On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group’s efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/ NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in whic...

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The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information.

ND, not determined. a All values in µg/kg/day based on a maximum creatinine clearance of 20 mg/kg/day. b Estimated intake taken from ATSDR, IPCS, or EU draft risk assessments. c From Doull et al. (4) using ATSDR estimates.

ND, not determined. a All values in µg/kg/day based on a maximum creatinine clearance of 20 mg/kg/day. b Estimated intake taken from ATSDR, IPCS, or EU draft risk assessments. c From Doull et al. (4) using ATSDR estimates.

The need for high quality and timely disaster research has been a topic of great discussion over the past several years. Recent high profile incidents have exposed gaps in knowledge about the health impacts of disasters or the benefits of specific interventions—such was the case with the 2010 Gulf Oil Spill and recent events associated with lead-contaminated drinking water in Flint, Michigan, and the evolving health crisis related to Zika virus disease. Our inability to perform timely research to inform the community about health and safety risks or address specific concerns further heightens anxiety and distrust. Since nearly all disasters, whether natural or man-made, have an environmental health component, it is critical that specialized research tools and trained researchers be readily available to evaluate complex exposures and health effects, especially for vulnerable sub-populations such as the elderly, children, pregnant women, and those with socioeconomic and environmental disparities. In response, the National Institute of Environmental Health Science has initiated a Disaster Research Response Program to create new tools, protocols, networks of researchers, training exercises, and outreach involving diverse groups of stakeholders to help overcome the challenges of disaster research and to improve our ability to collect vital information to reduce the adverse health impacts and improve future preparedness.

Phthalates are important industrial chemicals used in the manufacture of a wide range of plastic and nonplastic products and can be divided into two basic groups: those used as plasticizers for synthetic polymers that are incorporated into food wrap, medical tubing, and molded toys, and those used primarily in consumers products such as varnishes, perfumes, nail polishes, and insect repellents. It is conceivable that the route of exposure of an organism to phthalates is an important parameter when considering metabolism of these chemicals in vivo. Phthalates are readily metabolized in the gut, such that oral exposure would not lead to accumulation of high concentrations of these chemicals (1). However, few data are available on the metabolism of this group of chemicals after inhalation or dermal exposure. The primary route of phthalate exposure to the general human population has been presumed to be ingestion. Lower molecular-weight phthalates such as diethyl phthalate (DEP) and di-nbutyl phthalate (DBP) can be absorbed percutaneously, and the more volatile congeners can be inhaled. Dermal absorption is important for products applied to skin. (3) applied a simple pharmacokinetic model to estimate the total daily intake of phthalates that would result in the reported urinary concentrations of monoester metabolites. These intake estimates were used as a measure of total exposure to diethyl phthalate (DEP), di-n-butyl phthalate (DBP), n-butyl benzyl phthalate (BBP), dicyclohexyl phtha-Blount et al. (2) reported a considerable number of observations in which the analyte levels in urine were below the limit of detection (LOD) for the procedure being used. This analysis excluded analytes for which more than 25% of the studied individuals were below the LOD and discarded individuals below the LOD for analytes they did analyze. This represents a substantial loss of information. Maximum likelihood methods for censored observations (4-7) have been used for many years to analyze survival data and data for which some observations cannot be seen, but it is known that the observation is beyond some critical point. For urinary metabolite data, an observation below the LOD can be assumed to have a metabolite concentration less than the LOD. Methods have been developed for analyzing biomarkers of exposure-including observations below the LOD-by using statistical likelihoods and regression methods for censored data (8). Using a likelihood for censored data, these fractional pieces of information contribute to the overall interpretation of the data and can be used in a natural framework to estimate parameters and test for population differences. To account for strata differences of demographic factors, we estimated population-based exposures to phthalates using a weighted analysis in which weights were assigned for each individual group depending on the frequency of their demographic variables in the general U.S. population.The aim of this study was to present methods for the analysis of exposure estimates based on urinary biomar...