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1.
Toxicol Sci ; 62(1): 36-45, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11399791

ABSTRACT

Polychlorinated biphenyls (PCBs) are liver-tumor promoters in rodents, but the underlying mechanisms have not been fully elucidated. Tissue sections from the PCB bioassay reported by Mayes et al. 1998, Toxicol Sci., 41-66, were evaluated by histopathological techniques that included immunohistochemistry. In females, and to a much lesser extent in males, iron accumulation in hepatocytes was found at the 26th-week sacrifice, which was pronounced in the mid- and high-dose Aroclor-1254 and -1260 groups. At 52 weeks, large accumulations of iron were also present in Kupffer cells of females, and dose-related increases in proliferating cell nuclear antigen (PCNA) hepatocyte labeling indices were found in both males and females. These changes preceded the formation of liver tumors, which were not generally found until 78 weeks. Glutathione S-transferase placental (GSTP) positive foci were present at 52 weeks in high-dose Aroclor-1254 and -1260 female groups, and small foci were found in some Aroclor 1254-exposed female rats at 26 weeks, along with centrilobular hepatocytes expressing GSTP. The results of this study suggest that PCB-induced iron accumulation in hepatocytes is an early event that may be related to tumor formation, especially in female rats. In both males and females, increases in cell proliferation at 52 weeks were statistically significantly correlated with tumor incidences at termination among the various PCB dosage groups. Consequently, iron accumulations producing oxidative damage, and enhanced cell proliferation resulting in tumor promotion may be components in the mode of action for PCB-induced hepatocarcinogenesis in rodents.


Subject(s)
Carcinogens/toxicity , Hepatocytes/drug effects , Iron/metabolism , Liver Neoplasms, Experimental/chemically induced , Liver/drug effects , Adenocarcinoma/chemically induced , Adenocarcinoma/enzymology , Adenocarcinoma/pathology , Animals , Carcinogenicity Tests , Cell Division/drug effects , Dose-Response Relationship, Drug , Female , Glutathione Transferase/metabolism , Hepatocytes/enzymology , Hepatocytes/pathology , Immunohistochemistry , Kupffer Cells/drug effects , Kupffer Cells/metabolism , Liver/enzymology , Liver/pathology , Liver Neoplasms, Experimental/enzymology , Liver Neoplasms, Experimental/pathology , Male , Precancerous Conditions/chemically induced , Precancerous Conditions/enzymology , Precancerous Conditions/pathology , Proliferating Cell Nuclear Antigen/metabolism , Rats , Rats, Sprague-Dawley , Sex Characteristics
3.
Am J Obstet Gynecol ; 182(3): 720-4, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10739536

ABSTRACT

Some epidemiologic studies have reported associations between perineal talc exposure and epithelial ovarian cancer, which raises parallel questions about the consequences of perineal exposure to cornstarch. Cornstarch powder is an alternative to talc powder that by its nature is a completely different substance. In this review of the literature the epidemiologic data on ovarian cancer risk and perineal application of both powders are reviewed, and the chemical natures of the two powders are compared. All available data indicate that whereas associations between talc exposure and ovarian cancer have suggested but not proved a casual relationship, the application of perineal powder containing cornstarch exclusively is not predicted to be a risk factor for ovarian cancer.


Subject(s)
Emollients/administration & dosage , Ovarian Neoplasms/etiology , Starch/administration & dosage , Talc/administration & dosage , Female , Humans , Odds Ratio , Ovarian Neoplasms/epidemiology , Perineum , Peritoneal Cavity , Powders , Risk Factors , Starch/chemistry , Talc/adverse effects , Talc/chemistry
4.
Food Chem Toxicol ; 37(9-10): 1027-38, 1999.
Article in English | MEDLINE | ID: mdl-10541460

ABSTRACT

Butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are widely used antioxidant food additives. They have been extensively studied for potential toxicities. This review details experimental studies of genotoxicity and carcinogenicity which bear on cancer hazard assessment of exposure to humans. We conclude that BHA and BHT pose no cancer hazard and, to the contrary, may be anticarcinogenic at current levels of food additive use.


Subject(s)
Antioxidants/toxicity , Butylated Hydroxyanisole/toxicity , Butylated Hydroxytoluene/toxicity , Food Additives , Administration, Oral , Animals , Anticarcinogenic Agents/metabolism , Butylated Hydroxyanisole/administration & dosage , Butylated Hydroxyanisole/metabolism , Butylated Hydroxytoluene/administration & dosage , Butylated Hydroxytoluene/metabolism , Carcinogenicity Tests , Carcinogens , Consumer Product Safety , Diet , Dose-Response Relationship, Drug , Methylnitronitrosoguanidine , Mutagenicity Tests
5.
Prev Med ; 28(5): 467-80, 1999 May.
Article in English | MEDLINE | ID: mdl-10329337

ABSTRACT

Whereas most idiosyncratic environmental sensitivity complaints do not fit known diagnoses, the multiple chemical sensitivities syndrome (MCS) is an extreme presentation that has defined diagnostic criteria. MCS symptomatics claim that they acquired a sensitized state as the result of a chemical exposure, usually to a solvent or pesticide, but not to a fragrance. Before this exposure, they did not experience symptoms. Following sensitization, symptoms increasing in number and severity with time are attributed by the MCS symptomatic to various exposures that are innocuous to most individuals. Although phenomenological studies have provided no evidence that particular odors elicit MCS symptoms, low levels of fragrances and perfumes are frequently associated with the reporting of MCS symptoms. This evaluation examines proposed mechanisms by which odorants and fragrances might cause either sensitization or elicitation of MCS symptoms, including altered odor sensitivity, primary irritancy or irritancy-induced upper airway reactivity, neurogenic switching of trigeminal irritancy signals, time-dependent sensitization and limbic kindling, CNS toxicity, and various psychiatric conditions. In no case was there persuasive evidence that any olfactory mechanism involving fragrance underlies either induction of a sensitized state or the triggering of MCS symptoms. Fragrances and other odorants could, however, be associated with symptoms as claimed by MCS symptomatics, because they are recognizable stimuli, but fragrance has not been demonstrated to be causal in the usual sense.


Subject(s)
Environmental Exposure/adverse effects , Multiple Chemical Sensitivity/etiology , Odorants , Perfume/adverse effects , Sensation Disorders/complications , Smell , Humans , Multiple Chemical Sensitivity/physiopathology , Risk Factors , Sensory Thresholds , Severity of Illness Index , Time Factors
6.
Regul Toxicol Pharmacol ; 27(3): 217-39, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9693074

ABSTRACT

Acrylonitrile (ACN) exposure is associated with tumors in rat brain, Zymbal gland, and mammary gland. Adducts affecting base pairing were formed in isolated DNA exposed in vitro to the ACN metabolite cyanoethylene oxide (CNEO). DNA from liver, which is not a cancer target organ in ACN-exposed rats, contained low levels of 7-(2-oxoethyl)guanine, and adduct believed not to interfere with base pairing. No adducts have been detected in brain DNA from ACN-exposed rats, suggesting that brain tumors may have arisen by mechanisms other than ACN-DNA reactivity. Genotoxicity assays of ACN have indicated no particular carcinogenic mechanism. Positive reverse mutagenesis in Salmonella typhimurium HisG46 base substitution tester strains by ACN is attributable to CNEO. Other in vitro genotoxicity test assays of ACN have yielded mixed results, without consistent effect of metabolic activation. Some positive genotoxicity data for ACN appear to result from artifacts or from non-DNA-reactive mechanisms. In vivo micronucleus, chromosome aberration, and autoradiographic unscheduled DNA synthesis assays were negative for ACN. The comparative genotoxicity of vinyl chloride and ACN indicates that despite other similarities, they cause rodent tumors by different mechanisms. Also, they absence of ACN-DNA adduct formation in the rat brain suggests the operation of epigenetic mechanisms.


Subject(s)
Acrylonitrile/toxicity , Brain Neoplasms/chemically induced , Chromosome Aberrations , DNA Adducts , Acrylonitrile/pharmacology , Animals , Autoradiography , Brain Neoplasms/physiopathology , DNA/biosynthesis , Mutagenicity Tests , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Salmonella typhimurium/drug effects , Salmonella typhimurium/genetics
7.
Arch Toxicol ; 72(7): 429-38, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9708882

ABSTRACT

Acrylonitrile (ACN) produces tumors in rats, particularly gliomas of the brain, but tests for genotoxicity have yielded mixed results and no ACN-DNA adducts have been identified in the brain. To examine the possibility that ACN-related brain tumors were not a consequence of binding of ACN to brain DNA, experiments were conducted to investigate possible epigenetic mechanisms. Male Sprague-Dawley rats were exposed to 0, 3, 30, and 300 ppm ACN in drinking water for 21 days, a range that includes doses associated with brain tumorigenesis. In the 30 and 300 ppm ACN groups, 8-oxodeoxyguanosine (8-oxodG) levels were two fold greater than in the controls. Measures of glutathione levels, glutathione peroxidase and catalase were not significantly changed, but cyst(e)ine was somewhat increased. No changes were found in brain cytochrome oxidase activity, which indicates a lack of metabolic hypoxia. Also, no effects on thiobarbituric acid reactive substances were found, indicating a lack of lipid peroxidation. In an additional experiment, male Sprague-Dawley rats were exposed to 0 or 100 ppm ACN in drinking water for 94 days; interim sacrifices were conducted at 3, 10, and 31 days. Levels of brain nuclear DNA 8-oxodG were significantly increased in ACN-exposed rats compared with controls. Another group of animals were given weekly i.v. injections of 5 mg/kg methylnitrosurea and no increases in 8-oxodG were found. These studies suggest the possibility that ACN-induced tumors may be produced by a mode of action involving 8-oxodG. The formation of 8-oxodG is not understood, but does not appear to involve lipid peroxidation or disruption of antioxidant defenses.


Subject(s)
Acrylonitrile/pharmacology , Brain Chemistry/drug effects , DNA/drug effects , Deoxyguanosine/analogs & derivatives , 8-Hydroxy-2'-Deoxyguanosine , Animals , Chromatography, High Pressure Liquid , Cysteine/analysis , DNA/metabolism , Deoxyguanosine/analysis , Dose-Response Relationship, Drug , Glutathione/analysis , Liver/chemistry , Liver/drug effects , Male , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley
8.
Toxicol Appl Pharmacol ; 148(1): 14-23, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9465259

ABSTRACT

Phenobarbital (PB), polychlorinated biphenyls (PCBs), and chlordane (CLD) increase liver tumor incidences in rodents, and all are tumor promoters. Most indirect tests for DNA reactivity, including mutagenicity and chromosomal damage, have been negative with these agents. Consequently, the modes of action for tumorigenesis by these compounds are not believed to involve direct DNA reactivity; however, only limited information from direct tests is available for the lack of DNA adduct formation. PB, PCBs, and CLD were tested for DNA adduct formation in the liver of male and female B6C3F1 mice after either single or 2-week dietary exposures. Single gavage dose levels were as follows: PB, 200 mg/kg; PCBs, 50 mg/kg; and CLD, 50 mg/kg. Dietary dose levels were as follows: PB, 1000 ppm; PCBs, 200 ppm and CLD, 200 ppm. Animals were killed 24 h following the end of test-substance administration. DNA was extracted from the liver, and DNA adduct concentrations were enriched using either 1-butanol extraction of adducted nucleotides or nuclease P1 digestion of unadducted nucleotides. Using this protocol, none of the three test compounds produced DNA adducts detected by 32P-postlabeling. Similar negative results were obtained for DNA from the livers of both male and female mice receiving either single or 2-week exposures. The two positive controls, benzidine for the 1-butanol extraction procedure and 2-acetylaminofluorene for the nuclease P1 procedure, showed the expected patterns of DNA adducts. These results support the conclusion that the carcinogenicity of PB, PCBs, and CLD in experimental animals is not the result of direct DNA reactivity, but involves epigenetic mechanisms.


Subject(s)
Carcinogens/toxicity , Chlordan/toxicity , DNA Adducts/metabolism , Insecticides/toxicity , Liver/drug effects , Phenobarbital/toxicity , Polychlorinated Biphenyls/toxicity , 2-Acetylaminofluorene/chemistry , 2-Acetylaminofluorene/toxicity , Animals , Benzidines/chemistry , Benzidines/toxicity , Carcinogens/chemistry , Chlordan/chemistry , Chromatography, Thin Layer , DNA/metabolism , Female , Insecticides/chemistry , Liver/metabolism , Liver/pathology , Male , Mice , Organ Size/drug effects , Phenobarbital/chemistry , Phosphorus Radioisotopes , Polychlorinated Biphenyls/chemistry
10.
Toxicol Pathol ; 25(2): 132-43, 1997.
Article in English | MEDLINE | ID: mdl-9125771

ABSTRACT

Hydroquinone exposure has been reported by the National Toxicology Program (NTP) to produce renal tubule adenomas and to exacerbate spontaneous chronic progressive nephropathy (CPN) in male F344 rats. A mechanism for hydroquinone-related tumorigenesis has not been established, but CPN is known to involve, and hydroquinone produces, enhanced renal tubule cell proliferation. Through an independent review of the renal histopathology from the NTP study, the grade of CPN and the presence of atypical tubule hyperplasia and adenomas was evaluated. Hydroquinone exposure in males at 50 mg/kg, produced a statistically significant increase in the grade of CPN. At 0, 25, and 50 mg/kg, 0/44, 4/49, and 15/51 male rats had either atypical tubule hyperplasias or adenomas; all were within areas of severe or end-stage CPN and were statistically significantly associated with CPN grade. Additionally, there was a dose-related increase in profiles believed to represent new tubule proliferation within areas of advanced CPN, as well as an apparent expansion of these into unusual complex tubule profiles in end-stage kidneys of the high-dose male group. In summary, this histopathological review suggest a mechanism for hydroquinone-related adenoma formation that includes enhancement of the severity of CPN coupled with stimulation of tubule proliferation.


Subject(s)
Carcinogens/toxicity , Hydroquinones/toxicity , Kidney Failure, Chronic/chemically induced , Kidney Neoplasms/chemically induced , Adenoma/chemically induced , Adenoma/mortality , Adenoma/pathology , Animals , Disease Progression , Female , Hyperplasia , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/pathology , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Kidney Tubules/pathology , Life Tables , Male , Rats , Rats, Inbred F344 , Survival Analysis
11.
Exp Toxicol Pathol ; 48(2-3): 189-95, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8672874

ABSTRACT

Regulatory policies in the U.S. have been developed based upon a single model of cancer causation, which assumes chemical-induced genetic alterations. Such a model predicts some degree of cancer risk even at extremely low exposure levels. Many chemicals that produce tumors in experimental animals have been shown to act by epigenetic mechanisms that do not involve an attack by the chemical on DNA leading to subsequent genetic alteration. Such indirect mechanisms require prolonged exposures to high levels of chemicals for the production of tumors. For chemicals that are carcinogenic in this manner, the cancer mechanism would not be operative at exposures below a threshold at which the relevant cellular effect does not occur. Also, in contrast to DNA-reactive mechanisms, epigenetic effects may be unique to the rodent species used for testing. Certain chemical tumorigens have been well studied and provide examples for the use of mechanistic information in risk assessment. Butylated hydroxyanisole and saccharin are nongenotoxic food additives for which no risk to humans is predicted based upon low exposure levels and the likelihood that humans are either insensitive or much less sensitive to the tumorigenic effects found in rodent test species. For another non-genotoxic food additive d-limonene, the mechanism that underlies kidney tumor development in male rats is not expected to be operative in humans at all. The pharmaceutical phenobarbital represents a large group of non-genotoxic liver microsome enzyme inducers, which produce liver cancer in mice at levels that are near to therapeutic doses in humans. Epidemiology studies have not shown phenobarbital-related tumors in humans, indicating that humans may be less sensitive to the effects of phenobarbital. The mechanistic considerations involved in the risk assessment of these agents demonstrate that humans are not at risk from current exposure levels of many epigenetic carcinogens.


Subject(s)
Carcinogens/toxicity , DNA/drug effects , Neoplasms, Experimental/chemically induced , Animals , Butylated Hydroxyanisole/toxicity , Cyclohexenes , Humans , Limonene , Neoplasms, Experimental/genetics , Phenobarbital/toxicity , Risk Assessment , Saccharin/toxicity , Terpenes/toxicity
12.
Pharmacol Ther ; 71(1-2): 7-28, 1996.
Article in English | MEDLINE | ID: mdl-8910947

ABSTRACT

Vinyl chloride produced several tumor types among species. Angiosarcoma of the liver is found in all tested species, including humans with occupational exposures. Vinyl chloride is biotransformed by CYP2E1 to DNA-reactive chloroethylene oxide producing cyclic etheno adducts, which are mutagenic. The dose-response for angiosarcoma of the liver formation in rodents is supralinear, which is consistent with saturation of metabolic activation, and the tumor rate in humans at occupational exposure levels is similar to that for equivalent exposures in rodents.


Subject(s)
Carcinogens/toxicity , DNA/drug effects , Neoplasms/chemically induced , Vinyl Chloride/toxicity , Animals , Carcinogenicity Tests , Cricetinae , DNA/metabolism , Humans , Mice , Rats , Risk Assessment , Rodentia , Species Specificity
13.
Pharmacol Ther ; 71(1-2): 29-55, 1996.
Article in English | MEDLINE | ID: mdl-8910948

ABSTRACT

Exposures of rodents to airborne formaldehyde (FA) produce dose-related toxicity, enhanced cell proliferation and squamous cell carcinomas in the nasal passages. The mechanism of FA-induced tumor formation involves DNA-protein crosslink formation and enhanced cell proliferation secondarily to cytotoxicity. The mucociliary apparatus and glutathione protect against low-dose FA-induced effects. Consequently, the mechanistic information is consistent with a very sublinear dose-response curve for tumor formation. The sublinear dose-response of nasal DNA-protein crosslinks levels in rodents and monkeys has been used in the risk assessment of FA.


Subject(s)
Carcinogens/toxicity , DNA Adducts/biosynthesis , Formaldehyde/toxicity , Neoplasms/chemically induced , Animals , Carcinogenicity Tests , Carcinogens/metabolism , Carcinogens/pharmacokinetics , Cricetinae , DNA/drug effects , DNA/metabolism , Formaldehyde/metabolism , Formaldehyde/pharmacokinetics , Humans , Macaca fascicularis , Mice , Rats , Risk Assessment
14.
Pharmacol Ther ; 71(1-2): 57-81, 1996.
Article in English | MEDLINE | ID: mdl-8910949

ABSTRACT

N-Nitrosodiethylamine (NDEA) is DNA reactive after bioactivation and produces tumors in every animal species tested. Bioactivation is effected by several P450 isozymes including CYP2E1, which is ethanol inducible. Tumor formation in rat liver was proportional to O4-ethyldeoxythymidine formation in DNA, which was generally proportional to NDEA dose. At low doses in the 0.033-1.1 ppm range, the dose-response for esophageal tumor formation was sublinear, possibly due to DNA repair. Although no epidemiological studies have specifically evaluated NDEA, sufficient exposure levels would be expected to cause cancer in humans.


Subject(s)
Carcinogens/pharmacokinetics , Carcinogens/toxicity , DNA Adducts/biosynthesis , Diethylnitrosamine/pharmacokinetics , Diethylnitrosamine/toxicity , Neoplasms/chemically induced , Animals , Biotransformation , DNA/drug effects , DNA/metabolism , Humans , Mutagenicity Tests , Neoplasms/genetics , Rats , Risk Assessment
15.
Pharmacol Ther ; 71(1-2): 83-105, 1996.
Article in English | MEDLINE | ID: mdl-8910950

ABSTRACT

The aromatic amine 2-acetylaminofluorene (AAF) produced neoplasms in diverse target organs of many animal species. AAF was DNA-reactive after N-hydroxylation by CYP1A2 in the liver and nitrenium ion formation at the target site. In mouse bladder, AAF-DNA adducts were proportional to dose. An epigenetic component for tumor formation was also present since tumor incidence and hyperplasia showed a threshold dose and decreased following discontinuation of AAF exposure. In contrast, both adduct and tumor formation in the liver were proportional to dose, and discontinuation of AAF did not reduce tumor incidence.


Subject(s)
2-Acetylaminofluorene/toxicity , Carcinogens/toxicity , DNA/drug effects , Neoplasms/chemically induced , 2-Acetylaminofluorene/metabolism , 2-Acetylaminofluorene/pharmacokinetics , Animals , Carcinogenicity Tests , Carcinogens/metabolism , Carcinogens/pharmacokinetics , Cell Division/drug effects , DNA/metabolism , Humans , Mice , Neoplasms/metabolism , Neoplasms/pathology , Risk Assessment
16.
Pharmacol Ther ; 71(1-2): 107-26, 1996.
Article in English | MEDLINE | ID: mdl-8910951

ABSTRACT

The aromatic amine benzidine (BZ) has produced various tumors, including liver tumors, in mice, rats and hamsters. BZ forms DNA adducts in rodent liver, and it is positive in most genotoxicity tests. Only bladder tumors are produced in dogs and in humans who have been occupationally exposed, possibly related to the slow rate of liver detoxification by acetylation, allowing activation of BZ or its metabolites in urine. Despite these differences, risk assessment for humans, based on liver tumors in mice, was approximately predictive of the incidence of bladder tumors observed in industrially exposed humans.


Subject(s)
Benzidines/pharmacokinetics , Benzidines/toxicity , Carcinogens/pharmacokinetics , Carcinogens/toxicity , Neoplasms/chemically induced , Organ Specificity , Animals , Biotransformation , Carcinogenicity Tests , Cricetinae , Dogs , Humans , Mice , Rats , Risk Assessment , Species Specificity
17.
Pharmacol Ther ; 71(1-2): 127-36, 1996.
Article in English | MEDLINE | ID: mdl-8910952

ABSTRACT

d-Limonene produces tumors only in the kidneys of male rats in association with hyaline-droplet nephropathy, which is due to the accumulation of the rat-specific, low molecular weight protein alpha(2u)-globulin in the P2 segment cells of renal proximal tubules. Human urine contains no alpha(2u)-globulin and, compared with the male rat, much less protein and almost no low molecular weight protein. Genotoxicity tests for d-limonene are negative, and the mechanism of tumorigenesis involves tumor promotion and enhanced cell proliferation. There is no risk of cancer for humans from d-limonene, since the binding of d-limonene to alpha(2u)-globulin would not occur.


Subject(s)
Carcinogens/toxicity , Kidney Neoplasms/chemically induced , Terpenes/toxicity , Animals , Carcinogenicity Tests , Cell Division/drug effects , Cyclohexenes , Female , Humans , Kidney Neoplasms/pathology , Limonene , Male , Rats , Risk Assessment , Species Specificity
18.
Pharmacol Ther ; 71(1-2): 137-51, 1996.
Article in English | MEDLINE | ID: mdl-8910953

ABSTRACT

Butylated hydroxyanisole (BHA), at high doses, has been found to induce forestomach squamous cell carcinomas in rodents, but not glandular cell or other types of neoplasms. BHA is not DNA-reactive, and the epigenetic mechanism of tumor formation involves cytotoxicity and enhanced cell proliferation, which are mostly reversible. Humans lack a forestomach and, therefore, are predicted to be much less sensitive than rodents to the effects of BHA. Also, the exposures to humans are well below doses producing the epigenetic effects in rodents. It has been concluded that BHA is an agent whose rodent carcinogenicity is conditionally species-specific and not relevant to humans.


Subject(s)
Butylated Hydroxyanisole/toxicity , Carcinogens/toxicity , Neoplasms/chemically induced , Animals , Carcinogenicity Tests , Cell Division/drug effects , Humans , Rats , Risk Assessment , Species Specificity
19.
Pharmacol Ther ; 71(1-2): 153-91, 1996.
Article in English | MEDLINE | ID: mdl-8910954

ABSTRACT

Chronic exposure to high doses of phenobarbital (PB) causes hepatocellular adenomas in both mice and rats and hepatocellular carcinomas in some strains of mice. Long-term PB therapy has not been found to cause human tumors. PB is not DNA reactive, and most genotoxicity tests have yielded negative results. PB has been extensively studied as an epigenetic, rodent liver tumor promoter. At exposures causing rodent liver tumors, PB has measurable effects on hepatocytes: PB inhibits cell-to-cell communication; PB induces enzymes, including P450 cytochromes; PB stimulates proliferation and inhibits apoptosis of hepatocytes in neoplastic foci. Threshold exposures for some of these endpoints coincide with the threshold exposure for tumorigenesis.


Subject(s)
Carcinogens/toxicity , Neoplasms/chemically induced , Phenobarbital/toxicity , Animals , Biotransformation , Carcinogenicity Tests , Carcinogens/pharmacokinetics , Cell Division/drug effects , Enzyme Induction/drug effects , Humans , Liver Neoplasms, Experimental/chemically induced , Liver Neoplasms, Experimental/enzymology , Liver Neoplasms, Experimental/pathology , Mice , Neoplasms/enzymology , Neoplasms/pathology , Phenobarbital/pharmacokinetics , Rats , Risk Assessment
20.
Pharmacol Ther ; 71(1-2): 225-52, 1996.
Article in English | MEDLINE | ID: mdl-8910956

ABSTRACT

Sodium saccharin (NaSac) produces bladder tumors consistently in male rats only after lifetime exposure that begins at birth. NaSac is not metabolized and is negative in most genotoxicity tests. NaSac-induced cell damage and proliferation have been proposed as important factors in tumor promotion, and dose-response information demonstrating a threshold for these parameters is available. One theory proposes that high levels of NaSac, combined with protein in a high Na+, high pH environment found only in the male rat, form toxic microscopic crystals; therefore, NaSac-induced tumors may not be relevant to human carcinogenesis.


Subject(s)
Carcinogens/metabolism , Carcinogens/toxicity , Saccharin/metabolism , Saccharin/toxicity , Sweetening Agents/metabolism , Sweetening Agents/toxicity , Urinary Bladder Neoplasms/chemically induced , Urine/chemistry , Animals , Carcinogenicity Tests , Cell Division/drug effects , Female , Humans , Male , Rats , Risk Assessment , Urinary Bladder Neoplasms/pathology
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