Dosimetry of inhaled elongate mineral particles in the respiratory tract: The impact of shape factor.

Inhalation exposure to some types of fibers (e.g., asbestos) is well known to be associated with respiratory diseases and conditions such as pleural plaques, fibrosis, asbestosis, lung cancer, and mesothelioma. In recent years, attention has expanded to other types of elongate mineral particles (EMPs) that may share similar geometry with asbestos fibers but which may differ in mineralogy. Inhalability, dimensions and orientation, and density are major determinants of the aerodynamic behavior for fibers and other EMPs; and the resultant internal dose is recognized as being the critical link between exposure and pathogenesis. Insufficient data are available to fully understand the role of specific physicochemical properties on the potential toxicity across various types of fiber materials. While additional information is required to assess the potential health hazards of EMPs, dosimetry models are currently available to estimate the initially deposited internal dose, which is an essential step in linking airborne exposures to potential health risks. Based on dosimetry model simulations, the inhalability and internal dose of EMPs were found to be greater than that of spherical particles having the same mass or volume. However, the complexity of the dependence of internal dose on EMPs dimensions prevented a straightforward formulation of the deposition-dimension (length or diameter) relationship. Because health outcome is generally related to internal dose, consideration of the factors that influence internal dose is important in assessing the potential health hazards of airborne EMPs.

Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans.

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.

A quantitative framework to group nanoscale and microscale particles by hazard potency to derive occupational exposure limits: Proof of concept evaluation.

The large and rapidly growing number of engineered nanomaterials (ENMs) presents a challenge to assessing the potential occupational health risks. An initial database of 25 rodent studies including 1929 animals across various experimental designs and material types was constructed to identify materials that are similar with respect to their potency in eliciting neutrophilic pulmonary inflammation, a response relevant to workers. Doses were normalized across rodent species, strain, and sex as the estimated deposited particle mass dose per gram of lung. Doses associated with specific measures of pulmonary inflammation were estimated by modeling the continuous dose-response relationships using benchmark dose modeling. Hierarchical clustering was used to identify similar materials. The 18 nanoscale and microscale particles were classified into four potency groups, which varied by factors of approximately two to 100. Benchmark particles microscale TiO2 and crystalline silica were in the lowest and highest potency groups, respectively. Random forest methods were used to identify the important physicochemical predictors of pulmonary toxicity, and group assignments were correctly predicted for five of six new ENMs. Proof-of-concept was demonstrated for this framework. More comprehensive data are needed for further development and validation for use in deriving categorical occupational exposure limits.

Bayesian evaluation of a physiologically-based pharmacokinetic (PBPK) model of long-term kinetics of metal nanoparticles in rats.

Biomathematical modeling quantitatively describes the disposition of metal nanoparticles in lungs and other organs of rats. In a preliminary model, adjustable parameters were calibrated to each of three data sets using a deterministic approach, with optimal values varying among the different data sets. In the current effort, Bayesian population analysis using Markov chain Monte Carlo (MCMC) simulation was used to recalibrate the model while improving assessments of parameter variability and uncertainty. The previously-developed model structure and some physiological parameter values were modified to improve physiological realism. The data from one of the three previously-identified studies and from two other studies were used for model calibration. The data from the one study that adequately characterized mass balance were used to generate parameter distributions. When data from a second study of the same nanomaterial (iridium) were added, the level of agreement was still acceptable. Addition of another data set (for silver nanoparticles) led to substantially lower precision in parameter estimates and large discrepancies between the model predictions and experimental data for silver nanoparticles. Additional toxicokinetic data are needed to further evaluate the model structure and performance and to reduce uncertainty in the kinetic processes governing in vivo disposition of metal nanoparticles.

Airborne fiber size characterization in exposure estimation: Evaluation of a modified transmission electron microcopy protocol for asbestos and potential use for carbon nanotubes and nanofibers.

BACKGROUND: Airborne fiber size has been shown to be an important factor relative to adverse lung effects of asbestos and suggested in animal studies of carbon nanotubes and nanofibers (CNT/CNF). MATERIALS AND METHODS: The International Standards Organization (ISO) transmission electron microscopy (TEM) method for asbestos was modified to increase the statistical precision of fiber size determinations, improve efficiency, and reduce analysis costs. Comparisons of the fiber size distributions and exposure indices by laboratory and counting method were performed. RESULTS: No significant differences in size distributions by the ISO and modified ISO methods were observed. Small but statistically-significant inter-lab differences in the proportion of fibers in some size bins were found, but these differences had little impact on the summary exposure indices. The modified ISO method produced slightly more precise estimates of the long fiber fraction (>15 µm). CONCLUSIONS: The modified ISO method may be useful for estimating size-specific structure exposures, including CNT/CNF, for risk assessment research.

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation.

The purpose of this article is to provide an overview and practical guide to occupational health professionals concerning the derivation and use of dose estimates in risk assessment for development of occupational exposure limits (OELs) for inhaled substances. Dosimetry is the study and practice of measuring or estimating the internal dose of a substance in individuals or a population. Dosimetry thus provides an essential link to understanding the relationship between an external exposure and a biological response. Use of dosimetry principles and tools can improve the accuracy of risk assessment, and reduce the uncertainty, by providing reliable estimates of the internal dose at the target tissue. This is accomplished through specific measurement data or predictive models, when available, or the use of basic dosimetry principles for broad classes of materials. Accurate dose estimation is essential not only for dose-response assessment, but also for interspecies extrapolation and for risk characterization at given exposures. Inhalation dosimetry is the focus of this paper since it is a major route of exposure in the workplace. Practical examples of dose estimation and OEL derivation are provided for inhaled gases and particulates.

Systems Biology and Biomarkers of Early Effects for Occupational Exposure Limit Setting.

In a recent National Research Council document, new strategies for risk assessment were described to enable more accurate and quicker assessments. This report suggested that evaluating individual responses through increased use of bio-monitoring could improve dose-response estimations. Identification of specific biomarkers may be useful for diagnostics or risk prediction as they have the potential to improve exposure assessments. This paper discusses systems biology, biomarkers of effect, and computational toxicology approaches and their relevance to the occupational exposure limit setting process. The systems biology approach evaluates the integration of biological processes and how disruption of these processes by chemicals or other hazards affects disease outcomes. This type of approach could provide information used in delineating the mode of action of the response or toxicity, and may be useful to define the low adverse and no adverse effect levels. Biomarkers of effect are changes measured in biological systems and are considered to be preclinical in nature. Advances in computational methods and experimental -omics methods that allow the simultaneous measurement of families of macromolecules such as DNA, RNA, and proteins in a single analysis have made these systems approaches feasible for broad application. The utility of the information for risk assessments from -omics approaches has shown promise and can provide information on mode of action and dose-response relationships. As these techniques evolve, estimation of internal dose and response biomarkers will be a critical test of these new technologies for application in risk assessment strategies. While proof of concept studies have been conducted that provide evidence of their value, challenges with standardization and harmonization still need to be overcome before these methods are used routinely.

Application of Markov chain Monte Carlo analysis to biomathematical modeling of respirable dust in US and UK coal miners.

A biomathematical model was previously developed to describe the long-term clearance and retention of particles in the lungs of coal miners. The model structure was evaluated and parameters were estimated in two data sets, one from the United States and one from the United Kingdom. The three-compartment model structure consists of deposition of inhaled particles in the alveolar region, competing processes of either clearance from the alveolar region or translocation to the lung interstitial region, and very slow, irreversible sequestration of interstitialized material in the lung-associated lymph nodes. Point estimates of model parameter values were estimated separately for the two data sets. In the current effort, Bayesian population analysis using Markov chain Monte Carlo simulation was used to recalibrate the model while improving assessments of parameter variability and uncertainty. When model parameters were calibrated simultaneously to the two data sets, agreement between the derived parameters for the two groups was very good, and the central tendency values were similar to those derived from the deterministic approach. These findings are relevant to the proposed update of the ICRP human respiratory tract model with revisions to the alveolar-interstitial region based on this long-term particle clearance and retention model.

Increased lung cancer mortality among chrysotile asbestos textile workers is more strongly associated with exposure to long thin fibres.

BACKGROUND: Animal data and physical models suggest that the carcinogenicity of asbestos fibres is related to their size and shape. OBJECTIVES: To investigate the influence of fibre length and diameter on lung cancer risk in workers at asbestos textile mills in North Carolina and South Carolina, USA. METHODS: Men and women (n=6136) who worked ≥30 days in production and were employed between 1940 and 1973 were enumerated and followed for vital status through 2003. A matrix of fibre size-specific exposure estimates was constructed using determinations of fibre numbers and dimensions through analysis of 160 historical dust samples by transmission electron microscopy. Associations of lung cancer mortality with metrics of fibre exposure were estimated by Poisson regression with adjustment for age, sex, race and calendar year. RESULTS: Exposure to fibres throughout the range of length and diameter was significantly associated with increased risk of lung cancer. Models for fibres >5 µm long and <0.25 µm in diameter provided the best fit to the data, while fibres 5-10 µm long and <0.25 µm in diameter were associated most strongly with lung cancer mortality (log rate about 4% per IQR, p<0.001). When indicators of mean fibre length and diameter were modelled simultaneously, lung cancer risk increased as fibre length increased and diameter decreased. CONCLUSIONS: The findings support the hypothesis that the occurrence of lung cancer is associated most strongly with exposure to long thin asbestos fibres. The relationship of cancer risk and fibre dimensions should be examined in cohorts exposed to other types of fibres.

Risk assessment and risk management of nanomaterials in the workplace: translating research to practice.

In the last decade since the rise in occupational safety and health (OSH) research focusing on nanomaterials, some progress has been made in generating the health effects and exposure data needed to perform risk assessment and develop risk management guidance. Yet, substantial research gaps remain, as do challenges in the translation of these research findings to OSH guidance and workplace practice. Risk assessment is a process that integrates the hazard, exposure, and dose-response data to characterize risk in a population (e.g. workers), in order to provide health information needed for risk management decision-making. Thus, the research priorities for risk assessment are those studies that will reduce the uncertainty in the key factors that influence the estimates. Current knowledge of OSH in nanotechnology includes the following: (i) nanomaterials can be measured using standard measurement methods (respirable mass or number concentration), (ii) workplace exposures to nanomaterials can be reduced using engineering controls and personal protective equipment, and (iii) current toxicity testing and risk assessment methods are applicable to nanomaterials. Yet, to ensure protection of workers' health, research is still needed to develop (i) sensitive and quantitative measures of workers' exposure to nanomaterials, (ii) validation methods for exposure controls, and (iii) standardized criteria to categorize hazard data, including better prediction of chronic effects. This article provides a state-of-the-art overview on translating current hazard research data and risk assessment methods for nanomaterials to the development and implementation of effective risk management guidance.

Focused actions to protect carbon nanotube workers.

There is still uncertainty about the potential health hazards of carbon nanotubes (CNTs) particularly involving carcinogenicity. However, the evidence is growing that some types of CNTs and nanofibers may have carcinogenic properties. The critical question is that while the carcinogenic potential of CNTs is being further investigated, what steps should be taken to protect workers who face exposure to CNTs, current and future, if CNTs are ultimately found to be carcinogenic? This paper addresses five areas to help focus action to protect workers: (i) review of the current evidence on the carcinogenic potential of CNTs; (ii) role of physical and chemical properties related to cancer development; (iii) CNT doses associated with genotoxicity in vitro and in vivo; (iv) workplace exposures to CNT; and (v) specific risk management actions needed to protect workers.

Towards health-based nano reference values (HNRVs) for occupational exposure: Recommendations from an expert panel.

Unique physicochemical characteristics of engineered nanomaterials (ENMs) suggest the need for nanomaterial-specific occupational exposure limits (OELs). Setting these limits remains a challenge. Therefore, the aim of this study was to set out a framework to evaluate the feasibility of deriving advisory health-based occupational limit values for groups of ENMs, based on scientific knowledge. We have used an expert panel approach to address three questions: 1) What ENM-categories should be distinguished to derive advisory health-based occupational limit values (or health-based Nano Reference Values, HNRVs) for groups of ENMs? 2) What evidence would be needed to define values for these categories? And 3) How much effort would it take to achieve this? The panel experts distinguished six possible categories of HNRVs: A) WHO-fiber-like high aspect ratio ENMs (HARNs), B) Non-WHO-fiber-like HARNs and other non-spheroidal ENMs, C) readily soluble spheroidal ENMs, D) biopersistent spheroidal ENMs with unknown toxicity, E) biopersistent spheroidal ENMs with substance-specific toxicity and F) biopersistent spheroidal ENMs with relatively low substance-specific toxicity. For category A, the WHO-fiber-like HARNs, agreement was reached on criteria defining this category and the approach of using health-based risk estimates for asbestos to derive the HNRV. For category B, a quite heterogeneous category, more toxicity data are needed to set an HNRV. For category C, readily soluble spheroidal ENMs, using the OEL of their molecular or ionic counterpart would be a good starting point. For the biopersistent ENMs with unknown toxicity, HNRVs cannot be applied as case-by-case testing is required. For the other biopersistent ENMs in category E and F, we make several recommendations that can facilitate the derivation of these HNRVs. The proposed categories and recommendations as outlined by this expert panel can serve as a reference point for derivation of HNRVs when health-based OELs for ENMs are not yet available.

Estimates of historical exposures by phase contrast and transmission electron microscopy for pooled exposure--response analyses of North Carolina and South Carolina, USA asbestos textile cohorts.

OBJECTIVES: To develop pooled size-specific asbestos fiber exposure estimates for North Carolina and South Carolina asbestos textile plants. METHODS: Airborne sample data and prior exposure estimates by phase-contrast microscopy (PCM) for the two cohorts were reviewed and compared. Estimates by transmission electron microscopy (TEM) for 160 membrane filter samples from all plant were pooled. Poisson regression models were developed to predict bivariate diameter/length airborne fiber size distributions based on independent categorical variables for fiber diameter, fiber length, plant, and exposure zone. The model predicted bivariate diameter/length distributions were expressed as the proportion of fibers in 28 size-specific cells and these data were used to calculate PCM to TEM adjustment factors in order to estimate fiber size-specific exposures for the pooled cohort. RESULTS: Exposure levels in the North Carolina plants were in excess of 50 f/cc for many operations through about 1955 owing to lack of dust control measures in early years whereas levels in the South Carolina plant were generally less than 10 f/cc by about 1950. The Poisson regression models found covariates for plant department to be a stronger predictor of bivariate size proportions than plant; however, a plant effect was observed. The final Poisson models demonstrated good fit to the observed data. CONCLUSIONS: Consistent with early studies, fiber exposures in the North Carolina plants were much higher than in South Carolina plant. Use of the predicted size-specific TEM exposures by plant and department based on the Poisson model predictions should reduce exposure.

Utilizing literature-based rodent toxicology data to derive potency estimates for quantitative risk assessment.

Evaluating the potential occupational health risk of engineered nanomaterials is an ongoing need. The objective of this meta-analysis, which consisted of 36 studies containing 86 materials, was to assess the availability of published in vivo rodent pulmonary toxicity data for a variety of nanoscale and microscale materials and to derive potency estimates via benchmark dose modeling. Additionally, the potency estimates based on particle mass lung dose associated with acute pulmonary inflammation were used to group materials based on toxicity. The commonalities among the physicochemical properties of the materials in each group were also explored. This exploration found that a material's potency tended to be associated primarily with the material class based on chemical composition and form (e.g. carbon nanotubes, TiO2, ZnO) rather than with particular physicochemical properties. Limitations in the data available precluded a more extensive analysis of these associations. Issues such as data reporting and appropriate experimental design for use in quantitative risk assessment are the main reasons publications were excluded from these analyses and are discussed.

A methodology for developing key events to advance nanomaterial-relevant adverse outcome pathways to inform risk assessment.

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.

Contributions of dust exposure and cigarette smoking to emphysema severity in coal miners in the United States.

RATIONALE: Previous studies have shown associations between dust exposure or lung burden and emphysema in coal miners, although the separate contributions of various predictors have not been clearly demonstrated. OBJECTIVES: To quantitatively evaluate the relationship between cumulative exposure to respirable coal mine dust, cigarette smoking, and other factors on emphysema severity. METHODS: The study group included 722 autopsied coal miners and nonminers in the United States. Data on work history, smoking, race, and age at death were obtained from medical records and questionnaire completed by next-of-kin. Emphysema was classified and graded using a standardized schema. Job-specific mean concentrations of respirable coal mine dust were matched with work histories to estimate cumulative exposure. Relationships between various metrics of dust exposure (including cumulative exposure and lung dust burden) and emphysema severity were investigated in weighted least squares regression models. MEASUREMENTS AND MAIN RESULTS: Emphysema severity was significantly elevated in coal miners compared with nonminers among ever- and never-smokers (P < 0.0001). Cumulative exposure to respirable coal mine dust or coal dust retained in the lungs were significant predictors of emphysema severity (P < 0.0001) after accounting for cigarette smoking, age at death, and race. The contributions of coal mine dust exposure and cigarette smoking were similar in predicting emphysema severity averaged over this cohort. CONCLUSIONS: Coal dust exposure, cigarette smoking, age, and race are significant and additive predictors of emphysema severity in this study.

Sharpening the focus on occupational safety and health in nanotechnology.

Increasing numbers of workers are involved with the production, use, distribution, and disposal of nanomaterials. At the same time, there is a growing number of reports of adverse biological effects of engineered nanoparticles in test systems. It is useful, at this juncture, to identify critical questions that will help address knowledge gaps concerning the potential occupational hazards of these materials. The questions address (i) hazard classification of engineered nanoparticles, (ii) exposure metrics, (iii) the actual exposures to the different engineered nanoparticles in the workplace, (iv) the limits of engineering controls and personal protective equipment with respect to engineered nanoparticles, (v) the kinds of surveillance programs that may be required at workplaces to protect potentially exposed workers, (vi) whether exposure registers should be established for workers potentially exposed to engineered nanoparticles, and, (vii) whether engineered nanoparticles should be treated as "new" substances and evaluated for safety and hazards?

Occupational risk management of engineered nanoparticles.

The earliest and most extensive societal exposures to engineered nanoparticles are likely to occur in the workplace. Until toxicologic and health effects research moves forward to characterize more broadly the potential hazards of nanoparticles and to provide a scientific basis for appropriate control of nanomaterials in the workplace, current and future workers may be at risk from occupational exposures. This article reviews a conceptual framework for occupational risk management as applied to engineered nanomaterials and describes an associated approach for controlling exposures in the presence of uncertainty. The framework takes into account the potential routes of exposure and factors that may influence biological activity and potential toxicity of nanomaterials; incorporates primary approaches based on the traditional industrial hygiene hierarchy of controls involving elimination or substitution, engineering controls, administrative controls, and use of personal protective equipment; and includes valuable secondary approaches involving health surveillance and medical monitoring.

Control Banding Tools for Engineered Nanoparticles: What the Practitioner Needs to Know.

Control banding (CB) has been widely recommended for the selection of exposure controls for engineered nanomaterials (ENMs) in the absence of ENM-specific occupational exposure limits (OELs). Several ENM-specific CB strategies have been developed but have not been systematically evaluated. In this article, we identify the data inputs and compare the guidance provided by eight CB tools, evaluated on six ENMs, and assuming a constant handling/use scenario. The ENMs evaluated include nanoscale silica, titanium dioxide, silver, carbon nanotubes, graphene, and cellulose. Several of the tools recommended the highest level of exposure control for each of the ENMs in the evaluation, which was driven largely by the hazard banding. Dustiness was a factor in determining the exposure band in many tools, although most tools did not provide explicit guidance on how to classify the dustiness (high, medium, low), and published data are limited on this topic. The CB tools that recommended more diverse control options based on ENM hazard and dustiness data appear to be better equipped to utilize the available information, although further validation is needed by comparison to exposure measurements and OELs for a variety of ENMs. In all CB tools, local exhaust ventilation was recommended at a minimum to control exposures to ENMs in the workplace. Generally, the same or more stringent control levels were recommended by these tools compared with the OELs proposed for these ENMs, suggesting that these CB tools would generally provide prudent exposure control guidance, including when data are limited.