly high in the 0.3 and 1.5% groups of males. In females, significant increases were found in the incidences of papillomas and squamous cell carcinomas (combined) of the 1.5% group, and in those of leukemias of the 0.3 and 1.5% groups. Under the conditions of this study, orally administered TCEP was carcinogenic to ddY mice, causing significantly high incidences of tumors in the kidney and liver of male mice and in the forestomach and hematopoietic organ of female mice.

Toxicity and carcinogenicity of chlorodibromomethane in Fischer 344/N rats and B6C3F 1 mice

Chlorodibromomethane, a trihalomethane found in water supplies after chlorination, was administered by gavage in corn oil to male and female Fischer 344/N rats and B6C3F 1 mice in toxicity studies of 13 weeks and 2 years duration. Doses used in the 13-week study were 0, 15, 30, 60, 125, and 250 mg/kg in rats and mice. At 250 mg/kg, hepatic and renal toxicity was produced in male and female rats and male mice, and mortality was increased in male and female rats. In the chronic study, male and female rats were administered the chemical at 0, 40, and 80 mg/kg. No adverse effects on survival in treated rats were observed. Male rats receiving 80 mg/kg had reduced body weight gains relative to controls. Fatty change and cytoplasmic changes were seen in the liver of treated male and female rats. The male and female mice in the chronic study received doses of 0, 50, and 100 mg/kg of chemical. A dosing accident rendered the number of low-dose male mice inadequate for statistical analysis. High-dose male mice had reduced survival relative to controls. Survival was similar in dosed and control female mice. Dosed male and high-dose female mice had reduced body weight relative to controls. Non-neoplastic hepatic lesions were seen in treated male mice (necrosis and hepatocytomegaly) and in treated female mice (calcification and fatty change); nephrosis was seen in treated male mice. The incidence of hepatocellular adenoma and carcinoma (combined) was increased in treated female mice, but only marginally so in treated male mice. Chlorodibromomethane, like chloroform, is toxic to liver and kidneys, and like chloroform induces hepatocellular tumors in mice.

3 Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate

Dioctyl Adipate, the diester of octyl alcohol and adipic acid, and Diisopropyl Adipate, the diester of isopropyl alcohol, are used in cosmetics as emollients and bases. These two ingredients have a low acute oral and percutaneous toxicity. Undiluted Dioctyl Adipate and Diisopropyl Adipate were, at most, only very mild, transient eye irritants. Primary dermal irritation tests indicated that Dioctyl Adipate was a very mild irritant and Diisopropyl Adipate was minimally irritating. Dioctyl Adipate was not a skin sensitizer in guinea pigs. An Ames test for the mutagenic potential of Dioctyl Adipate was negative. An assay of the carcinogenic potential of Dioctyl Adipate produced no untoward effects and was noncarcinogenic to rats. Mice studies indicated a dose- related body weight reduction and a higher incidence of hepatocellular adenoma and carcinoma than controls. In a lifetime study Dioctyl Adipate caused no skin tumors when 10 mg was applied weekly to the back skin of mice. The teratogenicity potential of Dioctyl Adipate is reviewed. Clinical assessment of Dioctyl Adipate in formulations showed, at most, minimal erythema and papules when applied under occlusion. No UV sensitization occurred. Undiluted Diisopropyl Adipate produced no irritation in 24 h patch tests, but was moderately irritating in a 21-day cumulative irritancy test. Formulations containing up to 20% Diisopropyl Adipate caused minimal to mild irritation, no sensitization and no photosensitization. On the basis of available data, it is concluded that Dioctyl Adipate and Diisopropyl Adipate are safe as presently used in cosmetics.

Studies on the carcinogenicity of pentachloroethane in rats and mice

The carcinogenicity of chronically administered (41 to 103 weeks) technical-grade pentachloroethane (PCE) was assessed in groups of 50 male and female Fischer 344 rats and B6C3F 1mice. The major contaminant in the PCE sample used for the chronic study was hexachloroethane (4.2%). Prechronic studies (two and 13 weeks repeated dose) employing gavage doses of from 5.0 to 1000 mg/kg/day of PCE failed to reveal specific target organ toxicity in these species. In the absence of treatment-related pathological changes during the prechronic tests, the doses for the chronic studies were set on the basis of survival and body weight gains during the 13-week repeated dose study. During the chronic studies dose levels of 75 and 150 mg/kg for rats and 250 and 500 mg/kg for mice were administered, by gavage, five days per week. The survival of high-dose rats (both sexes) was significantly reduced as compared to the survival of control animals and that of the low-dose males was slightly, but not significantly, reduced. Although the administration of PCE to rats did not increase the incidence of primary tumors, it did produce a significant dose-related increase in the incidence of chronic renal inflammation among males. The survival times of all treated groups of mice were significantly shortened by PCE administration. Despite this reduced survival time, the incidence of hepatocellular carcinoma was significantly increased in all treated groups. With the exception of a dose-related increase in the incidence of hepatocellular adenoma among females, there were no other significant increases in primary tumor incidence in mice. Neither renal lesions in rats nor hepatocellular carcinoma in mice were considered to be adequate explanations for the decreased survivals. Complete histopathological examinations failed to reveal the cause of decreased survival. The results of the study show that technical-grade PCE, like numerous other chlorinated ethanes, is an hepatocarcinogen for B6C3F 1mice. This interpretation for PCE per se, however, must be tempered because the major contaminant, hexachloroethane, has been shown to produce hepatocellular carcinoma in mice. While the results obtained in rats suggest a species difference in susceptibility, the reduced survival in this species may have contributed to the absence of a carcinogenic effect.

Studies on the Carcinogenicity of Pentachloroethane in Rats and Mice

Studies on the Carcinogenicity of Pentachloroethane in Rats and Mice. Mennear, J.H., Haseman, J.K., Sullivan, D.J., Bernal, E. and Hildebrandt, P.K. (1982). Fundam. Appl. Toxicol. 2:82–87. The carcinogenicity of chronically administered (41 to 103 weeks) technical-grade pentachloroethane (PCE) was assessed in groups of 50 male and female Fischer 344 rats and B6C3F1 mice. The major contaminant in the PCE sample used for the chronic study was hexachloroethane (4.2%). Prechronic studies (two and 13 weeks repeated dose) employing gavage doses of from 5.0 to 1000 mg/kg/day of PCE failed to reveal specific target organ toxicity in these species. In the absence of treatment-related pathological changes during the prechronic tests, the doses for the chronic studies were set on the basis of survival and body weight gains during the 13-week repeated dose study. During the chronic studies dose levels of 75 and 150 mg/kg for rats and 250 and 500 mg/kg for mice were administered, by gavage, five days per week. The survival of high-dose rats (both sexes) was significantly reduced as compared to the survival of control animals and that of the low-dose males was slightly, but not significantly, reduced. Although the administration of PCE to rats did not increase the incidence of primary tumors, it did produce a significant dose-related increase in the incidence of chronic renal inflammation among males. The survival times of all treated groups of mice were significantly shortened by PCE administration. Despite this reduced survival time, the incidence of hepato-cellular carcinoma was significantly increased in all treated groups. With the exception of a dose-related increase in the incidence of hepatocellular adenoma among females, there were no other significant increases in primary tumor incidence in mice. Neither renal lesions in rats nor hepatocellular carcinoma in mice were considered to be adequate explanations for the decreased survivals. Complete histopathological examinations failed to reveal the cause of decreased survival. The results of the study show that technical-grade PCE, like numerous other chlorinated ethanes, is an hepato-carcinogen for B6C3F1 mice. This interpretation for PCE per se, however, must be tempered because the major contaminant, hexachloroethane, has been shown to produce hepatocellular carcinoma in mice. While the results obtained in rats suggest a species difference in susceptibility, the reduced survival in this species may have contributed to the absence of a carcinogenic effect.