Role of mutagenicity in asbestos fiber-induced carcinogenicity and other diseases.

The cellular and molecular mechanisms of how asbestos fibers induce cancers and other diseases are not well understood. Both serpentine and amphibole asbestos fibers have been shown to induce oxidative stress, inflammatory responses, cellular toxicity and tissue injuries, genetic changes, and epigenetic alterations in target cells in vitro and tissues in vivo. Most of these mechanisms are believe to be shared by both fiber-induced cancers and noncancerous diseases.

Mutant human tumor suppressor p53 modulates the activation of mitogen-activated protein kinase and nuclear factor-kappaB, but not c-Jun N-terminal kinase and activated protein-1.

The roles of the mitogen-activated kinase protein (MAPK) pathway, nuclear factor-kappa B (NF-kappaB), and activator protein-1 (AP-1) in cellular responses to growth factors and mitogen are well established. However, the manner by which these proliferative pathways are affected by the tumor suppressor protein p53 is not fully understood. We report here the results of an investigation of the status of p53 on two human melanoma cell lines with wild-type p53 (SK-Mel-186) or mutant p53 (SK-Mel-110).

Genotoxicity of benzene and its metabolites.

The potential role of genotoxicity in human leukemias associated with benzene (BZ) exposures was investigated by a systematic review of over 1400 genotoxicity test results for BZ and its metabolites. Studies of rodents exposed to radiolabeled BZ found a low level of radiolabel in isolated DNA with no preferential binding in target tissues of neoplasia. Adducts were not identified by 32P-postlabeling (equivalent to a covalent binding index <0.

Mutagenicity of benzo[b]phenanthro[2,3-d]thiophene (BPT) and its metabolites in TA100 and base-specific tester strains (TA7001-TA7006) of Salmonella typhimurium: evidence of multiple pathways for the bioactivation of BPT.

Benzo[b]phenanthro[2,3-d]thiophene (BPT), and a number of its metabolites, including BPT-3,4-diol, BPT sulfoxide, BPT sulfone, and 3-hydroxyBPT were assessed for their mutagenic activity in Salmonella typhimurium strain TA100, and S. typhimurium base-specific strains TA7001, TA7002, TA7003, TA7004, TA7005, and TA7006. Among the compounds tested in strain TA100, BPT, BPT sulfone, and 3-hydroxyBPT did not show any significant mutagenic response in the presence of S9.

N-nitroso compounds and mutagens in Chinese fermented (sour) corn pancakes.

Stomach cancer rates in rural Linqu County, Shandong Province, China, are exceptionally high. A previous case-control study revealed that the risk of stomach cancer was 30% higher among those who consumed sour (fermented) corn pancakes at least daily. A previous study of the sour pancakes reported volatile nitrosamines in most specimens, and almost half reportedly showed mutagenic activity.

Inhibition of benzo(a)pyrene-induced lung tumorigenesis in A/J mice by dietary N-acetylcysteine conjugates of benzyl and phenethyl isothiocyanates during the postinitiation phase is associated with activation of mitogen-activated protein kinases and p53 activity and induction of apoptosis.

Recent studies in cell culture have shown that isothiocyanates (ITCs) induce apoptosis via activation of mitogen-activated protein (MAP) kinases and p53 pathways, suggesting a potential for ITCs or their conjugates to inhibit tumorigenesis during the postinitiation phase. To evaluate whether ITC compounds administered after carcinogen treatment inhibit lung tumorigenesis, we investigated in A/J mice the effects of the N-acetylcysteine (NAC) conjugates of benzyl (BITC-NAC) and phenethyl ITC (PEITC-NAC) in the diet (15 micromol/g) administered after a single dose of 20 micromol benzo(a)pyrene [B(a)P]. The formation of lung adenomas was examined 140 days after B(a)P dosing.

Hepatocellular iron accumulation and increased cell proliferation in polychlorinated biphenyl-exposed Sprague-Dawley rats and the development of hepatocarcinogenesis.

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.

Perineal application of talc and cornstarch powders: evaluation of ovarian cancer risk.

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.

Safety assessment of butylated hydroxyanisole and butylated hydroxytoluene as antioxidant food additives.

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.

Olfaction and symptoms in the multiple chemical sensitivities syndrome.

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.

Formation of 8-oxodeoxyguanosine in brain DNA of rats exposed to acrylonitrile.

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.

Evaluation of possible genotoxic mechanisms for acrylonitrile tumorigenicity.

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.

Absence of DNA adduct formation by phenobarbital, polychlorinated biphenyls, and chlordane in mouse liver using the 32P-postlabeling assay.

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.

Relationship of hydroquinone-associated rat renal tumors with spontaneous chronic progressive nephropathy.

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.

Epigenetic carcinogens: evaluation and risk assessment.

Regulatory policies in the U.S. have been developed based upon a single model of cancer causation, which assumes chemical-induced genetic alterations.

Saccharin mechanistic data and risk assessment: urine composition, enhanced cell proliferation, and tumor promotion.

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.

2,3,7,8-Tetrachlorodibenzo-p-dioxin mechanistic data and risk assessment: gene regulation, cytotoxicity, enhanced cell proliferation, and tumor promotion.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been found to cause several tumor types in rodents, but TCDD has not been proven to cause cancer in humans, although there have been reported associations. TCDD does not bind to DNA, and indirect tests for DNA damage have been mostly negative. Tumorigenicity by TCDD in rodents has been linked to cellular necrosis, enhanced cell proliferation and tumor promotion.

Phenobarbital mechanistic data and risk assessment: enzyme induction, enhanced cell proliferation, and tumor promotion.

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.

Butylated hydroxyanisole mechanistic data and risk assessment: conditional species-specific cytotoxicity, enhanced cell proliferation, and tumor promotion.

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.

d-limonene mechanistic data and risk assessment: absolute species-specific cytotoxicity, enhanced cell proliferation, and tumor promotion.

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.

Benzidine mechanistic data and risk assessment: species- and organ-specific metabolic activation.

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.

2-Acetylaminofluorene mechanistic data and risk assessment: DNA reactivity, enhanced cell proliferation and tumor initiation.

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.

N-nitrosodiethylamine mechanistic data and risk assessment: bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation.

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.