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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The NIH-07 open-formula nonpurified diet was the selected diet for rodents in the National Toxicology Program's toxicology and carcinogenesis studies from 1980 to 1994. Protein and mineral concentrations of the NIH-07 diet may have increased some diet- and age-associated lesions such as nephropathy. A number of experimental nonpurified diets with lower protein and higher fat and fiber (approximately 15% protein, 7-8.5% fat, and 9-14% crude fiber) than the NIH-07 diet were formulated and evaluated in Fischer 344 (F344) rats. Decreasing protein content of the diet decreased protein consumption by approximately 30% and decreased severity of nephropathy without affecting growth. Increased fat intake seemed to have decreased the incidence or severity of leukemia, a lethal neoplasm of F344 rats. Increasing fiber content without decreasing the caloric density lowered body weight gain and slowed growth of mammary tumors. Higher fat and/or fiber intake decreased the incidences of adrenal pheochromocytomas and medullary hyperplasia in male rats. Nonpurified diets with lower protein and higher fat and fiber concentrations than the NIH-07 diet decreased or delayed diet- and age-associated lesions and increased survivals in 2-y studies. On the basis of these results, a new cereal-based nonpurified diet, designated as NTP-2000, was formulated with approximately 14.5% protein, approximately 8.2% fat, approximately 9.3% fiber and a calcium:phosphorus molar ratio of approximately 1.3. The NTP-2000 diet was compared with the NIH-07 diet in a 13-wk study in F344 rats. The NTP-2000 diet was adequate for growth, did not affect the hematological parameters and did not cause substantial changes in blood chemistry, serum enzyme or serum electrolyte values. The NTP-2000 diet decreased liver and kidney weights, prevented nephrocalcinosis and decreased the severity of diet- and possibly age-associated lesions.
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PMID:New nonpurified diet (NTP-2000) for rodents in the National Toxicology Program's toxicology and carcinogenesis studies. 916 50

Data on transgenic rodent mutagenicity of five human carcinogens were summarised and compared with the results from rodent carcinogenicity studies. Four out of five carcinogens showed mutagenic activity already at daily dose levels which induced cancer in long-term rodent bioassays in at least one target tissue of carcinogenesis. In several of these studies, even single dose applications were sufficient to significantly increase the mutation frequency in vivo. Other genotoxic carcinogens required application of multiple dosing at dose-levels used in rodent cancer bioassays to show their in vivo mutagenicity. A rodent respiratory tract carcinogen, 1,2-dibromoethane (DBE), following inhalation exposure, displayed no mutagenic activity, neither in lung nor in nasal mucosa, at a single 2-h exposure to 30 ppm, which is below the highest concentration used in a NTP cancer bioassay. In contrast, after multiple treatment for 10 days at the same daily doses, a significant increase of the mutation frequency in nasal mucosa was apparent. We conclude, that especially when studying new chemicals in these transgenic rodent mutation assays, a multiple dosing protocol should be preferred. For dose selection, the same criteria could be applied as for chronic rodent bioassays.
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PMID:Mutagenic activity of carcinogens detected in transgenic rodent mutagenicity assays at dose levels used in chronic rodent cancer bioassays. 974 72

This paper discusses a general way of incorporating the growth kinetics of malignant tumors with the two-stage carcinogenesis model. The model is presented using time-homogeneous rate parameters. In that case, the differential equations comprising the model are straightforward to solve using standard numerical techniques and software. An extension of the method to time-dependent rate parameters is included in Appendix A. Allowing the rate parameters to be time-dependent does incur computational cost. An expression is given for the expected time without visible tumor, a generalization of the expected time to an observable tumor that includes the possibility of tumor regression. The model is illustrated using incidental liver tumor data in control rats from NTP rodent carcinogenicity studies, using linear birth-death kinetics of tumors combined with a non-absorbing detection limit. The approach is also shown to be potentially useful with tumor observability thresholds having more complicated features.
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PMID:Incorporating observability thresholds of tumors into the two-stage carcinogenesis model. 1065 46

The rates of cell proliferation and cell loss in conjunction with the differentiation status of a tissue are among the many factors contributing to carcinogenesis. Nongenotoxic (non-DNA reactive) chemicals may affect this balance by increasing proliferation through direct mitogenesis or through a regenerative response following loss of cells through cytotoxic (oncotic) or apoptotic necrosis. In a recent NTP study in Fischer rats and B6C3F(1) mice, the mycotoxin fumonisin B(1) caused renal carcinomas in male rats and liver cancer in female mice. In an earlier study in male BD-IX rats, fumonisin B(1) caused hepatic toxicity and hepatocellular carcinomas. An early effect of fumonisin B(1) exposure in these target organs is apoptosis. However, there is also some evidence of oncotic necrosis following fumonisin B(1) administration, especially in the liver. Induction of apoptosis may be a consequence of ceramide synthase inhibition and disruption of sphingolipid metabolism by fumonisin B(1). Fumonisin B(1) is not genotoxic in bacterial mutagenesis screens or in the rat liver unscheduled DNA-synthesis assay. Fumonisin B(1) may be the first example of an apparently nongenotoxic (non-DNA reactive) agent producing tumors through a mode of action involving apoptotic necrosis, atrophy, and consequent regeneration.
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PMID:Implications of apoptosis for toxicity, carcinogenicity, and risk assessment: fumonisin B(1) as an example. 1129 69

Criticisms of the scientific value of rodent carcinogenicity bioassays have focused on the arguments that the studies are too long and that most organ-specific carcinogenic effects observed in experimental animals have little or no relevance to humans. For example, Davies et al. (Davies, T.S., Lynch, B.S., Monro, A.M., Munro, I.C., Nestmann, E.R., 2000. Rodent carcinogenicity tests need be no longer than 18 months: an analysis based on 210 chemicals in the IARC Monographs. Food and Chemical Toxicology 38, 219-235) concluded that the duration of rodent bioassays should be no more than 18 months, based on their analysis of 210 International Agency for Research on Cancer (IARC) rodent carcinogens in which they report that most chemicals showed "tumorigenic effects" at or before 12 months. However, many of these "tumorigenic effects" reflect the occurrence of a single neoplasm, with most tumors occurring much later in the study. Reliance on a single tumor at an early time point as providing definitive evidence of rodent carcinogenicity is a dangerous practice that could produce both false positive and false negative outcomes. An extensive evaluation of the NTP database reveals that many rodent carcinogens produce later-appearing tumors that would not be detected as statistically significant in a 12-18 month study. Such a shortened duration study would be roughly equivalent to evaluating human cancer in subjects 30-50 years of age, which would result in markedly reduced study sensitivity. In fact, many investigators recommend extending the duration of rodent studies to 30 months or to a true lifetime to increase study sensitivity. We also do not agree with the second conclusion of Davies et al. (2000) that the mode of action of rodent carcinogenesis is sufficiently well understood to justify discounting the majority of organ-specific carcinogenic effects found in these studies. The consequences of performing rodent carcinogenicity studies with inadequate sensitivity, and then discounting most of the carcinogenic effects that are observed will be that potential human carcinogens will not be detected, thus forcing near total reliance on human studies for this purpose. This is not prudent public health policy.
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PMID:Carcinogenesis bioassays: study duration and biological relevance. 1139 20

1,4-Butanediol is an industrial chemical used in the manufacture of other organic chemicals. It was nominated by the National Cancer Institute and selected for evaluation by the NTP because of high production volume, the potential for worker exposure, the lack of adequate toxicological characterization, and the lack of evaluation for carcinogenic potential. As documented in the scientific literature, 1,4-butanediol is rapidly absorbed and metabolized to gamma-hydroxybutyric acid in animals and humans. A metabolism and disposition study conducted in F344/N rats by the NTP confirmed the rapid and extensive conversion of 1-[14C]-1,4-butanediol to 14CO2. Because of this rapid and extensive conversion, the toxicological profile of 1,4-butanediol reflects that of gamma-hydroxybutyric acid. gamma-Hydroxybutyric acid is a naturally occurring chemical found in the brain and peripheral tissues which is converted to succinate and processed through the tricarboxylic acid cycle. Although the function of gamma-hydroxybutyric acid in peripheral tissues is unknown, in the brain and neuronal tissue it is thought to function as a neuromodulator. gamma-Hydroxybutyric acid readily crosses the blood-brain barrier, and oral, intraperitoneal, or intravenous administration elicits characteristic neuropharmacologic responses. These same responses are observed after administration of 1,4-butanediol. The lactone of gamma-hydroxybutyric acid, gamma-butyrolactone, is also rapidly converted to gamma-hydroxybutyric acid by enzymes in the blood and liver of animals and humans. gamma-Butyrolactone was previously evaluated by the NTP in 14-day and 13-week toxicology studies and 2-year toxicology and carcinogenesis studies in F344/N rats and B6C3F1 mice. No organ-specific toxicity occurred in the toxicology studies. In the carcinogenesis studies, an equivocal response occurred in male mice, based on a marginal increase in the incidence of pheochromocytomas of the renal medulla. Because of the rapid and extensive conversion of gamma-butyrolactone to gamma-hydroxybutyric acid, the evaluation of gamma-butyrolactone was in fact an evaluation of gamma-hydroxybutyric acid. This summary report presents a review of the current literature which documents that both 1,4-butanediol and gamma-butyrolactone are rapidly metabolized to gamma-hydroxybutyric acid, and the pharmacologic and toxicologic responses to these chemicals are due to their metabolic conversion to gamma-hydroxybutyric acid. Because the toxicity and carcinogenicity of gamma-hydroxybutyric acid was fully evaluated in the NTP studies of gamma-butyrolactone, and a lack of organ-specific toxicity or carcinogenic potential was demonstrated, it is concluded that there is a high likelihood that 1,4-butanediol would be negative in a similar set of studies. For these reasons, it is the opinion of the NTP that 1,4-butanediol should be considered not carcinogenic in animals and no further evaluation of 1,4-butanediol is needed at this time.
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PMID:NTP summary report on the metabolism, disposition, and toxicity of 1,4-butanediol (CAS No. 110-63-4). 1180 99

D&C Yellow No. 11 is used to color topical drug preparations and cosmetics. It is also used in spirit lacquers, polystyrenes, polycarbonates, polyamides, acrylic resins, colored smokes, and hydrocarbon solvents. D&C Yellow No. 11 was nominated to the NTP for toxicity and carcinogenesis studies as part of a larger regulatory effort mandated by Congress and undertaken by the Food and Drug Administration to determine the safety of a number of provisionally listed dyes. D&C Yellow No. 11 is currently regulated for external use. The recommendation to study D&C Yellow No. 11 by dietary exposure was based on the fact that it is a contaminant of D&C Yellow No. 10, a candidate for permanent listing as a chemical for which there is a potential for ingestion. First-generation (F(0)) male and female F344/N rats were given D&C Yellow No. 11 (approximately 99% pure) in feed for up to 19 weeks and then mated, and exposure of second-generation (F(1)) males and females began in utero and continued for 2 years after weaning at 28 days of age. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood. REPRODUCTIVE TOXICITY STUDY: Groups of 60 male and 60 female F(0) rats were given 0, 500, 1,700, or 5,000 ppm D&C Yellow No. 11 in feed for up to 19 weeks, which resulted in average daily doses of 35, 120, or 350 mg D&C Yellow No. 11/kg body weight to males and 35, 120, or 370 mg/kg to females. All F(0) males and females survived until the end of the study. Prior to cohabitation, mean body weight gains of males given 500, 1,700, or 5,000 ppm and of females given 5,000 ppm were significantly lower than those of the controls. The mean body weight gains of exposed females during gestation and lactation were generally similar to those of the controls. Feed consumption by exposed groups of rats was generally similar to that by the control groups prior to cohabitation. The duration of gestation, the average litter size, the number of live pups on days 4 (precull) and 21, and the percentage of male pups for each exposure group were similar to those of the controls. The mean body weights of exposed litters were significantly less than those of the control litters on days 14 and 21; this effect was considered to be related to D&C Yellow No. 11 exposure. 2-YEAR STUDY: Groups of 60 male and 60 female F(1) rats were given 0, 500, 1,700, or 5,000 ppm D&C Yellow No. 11 in feed for 105 (males) or 106 (females) weeks after weaning (day 28); 6 to 10 rats per group were evaluated at 12 months. These exposure concentrations resulted in average daily doses of approximately 25, 85, or 250 mg D&C Yellow No. 11/kg body weight to males and 25, 100, or 280 mg/kg to females. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of males given 1,700 or 5,000 ppm was significantly less than that of the controls, and survival of 1,700 ppm females was significantly greater than that of the controls. Mean body weights of 1,700 and 5,000 ppm males and females were generally lower than those of the controls throughout the study. Feed consumption by exposed groups was similar to that by the controls. Chemical-related clinical findings included yellow discoloration of the entire body in all exposed males and females from day 1 and head swelling and edema in 1,700 and 5,000 ppm males. One 1,700 ppm and five 5,000 ppm males were moribund and were killed between weeks 49 and 81; these deaths were attributed to extensive edema. Hematology: A few minimal hematology changes occurred in male rats at the 12-month interim evaluation. There was evidence of minimal anemia in exposed males; this anemia was characterized by decreased hematocrit values, hemoglobin concentrations, and erythrocyte counts. The minimal anemia was characterized as normocytic, normochromic, and nonresponsive. There were no biologically or statistically significant differences in hematology parameters between control and exposed females. Pathology Findings: Absolute and relative liver weights of all exposed groups of md relative liver weights of all exposed groups of males and females were significantly greater than those of the controls at 12 months. At 2 years, the incidences of hepatocellular adenoma in 5,000 ppm males and of hepatocellular adenoma or carcinoma (combined) in 5,000 ppm females were significantly greater than those in the controls. At 12 months, the incidences of clear cell foci in 1,700 and 5,000 ppm females were significantly greater than that in the controls. At 2 years, the incidences of mixed cell foci in exposed males and of clear cell foci in exposed males (except 500 ppm) and females were significantly greater than those in the controls. Incidences of cytologic alterations (basophilia and granularity) of hepatocytes, and pigmentation in bile duct epithelium, hepatocytes, and Kupffer cells in exposed males and females were greater than those in the controls at both 12 months and 2 years. Renal tubule adenomas were observed in two 5,000 ppm males, and one renal tubule carcinoma was observed in a 1,700 ppm male. During an extended evaluation, renal tubule adenomas were observed in two additional 5,000 ppm males, four 1,700 ppm males, and two 500 ppm males. Renal tubule hyperplasia was observed in exposed groups of males but not in controls, and the incidences in 1,700 ppm males from both standard and extended evaluations were significantly greater than those in the controls. Necrosis and regeneration of the renal tubule epithelium were observed in all control and exposed male rats and in most female rats at 12 months and 2 years. The severity of nephropathy in exposed males and females was significantly greater than that in the controls. In exposed males and 1,700 ppm females at 2 years, the incidences of hyperplasia of the transitional epithelium in the kidney, which commonly accompanies advanced nephropathy, were greater than those of the controls, and the severity of this lesion in exposed males and females was greater than that in the controls. The incidences of renal tubule pigmentation in all exposed groups of males and females at 12 months and 2 years were significantly greater than those in the controls. Squamous cell carcinomas of the tongue were observed in one 500 ppm male at 12 months and one 5,000 ppm female at 2 years, and one squamous cell carcinoma of the oral mucosa was observed in each group of exposed males and in one 5,000 ppm female at 2 years. At 2 years, squamous cell papillomas were observed in the oral cavity (oral mucosa or tongue) of one control, one 500 ppm, two 1,700 ppm, and four 5,000 ppm males; this lesion was also observed in one control and one 500 ppm female. GENETIC TOXICOLOGY: Results of mutagenicity tests with D&C Yellow No. 11 in Salmonella typhimurium were equivocal in one study, based on responses observed in strain TA100 with induced rat liver S9, and weakly positive in a second study, based on responses observed in strains TA98 and TA100 with induced rat or hamster liver S9. D&C Yellow No. 11 induced sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells, with and without S9. No increase in the frequency of micronucleated normochromatic erythrocytes was observed in peripheral blood samples from male and female B6C3F(1) mice administered D&C Yellow No. 11 in feed for 13 weeks. CONCLUSIONS: Under the conditions of this perinatal exposure followed by a 2-year dosed feed study, there was some evidence of carcinogenic activity of D&C Yellow No. 11 in male F344/N rats based on increased incidences of hepatocellular adenoma, renal tubule neoplasms, and squamous cell neoplasms of the oral cavity. There was some evidence of carcinogenic activity in female F344/N rats based on increased inci dences of hepatocellular neoplasms. Incidences of uncommon squamous cell carcinoma of the oral cavity in females may have been related to chemical treatment. Exposure of rats to D&C Yellow No. 11 in feed for 2 years resulted in increased incidences of nonneoplastic liver lesions including clear cell foci, increased basophilia and granularity in the cytoplasm of hepatocytes, and bile duct, hepatocyte, and Kupffer cell pigmentation in males and females and mixed cell foci in males. In the kidney, there were increased incidences of renal tubule pigmentation and transitional epithelial hyperplasia in males and females and renal tubule hyperplasia in males. The severity of nephropathy was increased in exposed males and females. Synonyms: 2-(2-Quinolinyl)-1H-indene-1,3-(2H)-dione; 2-(2-quinolyl)-1,3-indandione Trade names: Arlosol Yellow S, Chinoline Yellow D (soluble in spirits), Chinoline Yellow ZSS, C.I. 47000, C.I. Solvent Yellow 33, Nitro Fast Yellow SL, Oil Yellow SIS, Petrol Yellow C, Quinoline Yellow A Spirit Soluble, Quinoline Yellow Base, Quinoline Yellow Spirit Soluble, Quinoline Yellow SS, Solvent Yellow 33, Waxoline Yellow T
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PMID:NTP Toxicology and Carcinogenesis Studies of D&C Yellow No. 11 (CAS No. 8003-22-3) in F344/N Rats (Feed Studies). 1258 13

Studies were conducted to compare outcomes when four chemicals were evaluated under typical NTP bioassay conditions as well as under protocols employing dietary restriction. Specific experiments were designed to evaluate the effect of diet restriction on the sensitivity of the bioassay toward chemical-induced chronic toxicity and carcinogenicity and to evaluate the effect of weight-matched control groups on the sensitivity of the bioassays. Two chemicals, butyl benzyl phthalate and t-butylhydroquinone, were administered in feed; one chemical, salicylazosulfapyridine, was administered in corn oil by gavage; and one chemical, scopolamine hydrobromide trihydrate, was administered in distilled water by gavage. In each of four protocols, the effects of the chemical were assessed by a comparison between a group exposed to a single dose concentration of the study chemical and a nonexposed control group. F344/N rats and B6C3F1 mice were fed NIH-07 diet either ad libitum or in amounts that restricted mean body weights according to the following design requirements. For the core bioassay, groups of 50 to 60 ad libitum-fed animals were allotted to a control group and three dosed groups for approximately 104 weeks or up to 128 weeks (t-butylhydroquinone study). The comparison between the control group and the group receiving the highest dose was used to represent the outcome of the bioassay under ad libitum feeding protocols. In a second comparison, outcomes from the group receiving the highest dose were compared with a weight-matched group of 50 to 60 untreated controls; the weight-matched controls received feed in amounts restricted so that the mean body weight matched the mean body weight of the dosed group. Two additional groups of 48 to 60 animals (one control and one dosed group) were offered feed in amounts that limited the mean body weight of the control group to approximately 85% that of the controls fed ad libitum under the first protocol. Animals assigned to this dietary restriction paradigm were evaluated after 104 weeks or 130 weeks (t-butylhydroquinone). A fourth protocol was em- loyed to evaluate whether an additional period of exposure (up to 1 year) would influence the neoplasm profile of animals fed a restricted diet. Two groups of approximately 50 animals (one control and one dosed group) in the butyl benzyl phthalate, salicylazosulfapyridine, and scopolamine hydrobromide trihydrate studies received restricted diets, as under the third protocol, for 3 years or until survival in either group was reduced to 20%. Butyl benzyl phthalate caused an increased incidence of pancreatic acinar cell neoplasms in ad libitum-fed male rats relative to ad libitum-fed and weight-m atched controls. This change did not occur in rats in the restricted feed protocol after 2 years; however, acinar cell adenomas were observed in three exposed, feed-restricted males at 30 months. Feed restriction is known to influence the incidence of pancreatic acinar cell neoplasms and may have prevented the full expression of this chemical-induced effect. Butyl benzyl phthalate also caused an increased incidence of urinary bladder neoplasms in female rats in the 32-month restricted feed protocol. The incidences of urinary bladder neoplasms were not significantly increased in female rats in any of the 2-year protocols, suggesting that the length of study, and not body weight, was the primary factor in the detection of this carcinogenic response. Salicylazosulfapyridine caused an increased incidence of urinary bladder papillomas in male rats fed ad libitum relative to ad libitum-fed and weight- matched controls. This increase was associated with an increased incidence of urinary bladder calculi; the incidences of urinary bladder concretions, dilatation, and hyperplasia were also increased in dosed males. The incidences of urinary bladder papillomas and calculi were not increased in male rats receiving salicylazosulfapyridine that were fed restricted diets. In male mice, salicylazosulfapyridine caused an increased incidence of liver neoplasms relative tsms relative to the ad libitum-fed and weight-matched controls. This increase did not occur in the restricted feed protocols. Liver neoplasms in mice are greatly influenced by body weight, and the marked mean body weight reduction observed in dosed male mice in the restricted feed protocols may have overridden the carcinogenic response. Neither t-butylhydroquinone nor scopolamine hydro bromide trihydrate caused increased neoplasm incidences under any of the experimental protocols. Results consistently show that feed restriction caused decreased incidences of neoplasms and nonneoplastic lesions at a variety of anatomic sites in control and dosed animals. Furthermore, the sensitivity of the bioassay to detect a carcinogenic response was altered by dietary restriction: two of the four chemicals caused increased incidences of neoplasms at three sites when evaluated under a standard ad libitum feeding protocol for 104 weeks. When control and dosed groups were subjected to dietary restriction, none of these three sites was detected as a target of carcinogenesis after 2 to 3 years. Rather, one different site of carcinogenesis was detected after 32 months. When dosed animals in the ad libitum feeding protocol were compared to weight-matched control groups, three sites were identified as targets of carcinogenesis and corresponded to the three sites discovered under the ad libitum feeding protocol. The magnitude of the response was greater when the weight-matched controls protocol was used. Dietary restriction of dosed and control animals decreased the sensitivity of these carcinogenesis bioassays. Regarding the future use of dietary restriction regimens in long-term studies, only limited conclusions can be drawn because only four chemicals were evaluated and none of these proved to be a strong carcinogen. However, the results of these studies are consistent with previous findings that dietary restriction increases survival rates and decreases the incidences of neoplasms and nonneoplastic lesions at a variety of sites in rats and mice. This association between reduced body weights and decreased neoplasm incidences underlines the necessity that the doses selected for chronic studies not exceed "minimally toxic doses" so that no marked body weight reductions (or increases) will occur in the dosed groups. Such body weight changes complicate the detection of carcinogenic effects. The following tables summarize and compare the findings from ad libitum-fed, weight-matched, and feed-restricted groups for each chemical. Tabular Summary of Dietary Restriction Study of Butyl Benzyl Phthalate is available in web version of this document. TabularSummary of the Dietary Restriction Study of t-Butylhydroquinone is available in web version of this document. TabularSummary of the Dietary Restriction Studies of Salicylazosulfapyridine is available in web version of this document. TabularSummary of the Dietary Restriction Study of Scopolamine Hydrobromide Trihydrate is available in web version of this document.
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PMID:Effect of Dietary Restriction on Toxicology and Carcinogenesis Studies in F344/N Rats and B6C3F1 Mice. 1258 16

1,3-Butadiene is produced in large volumes for use in the manufacture of synthetic rubber and of thermoplastic resins. In previous inhalation studies conducted by the NTP (NTP, 1984) there was clear evidence of multiple organ carcinogenicity in male and female mice exposed to 625 or 1,250 ppm 1,3-butadiene for 60 or 61 weeks. To better characterize exposure-response relationships for neoplasms and nonneoplastic lesions, toxicology and carcinogenesis studies were conducted by exposing groups of male and female B6C3F1 mice to air containing 1,3-butadiene (greater than 99% pure) for up to 2 years. An additional study in male B6C3F1 mice, in which exposure to 1,3-butadiene was stopped after limited exposure periods (13, 26, 40, or 52 weeks), was performed to assess the effects of varying concentration and duration of exposure on the incidences of 1,3-butadiene-induced neoplasms. In vitro genetic toxicology studies were conducted in Salmonella typhimurium and mouse lymphoma cells. In vivo genetic effects were assayed in germ cells of male Drosophila melanogaster and in bone marrow and peripheral blood cells of B6C3F1 mice. 2-Year Studies: Groups of 70 male and 70 female mice were exposed to air containing 0, 6.25, 20, 62.5, or 200 ppm 1,3-butadiene for 6 hours per day, 5 days per week for up to 2 years; groups of 90 male and 90 female mice were exposed to 625 ppm 1,3-butadiene on the same schedule. Up to 10 animals from each group were examined after 9 and 15 months of exposure. Survival and Body Weight in the 2-Year Studies: Two-year survival was decreased for males and females exposed to concentrations of 20 ppm or above, primarily due to the development of chemical-related malignant neoplasms. No female mice exposed to 200 or 625 ppm or males exposed to 625 ppm survived to the end of the studies (males: 35/50, 39/50, 24/50, 22/50, 4/50, 0/70; females: 37/50, 33/50, 24/50, 11/50, 0/50, 0/70). Mean body weights of exposed male and female mice were similar to those of the controls. Hematologic Effects in the 2-Year Studies: Hematologic parameters were evaluated after 9 and 15 months of exposure. At 9 months, decreases in erythrocyte counts, hemoglobin concentration, and packed red cell volume were observed in male mice exposed to 62.5 ppm or above and in female mice exposed to 200 or 625 ppm. Mean erythrocyte volume was increased in male mice exposed to 625 ppm and in females exposed to 200 or 625 ppm. At 15 months, decreases in erythrocyte counts, hemoglobin concentration, and packed red cell volume and increases in mean erythrocyte volume were observed in male and female mice exposed to 625 ppm. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: Exposure of mice to 1,3-butadiene induced benign and malignant neoplasms at multiple sites. Statistically significant increases in the incidences of neoplasms at one or more sites were seen at concentrations of 20 ppm and higher in males and 6.25 ppm and higher in females. There was no exposure level in this study at which a significant carcinogenic response was not observed. Statistically significant increases occurred in the incidences of malignant lymphoma; histiocytic sarcoma; cardiac hemangiosarcoma; harderian gland adenoma; hepatocellular adenoma and carcinoma; alveolar/bronchiolar adenoma and carcinoma; mammary gland carcinoma, adenoacanthoma, and malignant mixed tumor (females only); benign and malignant ovarian granulosa cell tumor; and forestomach squamous cell papilloma and carcinoma. Low incidences of uncommon neoplasms also occurred in exposed male and female mice, including intestinal carcinomas in males, renal tubule adenomas in males and females, skin sarcomas (all types combined) in females, and Zymbal's gland adenomas and carcinomas in females. Lymphocytic lymphomas appeared as early as week 23 and were the principal cause of death of male and female mice exposed to 625 ppm 1,3-butadiene. The early and extensive development of lethal lymphocytic lymphomas in mice exposed to 625 ppm resulted in a reduced number of mice at risk for neoplasms developing laterg later at other sites. Exposure-response relationships for 1,3-butadiene-induced neoplasms were more clearly characterized at concentrations below 625 ppm and after adjustment for intercurrent mortality. Increased incidences of nonneoplastic lesions in exposed mice included bone marrow atrophy; testicular atrophy; ovarian atrophy, angiectasis, germinal epithelial hyperplasia, and granulosa cell hyperplasia; uterine atrophy; cardiac endothelial hyperplasia and mineralization; alveolar epithelial hyperplasia; forestomach epithelial hyperplasia; and harderian gland hyperplasia. Stop-Exposure Study: The stop-exposure study consisted of groups of 50 male mice exposed to 1,3-butadiene at concentrations of 200 ppm for 40 weeks, 625 ppm for 13 weeks, 312 ppm for 52 weeks, or 625 ppm for 26 weeks. After the exposures were completed, these groups were placed in control chambers for the remainder of the 2-year study. The total exposure of 1,3-butadiene (concentration times duration of exposure) of the 13- and 40-week stop-exposure groups was approximately 8,000 ppm-weeks, while that of the 26- and 52-week stop-exposure groups was approximately 16,000 ppm-weeks. The survival of all stop-exposure groups was markedly lower than that of the controls. The incidences of lymphocytic lymphoma, histiocytic sarcoma, cardiac hemangiosarcoma, alveolar/bronchiolar adenoma and carcinoma, forestomach squamous cell papilloma and carcinoma, hepatocellular adenoma, harderian gland adenoma and adenocarcinoma, and preputial gland carcinoma were significantly increased. Neoplasms were induced at most of these sites after only 13 weeks of exposure to 1,3-butadiene. Additionally, low numbers of malignant gliomas and neuroblastomas of the brain and Zymbal's gland carcinomas occurred in one or more stop-exposure groups. At similar total exposures, the incidence of lymphocytic lymphoma was greater with exposure to a higher concentration of 1,3-butadiene for a short time compared with exposure to a lower concentration for an extended period (34% at 625 ppm for 13 weeks versus 12% at 200 ppm for 40 weeks; 60% at 625 ppm for 26 weeks versus 8% at 312 ppm for 52 weeks). Genetic Toxicology: 1,3-Butadiene has been tested both in vitro and in vivo for mutagenic activity. In vitro, positive results were obtained in the Salmonella typhimurium gene mutation assay with strain TA1535; mutagenic activity was not observed in other S. typhimurium strains (TA100, TA97, and TA98). 1,3-Butadiene was negative in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells with and without S9. In vivo, 1,3-butadiene did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster; however, it did induce significant increases in chromosomal aberrations and sister chromatid exchanges in bone marrow cells of mice exposed for 2 weeks by inhalation. In addition, significant increases in micronucleated erythrocytes were observed in peripheral blood samples obtained from male and female mice exposed to 1,3-butadiene for 2 or 13 weeks or 15 months by inhalation. Conclusions: The previous inhalation studies of 1,3-butadiene (TR-288) in male and female B6C3F1 mice provided clear evidence of carcinogenicity at exposure concentrations of 625 or 1,250 ppm. The present inhalation studies - 2-year exposures of 6.25, 20, 62.5, 200, or 625 ppm or shorter duration exposures of 200, 312, or 625 ppm - provide a better characterization of the concentration-dependent responses for 1,3-butadiene-induced neoplasms and nonneoplastic lesions. The present studies confirmed the clear evidence of carcinogenicity of 1,3-butadiene in male B6C3F1 mice based on increased incidences of neoplasms in the hematopoietic system, heart, lung, forestomach, liver, harderian gland, preputial gland, brain, and kidney. There was clear evidence of carcinogenicity of 1,3-butadiene in female B6C3F1 mice based on increased incidences of neoplasms in the hematopoietic system, heart, lung, forestomach, liver, harderian gland, ovary, and mammary gland. Low incidences of intestinal carcinomas in male mice, Zymbal's gland carcinomas in male and female mice, and renal tubule adenomas and skin sarcomas in female mice may also have been related to administration of 1,3-butadiene. Synonyms: alpha,gamma-Butadiene; bivinyl; divinyl; erythrene; vinylethylene; biethylene; pyrrolylene
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PMID:NTP Toxicology and Carcinogenesis Studies of 1,3-Butadiene (CAS No. 106-99-0) in B6C3F1 Mice (Inhalation Studies). 1261 97

C.I. Acid Red 114 is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. C.I. Acid Red 114 was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. Toxicology and carcinogenesis studies were conducted by administering desalted, industrial grade C.I. Acid Red 114 in drinking water to groups of F344/N rats of each sex for 13 days, 13 weeks, 9 or 15 months, or 2 years. These studies were performed only in rats because studies of benzidine congeners were being performed in mice at the National Center for Toxicological Research (NCTR). Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary cells, and Drosophila melanogaster. 13-Day Studies: Rats were exposed to C.I. Acid Red 114 in drinking water at doses of 0, 10,000, 20,000, or 30,000 ppm. All control and dosed rats survived except one male rat in the 20,000 ppm dose group. Final mean body weights in the three dosed groups were 94%, 83%, or 77% of controls for males and 92%, 88%, or 80% of controls for females. Water consumption declined with increased dose. Clinical findings included red stained fur, ears, and tail in all test animals. On gross necropsy, organs and tissues were also stained red. 13-Week Studies: C.I. Acid Red 114 was administered in drinking water at doses of 0, 600, 1,200, 2,500, 5,000, or 10,000 ppm. All control and dosed animals survived until the end of the study. Final mean body weights in the five dosed groups were 97%, 89%, 87%, 87%, or 85% of controls for males and 97%, 94%, 94%, 92%, or 89% of controls for females. Water consumption was decreased in dosed animals. As was seen in the 13-day studies, major organs and tissues from treated animals were stained red. Kidney toxicity characterized by regeneration and karyomegaly of tubule epithelial cells with chronic inflammation was observed in female rats at doses of 1,200 ppm or above. Treatment-related increases in relative liver weights and elevated liver enzyme levels were seen in males and females, centrilobular pallor in the liver was seen in all male dose groups. Because of these body weight differences, decreases in water consumption, and organ toxicity, the doses chosen for the 2-year studies were 70,150, and 300 ppm for males and 150, 300, and 600 for females. 2-Year Studies: Male rats received doses of 0, 70, 150, or 300 ppm of C.I. Acid Red 114, and female rats received 0, 150, 300, or 600 ppm. Seventy animals were in the control and high-dose groups, 45 in the low-dose groups, and 75 in the mid-dose groups. Ten animals were evaluated from the control and high-dose groups at 9 months, and ten animals from all dose groups were evaluated at 15 months. The average amount of compound consumed per day was 4, 8, or 20 mg/kg for males and 9, 20, or 70 mg/kg for females. Survival and Body Weights: Survival at 105 weeks for male rats receiving 0, 70, 150, or 300 ppm was 24/50, 15/35, 26/65, and 1/50; for females receiving 0, 150, or 300 ppm, survival was 36/50, 13/35, and 6/64. All female rats receiving 600 ppm died by week 89. The decreased survival in treated groups was due primarily to the development of chemical-related neoplasms. Of the surviving animals, the final mean body weights for males receiving 70 or 150 ppm were 94% and 90% of control and for females receiving 150 or 300 ppm, 99% and 84% of control. These weight differences began in the second year of the studies and were attributed in part to the development of neoplasms in the dosed groups. Histopathologic Effects in the 2-Year Studies: At 9 and 15 months, a few neoplasms were seen in the liver, lung, clitoral gland, skin, Zymbal's gland, oral cavity epithelium, and small and large intestine, and the number of neoplasms at these sites increased as gland, skin, Zymbal's gland, oral cavity epithelium, and small and large intestine, and the number of neoplasms at these sites increased as the studies progressed. At 2 years, there was a clear carcinogenic response in the skin, Zymbal's gland, and liver of male and female rats, and in the clitoral gland, oral cavity epithelium, small and large intestine, and lung in female rats. Treatment-related increases were also seen in the incidence in neoplasms of the oral cavity epithelium, adrenal gland, and lung of male rats, and in mononuclear cell leukemia and in neoplasms of the mammary gland and adrenal gland in female rats. The incidence of these neoplasms was generally lower, but was significant and considered to be marginally related to chemical treatment. The same neoplastic effects have been previously observed in some or all of the NTP studies with dimethoxybenzidine, dimethylbenzidine, or C.I. Direct Blue 15. Genetic Toxicology: In a standard preincubation protocol, C.I. Acid Red 114 was mutagenic in Salmonella typhimurium strain TA98 in the presence of induced hamster liver S9, and an equivocal response was noted in strain TA100 with hamster liver S9. However, no significant mutagenic activity was noted in strains TA1535 or TA1537 with or without S9 activation. In a modified S. typhimurium gene mutation test which employed reductive metabolism followed by oxidative metabolism with S9 liver enzymes, C.I. Acid Red 114 was strongly mutagenic in strain TA1538. C.I. Acid Red 114 did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells with or without S9 activation; reductive metabolism was not used in these cytogenetic tests. No increase in sex-linked recessive lethal mutations was observed in germ cells of male Drosophila melanogaster administered C.I. Acid Red 114 by feeding or injection. Conclusions: Under the conditions of these 2-year drinking water studies, there was clear evidence of carcinogenic activity of C.I. Acid Red 114 for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, and liver. Increased incidences of neoplasms of the oral cavity epithelium, adrenal gland, and lung may have been related to chemical administration. There was clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity epithelium, small and large intestines, and lung. Increased incidences of mononuclear cell leukemia, mammary gland adenocarcinoma, and adrenal gland pheochromocytomas may have been related to chemical administration. Synonyms: 1,3-Naphthalenedisulfonic acid, 8-((3,3'-dimethyl-4'-((4-(((4-methylphenyl)sulfonyl)oxy)phenyl)azo)(1,1'-bipheny)-4-yl)azo)-7-hydroxy, disodium salt, Acid Leather Red BG, Acid Red 114, Amacid Milling Red PRS, Benzyl Fast Red BG, Benzyl Red BR, Cerven Kysela, C.I. 23635, Erionyl Red RS, Folan Red B, Kayanol Milling Red RS, Leather Fast Red B, Levanol Red GG, Midlon Red PRS, Milling Red B, Milling Red BB, Milling Red SWB, NCI C61096, Polar Red RS, Sandolan Red N-RS, Sella Fast Red RS, Sulphonol Fast Red R, Supranol Fast Red GG, Supranol Red PBX-CF, Supranol Red R, Telon Fast Red GG, Tertracid Milling Red B, Vondamol Fast Red RS
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PMID:Toxicology and Carcinogenesis Studies of C.I. Acid Red 114 (CAS No. 6459-94-5) in F344/N Rats (Drinking Water Studies). 1262 13


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