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In an evaluation of carbon nanotubes (CNTs) for the IARC Monograph 111, the Mechanisms Subgroup was tasked with assessing the strength of evidence on the potential carcinogenicity of CNTs in humans. The mechanistic evidence was considered to be not strong enough to alter the evaluations based on the animal data. In this paper, we provide an extended, in-depth examination of the in vivo and in vitro experimental studies according to current hypotheses on the carcinogenicity of inhaled particles and fibers. We cite additional studies of CNTs that were not available at the time of the IARC meeting in October 2014, and extend our evaluation to include carbon nanofibers (CNFs). Finally, we identify key data gaps and suggest research needs to reduce uncertainty. The focus of this review is on the cancer risk to workers exposed to airborne CNT or CNF during the production and use of these materials. The findings of this review, in general, affirm those of the original evaluation on the inadequate or limited evidence of carcinogenicity for most types of CNTs and CNFs at this time, and possible carcinogenicity of one type of CNT (MWCNT-7). The key evidence gaps to be filled by research include: investigation of possible associations between in vitro and early-stage in vivo events that may be predictive of lung cancer or mesothelioma, and systematic analysis of dose-response relationships across materials, including evaluation of the influence of physico-chemical properties and experimental factors on the observation of nonmalignant and malignant endpoints.

Significant advances have been made in the development of Adverse Outcome Pathways (AOPs) over the last decade, mainly focused on the toxicity mechanisms of chemicals. These AOPs, although relevant to manufactured nanomaterials (MNs), do not currently capture the reported roles of size-associated properties of MNs on toxicity. Moreover, some AOs of relevance to airborne exposures to MNs such as lung inflammation and fibrosis shown in animal studies may not be targeted in routine regulatory decision making. The primary objective of the present study was to establish an approach to advance the development of AOPs of relevance to MNs using existing, publicly available, nanotoxicology literature. A systematic methodology was created for curating, organizing and applying the available literature for identifying key events (KEs). Using a case study approach, the study applied the available literature to build the biological plausibility for 'tissue injury', a KE of regulatory relevance to MNs. The results of the analysis reveal the various endpoints, assays and specific biological markers used for assessing and reporting tissue injury. The study elaborates on the limitations and opportunities of the current nanotoxicology literature and provides recommendations for the future reporting of nanotoxicology results that will expedite not only the development of AOPs for MNs but also aid in application of existing data for decision making. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Research Recommendations for Selected IARC-Classified Agents," published in a previous issue.

Chronic inflammation is a key step in the pathogenesis of particle-elicited fibrosis and lung cancer in rats, and possibly in humans. In this study, we compute the excess risk estimates for lung cancer in humans with occupational exposure to crystalline silica, using both rat and human data, and using both a threshold approach and linear models. From a toxicokinetic/dynamic model fit to lung burden and pulmonary response data from a subchronic inhalation study in rats, we estimated the minimum critical quartz lung burden (Mcrit) associated with reduced pulmonary clearance and increased neutrophilic inflammation. A chronic study in rats was also used to predict the humanexcess risk of lung cancer at various quartz burdens, including meanMcrit (0.39 mg/g lung). We used a human kinetic lung model to link the equivalent lung burdens to external exposures in humans. We then computed the excess risk of lung cancer at these external exposures, using data of workers exposed to respirable crystalline silica and using Poisson regression and lifetable analyses. Finally, we compared the lung cancer excess risks estimated from male rat and human data. We found that the ratbased linear model estimates were approximately three times higher than those based on human data (e.g., 2.8% in rats vs. 0.9-1% in humans, at mean Mcrit lung burden or associated mean working lifetime exposure of 0.036 mg/m3). Accounting for variability and uncertainty resulted in 10(1-1000 times lower estimates of human critical lung burden and airborne exposure. This study illustrates that assumptions about the relevant biological mechanism, animal model, and staff tistical approach can all influence the magnitude of lung cancer risk estimates in humans exposed to crystalline silica. [ABSTRACT FROM AUTHOR]

The excess (exposure-attributable) risks of certain respiratory diseases and outcomes were estimated for U.S. coal miners exposed to respirable coal mine dust for various durations and concentrations, including a 45-year working lifetime at the current 2-mg/m3 standard. Multiple linear and logistic regression models were used to compute predicted prevalence and excess risk of disease, using data andregression results from published epidemiological studies of U.S. coal miners. Disease outcomes evaluated include simple coal workers' pneumoconiosis, progressive massive fibrosis, and clinically significant deficits in lung function, measured as forced expiratory volume in 1 second of < 80% or < 65% of predicted normal values. Point estimates of excess risk of progressive massive fibrosis ranged from 1/1000 to 167/1000 among coal miners exposed to respirable coal mine dust at a mean concentration of 2 mg/m3 for 45 years. This range reflects coal rank and study differences. Point estimates for an excess risk of forced expiratory volume in 1 second of < 65% of predicted normal values ranged from 9/1000 to 188/1000 among miners with the same exposures noted above (the range reflects smoking status, geographical region, and study differences). Excess risks for all disease outcomes studied exceeded 1/1000 among miners exposed to mean concentrations as low as 0.5 mg/m3 and durations as low as 15 years (most coal ranks). Sources of uncertainty associated with these results were considered. Based on these and previous analyses, U.S. coal miners are predicted to have a substantial risk of developing occupational respiratory diseases from working lifetime exposures to respirable coal mine dust at the current 2-mg/m3 standard. To reduce this risk, the National Institute for Occupational Safety and Health (NIOSH) recommends that worker exposures to respirable coal mine dust be kept below 1.0 mg/m3 during each work shift (as a ti [ABSTRACT FROM AUTHOR]