Induction by mycotoxins of somatic mosaicism in Drosophila and DNA repair in mammalian liver cell cultures

The genotoxic activity of four mycotoxins has been studied. High level of somatic mutagenesis in imaginal discs of Drosophila melanogaster larvae and DNA repair synthesis in human embryo and adult rat liver cell cultures were inducible only by highly carcinogenic aflatoxin B1. Patulin, a weak direct-action carcinogenic substance, slightly elevated the mutagenesis in somatic cells of Drosophila but did not induce DNA repair synthesis in liver cell cultures. Citrinin that did not exhibit any carcinogenic properties when used alone and stachybotrotoxin with non-reported carcinogenic activity appeared inactive in the test-systems applied. The possibilities of rapid recognition of carcinogenic mycotoxins by detecting their genotoxic properties are discussed.     

Mutagenicities of quinoline and its derivatives.

Quinoline, recently reported to be carcinogenic in rats [12], was mutagenic to Salmonella typhimurium tester strains TA100 and TA98 in the presence of the metabolic activation system S-9 mix. 2-Chloroquinoline, a non-carcinogen [12], was non-mutagenic with or without S-9 mix. 8-Hydroxyquinoline, which is t known to be carcinogenic, was mutagenic with S-9 mix to both bacterial strains. The mutagenicities of 17 other quinoline derivatives that are not known to be carcinogenic were tested, and 12 of these compounds were mutagenic.     

Mutagenic and carcinogenic actions of some polycyclic aromatic hydrocarbons]

The carcinogenic and mutagenic actions of benz(a)pyrene (BP) and its derivatives 6-methyl-, 6-formyl-, 6-chloro-, 6-hydroxy-, 6-acetoxy-, 6-methoxy- and 4(5)-methoxy-BP were studied in mice and bacteria Salmonella typhimurium TA-98 and TA-100, respectively. The potent carcinogenic agents BP, 6-methyl-, 6-formyl-BP proved also mutagenic in bacteria of both strains. Weak carcinogenic compounds (6-chloro-, 6-methoxy-, 4(5)-methoxy-BP) and noncarcinogenic ones (6-acetoxy-, 6-hydroxy-BP) either turned out nonmutagenic or mutagenic in one of two bacterial strains tested. The differences in carcinogenic and mutagenic actions of the substances under study are not relative to the rate of their oxidation in the enzymatic system.     

Human Papillomavirus Prevalence in a Population of Women Living in Port-au-Prince and Leogane,Haiti

Background

There have been no published studies of carcinogenic human papillomavirus (HPV)--the necessary cause of cervical cancer--in Haiti, a nation that has one of the greatest burdens of cervical cancer globally.

Objective

Characterize prevalence of carcinogenic HPV and the prevalence of individual carcinogenic HPV genotypes in women with cervical precancer or cancer, cervical intraepithelial neoplasia grade 2 (CIN2) or more severe (CIN2+).

Methods

Women (n=9,769; aged 25-60 years) were screened for carcinogenic HPV by Hybrid Capture 2 (HC2; Qiagen, Gaithersburg, MD). Carcinogenic HPV positives underwent colposcopy and visible lesions were biopsied. A subset of carcinogenic HPV positives was tested for individual HPV genotypes using a GP5+/6+ assay.

Results

The prevalence of carcinogenic HPV was 19.0% (95% confidence interval: 18.4%-19.9%) and decreased with increasing age (p_trend < 0.001). Women with 3 or more sexual partners and who started sex before the age of 18 years had twice the age-adjusted prevalence of carcinogenic HPV of women with one partner and who started sex after the age of 21 (24.3% vs. 12.9%, respectively). HPV16 and HPV35 were the most common HPV genotypes detected in CIN2+ and more common in women with CIN2+ than those without CIN2+. HPV16 and/or HPV18 were detected in 21.0% of CIN2 (n = 42), 46.2% of CIN3 (n = 52), and 80% of cancers (n = 5).

Conclusions

The prevalence of carcinogenic HPV in Haiti was much greater than the prevalence in other Latin American countries. High carcinogenic HPV prevalence and a lack of cervical cancer screening may explain the high burden of cervical cancer in Haiti.     

The carcinogenic potential of extractable organic matter from urban airborne particles in Shanghai,China

The genotoxicity of extractable organic matter (EOM) from airborne particles in Shanghai has been determined using short-term bioassays. EOM samples were investigated using cell morphological transformation and two-stage model of mouse skin tumorigenicity assays to detect their carcinogenic activity. DNA adducts were detected using the 32P-postlabeling technique. The results showed that EOMs induced cell morphological transformation and played a role in tumor-initiating carcinogenesis. The EOMs of airborne particles from different districts of Shanghai had similar carcinogenic activity except the result of sample E (at downtown of Shanghai) was relatively high. The polycyclic aromatic hydrocarbon (PAH) fraction makes a major contribution to carcinogenic activity according to the results of cell morphological transformation assay. DNA adducts were also detected in skin, liver, and kidney of mouse after treatment with EOMs. It is suggested that the urban airborne particles in Shanghai, which show carcinogenic potential and genotoxic activity in our bioassays, may be responsible for the increased incidence of lung cancer in Shanghai in last few years.     

Health risk assessment of some heavy metals in urban community garden soils of Baghdad City,Iraq

The objective of this study is the evaluation of health risk of heavy metals in soils of urban community gardens of Baghdad City in Iraq. The soil samples were collected from 14 community gardens and analyzed for Cd, Cr, Cu, Ni, Pb and Zn. The non-carcinogenic hazard index (HI) and carcinogenic risk index (RI) were utilized to evaluate human health risk of heavy metals. The health hazard evaluation showed that there is no non-carcinogenic hazard in light of the fact that the HI values were beneath the threshold value (HI < 1). The HI for children and adults has a descending order of Cd < Cr < Cu < Ni < Pb < Zn. The carcinogenic RI values for Cd, Cr and Ni were over the unacceptable threshold value (RI < 1 × 10^?4), demonstrating that there is a serious carcinogenic risk for children and adults in the study area. The carcinogenic RI for children and adults has a descending order of Cr < Cd < Ni. These findings give environment administrators and leaders data on whether therapeutic activities are required to decrease exposure.     

Measurement of DNA-excision repair in suspensions of freshly isolated rat hepatocytes after exposure to some carcinogenic compounds: its possible use in carcinogenicity screening.

When suspensions of freshly isolated rat hepatocytes were exposed to a number of carcinogenic compounds, it was possible to measure an increased UDS by a rapid procedure via liquid-scintillation counting. For a number of carcinogenic compounds and some of their non-carcinogenic structural analogues a good correlation between the carcinogenic property and the ability to induce UDS was demonstrable. Out of 12 carcinogenic compounds, belonging to several different chemical classes, 10 gave rise to an increased UDS, whereas only 2 compounds, the polycyclic aromatic hydrocarbons benzo[alpha]pyrene and benz[alpha]anthracene, did not. All 4 noncarcinogenic compounds tested were negative. Possibly this method can be of value as a routine screening test, in combination with other short-term test systems, thus improving the predictive value of screening in vitro with respect to carcinogenicity.     

Quantum chemical studies of polycyclic aromatic hydrocarbons and their metabolites: correlations to carcinogenicity.

In the context of the bay region hypothesis for polycyclic aromatic hydrocarbon (PAH) carcinogenesis, molecular properties were calculated for seventeen polycyclic aromatic hydrocarbons related to (1) intrinsic substrate reactivities towards activating and detoxifying metabolism and (2) the stabilities of the putative carbocation ultimate carcinogens. All-valence electron methods were used, avoiding the inherent difficulties found in the pi-electron methods. The calculated substrate reactivities were found to predict major metabolites successfully, supporting the validity of their use in attempted correlations with observed carcinogenic potencies. Positive correlations were found between observed carcinogenic potencies and (1) the reactivities of the parent polycyclic aromatic hydrocarbons towards the initial distal bay region epoxidation and (2) the stabilities of the diol epoxide carbocations. The reactivities of the distal bay region diol epoxides, were high for both carcinogenic and non-carcinogenic compounds, implying that the second epoxidation does not determine relative carcinogenic activity. Support for a possible alternative hypothesis, that polycyclic aromatic hydrocarbons are activated by one electron oxidation, was also found.     

Bacterial mutagenicity and carcinogenic potential of some azapyrene derivatives

The mutagenic and carcinogenic activities of 5 azapyrenes, which are suspected of being environmental pollutants, were assessed using the Salmonella assay and the anchorage-independent survival assay. The compounds tested were: 1-azapyrene, 2-azapyrene, 4-azapyrene, 1-aza-2-hydroxypyrene, and 2-aza-1-hydroxypyrene. The compounds were mutagenic and some were also carcinogenic.     

Evaluation of the dermal carcinogenic potential of liquids produced from the Cold Lake heavy oil deposits of northeast Alberta

This study assessed the dermal carcinogenic potential of raw bitumen derived from the Cold Lake Oil Sands deposit (located in Northeast Alberta, Canada) and two liquids which were under evaluation as part of a process to refine the crude bitumen at the Cold Lake site. The crude bitumen was dermally carcinogenic, inducing tumors in 26% of the treated animals with a median latency of 106 weeks. This response was significantly greater than the tumor yield previously reported for a raw bitumen derived from Athabasca tar sands by the Syncrude process, but was not substantially different from the carcinogenic potential of two crude petroleum oils. The GO-FINING product, a high boiling (259-519 degrees C), catalytically cracked gas oil was a relatively potent dermal carcinogen, inducing tumors in 86% of the treated animals with a median latency of 46 weeks. This result is consistent with the fact that the GO-FINING product contained appreciable levels of high boiling aromatic compounds. The HYCRACKING product, a high boiling (102-498 degrees C), severely hydroprocessed liquid was noncarcinogenic. This result was also consistent with the compositional data; the high boiling components were predominantly saturated species. Thus the carcinogenic properties of the liquid products prepared by these two processes were as predicted from the compositional information.     

Decreased electrophilicity of chemicals carcinogenic only at the maximum tolerated dose.

While there was no significant difference between the actual or predicted mutagenicity and clastogenicity of a group of chemicals carcinogenic only at the maximum tolerated dose (MTD) and a group of chemicals carcinogenic below the MTD, as a group, the chemicals carcinogenic below the MTD exhibited a significantly decreased LUMO (Lowest Unoccupied Molecular Orbital) energy, indicative of increased electrophilicity (i.e. DNA reactivity). These findings suggest that chemicals carcinogenic only at the MTD either require increased doses of "weak" electrophiles to be carcinogenic or that they may act by a "non-genotoxic" mechanism.     

Effect of the antioxidant fenozan on the physicochemical properties of the kidney cell membranes of rats during nitrosodimethylamine-induced carcinogenesis

The lipid peroxidation level, microviscosity and arrangement of lipid bilayer in mitochondria and microsomal membranes of kidney cell in rats were increased a month after the treatment with carcinogenic nitrosodimethylamine. The additional injection of antioxidant fenozan-1K prevented the activation of lipid peroxidation in early stage of carcinogenesis and decreased the microviscosity and arrangement of membrane lipids both in early and progressive stages of carcinogenesis, and inhibited the carcinogenic process in the kidneys.     

DNA adducts as a biomarker of polycyclic aromatic hydrocarbon exposure in aquatic organisms: relationship to carcinogenicity

The use of DNA adduct measurement as a biomarker of exposure to polycyclic aromatic hydrocarbons (PAHs) is now well established in ecotoxicology. In particular, DNA adduct levels in aquatic organisms has been found to produce a better correlation with PAH exposure than PAH concentrations in organisms. DNA adducts levels are most commonly determined using the ³²P-postlabelling assay which measures total aromatic adducts. The relationship between relative DNA adduct formation and carcinogenicity has been investigated for a number of carcinogenic and non-carcinogenic PAHs using an in vitro system. Our results demonstrate that relatively high levels of DNA adducts can be produced by some non-carcinogenic PAHs, while other non-carcinogenic compounds do not produce detectable adducts. In addition, it has been shown that all carcinogenic PAHs investigated produce DNAadducts and that a relationship exists between relative adduct formation and carcinogenic potency. An investigation of adduct levels in fish liver and crustacean hepatopancreas in Oxley Ck, Brisbane has shown that higher than expected DNA adduct levels were correlated with the presence of carcinogenic and non-carcinogenic PAHs with high relative adduct forming potential.     

Statistical Comparison of Carcinogenic Effects and Dose–Response Relationships in Rats and Mice for 2,4-Toluene Diamine to those Ascribed to Toluene Diisocyanate

The U.S. National Toxicology Program (NTP) conducted 2-year bioassays of commercial grade toluene diisocyanate (TDI) (80% 2,4-TDI and 20% 2,6-TDI) and 2,4-toluene diamine (TDA) and concluded that both were carcinogenic in rodents. In the TDI study, there was an unproven but likely formation of TDA either because of flawed test-substance handling and storage conditions and/or the atypical exposure conditions employed. Although the carcinogenic responses in both studies were qualitatively similar, several statistical analyses were performed to substantiate this possibility more rigorously. Seven different statistical approaches combine to yield a robust and consistent conclusion that, if only a small fraction (approximately 5%) of the dose of TDI were hydrolyzed to TDA in the TDI study, then that would be sufficient to explain the observed carcinogenic responses in the TDI study.     

Carcinogenesis: Mechanism and Criteria of Carcinogenic Activity

The pattern of carcinogenic action is described for locally acting as well as for remotely acting carcinogens. Whether applied locally, injected subcutaneously or given by mouth, aromatic polycyclic hydrocarbons are potentially carcinogenic for all tissues, whereas other known locally acting carcinogens have no such wide action. Solubility and diffusibility of the compound should be considered, but the question of localization of induced tumours is a problem of dose-response relationship.The method for evaluating carcinogenic action of a compound is based on the readiness with which the tumour is induced, and not in terms of the intensity of the response. The average latent period and the percentage of tumour yield are the two measures used. Since, at the present time, no chemical tests are available to determine whether a substance is carcinogenic, one must resort to biological methods of testing carcinogenic activity.The value of a long-term test for carcinogenesis, under a given set of rigidly controlled conditions, is emphasized, since there are so many variables which singly or in combination may alter the final effect of a given substance.     

Coenzymatic Activity of Epinephrine for Vitamin B2-Aldehyde Forming Enzyme and Its Physiological Significance

The effects of artificial food dyes on the mutagenicity of carcinogenic mutagens were examined using the Salmonella/microsome system. Indigocarmine (IC), an indigoid dye widely used for coloring foods and for clinical tests, enhanced the mutagenic activity of Trp-P-1, a carcinogenic pyrolysate of tryptophan, depending on the dose of IC. His⁺ revertants of TA 98 induced by Trp-P-1 were two to four times greater in the presence of 10 to 50 μg/plate of IC than those in the absence of IC.

IC also enhanced the mutagenicity of Trp-P-2, another carcinogenic pyrolysate of tryptophan, while the activities of other mutagens such as MNNG, 4-NQO, AF-2, BP, Glu-P-1 were not affected.     

Mutagenicity of cyclic nitrosamines in Salmonella typhimurium: effect of ring size.

Mutagenicity of cyclic nitrosamines with varying carcinogenic potentials was assayed in the Salmonella histidine-reversion system. Mutagenicity in the pour-plate assay was compared with that in the liquid pre-incubation test. The smaller ring compounds (nitrosoazetidine, nitrosopyrrolidine, and nitrosopiperidine) exhibited a similar effect in both assays. The large ring compounds (nitrosohexamethyleneimine, nitrosoheptamethyleneimine, nitrosooctamethyleneimine, and nitrosododecamethyleneimine) were more effective in the liquid pre-incubation test. Our results suggest a reasonable relationship between their mutagenic and carcinogenic activities.     

The oncogenic action of nonfibrous mineral dusts]

Nonfibrous mineral dusts antigorite, basalt, cement, zeolite-klinoptilolite and gamma-alumina were tested for carcinogenic activity in rat experiments. Intraperitoneal injections of zeolite-klinoptilolite and gamma-alumina led to development of peritoneal mesotheliomas, whereas antigorite and cement had no carcinogenic potential. There is no differences in physicochemical and chemical properties between carcinogenically active and inactive nonfibrous dusts. A new class of carcinogenic substances is defined including basalt, zeolite-klinoptilolite and quartz which belong to nonfibrous mineral dusts.