Quantitative Risk Assessment: Developing a Bayesian Approach to Dichotomous Dose-Response Uncertainty.

Model averaging for dichotomous dose-response estimation is preferred to estimate the benchmark dose (BMD) from a single model, but challenges remain regarding implementing these methods for general analyses before model averaging is feasible to use in many risk assessment applications, and there is little work on Bayesian methods that include informative prior information for both the models and the parameters of the constituent models. This article introduces a novel approach that addresses many of the challenges seen while providing a fully Bayesian framework. Furthermore, in contrast to methods that use Monte Carlo Markov Chain, we approximate the posterior density using maximum a posteriori estimation. The approximation allows for an accurate and reproducible estimate while maintaining the speed of maximum likelihood, which is crucial in many applications such as processing massive high throughput data sets. We assess this method by applying it to empirical laboratory dose-response data and measuring the coverage of confidence limits for the BMD. We compare the coverage of this method to that of other approaches using the same set of models. Through the simulation study, the method is shown to be markedly superior to the traditional approach of selecting a single preferred model (e.g., from the U.S. EPA BMD software) for the analysis of dichotomous data and is comparable or superior to the other approaches.

Safety Assessment of Electronic Cigarettes and Their Relationship with Cardiovascular Disease.

Smoking leads to the occurrence and development of a variety of diseases. Most importantly, it is an independent risk factor of cardiovascular atherosclerosis. In recent years, electronic cigarettes have become a popular alternative to traditional cigarettes, since modern micro-electronic techniques provide the possibility of simulating the process of traditional smoking. Additionally, it is convenient and fashionable. Nevertheless, comments about the safety of electronic cigarettes remain controversial. Although the research about electronic cigarettes increased exponentially, there has been no systematic study of its safety. The aim of the current study is to review the literature reports about the safety of electronic cigarettes, and to understand their hazards and disadvantages. It was found that most of the current research about electronic cigarettes comprises short-term and in vitro studies. There are few reports of in vivo and long-term studies. Notably, the level of harmful components such as volatile organic compounds, tobacco-specific nitrosamines and heavy metals in electronic cigarettes are even higher than in traditional cigarettes. Therefore, the harm of electronic cigarettes should not be underestimated. In conclusion, the question of whether electronic cigarettes are a safe and sufficient substitute for traditional smoking needs further investigation.

Recommended approaches in the application of toxicogenomics to derive points of departure for chemical risk assessment.

There is increasing interest in the use of quantitative transcriptomic data to determine benchmark dose (BMD) and estimate a point of departure (POD) for human health risk assessment. Although studies have shown that transcriptional PODs correlate with those derived from apical endpoint changes, there is no consensus on the process used to derive a transcriptional POD. Specifically, the subsets of informative genes that produce BMDs that best approximate the doses at which adverse apical effects occur have not been defined. To determine the best way to select predictive groups of genes, we used published microarray data from dose-response studies on six chemicals in rats exposed orally for 5, 14, 28, and 90 days. We evaluated eight approaches for selecting genes for POD derivation and three previously proposed approaches (the lowest pathway BMD, and the mean and median BMD of all genes). The relationship between transcriptional BMDs derived using these 11 approaches and PODs derived from apical data that might be used in chemical risk assessment was examined. Transcriptional BMD values for all 11 approaches were remarkably aligned with corresponding apical PODs, with the vast majority of toxicogenomics PODs being within tenfold of those derived from apical endpoints. We identified at least four approaches that produce BMDs that are effective estimates of apical PODs across multiple sampling time points. Our results support that a variety of approaches can be used to derive reproducible transcriptional PODs that are consistent with PODs produced from traditional methods for chemical risk assessment.

Human health risk assessment of nitrosamines and nitramines for potential application in CO2 capture.

Emission and accumulation of carbon dioxide (CO2) in the atmosphere exert an environmental and climate change challenge. An attempt to deal with this challenge is made at Mongstad by application of amines for CO2 capture and storage (CO2 capture Mongstad (CCM) project). As part of the CO2 capture process, nitrosamines and nitramines may be emitted. Toxicological testing of nitrosamines and nitramines indicate a genotoxic potential of these substances. Here we present a risk characterization and assessment for five nitrosamines (N-Nitrosodi-methylamine (NDMA) N-Nitrosodi-ethylamine (NDEA), N-Nitroso-morpholine (NNM), N-Nitroso-piperidine (NPIP), and Dinitroso-piperazine (DNP)) and two nitramines (N-Methyl-nitramine (NTMA), Dimethyl-nitramine (NDTMA)), which are potentially emitted from the CO2 capture plant (CCP). Human health risk assessment of genotoxic non-threshold substances is a heavily debated topic, and no consensus methodology exists internationally. Extrapolation modeling from high-dose animal exposures to low-dose human exposures can be crucial for the final risk calculation. In the work presented here, different extrapolation models are discussed, and suggestions on applications are given. Then, preferred methods for calculating derived minimal effect level (DMEL) are presented with the selected nitrosamines and nitramines.

Dose-dependent induction of preneoplastic lesions by the tobacco-specific nitrosamine carcinogen NNK in the in ovo carcinogenicity assessment (IOCA) assay.

The potential of the carcinogenic tobacco specific nitrosamine 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-1-butanone (NNK) to induce preneoplastic hepatocellular altered foci (HAF) was tested in the in ovo carcinogenicity assessment (IOCA) assay. Single doses of NNK over a dose range from 0.1 mg to 6 mg were injected into fertilized turkey eggs prior to incubation for 24 days. The livers were investigated by histological, histochemical and morphometric methods. Mortality was increased for eggs exposed to 6 mg. In this group, the whole livers were severely altered, showing pronounced changes of nucleus size and signs of cell death. At the dose of 2 mg various types of foci of altered hepatocytes (HAF) were observed. Basophilic cell foci of the solid or tubular type were most frequent. The NNK-induced HAF were very similar to the preneoplastic lesions that occur in the livers of mammals during hepatocarcinogenesis which are regarded as early indicators of carcinogenesis. The similarity to the HAF in rodents included histochemically detectable alterations like decreased activities of glucose-6-phosphatase, adenosine triphosphatase and glycogen phosphorylase. At doses of 1 mg or below, no HAF were detected. At all dose levels an increased occurrence of enlarged hepatocytes with enlarged nuclei and prominent nucleoli (karyomegalic hepatocytes) were observed. The increase in karyomegalic hepatocytes was also statistically significant at the low dose of 0.1 mg/kg NNK but the dose-effect curve for their induction was clearly non-linear. Induction of HAF and karyomegalic hepatocytes in ovo is a simple (one dose), rapid (24 days) and inexpensive (no animal purchase or housing) experimental approach for studies on chemically induced hepatocarcinogenesis.