Eileen D. Kuempel

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.

An Approach to Risk Assessment for TiO2

Titanium dioxide (TiO2) is a poorly soluble, low-toxicity (PSLT) particle. Fine TiO2 (<2.5 μm) has been shown to produce lung tumors in rats exposed to 250 mg/m3, and ultrafine TiO2 (< 0.1 μm diameter) has been shown to produce lung tumors in rats at 10 mg/m3. We have evaluated the rat dose-response data and conducted a quantitative risk assessment for TiO2. Preliminary conclusions are: (1) Fine and ultrafine TiO2 and other PSLT particles show a consistent dose-response relationship when dose is expressed as particle surface area; (2) the mechanism of TiO2 tumor induction in rats appears to be a secondary genotoxic mechanism associated with persistent inflammation; and (3) the inflammatory response shows evidence of a nonzero threshold. Risk estimates for TiO2 depend on both the dosimetric approach and the statistical model that is used. Using 7 different dose-response models in the U.S. Environmental Protection Agency (EPA) benchmark dose software, the maximum likelihood estimate (MLE) rat lung dose associated with a 1 per 1000 excess risk ranges from 0.0076 to 0.28 m2/g-lung of particle surface area, with 95% lower confidence limits (LCL) of 0.0059 and 0.042, respectively. Using the ICRP particle deposition and clearance model, estimated human occupational exposures yielding equivalent lung burdens range from approximately 1 to 40 mg/m3 (MLE) for fine TiO2, with 95% LCL approximately 0.7–6 mg/m3. Estimates using an interstitial sequestration lung model are about one-half as large. Bayesian model averaging techniques are now being explored as a method for combining the various estimates into a single estimate, with a confidence interval expressing model uncertainty.

An epidemiological study of the role of chrysotile asbestos fibre dimensions in determining respiratory disease risk in exposed workers

Background: Evidence from toxicological studies indicates that the risk of respiratory diseases varies with asbestos fibre length and width. However, there is a total lack of epidemiological evidence concerning this question. Methods: Data were obtained from a cohort mortality study of 3072 workers from an asbestos textile plant which was recently updated for vital status through 2001. A previously developed job exposure matrix based on phase contrast microscopy (PCM) was modified to provide fibre size-specific exposure estimates using data from a re-analysis of samples by transmission electron microscopy (TEM). Cox proportional hazards models were fit using alternative exposure metrics for single and multiple combinations of fibre length and diameter. Results: TEM-based cumulative exposure estimates were found to provide stronger predictions of asbestosis and lung cancer mortality than PCM-based estimates. Cumulative exposures based on individual fibre size-specific categories were all found to be highly statistically significant predictors of lung cancer and asbestosis. Both lung cancer and asbestosis were most strongly associated with exposure to thin fibres (<0.25 μm). Longer (>10 μm) fibres were found to be the strongest predictors of lung cancer, but an inconsistent pattern with fibre length was observed for asbestosis. Cumulative exposures were highly correlated across all fibre size categories in this cohort (0.28–0.99, p values <0.001), which complicates the interpretation of the study findings. Conclusions: Asbestos fibre dimension appears to be an important determinant of respiratory disease risk. Current PCM-based methods may underestimate asbestos exposures to the thinnest fibres, which were the strongest predictor of lung cancer or asbestosis mortality in this study. Additional studies are needed of other asbestos cohorts to further elucidate the role of fibre dimension and type.

A Multi-Stakeholder Perspective on the Use of Alternative Test Strategies for Nanomaterial Safety Assessment

There has been a conceptual shift in toxicological studies from describing what happens to explaining how the adverse outcome occurs, thereby enabling a deeper and improved understanding of how biomolecular and mechanistic profiling can inform hazard identification and improve risk assessment. Compared to traditional toxicology methods, which have a heavy reliance on animals, new approaches to generate toxicological data are becoming available for the safety assessment of chemicals, including high-throughput and high-content screening (HTS, HCS). With the emergence of nanotechnology, the exponential increase in the total number of engineered nanomaterials (ENMs) in research, development, and commercialization requires a robust scientific approach to screen ENM safety in humans and the environment rapidly and efficiently. Spurred by the developments in chemical testing, a promising new toxicological paradigm for ENMs is to use alternative test strategies (ATS), which reduce reliance on animal testing through the use of in vitro and in silico methods such as HTS, HCS, and computational modeling. Furthermore, this allows for the comparative analysis of large numbers of ENMs simultaneously and for hazard assessment at various stages of the product development process and overall life cycle. Using carbon nanotubes as a case study, a workshop bringing together national and international leaders from government, industry, and academia was convened at the University of California, Los Angeles, to discuss the utility of ATS for decision-making analyses of ENMs. After lively discussions, a short list of generally shared viewpoints on this topic was generated, including a general view that ATS approaches for ENMs can significantly benefit chemical safety analysis.

Lung Dosimetry and Risk Assessment of Nanoparticles: Evaluating and Extending Current Models in Rats and Humans

Risk assessment of occupational exposure to nanomaterials is needed. Human data are limited, but quantitative data are available from rodent studies. To use these data in risk assessment, a scientifically reasonable approach for extrapolating the rodent data to humans is required. One approach is allometric adjustment for species differences in the relationship between airborne exposure and internal dose. Another approach is lung dosimetry modeling, which provides a biologically-based, mechanistic method to extrapolate doses from animals to humans. However, current mass-based lung dosimetry models may not fully account for differences in the clearance and translocation of nanoparticles. In this article, key steps in quantitative risk assessment are illustrated, using dose-response data in rats chronically exposed to either fine or ultrafine titanium dioxide (TiO2), carbon black (CB), or diesel exhaust particulate (DEP). The rat-based estimates of the working lifetime airborne concentrations associated with 0.1% excess risk of lung cancer are approximately 0.07 to 0.3 mg/m3 for ultrafine TiO2, CB, or DEP, and 0.7 to 1.3 mg/m3 for fine TiO2. Comparison of observed versus model-predicted lung burdens in rats shows that the dosimetry models predict reasonably well the retained mass lung burdens of fine or ultrafine poorly soluble particles in rats exposed by chronic inhalation. Additional model validation is needed for nanoparticles of varying characteristics, as well as extension of these models to include particle translocation to organs beyond the lungs. Such analyses would provide improved prediction of nanoparticle dose for risk assessment.

Development of risk-based nanomaterial groups for occupational exposure control.

Given the almost limitless variety of nanomaterials, it will be virtually impossible to assess the possible occupational health hazard of each nanomaterial individually. The development of science-based hazard and risk categories for nanomaterials is needed for decision-making about exposure control practices in the workplace. A possible strategy would be to select representative (benchmark) materials from various mode of action (MOA) classes, evaluate the hazard and develop risk estimates, and then apply a systematic comparison of new nanomaterials with the benchmark materials in the same MOA class. Poorly soluble particles are used here as an example to illustrate quantitative risk assessment methods for possible benchmark particles and occupational exposure control groups, given mode of action and relative toxicity. Linking such benchmark particles to specific exposure control bands would facilitate the translation of health hazard and quantitative risk information to the development of effective exposure control practices in the workplace. A key challenge is obtaining sufficient dose–response data, based on standard testing, to systematically evaluate the nanomaterials’ physical–chemical factors influencing their biological activity. Categorization processes involve both science-based analyses and default assumptions in the absence of substance-specific information. Utilizing data and information from related materials may facilitate initial determinations of exposure control systems for nanomaterials.

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.

Research Recommendations for Selected IARC-Classified Agents

Objectives There are some common occupational agents and exposure circumstances for which evidence of carcinogenicity is substantial but not yet conclusive for humans. Our objectives were to identify research gaps and needs for 20 agents prioritized for review based on evidence of widespread human exposures and potential carcinogenicity in animals or humans. Data sources For each chemical agent (or category of agents), a systematic review was conducted of new data published since the most recent pertinent International Agency for Research on Cancer (IARC) Monograph meeting on that agent. Data extraction Reviewers were charged with identifying data gaps and general and specific approaches to address them, focusing on research that would be important in resolving classification uncertainties. An expert meeting brought reviewers together to discuss each agent and the identified data gaps and approaches. Data synthesis Several overarching issues were identified that pertained to multiple agents; these included the importance of recognizing that carcinogenic agents can act through multiple toxicity pathways and mechanisms, including epigenetic mechanisms, oxidative stress, and immuno- and hormonal modulation. Conclusions Studies in occupational populations provide important opportunities to understand the mechanisms through which exogenous agents cause cancer and intervene to prevent human exposure and/or prevent or detect cancer among those already exposed. Scientific developments are likely to increase the challenges and complexities of carcinogen testing and evaluation in the future, and epidemiologic studies will be particularly critical to inform carcinogen classification and risk assessment processes.

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.

Options for occupational health surveillance of workers potentially exposed to engineered nanoparticles: state of the science.

Objective: Health authorities, employers, and worker representatives are increasingly faced with making decisions about occupational health surveillance of workers potentially exposed to engineered nanoparticles. This article was developed to identify options that can be considered. Methods: The published scientific literature on health effects from engineered and incidental nanoparticles and the principles of occupational health surveillance were reviewed to describe possible options and the evidence base for them. Results: Various options for occupational health surveillance were identified. The options ranged from no action targeted to nanotechnology workers to an approach that includes documentation of the presence of engineered nanoparticles, identification of potentially exposed workers, and general and targeted medical testing. Conclusions: Although the first priority should be to implement appropriate primary preventive measures, additional efforts to monitor employee health may be warranted. Continued research is needed, and the collection of such information for exposure registries may be useful for future epidemiologic studies.