Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously described an immunoaffinity/gas chromatography/electron capture negative chemical ionization high-resolution mass spectrometry (IA/GC/ECNCI-HRMS) assay for quantitation of the promutagenic DNA adduct N(2),3-ethenoguanine (N(2),3-epsilonGua) in vivo. Here we present an expanded assay that allows simultaneous quantitation of its structural isomer, 1,N(2)-ethenoguanine (1,N(2)-epsilonGua), in the same DNA sample. 1,N(2)-epsilonGua and N(2),3-epsilonGua were purified together from hydrolyzed DNA using two immobilized polyclonal antibodies. GC/ECNCI-HRMS was used to quantitate the 3,5-bis(pentafluorobenzyl) (PFB) derivative of each adduct against an isotopically labeled analogue. Selected ion monitoring was used to detect the [M - 181](-) fragments of 3,5-(PFB)(2)-N(2),3-epsilonGua and 3,5-(PFB)(2)-[(13)C(4),(15)N(2)]-N(2),3-epsilonGua and the [M - 201](-) fragments of 3,5-(PFB)(2)-1,N(2)-epsilonGua and 3,5-(PFB)(2)-[(13)C(3)]-1,N(2)-epsilonGua. The demonstrated limits of quantitation in hydrolyzed DNA were 7.6 fmol of N(2),3-epsilonGua and 15 fmol of 1,N(2)-epsilonGua in approximately 250 microg of DNA, which corresponded to 5.0 N(2),3-epsilonGua and 8.7 1,N(2)-epsilonGua adducts/10(8) unmodified Gua bases, respectively. 1,N(2)-epsilonGua was found to be the predominant ethenoguanine adduct formed in reactions of lipid peroxidation products with DNA. The respective ratios of 1,N(2)-epsilonGua to N(2),3-epsilonGua were 5:1 and 38:1 when calf thymus DNA was treated with ethyl linoleate or 4-hydroxynonenal, respectively, under peroxidizing conditions. Only N(2),3-epsilonGua was detected in DNA treated with the vinyl chloride (VC) metabolite 2-chloroethylene oxide and in hepatocyte DNA from rats exposed to 1100 ppm VC for 4 weeks (6 h/day for 5 days/week). These data suggest that 1,N(2)-epsilonGua plays a minor role relative to N(2),3-epsilonGua in VC-induced carcinogenesis, but that 1,N(2)-epsilonGua may be formed to a larger extent from endogenous oxidative processes.
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PMID:Simultaneous quantitation of N(2),3-ethenoguanine and 1,N(2)-ethenoguanine with an immunoaffinity/gas chromatography/high-resolution mass spectrometry assay. 1125 83

Mutant p53 protein and anti-p53 antibody in circulating blood can be detectedamong individuals with mutations of the p53 tumor suppressor gene. Plasma mutant p53 protein and anti-p53 antibody have also been associated with vinyl chloride monomer (VCM) exposure, although the mechanism of VCM-related carcinogenesis remains unclear. Polymorphisms of metabolic and DNA repair genes have been implicated in chemical exposure-related carcinogenesis. The aim of this study is to explore the association between polymorphisms of metabolic and DNA repair genes with mutant p53 protein and anti-p53 antibody expression induced by VCM. Study subjects comprised 333 male workers occupationally exposed to VCM. Plasma mutant p53 protein and anti-p53 antibody detected with ELISA were grouped together as p53 overexpression. Genotypes of cytochrome P450 2E1 (CYP2E1), aldehyde dehydrogenase 2 (ALDH2), glutathione S-transferase T1 (GSTT1), and X-ray repair cross-complementing group 1 (XRCC1, exon 10) genes were identified by the PCR. High VCM exposure group had significantly higher p53 overexpression as compared with low exposure group [odds ratio (OR), 2.1; 95% confidence interval (CI), 1.1-3.8]. Individuals having experienced a high VCM exposure and displaying a XRCC1 Gln-Gln genotype had a highest risk of p53 overexpression among those having different combinations of VCM exposure and XRCC1 genotypes (OR, 6.5; 95% CI, 1.7-24.2). Interestingly, those subjects reflecting a CYP2E1 c2c2 genotype among the low VCM-exposure group demonstrated a greater risk of p53 overexpression (OR, 9.8; 95% CI, 1.2-81.6) as compared with those experiencing a low VCM exposure and CYP2E1 c1c1/c1c2 genotypes. Additional analysis revealed that individuals possessing more susceptible XRCC1 Gln-Gln, CYP2E1 c2c2, ALDH2 1-2/2-2, and non-null GSTT1 genotypes were more likely to reveal p53 overexpression. Our results suggest that susceptible XRCC1 and CYP2E1 genotypes may modulate the mutation of the p53 gene among VCM-exposed workers.
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PMID:XRCC1 and CYP2E1 polymorphisms as susceptibility factors of plasma mutant p53 protein and anti-p53 antibody expression in vinyl chloride monomer-exposed polyvinyl chloride workers. 1201 Aug 62

Although vinyl chloride (VC) clearly induces hepatic angiosarcoma in humans and rodents, a causal association with brain tumors has not been definitively established with the available epidemiological and experimental evidence. Because VC acts by genotoxic mechanisms, DNA adduct formation is thought to be a sensitive biomarker of early events in carcinogenesis. Adult male Sprague Dawley rats were exposed to 0 or 1100 ppm VC for 1 or 4 weeks (6 h/day, 5 days/week) by inhalation. Male weanlings were similarly exposed for 5 days. Another group of male adults was exposed to 1100 ppm [(13)C(2)]VC in a nose-only inhalation apparatus for 5 days (6 h/day). A sensitive gas chromatography high-resolution mass spectrometry assay was used to measure the major promutagenic DNA adduct, N(2),3-ethenoguanine (N(2),3-epsilonG), in rat brain and hepatocyte (HEP) DNA. The respective concentrations of N(2),3-epsilonG in control rat brain DNA at 1 and 4 weeks were 5.0 +/- 0.9 and 5.6 +/- 1.1 N(2),3-epsilonG/10(8) unmodified guanine. There was no change in N(2),3-epsilonG in adult rat brain after exposure to 1100 ppm VC for 1 or 4 weeks. In HEPs from the same animals, these adduct concentrations increased from 5.5 +/- 1.4 to 55 +/- 2.0 N(2),3-epsilonG/10(8) unmodified guanine after a 1-week exposure and from 3.0 +/- 0.3 to 110 +/- 20 N(2),3-epsilonG/10(8) unmodified guanine after a 4-week exposure. When weanlings were exposed to 1100 ppm VC for 5 days, there was a statistically significant (P = 0.04) increase in N(2),3-epsilonG in brain from 1.5 +/- 0.2 to 4.4 +/- 1.1 N(2),3-epsilonG/10(8) unmodified guanine. Weanlings exposed to 1100 ppm VC had an even greater increase in N(2),3-epsilonG in HEPs from 1.6 +/- 0.1 to 97 +/- 5.0 N(2),3-epsilonG/10(8) unmodified guanine. [(13)C(2)]N(2),3-epsilonG was not detected in brain DNA from adult rats exposed to 1100 ppm [(13)C(2)]VC for 5 days but was present in HEP DNA at 55 +/- 4.0 [(13)C(2)]N(2),3-epsilonG/10(8) unmodified guanine. The concentrations of the endogenous adduct in both organs were unchanged after this exposure. 7-(Oxoethyl)guanine (OEG), the major DNA adduct formed by VC, was reduced to 7-(2-hydroxyethyl)guanine and measured by liquid chromatography-electrospray ionization-tandom mass spectrometry in brain and HEP DNA from rats exposed to 1100 ppm VC for 1 week. Whereas 4.0 +/- 0.8 OEG/10(6) unmodified guanine were present in HEP DNA from VC-exposed rats, no adducts were detectable in brain DNA (detection limit, 0.3 OEG/10(6) unmodified guanine). These findings indicate that the genotoxic metabolite of VC is not formed in or transported to adult rat brain. Thus, it is unlikely that N(2),3-epsilonG or other VC-induced promutagenic DNA adducts play a significant role in initiating carcinogenesis in adult rat brain after exposure to VC. The data for weanling rats are less clear. Whereas a small increase in N(2),3-epsilonG in the brains of weanlings was found after exposure to 1100 ppm VC, the resulting adduct concentration was similar to that measured in unexposed adults. Future exposures of weanling rats to the stable isotopically labeled compound will be necessary to conclusively determine whether this increase was due to VC.
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PMID:Differential induction of N(2),3-ethenoguanine in rat brain and liver after exposure to vinyl chloride. 1223 82

Although the DNA adducts of vinyl chloride (VC) have been well characterized, previous studies have used single concentrations of VC that are well above contemporary human exposures. This study examined the exposure response to VC in male Sprague Dawley rats with respect to the molecular dose of the promutagenic DNA adduct N(2),3-ethenoguanine (N(2),3-epsilonG). Adult rats were exposed by inhalation to 0, 10, 100, or 1100 ppm VC for 1 or 4 weeks (6 h/day, 5 days/week). Weanling rats were similarly exposed for 5 days. The amount of N(2),3-epsilonG in hepatocyte (HEP) and nonparenchymal cell (NPC) fractions obtained from the liver was measured with a sensitive immunoaffinity/gas chromatography/high-resolution mass spectrometry assay. Endogenous N(2),3-epsilonG was present in HEPs and NPCs from all unexposed rats. The exposure response to VC in each group and cell population was supralinear, with a linear increase from 0 to 100 ppm, and a plateau between 100 and 1100 ppm. There was no statistically significant difference in N(2),3-epsilonG concentrations between HEPs and NPCs in any adult exposure group, which suggests that factors other than adduct concentrations contribute to the particular susceptibility of NPCs to VC-induced carcinogenesis. The accumulation of N(2),3-epsilonG with respect to time was nearly linear in rats exposed to 600 ppm VC for 1, 2, 4, or 8 weeks (4 h/day, 5 days/week), and no repair of N(2),3-epsilonG was detected in rats exposed to VC for 4 weeks and allowed to recover for 1 week. N(2),3-epsilonG concentrations in HEPs from weanling rats were 2-3-fold greater than those in adult rats exposed for the same time. Higher adduct concentrations in young rats may contribute to their greater susceptibility to VC-induced hepatic angiosarcoma as well as their particular susceptibility to hepatocellular carcinoma. The molecular dosimetry of N(2),3-epsilonG in liver appears to be a sensitive and informative biomarker of genotoxic effect after exposure to VC. N(2),3-epsilonG was the predominant etheno adduct measured in vivo after exposure to VC, and the saturable nature of VC metabolism was reflected in its molecular dose. The relationships between endogenous N(2),3-epsilonG and that formed by low exposures to VC were demonstrated. Conclusions drawn from these exposures may be more relevant for risk assessment purposes than those drawn from high exposures where activation, detoxication, and repair pathways may be saturated or otherwise perturbed. These data are well suited for consideration in future risk assessments of VC that incorporate nontumor mode of action data.
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PMID:Molecular dosimetry and repair of N(2),3-ethenoguanine in rats exposed to vinyl chloride. 1223 83

Tricresyl phosphate is an organophosphate plasticizer widely used in vinyl plastics and as a fire retardant additive for hydraulic fluids. Toxicology and carcinogenesis studies were conducted by administering a mixed isomer preparation of 79% tricresyl phosphate esters (consisting of 21% tri- m-cresyl phosphate, 4% tri- p-cresyl phosphate, less than 1% tri- o-cresyl phosphate, and other unidentified tricresyl phosphate esters) by gavage to groups of F344/N rats and B6C3F1 mice for 16 days and 13 weeks, and in feed to groups of F344/N rats and B6C3F1 mice for 13 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 16-DAY GAVAGE STUDY IN RATS: Groups of 10 male and 10 female rats received tricresyl phosphate in corn oil by gavage at doses of 0, 360, 730, 1,450, 2,900, or 5,800 mg/kg body weight, 5 days per week, for a total of 13 or 14 doses in a 16-day period. One female receiving 1,450 mg/kg and five males and eight females receiving 2,900 mg/kg died before the end of the study. Final mean body weights of male and female rats that received 1,450, 2,900, or 5,800 mg/kg were significantly lower than those of the controls. Necrosis of the mandibular lymph node, spleen, and thymus occurred primarily in rats receiving 2,900 and 5,800 mg/kg. Diffuse aspermatogenesis occurred in the testes of male rats that received 2,900 and 5,800 mg/kg. Changes in neurobehavioral parameters in groups that received 1,450, 2,900, or 5,800 mg/kg were confounded by mortality and reduced body weights and were not attributed to a direct neurotoxic response. 16-DAY GAVAGE STUDY IN MICE: Groups of 10 male and 10 female mice received tricresyl phosphate in corn oil by gavage at doses of 0, 360, 730, 1,450, 2,900, or 5,800 mg/kg body weight, 5 days per week, for a total of 13 or 14 doses in a 16-day period. Five males and all females that received 1,450 mg/kg, all mice that received 2,900 mg/kg, and four males and one female that received 5,800 mg/kg died before the end of the study. Final mean body weights of male mice that received 1,450 and 5,800 mg/kg were significantly lower than that of the controls. Final mean body weights of female mice that received 360, 730, or 5,800 mg/kg were significantly greater than that of the controls. Necrosis of the mandibular lymph node, thymus, and spleen occurred primarily in mice receiving 2,900 and 5,800 mg/kg. Hindlimb grip strengths of male mice that received 360 and 1,450 mg/kg and male and female mice that received 730 and 5,800 mg/kg were significantly lower than those of the controls at the end of the study. 13-WEEK GAVAGE STUDY IN RATS: Groups of 10 male and 10 female rats received tricresyl phosphate in corn oil by gavage at doses of 0, 50, 100, 200, 400, or 800 mg/kg body weight. All rats survived to the end of the study. Final mean body weights of male rats receiving 200, 400, and 800 mg/kg were significantly lower than that of the controls. Cytoplasmic vacuolization of the adrenal cortex occurred in all dosed groups and the severity increased with dose. Ovarian interstitial cell hypertrophy occurred in all dosed groups of females. Atrophy of the seminiferous tubules occurred in male rats that received 400 and 800 mg/kg. There were no biologically significant changes in neurobehavioral parameters in rats. 13-WEEK GAVAGE STUDY IN MICE: Groups of 10 male and 10 female mice received tricresyl phosphate in corn oil by gavage at doses of 0, 50, 100, 200, 400, or 800 mg/kg body weight. All mice survived to the end of the study. Final mean body weights of male mice receiving 200 mg/kg and of male and female mice receiving 400 and 800 mg/kg were significantly lower than those of the controls. Cytoplasmic vacuolization of the adrenal cortex occurred in all dosed groups of mice and the severity increased with dose. Ovarian interstitial cell hypertrophy was present in all dosed groups of female mice. Multifocal degeneration of the spinal cord occurred in males and females that received 100, 200, 400, and 800 mg/kg, and multifocal degenerg/kg, and multifocal degeneration of the sciatic nerve occurred in males that received 200, 400, and 800 mg/kg and females that received 100, 200, 400, and 800 mg/kg. Hindlimb grip strengths of male mice that received 200, 400, or 800 mg/kg were significantly lower than that of the controls at the end of the study. 13-WEEK FEED STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 900, 1,700, 3,300, 6,600, or 13,000 ppm of tricresyl phosphate. All rats survived to the end of the study. Final mean body weights of males and females exposed to 6,600 and 13,000 ppm and females exposed to 3,300 ppm were significantly lower than those of controls. Feed consumption by male and female rats exposed to 13,000 ppm was lower than that by controls during the first week of the study. Dietary levels of 900, 1,700, 3,300, 6,600 or 13,000 ppm tricresyl phosphate were estimated to deliver daily doses of 55, 120, 220, 430, or 750 mg/kg body weight (males) and 65, 120, 230, 430, or 770 mg/kg (females). There were no biologically significant changes in neurobehavioral parameters in rats. Cytoplasmic vacuolization of the adrenal cortex occurred in all exposed groups of rats. Hyperplasia of ovarian interstitial cells and inflammation of the ovarian interstitium occurred in all exposed groups of females. Renal papillary edema and renal papillary necrosis occurred in 13,000 ppm males and females and in 6,600 ppm females. Basophilic hypertrophy of the pituitary gland pars distalis and atrophy of the seminiferous tubules occurred in 6,600 and 13,000 ppm males. Dose selection for the 2-year study in rats was based on lower mean body weights; toxic responses observed in the kidney, pituitary gland, and testis of males and the kidney of females exposed to 6,600 and 13,000 ppm; the presence of cytoplasmic vacuolization of the adrenal cortex in exposed males and females; and the occurrence of ovarian interstitial cell hyperplasia in females exposed to 900 and 1,700 ppm. 13-WEEK FEED STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 250, 500, 1,000, 2,100, or 4,200 ppm of tricresyl phosphate. All mice survived to the end of the study. Mean body weights of 4,200 ppm males and of females exposed to 2,100 and 4,200 ppm were lower than those of controls throughout the study. Feed consumption by females exposed to 1,000, 2,100, or 4,200 ppm was lower than that by controls during week 12. Dietary levels of 250, 500, 1,000, 2,100, or 4,200 ppm tricresyl phosphate were estimated to deliver average daily doses of 45, 110, 180, 380, or 900 mg/kg body weight (males) and 65, 130, 230, 530, or 1,050 mg/kg (females). Interpretation of grip strength changes observed in groups receiving 2,100 or 4,200 ppm were confounded by the reduced body weights of these groups. Cytoplasmic vacuolization of the adrenal cortex occurred in all exposed groups of male and female mice with the exception of 250 ppm males. Papillary hyperplasia of the gallbladder mucosa occurred in male mice exposed to 500 ppm or more and in female mice exposed to 1,000 ppm or more. Axonal degeneration occurred in males and females exposed to 2,100 and 4,200 ppm and females exposed to 1,000 ppm. Renal tubule regeneration occurred in all 4,200 ppm male mice. Dose selection for the 2-year study in mice was based on the presence of axonal degeneration at concentrations of 1,000 ppm or more and cytoplasmic vacuolization of the adrenal cortex at concentrations of 500 ppm or more in males and in all exposed groups of females. 2-YEAR FEED STUDY IN RATS: Groups of 95 male and 95 female rats were fed diets containing 0, 75, 150, or 300 ppm of tricresyl phosphate. An additional group of 95 male and 95 female rats were fed diets containing 600 ppm of tricresyl phosphate for 22 weeks and then received only control feed. After 3, 9, and 15 months of chemical exposure, up to 15 males and 15 females per group were evaluated for forelimb and hindlimb grip strength, then necropsied and evaluated for histopathologic lesions. Survival, Mean Body Weights, and Feed Consumption: Survival of exposed rats was similar to that of controls. The final mean body weights of all exposed groups of males and females were similar to those of the controls. Feed consumption by exposed groups of male and female rats was similar to that by the controls. Dietary levels of 75, 150, or 300 ppm tricresyl phosphate were estimated to deliver average daily doses of 3, 6, or 13 mg/kg body weight (males) and 4, 7, or 15 mg/kg (females). Pathology Findings: There were no chemical-related increased incidences of neoplasms in rats. Cytoplasmic vacuolization of the adrenal cortex occurred in 600 ppm males and 150, 300, and 600 ppm females at the 3-month interim evaluation. At 9 and 15 months, cytoplasmic vacuolization occurred only in female rats, primarily in the 300 ppm group. Cytoplasmic vacuolization of the adrenal cortex and ovarian interstitial cell hyperplasia occurred in female rats exposed to 300 ppm throughout the 2-year study and the incidence and severity were significantly increased at the end of the study. 2-YEAR FEED STUDY IN MICE: Groups of 95 male and 95 female mice were fed diets containing 0, 60, 125, or 250 ppm of tricresyl phosphate. After 3, 9, and 15 months of chemical exposure, up to 15 males and 15 females per group were evaluated for forelimb and hindlimb grip strength, then necropsied and evaluated for histopathologic lesions. Survival, Mean Body Weights, and Feed Consumption: Survival of exposed groups of male and female mice was similar to that of the controls. The final mean body weights of males and females receiving tricresyl phosphate were similar to those of controls. Feed consumption by exposed groups of male and female mice was similar to that by the controls. Dietary levels of 60, 125, or 250 ppm tricresyl phosphate were estimated to deliver average daily doses of 7, 13, or 27 mg/kg body weight (males) and 8, 18, or 37 mg/kg (females). Pathology Findings: There were no chemical-related increased incidences of neoplasms in mice. Ceroid pigmentation of the adrenal cortex occurred in all groups of mice throughout most of the 2-year study, with the exception of 60 and 125 ppm females at the 3-month interim evaluation; however, the severity was markedly increased in female mice receiving 250 ppm. Incidences of clear cell foci, fatty change, and ceroid pigmentation of the liver were significantly increased in male mice that received 125 or 250 ppm. GENETIC TOXICOLOGY: Tricresyl phosphate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, nor did it induce chromosomal aberrations or sister chromatid exchanges in cultured Chinese hamster ovary cells. These in vitro assays were all conducted with and without exogenous metabolic activation (S9). CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of tricresyl phosphate in male or female F344/N rats that received 75, 150, or 300 ppm. There was no evidence of carcinogenic activity of tricresyl phosphate in male or female B6C3F1 mice that received 60, 125, or 250 ppm. Nonneoplastic lesions associated with exposure to tricresyl phosphate included cytoplasmic vacuolization of the adrenal cortex and ovarian interstitial cell hyperplasia in female rats, increased incidences of clear cell focus, fatty change, and ceroid pigmentation of the liver in male mice, and increased severity of ceroid pigmentation of the adrenal cortex in female mice.
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PMID:NTP Toxicology and Carcinogenesis Studies of Tricresyl Phosphate (CAS No. 1330-78-5) in F344/N Rats and B6C3F1 Mice (Gavage and Feed Studies). 1261 98

Primary hepatocellular carcinoma (HCC) is one of the most common malignancies and has the fourth highest mortality rate worldwide. The major risk factors, including chronic infections with the hepatitis B or C virus, are exposure to dietary aflatoxin B1(AFB1), vinyl chloride, or alcohol consumption. Southern China and sub-Saharan Africa have the highest dietary AFB1 exposure, making it and hepatitis B virus (HBV) the major causes of cancer mortality in these geographic areas. Recent studies have discovered genetic and epigenetic changes involved in the molecular pathogenesis of HCC, including somatic mutations in the p53 tumor suppressor gene (TP53). AFB1 induces typical G:C to T:A transversions at the third base in codon 249 of p53. Chronic active hepatitis B and C (HCV) infection, and further inflammatory and oxyradical disorders including Wilson disease (WD) or hemochromatosis, generate reactive oxygen/nitrogen species that can damage DNA and mutate the p53 gene. The X gene of HBV (HBx) is the most common open reading frame integrated into the host genome in HCC. The integrated HBx is frequently mutated and has a diminished ability to function as a transcriptional cotransactivator and to activate the NF-kappa B pathway. However, the mutant HBx proteins still retain their ability to bind to and abrogate p53-mediated apoptosis. In summary, both viruses and chemicals are implicated in the etiology and molecular pathogenesis of HCC. The resultant molecular changes in the ras and Wnt signal-transduction pathways, and the p53 and Rb tumor suppressor pathways significantly contribute to liver carcinogenesis
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PMID:TP53 and liver carcinogenesis. 1261 6

Allyl glycidyl ether is used as a resin intermediate and as a stabilizer of chlorinated compounds, vinyl resins, and rubber. NTP Toxicology and Carcinogenesis studies were conducted by exposing groups of Osborne-Mendel rats and B6C3F1 of each sex to allyl gylcidyl ether (greater than 97% pure) by inhalation for 6 hours per day, 5 days per week for 2 weeks, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. Studies of reproductive effects were conducted in rats and mice exposed to allyl glycidyl ether for 8 weeks. Two-Week Studies: Exposure concentrations ranged up to 500 ppm in rats and 100 ppm in mice. All rats that were exposed to 500 ppm died; no deaths occurred at the next lower (200 ppm) exposure concentration. All male mice and 3/5 female mice exposed to 100 ppm and 2/5 male mice and 1/5 female mice exposed to 50 ppm died. Compound-related lesions in rats and mice included acute inflammation of the nasal passage and major airways. Eight-Week Studies of Reproductive Effects: Rats were exposed to 0-200 ppm allyl glycidyl ether, and mice were exposed to 0-30 ppm, 6 hours per day, 5 days per week for 8 weeks. The mating performance of exposed male rats was markedly reduced; however, sperm motility and number were not affected. No deficiencies were seen in the reproductive performance of exposed female rats or male or female mice. Thirteen-Week Studies: Exposure concentrations ranged up to 200 ppm for rats and 30 ppm for mice. All rats lived to the end of the studies. The final mean body weights of male rats exposed to 10-200 ppm were 7%-24% lower than that of controls. Clinical signs attributable to irritation of the upper respiratory tract and eyes were seen in exposed animals. Histologic lesions included squamous metaplasia of the nasal passage in all exposure groups (4 ppm, lowest concentration) and involved both the respiratory epithelium and the olfactory epithelium. The lesions were more severe anteriorly and dorsally and with increasing concentration. At 30 ppm and higher, erosion was seen in the nasal passage and squamous metaplasia was seen in the upper airways. There were no compound-related deaths in mice. The final mean body weights of mice exposed to 30 ppm were 12% lower than those of controls for both males and females. Mice exposed to 10 or 30 ppm allyl glycidyl ether had squamous metaplasia of the nasal passage, involving both the respiratory epithelium and the olfactory epithelium, which tended to be more severe in the anterior and dorsal portions of the nasal passage. In mice exposed to 30 ppm, epithelial erosions were also found. Body Weights and Survival in the Two-Year Studies: Two-year studies were conducted by exposing groups of 50 Osborne-Mendel rats and B6C3F1 mice of each sex to 0, 5, or 10 ppm allyl glycidyl ether by inhalation for 6 hours per day, 5 days per week for 102 or 103 weeks. Mean body weights of the exposed rats were within 8% of those of controls throughout the studies. Mean body weights of mice exposed to 5 or 10 ppm were 5%-20% lower than those of controls. Deaths were seen in all groups of male rats beginning at 1 year of age (final survival-- control, 12/50; 5 ppm, 11/50; 10 ppm, 8/50). Survival of female rats was not exposure related (24/50; 30/50; 25/50). Exposed mice had slightly increased survival (male mice: 38/50; 39/50; 46/50; female mice: 33/50; 42/50; 41/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: In male rats exposed to 10 ppm allyl glycidyl ether, three apparently unrelated neoplasms of the nasal passage were found. Two neoplasms, a papillary adenoma and a squamous cell carcinoma, appeared to arise from different cell types in the respiratory epithelium. One poorly differentiated adenocarcinoma in the olfactory region was also found. One papillary adenoma of respiratory epithelial origin was found in a female rat exposed to 5 ppm. Exposure-related nonneoplastic lesions of the nasal passages in rats included inflammation, squamous metaplasiin rats included inflammation, squamous metaplasia, respiratory metaplasia (replacement of olfactory epithelium by ciliated epithelium), hyperplasia of the respiratory epithelium, and degeneration of the olfactory epithelium. In male mice exposed to 10 ppm allyl glycidyl ether, a hemangioma and three papillary adenomas were present in the nasal passage. In female mice exposed to 10 ppm, a hemangioma and an adenoma were found in the nasal passage. Nonneoplastic lesions of the nasal passages in mice included inflammation, squamous metaplasia, hyperplasia, basal cell hyperplasia, dysplasia of the respiratory epithelium, and metaplasia of the olfactory epithelium. In male mice, there was an exposure-related decrease in the incidences of hepatocellular neoplasms; in female mice, there was a decrease in the incidences of pituitary gland adenomas. Genetic Toxicology: Allyl glycidyl ether was mutagenic in S. typhimurium strains TA100 and TA1535 with and without exogenous metabolic activation; no mutagenic activity was observed in strains TA98 or TA1537. Allyl glycidyl ether induced sister chromatid exchanges and chromosomal aberrations in CHO cells both in the presence and the absence of metabolic activation. A significant increase in sex-linked recessive lethal mutations was recorded in the germ cells of male D. melanogaster fed a sucrose solution containing allyl glycidyl ether, but no increase in reciprocal translocations occurred in these cells. Conclusions: Under the conditions of these 2-year inhalation studies, there was equivocal evidence of carcinogenic activity of allyl glycidyl ether for male Osborne-Mendel rats, based on the presence of one papillary adenoma of respiratory epithelial origin, one squamous cell carcinoma of respiratory epithelial origin, and one poorly differentiated adenocarcinoma of olfactory epithelial origin, all occurring in the nasal passage of males exposed to 10 ppm. There was no evidence of carcinogenic activity of allyl glycidyl ether for female rats. One papillary adenoma of the respiratory epithelium was present in a female rat exposed to 5 ppm. There was some evidence of carcinogenic activity of allyl glycidyl ether for male B6C3F1 mice, based on the presence of three adenomas of the respiratory epithelium, dysplasia in four males, and focal basal cell hyperplasia of the respiratory epithelium in seven males in the nasal passage of mice exposed to 10 ppm. There was equivocal evidence of carcinogenic activity of allyl glycidyl ether for female mice, based on the presence of one adenoma of the respiratory epithelium and focal basal cell hyperplasia of the respiratory epithelium in seven females exposed to 10 ppm. The sensitivity of the assay to detect potential carcinogenicity may have been reduced in male rats because of poor survival in all groups. In exposed mice, body weights were decreased 10% or more, mortality was decreased, and there were lower incidences of liver neoplasms (males) and pituitary gland adenomas (females) compared with controls. Significant exposure-related nonneoplastic lesions were restricted to the nasal passage in both rats and mice and induced inflammation, metaplasia, respiratory epithelial hyperplasia, and olfactory epithelial degeneration. Basal cell hyperplasia and dysplasia of the respiratory epithelium of the nasal passage were found only in the mice. Synonyms: allyl 2,3-epoxypropyl ether; 1-allyloxy-2,3-epoxypropane; 1,2-epoxy-3-allyloxypropane; glycidyl allyl ether; ((2-propenyloxy)methyl)oxirane; 1-(allyloxy)-2,3-epoxypropane
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PMID:NTP Toxicology and Carcinogenesis Studies of Allyl Glycidyl Ether (CAS No. 106-92-3) in Osborne-Mendel Rats and B6C3F1 Mice (Inhalation Studies). 1269 45

Vinyl Toluene is used as a monomer in the plastics and surface-coating industries. NTP Toxicology and Carcinogenesis studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to vinyl toluene (mixed isomers: 65%-71% meta and 32%-35% para) by inhalation 6 hours per day, 5 days per week, for 15 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y cells, and Chinese hamster ovary (CHO) cells. Fifteen-Day Studies: Rats were exposed to 0, 200, 400, 800, or 1,300 ppm vinyl toluene, and mice were exposed to 0, 10, 25, 50, 100, or 200 ppm. All rats lived to the end of the studies. The mean body weights at necropsy of rats exposed to 400-1,300 ppm were 13%-19% lower than that of controls for males and 9%-13% lower for females. Most male rats exposed to 1,300 ppm had centrilobular necrosis and focal inflammatory cell infiltration of the liver, whereas minimal centrilobular vacuolization of the liver was seen in all female rats exposed to 1,300 ppm. Dysplasia of the bronchial epithelial lining, chronic bronchitis, and lymphoid hyperplasia of the lung were observed in all rats exposed to 1,300 ppm. Three of five male mice exposed to 200 ppm vinyl toluene died before the end of the studies. Four of five male mice exposed to 200 ppm had moderate-to-severe hepatocellular necrosis; all female mice exposed to 200 ppm had hyperplasia of the epithelium of the intrapulmonary bronchi and centrilobular necrosis, vacuolization, and inflammatory cell infiltrates in the liver. Thirteen-Week Studies: Rats were exposed to 0, 25, 60, 160, 400, or 1,000 ppm vinyl toluene. All rats lived to the end of the studies. The final mean body weights of rats exposed to 400-1,000 ppm were 8%-19% lower than that of controls for males and 6%-12% lower for females. Relative liver weights for rats at 1,000 ppm were significantly greater than those for controls. The severity of nephropathy was increased in male rats exposed to 160, 400, or 1,000 ppm. Compound-related lesions were not observed in female rats. Mice were exposed to 0, 10, 25, 60, or 160 ppm vinyl toluene. The final mean body weights of mice exposed to 25-160 ppm were 12%-20% lower than that of controls for males and 13%-16% lower for females. Inflammation of the lung was observed in 5/10 male and 3/9 female mice exposed to 160 ppm. Metaplasia of the nasal turbinates was seen in all exposed groups. Based on these results, 2-year studies were conducted by exposing groups of 49 or 50 rats of each sex to 0, 100, or 300 ppm vinyl toluene by inhalation, 6 hours per day, 5 days per week for 103 weeks. Groups of 50 mice of each sex were exposed to 0, 10, or 25 ppm on the same schedule. Body Weights and Survival in the Two-Year Studies: Mean body weights of male rats exposed to 300 ppm vinyl toluene and those of female rats exposed to 100 and 300 ppm were generally 4%-11% lower than those of controls. No significant differences in survival were seen between any groups of rats of either sex (male: control, 19/49; low dose, 17/50; high dose, 19/50; female: 31/50; 28/50; 26/50). Mean body weights of mice exposed to 25 ppm were 10%-23% lower than those of controls after week 8, whereas mice exposed to 10 ppm showed a weight decrement that was generally less than 10%. The survival of male mice exposed to 25 ppm was significantly greater than that of controls. No other significant differences in survival were seen between any groups of mice of either sex (male: 33/50; 30/50; 41/50; female: 36/50; 37/50; 34/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Degenerative and nonneoplastic proliferative lesions of the nasal mucosa were observed at increased incidences in exposed rats. These lesions included diffuse hyperplasia (goblet cell) of the respiratory epithelium with intraepithelial mucous cysts and focal erosion of the olfactory epithelium with cystic dilation (cysts) of the Bowman's glands. Focal respiratory epithelial metaplasia of the olfactory epithelium was seen in some exposed males, and cells with homoge) of the Bowman's glands. Focal respiratory epithelial metaplasia of the olfactory epithelium was seen in some exposed males, and cells with homogeneous eosinophilic cytoplasm in the olfactory epithelium occurred at increased incidences in exposed female rats. Neoplasms of the nasal mucosa were not seen in male or female rats. There were no chemically related increases in neoplasm incidence in exposed male or female rats. Degenerative and inflammatory lesions of the nasal mucosa were observed at increased incidences in exposed mice. These lesions included focal chronic active inflammation and diffuse hyperplasia of the respiratory epithelium. Chronic active inflammation of the bronchioles occurred in many exposed mice but not in controls. Neoplasms of the nasal passage were not observed in mice. There were no chemically related increases in neoplasm incidence in exposed male or female mice. Exposure-related decreased incidences included alveolar/bronchiolar neoplasms (control, 12/50; 10 ppm, 5/49; 25 ppm, 2/49) and malignant lymphomas (7/50; 3/50; 0/50) in males and hepatocellular neoplasms (9/48; 5/16; 2/49) in females. Genetic Toxicology: Vinyl toluene did not induce gene mutations in S. typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation (S9). Vinyl toluene was positive in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y/TK cells in the absence of S9; it was not tested with S9. Vinyl toluene did not induce sister chromatid exchanges or chromosomal aberrations in CHO cells with or without S9. Conclusions: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity for male or female F344/N rats exposed to 100 or 300 ppm vinyl toluene and no evidence of carcinogenic activity for male or female B6C3F1 mice exposed to 10 or 25 ppm. There was evidence of chemical-related toxicity to the nasal passage in both rats and mice. Synonyms: 3-vinyl toluene and 4-vinyl toluene (mixed isomers)
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PMID:NTP Toxicology and Carcinogenesis Studies of Vinyl Toluene (Mixed Isomers) (65%-71% meta-isomer and 32-35% para-isomer) (CAS No. 25013-15-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1269 46

Glycidol is a viscous liquid that is used as a stabilizer in the manufacture of vinyl polymers, as an additive for oil and synthetic hydraulic fluids, and as a diluent in some epoxy resins. NTP Toxicology and Carcinogenesis studies were conducted by administering glycidol (94% pure, containing 1.2% 3-methoxy-1,2-propanediol, 0.4% 3-chloro-1,2-propanediol, 2.8% diglycidyl ether, and 1.1% 2,6-dimethanol-1,4-dioxane) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, Drosophila melanogaster, and the bone marrow of male B6C3F1 mice. Sixteen-Day Studies: Glycidol doses for groups of five rats or five mice of each sex ranged from 37.5 to 600 mg/kg; vehicle controls received distilled water. All rats that received 600 mg/kg died between days 3 and 13. Edema and degeneration of the epididymal stroma, atrophy of the testis, and granulomatous inflammation of the epididymis occurred in males that received 300 mg/kg. All mice that received 600 mg/kg and two males and two females that received 300 mg/kg died by day 4 of the studies. Focal demyelination in the medulla and thalamus of the brain occurred in all female mice that received 300 mg/kg. Thirteen-Week Studies: Doses for groups of 10 rats ranged from 25 to 400 mg/kg, and doses for groups of 10 mice ranged from 19 to 300 mg/kg; vehicle controls received distilled water. All rats that received 400 mg/kg died by week 2; three males and one female that received 200 mg/kg died during weeks 11-12. Final mean body weights of male rats that received 50, 100, or 200 mg/kg were 96%-85% that of vehicle controls; final mean body weights of female rats receiving the same doses were 95%-89% that of vehicle controls. Sperm count and sperm motility were reduced in male rats that received 100 or 200 mg/kg. Necrosis of the cerebellum, demyelineation in the medulla of the brain, tubular degeneration and/or necrosis of the kidney, lymphoid necrosis of the thymus, and testicular atrophy and/or degeneration occurred in rats that received 400 mg/kg. All mice that received 300 mg/kg died by week 2; deaths of mice that received 150 mg/kg occurred during weeks 4-8 for males and weeks 1-5 for females. Mean body weights of chemically exposed mice surviving to the end of the studies were generally 90%-94% those of vehicle controls. Sperm count and sperm motility were reduced in dosed male mice. Compound-related histopathologic lesions included demyelination of the brain in males and females that received 150 or 300 mg/kg, testicular atrophy in males at all doses, and renal tubular cell degeneration in male mice that received 300 mg/kg. Based on reduced survival, reduced weight gain, and histopathologic lesions in the brain and kidney in rats that received 200 or 400 mg/kg and on reduced survival and histopathologic lesions of the brain in mice that received 150 or 300 mg/kg, doses selected for the 2-year studies of glycidol were 37.5 and 75 mg/kg for rats and 25 and 50 mg/kg for mice. Body Weights and Survival in the Two-Year Studies: Mean body weights of chemically exposed male rats generally ranged from 80% to 94% of those of vehicle controls, and mean body weights of chemically exposed female rats were from 90% to 97% those of vehicle controls. Mean body weights of chemically exposed male mice were similar to those of vehicle controls; mean body weights of chemically exposed female mice were 79%-95% of those of vehicle controls. Virtually all male and female rats that received glycidol died or were killed in a moribund condition as a result of the early induction of neoplastic disease (final survival--male: vehicle control, 16/50; low dose, 0/50; high dose, 0/50; female: 28/50; 4/50; 0/50). Survival of vehicle control male rats was lower than that usually observed; however, specific causes of deaths could not be determined. The survival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that resurvival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that received 50 mg/kg was lower than that of vehicle controls after week 101 (final survival--male: 33/50; 25/50; 27/50; female: 29/50; 27/50; 17/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Chemical-related nonneoplastic lesions in both rats and mice included hyperkeratosis and epithelial dysplasia of the forestomach. Fibrosis of the spleen was also present in rats of each sex, and cysts of the preputial gland and kidney were present in male mice. Exposure to glycidol induced dose-related increases in the incidences of neoplasms in numerous tissues in both rats and mice (see summary table on page 5 of the Technical Report). In male rats, mesotheliomas arising in the tunica vaginalis and frequently metastasizing to the peritoneum were considered the major cause of early death. Early deaths in female rats were associated with the presence of mammary gland neoplasms. Genetic Toxicology: Glycidol was mutagenic in a variety of in vitro and in vivo short-term tests. Mutagenic activity was observed in S. typhimurium strains TA97, TA98, TA100, TA1535, and TA1537 exposed to glycidol with and without exogenous metabolic activation. Glycidol was positive in the absence of exogenous metabolic activation in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y/TK cells; it was not tested with activation. In cytogenetic tests with CHO cells, glycidol induced both sister chromatid exchanges and chromosomal aberrations in the presence and absence of exogenous metabolic activation. Glycidol induced sex-linked recessive lethal mutations and reciprocal translocations in the germ cells of male D. melanogaster exposed by feeding. The incidence of micronucleated polychromatic erythrocytes was increased in the bone marrow of male B6C3F1 mice administered glycidol by intraperitoneal injection. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of glycidol for male F344/N rats, based on increased incidences of mesotheliomas of the tunica vaginalis; fibroadenomas of the mammary gland; gliomas of the brain; and neoplasms of the forestomach, intestine, skin, Zymbal gland, and thyroid gland. There was clear evidence of carcinogenic activity for female F344/N rats, based on increased incidences of fibroadenomas and adenocarcinomas of the mammary gland; gliomas of the brain; neoplasms of the oral mucosa, forestomach, clitoral gland, and thyroid gland; and leukemia. There was clear evidence of carcinogenic activity for male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, forestomach, skin, liver, and lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, based on increased incidences of neoplasms of the harderian gland, mammary gland, uterus, subcutaneous tissue, and skin. Other neoplasms that may have been related to the administration of glycidol were fibrosarcomas of the glandular stomach in female rats and carcinomas of the urinary bladder and sarcomas of the epididymis in male mice. Synonym: 2,3-epoxy-1-propanol
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PMID:NTP Toxicology and Carcinogenesis Studies of Glycidol (CAS No. 556-52-5) In F344/N Rats and B6C3F1 Mice (Gavage Studies). 1269 47

4-Vinyl-1-cyclohexene diepoxide is used a chemical intermediate and as a reactive diluent for diepoxides and epoxy resins. Toxicology and carcinogenesis studies were conducted by administering 4-vinyl-1-cyclohexene diepoxide (97% pure) in acetone by dermal application to individually housed F344/N rats and B6C3F1 mice for 14 days, 13 weeks, 15 months, and 2 years. Additional studies included evaluation of immune function after a 5-day dermal exposure and evaluation of the oral toxicity of 4-vinyl-1-cyclohexene diepoxide in 16-day and 13-week corn oil gavage studies. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day Dermal Studies: In the 14-day studies, all rats that received 924 mg/kg or higher (equivalent to 139 mg/rat or higher for males and 112 mg/rat of higher for females) died before the end of the studies. Final mean body weights were lower than those of vehicle controls in males receiving 68 mg/rat and in females receiving 57 mg/rat. Excoriations on the skin at the application site were observed in the groups receiving 57 mg/rat or more. Males receiving 139 mg/rat and females receiving 112 mg/rat had congestion and/or hypoplasia of the bone marrow; most had acute nephrosis. Skin lesions, including epidermal necrosis and ulceration, epidermal hyperplasia, and hyperkeratosis, were found in the 139 and 112 mg/rat group; similar lesions of lesser severity were seen in the two lowest dose groups of each sex. All mice that received 1,787 mg/kg (equivalent to 43/mouse for males and 37 mg/mouse for females) and 3/5 male mice and 5/5 female mice that received 889 mg/kg (equivalent to 19-21 mg/mouse) died before the end of the 14-day dermal studies. Final mean body weights of exposed and vehicle control mice were generally similar. Lesions of the skin at the site of application were seen in 4/5 males and 4/5 females receiving 5 mg/mouse and all mice receiving 10 and 21 (males) or 19 (females) mg/mouse and included epidermal and sebaceous gland hyperplasia, hyperkeratosis, and ulceration. Thirteen-Week Studies: In the 13-week dermal studies, all rats survived to the end of the studies (doses up to 60 mg/rat). The final mean body weights of the 60 mg/rat groups were 9%-14% lower than those of the vehicle controls. Compound-related clinical signs in the 60 mg/rat groups observed during the second half of the studies included redness, scabs, and ulceration at the application site and burrowing behavior after dermal application. Hyperplasia of the sebaceous glands and acanthosis (hyperplasia) and hyperkeratosis of the squamous epithelium were seen at the site of application. In mice, no compound-related deaths occurred after applications of up to 10 mg/mouse in 13-week dermal studies, and final mean body weights of exposed and vehicle control mice were similar. Relative liver and kidney weights increased with dose. Compound-related lesions of the skin included sebaceous gland hyperplasia and acanthosis (hyperplasia) and hyperkeratosis of the stratified squamous epithelium at the site of application; ovarian atrophy was also considered to be compound related. In the 13-week oral studies, the major target organ of toxicity in rats and mice was the forestomach, as indicated by hyperkeratosis and hyperplasia of the stratified squamous epithelium. In female mice, ovarian atrophy was seen in 4-vinyl-1-cyclohexene diepoxide-dosed groups. Two-year studies were conducted by administering 4-vinyl-1-cyclohexene diepoxide in acetone by dermal application, 5 days per week for 105 weeks to groups of 60 rats of each sex at 0, 15, or 30 mg/animal. Groups of 60 mice of each sex were administered 0, 2.5, 5, or 10 mg/animal on the same schedule for 103 weeks. None of the doses selected had produced ulceration of skin in 13-week studies. Ten animals from each group were killed and examined during month 15 for toxicologic evaluation. Immune Function Studies: The immunotoxic effects of 4-vinyl-1-cyclohexene diepoxide were studied in male B6C3F1 mice in male B6C3F1 mice after a 5-day dermal exposure at doses ranging from 2.5 to 10 mg/mouse per day. 4-Vinyl-1-cyclohexene diepoxide was immunosuppressive at 10 mg/mouse and, to a lesser extent, at 5 mg/mouse, as indicated by a decrease in peripheral lymphocytes and the in vitro lymphoproliferative response to phytohemagglutinin and concanavalin A in the high dose group and suppression of the antibody plaque-forming-cell response in the 5 and 10 mg/mouse groups. Fifteen-Month Evaluation: Two of 10 male rats that received 30 mg had a squamous cell carcinoma of the skin at or adjacent to the site of application. Acanthosis was seen in exposed rats (mild severity at 30 mg/rat and minimal severity at 15 mg/rat); hyperkeratosis was observed for rats in the 30 mg/rat groups. Compound-related nonneoplastic skin lesions in mice included acanthosis, hyperkeratosis, and sebaceous gland hyperplasia/hypertrophy. Squamous cell papillomas and carcinomas were seen in mice that received 5 or 10 mg/mouse; none was seen in vehicle control or low dose groups (papillomas--male: mid dose, 1/10; high dose, 2/10; female: 1/10; 1/10; carcinomas-- male: 2/10; 8/10; female: 2/10; 5/10). One vehicle control and all exposed female mice had atrophy of the ovary. Hyperplasia of the ovarian surface epithelium was seen in 8/10 females receiving 5 mg/mouse and 9/9 females receiving 10 mg/mouse. Two of nine females receiving 10 mg/mouse had granulosa cell tumors of the ovary, and 1/9 females receiving 10 mg/mouse had an ovarian papillary cystadenoma. Body Weights and Survival in the Two-Year Studies: In general, the body weights and survival were lower in mid and high dose groups than in vehicle controls. The survival was lower in exposed groups, primarily because of neoplasms (survival at week 105--male rats: vehicle control, 7/50; low dose, 8/50; high dose, 4/50; female rats: 27/50; 23/50; 15/50; male mice: vehicle control, 38/50; low dose, 35/50; mid dose, 4/50; high dose, 0/50; female mice: 30/50; 31/50; 15/50; 0/50). All high dose male mice died by week 83; the 10 surviving high dose female mice were killed during week 85. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Acanthosis and sebaceous gland hypertrophy of skin from the scapula or back were observed at substantially increased incidences in exposed male and female rats. Squamous cell papillomas in male rats and squamous cell carcinomas in male and female rats were observed only in exposed rats (squamous cell carcinomas--male: vehicle control, 0/50; low dose, 33/50; high dose, 36/50; female: 0/50; 16/50; 34/50). The incidences of basal cell adenomas or carcinomas (combined) were increased (male: 0/50; 1/50; 6/50; female: 0/50; 3/50; 4/50). For exposed mice, acanthosis, hyperkeratosis, and necrotizing inflammation of the skin were observed over the scapula or back. Squamous cell carcinomas were found only in exposed mice (male: vehicle control, 0/50; low dose, 14/50; mid dose, 39/50; high dose, 42/50; female: 0/50; 6/50; 37/50; 41/50). Follicular atrophy and tubular hyperplasia of the ovary in female mice were increased (atrophy: 12/50; 43/49; 47/50; tubular hyperplasia: 5/50; 35/49; 38/49; 34/50). Mid and high dose females had benign or malignant granulosa cell tumors (0/50; 0/49; 7/49; 12/50) and benign mixed tumors (0/50; 0/49; 11/49; 6/50). The combined incidences of luteomas, granulosa cell tumors, benign mixed tumors, or malignant granulosa cell tumors in mid and high dose female mice were increased (1/50; 0/49; 17/49; 18/50). The incidences of alveolar/bronchiolar adenomas or carcinomas (combined) in exposed female mice were marginally increased (4/50; 9/50; 11/50; 7/50). Genetic Toxicology: 4-Vinyl-1-cyclohexene diepoxide was mutagenic in S. typhimurium strains TA98, TA100, and TA1535 with and without exogenous metabolic activation; the compound was equivocally mutagenic in strain TA1537 without S9 but gave a positive response in the presence of activation. 4-Vinyl-1-cyclohexene diepoxide induced resistance to trifluorothymidine in mouse L5178Y/TK cells without exogenous metabolic activation; it was not tested with activation. 4-Vinyl-1-cyclohexene diepoxide induced sister chromatid exchanges and chromosomal aberrations in CHO cells in the presence and absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year dermal studies, there was clear evidence of carcinogenic activity of 4-vinyl-1-cyclohexene diepoxide for male and female F344/N rats, as shown by squamous cell and basal cell neoplasms of the skin. There was clear evidence of carcinogenic activity of 4-vinyl-1-cyclohexene diepoxide for male and female B6C3F1 mice, as shown by squamous cell carcinomas of the skin in males and squamous cell carcinomas of the skin and ovarian neoplasms in females; increased incidences of lung neoplasms in females may also have been related to chemical application. Synonyms: 4-vinylcyclohexene diepoxide; 4-vinyl-1,2-cyclohexene diepoxide; 1-vinyl-3-cyclohexene diepoxide; 4-vinylcyclohexene dioxide; 1,2-epoxy-4-(epoxyethyl) cyclohexane; 1-epoxyethyl-3,4-epoxycyclohexane
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PMID:Toxicology and Carcinogenesis Studies of 4-Vinyl-1-cyclohexene Diepoxide (CAS No. 106-87-6) in F344/N Rats and B6C3F1 Mice (Dermal Studies). 1269 79


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