Application of the Key Characteristics of Carcinogens to Bisphenol A.

The ten key characteristics (KCs) of carcinogens are based on characteristics of known human carcinogens and encompass many types of endpoints. We propose that an objective review of the large amount of cancer mechanistic evidence for the chemical bisphenol A (BPA) can be achieved through use of these KCs. A search on metabolic and mechanistic data relevant to the carcinogenicity of BPA was conducted and web-based software tools were used to screen and organize the results. We applied the KCs to systematically identify, organize, and summarize mechanistic information for BPA, and to bring relevant carcinogenic mechanisms into focus. For some KCs with very large data sets, we utilized reviews focused on specific endpoints. Over 3000 studies for BPA from various data streams (exposed humans, animals, in vitro and cell-free systems) were identified. Mechanistic data relevant to each of the ten KCs were identified, with receptor-mediated effects, epigenetic alterations, oxidative stress, and cell proliferation being especially data rich. Reactive and bioactive metabolites are also associated with a number of KCs. This review demonstrates how the KCs can be applied to evaluate mechanistic data, especially for data-rich chemicals. While individual entities may have different approaches for the incorporation of mechanistic data in cancer hazard identification, the KCs provide a practical framework for conducting an objective examination of the available mechanistic data without a priori assumptions on mode of action. This analysis of the mechanistic data available for BPA suggests multiple and inter-connected mechanisms through which this chemical can act.

Estimated Cancer Risks Associated with Nitrosamine Contamination in Commonly Used Medications.

Many nitrosamines are potent carcinogens, with more than 30 listed under California's Proposition 65. Recently, nitrosamine contamination of commonly used drugs for treatment of hypertension, heartburn, and type 2 diabetes has prompted numerous Food and Drug Administration (FDA) recalls in the US. These contaminants include the carcinogens NDMA (N-nitrosodimethylamine) and NDEA (N-nitrosodiethylamine) and the animal tumorigen NMBA (N-nitroso-N-methyl-4-aminobutyric acid). NMBA and NDEA are metabolically and/or structurally related to NDMA, an N-nitrosomethyl-n-alkylamine (NMA), and 12 other carcinogenic NMAs. These nitrosamines exhibit common genotoxic and tumorigenic activities, with shared target tumor sites amongst chemicals and within a given laboratory animal species. We use the drug valsartan as a case study to estimate the additional cancer risks associated with NDMA and NDEA contamination, based on nitrosamine levels reported by the US FDA, cancer potencies developed by California's Proposition 65 program and the US Environmental Protection Agency (EPA), and specific exposure scenarios. These estimates suggest that nitrosamine contamination in drugs that are used long-term can increase cancer risks and pose a serious concern to public health.

Cancer Hazard Identification Integrating Human Variability: The Case of Coumarin.

Coumarin is a naturally occurring sweet-smelling benzopyrone that may be extracted from plants or synthesized for commercial uses. Its uses include as a flavoring agent, fragrance enhancer, and odor-masking additive. We reviewed and evaluated the scientific evidence on the carcinogenicity of coumarin, integrating information from carcinogenicity studies in animals with mechanistic and other relevant data, including data from toxicogenomic, genotoxicity, and metabolism studies, and studies of human variability of a key enzyme, CYP2A6. Increases in tumors were observed in multiple studies in rats and mice in multiple tissues. Our functional pathway analysis identified several common cancer-related biological processes/pathways affected by coumarin in rat liver following in vivo exposure and in human primary hepatocytes exposed in vitro. When coumarin 7-hydroxylation by CYP2A6 is compromised, this can lead to a shift in metabolism to the 3,4-epoxidation pathway and increased generation of electrophilic metabolites. Mechanistic data align with 3 key characteristics of carcinogens, namely formation of electrophilic metabolites, genotoxicity, and induction of oxidative stress. Considerations of metabolism, human variability in CYP2A6 activity, and coumarin hepatotoxicity in susceptible individuals provide additional support for carcinogenicity concern. Our analysis illustrates the importance of integrating information on human variability in the cancer hazard identification process.

Association of Treponema spp. with canine periodontitis.

To evaluate the association of oral Treponema (T.) spp. with severity of canine periodontitis, subgingival plaque samples of dogs of various breeds undergoing surgery were investigated. A wide range of oral Treponema spp. was analysed by a molecular and culture-independent approach applying DNA-DNA dot blot hybridization analysis and fluorescence in situ hybridization using Treponema specific oligonucleotide probes specific for phylogenetic groups I-VII of oral treponemes as well as probes specific for T. socranskii and T. denticola. To assess the periodontal status of affected dogs clinical parameters were measured and the periodontal status was classified from grade 0 (physiological periodont) to 3 (severe periodontitis). The periodontal status correlated significantly with an increasing concentration of volatile sulfur compounds (VSC, r=0.854) determined with a Halimeter, indicating a positive correlation between the presence of VSC-producing bacteria and periodontitis. In this study Treponema spp. of phylogenetic groups III, V-VII were not detected in any sample, whereas T. denticola-like treponemes were found only in 2 of 51 animals. However, treponemes belonging to phylogenetic groups I, II and IV of oral treponemes or T. socranskii were found in up to 64.84% of the dogs. The detection rate of Treponema spp. was significantly associated with an increased periodontal status. Treponemes present in periodontal lesions were also visualized by fluorescence in situ hybridization of gingival biopsies showing Treponema spp. not only in the microbial biofilm but also within the gingival tissue. The data presented here indicate that oral Treponema spp. are associated with canine periodontitis. Similar to human periodontitis, treponemes of groups I, II and IV and T. socranskii were found more frequently the higher the degree of periodontitis was.

[Qualification of the Stewart variables for the assessment of the acid-base status in healthy dogs and dogs with different diseases]. / Eignung der Stewart-Variablen zur Beurteilung des Säuren-Basen-Status bei gesunden und unterschiedlich erkrankten Hunden.

Peter Stewart criticized the traditional theory of the acid-base status by Henderson-Hasselbalch as too simple and incomplete. He developed a new model with 3 independent variables: (1) pCO2, (2) SID (strong ion difference) and (3) Atot (Acid total). In healthy and ill dogs the diagnostic usefulness of both acid-base models were compared. This study included n=58 healthy dogs and 3 clinical cases of sick dogs. The age of the healthy dogs was 5.0 (2.0-7.0) years (= median (1.-3. quartil)). The 3 clinical cases included (1) a dog with septic shock, (2) with acute renal insufficiency, and (3) with hypovolaemic shock due to gastric torsion. Venous blood was taken of all dogs and the acid-base parameters were determined within < or =30 minutes. Electrolytes and albumin were determined in blood serum and used for calculation of the Stewart variables. Limits of reference intervals (x+/-1.96 - s) were determined for the healthy dogs yielding pCO2 = 3.6-6.5 kPa, [SID3] = 33.1-50.9 mmol/l resp. [SID4] = 31.8-49.6 mmol/l and [Al = 8.5-13.1 mmol/l. In Case 1 the Henderson-Hasselbalch parameters demonstrated the presence of a strong metabolic acidosis with mild respiratory influence (pH, [HCO3-], [BE] and PCO2 at upper range of normal). Analysis of the Stewart variables [SID3] resp. [SID4] revealed an electrolyte imbalance with [Cl-] and [lactate-] as the reason for metabolic acidosis. Case 2 showed a metabolic acidosis with respiratory compensation (pH, [HCO3-], [BE] and PCO2). Analysis of the Stewart variables with [SID3] resp. [SID4 caused by [K+], [Na+] and [lactate-]demonstrated the acidotic metabolism due to a renal malfunction. Case 3 had a metabolic acidosis (pH-value in the lower range) caused by electrolyte imbalances ([SID4]. The Stewart variables allow a better understanding of the causes of acid-base-disturbances in animals with implications for successful therapy via infusion.

[Estimation of reproducibility and repeatability in microbiological ring trials--robust versus conservative methods]. / Schätzung von Reproduzierbarkeit und Wiederholbarkeit bei mikrobiologischen Ringversuchen--robuste versus konservative Verfahren.

During the last years there was a lot of progress to be seen in the development of standardized methods for microbiological ring trials. The statistical analyzing strategies, in particular the calculation of estimations for the parameters repeatability and reproducibility, will be considered in this paper. Apart from the conservative method of the variance analysis robust methods are increasingly discussed. We will compare and discuss these methods using data of recently realized ring trials. If we can assume a normal distribution of our data, then all estimations are theoretically precise and efficient. But up to now, we know very little about the character of the robust estimations, if the normal distribution cannot be assumed. In addition to this, we have to mention once more, that the use of robust estimators is unreasonable without taking a critical look on the data themselves. Thus, we will show the possibilities of graphical presentation of all data to identify laboratories with critical results.