Occupational exposure limits for manufactured nanomaterials,a systematic review

Background: The toxicological properties of manufactured nanomaterials (MNMs) can be different from their bulk-material and uncertainty remains about the adverse health effects they may have on humans. Proposals for OELs have been put forward which can be useful for risk management and workers’ protection. We performed a systematic review of proposals for OELs for MNMs to better understand the extent of such proposals, as well as their derivation methods.

Methods: We searched PubMed and Embase with an extensive search string and also assessed the references in the included studies. Two authors extracted the data independently.

Results: We identified 20 studies that proposed in total 56 OEL values. Of these, two proposed a generic level for all MNMs, 14 proposed a generic OEL for a category of MNMs and 40 proposed an OEL for a specific nanomaterial. For specific fibers, four studies proposed a similar value but for carbon nanotubes (CNTs) the values differed with a factor ranging from 30 to 50 and for metals with a factor from 100 to 300. The studies did not provide explanations for this variation. We found that exposure to MNMs measured at selected workplaces may exceed even the highest proposed OEL. This indicates that the application and use of OELs may be useful for exposure reduction.

Conclusion: OELs can provide a valuable reference point for exposure reduction measures in workplaces. There is a need for more and better supported OELs based on a more systematic approach to OEL derivation.     

There's plenty of room at the forum: Potential risks and safety assessment of engineered nanomaterials

The celebrated physicist and Nobel laureate Richard Feynman was the first to predict the opportunities presented by the manipulation of matter at the level of individual atoms and molecules. Today, almost 50 years after his classic lecture on the wonders of the small world, the evolving nanotechnologies have the potential to bring about major changes in the lives of citizens. However, the very same properties that make engineered nanomaterials so promising from a technological perspective, such as their high degree of reactivity and the ability to cross biological barriers, could also make these novel materials harmful to human health and the environment. Therefore, exploitation of the full potential of the nanotechnologies requires close attention to safety issues. The 1st Nobel Forum mini-symposium on nanotoxicology was recently held in Stockholm, Sweden, and the program was devoted to the topic of definitions and standardization in nanotoxicological research, as well as nano-specific risk assessment and regulatory/legislative issues. Examples of recent and ongoing studies of carbon-based nanomaterials, including single-walled carbon nanotubes, using a wide range of in vitro and in vivo model systems were also presented. The current review will provide some highlights and conclusions from this exciting meeting.     

Research strategies for safety evaluation of nanomaterials, part IV: risk assessment of nanoparticles.

Nanoparticles are small-scale substances (<100 nm) with unique properties and, thus, complex exposure and health risk implications. This symposium review summarizes recent findings in exposure and toxicity of nanoparticles and their application for assessing human health risks. Characterization of airborne particles indicates that exposures will depend on particle behavior (e.g., disperse or aggregate) and that accurate, portable, and cost-effective measurement techniques are essential for understanding exposure. Under many conditions, dermal penetration of nanoparticles may be limited for consumer products such as sunscreens, although additional studies are needed on potential photooxidation products, experimental methods, and the effect of skin condition on penetration. Carbon nanotubes apparently have greater pulmonary toxicity (inflammation, granuloma) in mice than fine-scale carbon graphite, and their metal content may affect toxicity. Studies on TiO2 and quartz illustrate the complex relationship between toxicity and particle characteristics, including surface coatings, which make generalizations (e.g., smaller particles are always more toxic) incorrect for some substances. These recent toxicity and exposure data, combined with therapeutic and other related literature, are beginning to shape risk assessments that will be used to regulate the use of nanomaterials in consumer products.     

Risk metrics and cumulative risk assessment methodology for the FQPA

The Food Quality Protection Act (FQPA) of 1996 mandates that the U.S. Environmental Protection Agency consider both aggregate and cumulative risks. Aggregate assessments account for multiple sources and routes of exposure for a single chemical. Cumulative assessments combine exposures to two or more chemicals that share a common mechanism of toxicity. Probabilistic risk assessment methods are described for determining a population's distribution of the dose from exposure and the combination of that exposure characterization with appropriate toxicological information to form a risk assessment. An individual's dose from exposure is characterized as a set of chemical- and route-specific dose profiles over time. For each individual and each chemical and route, a margin of exposure (MOE) is calculated by dividing a toxicologically relevant benchmark dose (e.g., an ED(10)) by the individual's dose from exposure. The set of these MOEs for an individual is combined into the individual's Total MOE. The distribution of the Total MOEs in a population is compared to an Acceptable MOE. Advantages of the Total MOE approach over approaches based on reference doses are discussed. Some general comments on risk metrics are made, and some general guidance for cumulative risk assessments is provided.     

Derivation of a No-Significant-Risk-Level (NSRL) for diethanolamine (DEA)

Diethanolamine (DEA) has been listed on the State of California’s Proposition 65 List. This listing is based in part on tumors reported in a National Toxicology Program (NTP) 2-year dermal carcinogenicity study in mice which found clear evidence of carcinogenic activity in B6C3F₁ mice based on increased incidences of liver neoplasms in both sexes, and increased incidences of renal tubule neoplasms in males. Although considerable controversy exists on the relevance of the NTP study to humans, industries are obligated to comply with the Proposition 65 labeling requirement and drinking water discharge prohibition, unless they are able to demonstrate that DEA levels in their products are below a specific No Significant Risk Level (NSRL). The State of California has not published an NSRL for DEA. In this article, a NSRL of 5.6 μg/day and a life-stage-adjusted NSRL_adj of 1.4 μg/day are derived from the NTP carcinogenicity study using a benchmark dose modeling method based on the incidence of hepatocellular carcinomas in female mice, in accordance with the guidelines of California EPA.     

The role of exposure reconstruction in occupational human health risk assessment: Current methods and a recommended framework

Exposure reconstruction for substances of interest to human health is a process that has been used, with various levels of sophistication, as far back as the 1930s. The importance of robust and high-quality exposure reconstruction has been recognized by many researchers. It has been noted that misclassification of reconstructed exposures is relatively common and can result in potentially significant effects on the conclusions of a human health risk assessment or epidemiology study. In this analysis, a review of the key exposure reconstruction approaches described in over 400 papers in the peer-reviewed literature is presented. These approaches have been critically evaluated and classified according to quantitative, semiquantitative, and qualitative approaches. Our analysis indicates that much can still be done to improve the overall quality and consistency of exposure reconstructions and that a systematic framework would help to standardize the exposure reconstruction process in the future. The seven recommended steps in the exposure reconstruction process include identifying the goals of the reconstruction, organizing and ranking the available data, identifying key data gaps, selecting the best information sources and methodology for the reconstruction, incorporating probabilistic methods into the reconstruction, conducting an uncertainty analysis, and validating the results of the reconstruction. Influential emerging techniques, such as Bayesian data analysis, are highlighted. Important issues that will likely influence the conduct of exposure reconstruction into the future include improving statistical analysis methods, addressing the issue of chemical mixtures, evaluating aggregate exposures, and ensuring transparency with respect to variability and uncertainty in the reconstruction effort.     

Emissions and health risks from the use of 3D printers in an occupational setting

ABSTRACT

The aim of this study was to determine concentrations of particulates and volatile organic compounds (VOCs) emitted from 3D printers using polylactic acid (PLA) filaments at a university workroom to assess exposure and health risks in an occupational setting. Under typical-case (one printer) and worst-case (three printers operating simultaneously) scenarios, particulate concentration (total and respirable), VOCs and formaldehyde were measured. Air samples were collected in the printing room and adjacent hallway. Size-resolved levels of nano-diameter particles were also collected in the printing room. Total particulate levels were higher in the worst-case scenario (0.7 mg/m³) vs. typical-case scenario (0.3 mg/m³). Respirable particulate and formaldehyde concentrations were similar between the two scenarios. Size-resolved measurements showed that most particles ranged from approximately 27 to 116 nm. Total VOC levels were approximately 6-fold higher during the worst-case scenario vs. typical situation with isopropyl alcohol being the predominant VOC. Airborne concentrations in the hallway were generally lower than inside the printing room. All measurements were below their respective occupational exposure limits. In summary, emissions of particulates and VOCs increased when multiple 3D printers were operating simultaneously. Airborne levels in the adjacent hallway were similar between the two scenarios. Overall, data suggest a low risk of significant and persistent adverse health effects. Nevertheless, the health effects attributed to 3D printing are not fully known and adherence to good hygiene principles is recommended during use of this technology.     

Research strategies for safety evaluation of nanomaterials, Part III: nanoscale technologies for assessing risk and improving public health.

Risk assessment in the environmental health sciences focuses on understanding the nature of environmental exposures and the potential harm posed by those exposures which in turn is determined by the perturbation of biological pathways and the individual's susceptibility to damage. While there are extensive research efforts ongoing in these areas, progress in each is currently slowed by technological limitations including comprehensive assessment of multiple exposures in real time and dynamic assessment of biological response with high temporal and quantitative resolution. This Forum article discusses recent technological innovations capitalizing on the emergent properties of nanoscale materials and their potential adaptation to improving individual exposure assessment, determination of biological response, and environmental remediation. The ultimate goal is to raise the environmental health science community's awareness of these possibilities and encourage the development of improved strategies for assessing risk and improving public health.     

Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin‐of‐exposure values for hexavalent chromium

The current US Environmental Protection Agency (EPA) reference dose (RfD) for oral exposure to chromium, 0.003 mg kg^?1 day^?1, is based on a no‐observable‐adverse‐effect‐level from a 1958 bioassay of rats exposed to ≤25 ppm hexavalent chromium [Cr(VI)] in drinking water. EPA characterizes the confidence in this RfD as “low.” A more recent cancer bioassay indicates that Cr(VI) in drinking water is carcinogenic to mice at ≥30 ppm. To assess whether the existing RfD is health protective, neoplastic and non‐neoplastic lesions from the 2 year cancer bioassay were modeled in a three‐step process. First, a rodent physiological‐based pharmacokinetic (PBPK) model was used to estimate internal dose metrics relevant to each lesion. Second, benchmark dose modeling was conducted on each lesion using the internal dose metrics. Third, a human PBPK model was used to estimate the daily mg kg^?1 dose that would produce the same internal dose metric in both normal and susceptible humans. Mechanistic research into the mode of action for Cr(VI)‐induced intestinal tumors in mice supports a threshold mechanism involving intestinal wounding and chronic regenerative hyperplasia. As such, an RfD was developed using incidence data for the precursor lesion diffuse epithelial hyperplasia. This RfD was compared to RfDs for other non‐cancer endpoints; all RfD values ranged 0.003–0.02 mg kg^?1 day^?1. The lowest of these values is identical to EPA's existing RfD value. Although the RfD value remains 0.003 mg kg^?1 day^?1, the confidence is greatly improved due to the use of a 2‐year bioassay, mechanistic data, PBPK models and benchmark dose modeling.     

Application of a quantitative weight of evidence approach for ranking and prioritising occupational exposure scenarios for titanium dioxide and carbon nanomaterials

Substantial limitations and uncertainties hinder the exposure assessment of engineered nanomaterials (ENMs). The present deficit of reliable measurements and models will inevitably lead in the near term to qualitative and uncertain exposure estimations, which may fail to support adequate risk assessment and management. Therefore it is necessary to complement the current toolset with user-friendly methods for near-term nanosafety evaluation. This paper proposes an approach for relative exposure screening of ENMs. For the first time, an exposure model explicitly implements quantitative weight of evidence (WoE) methods and utilises expert judgement for filling data gaps in the available evidence-base. Application of the framework is illustrated for screening of exposure scenarios for nanoscale titanium dioxide, carbon nanotubes and fullerenes, but it is applicable to other nanomaterials as well. The results show that the WoE-based model overestimates exposure for scenarios where expert judgement was substantially used to fill data gaps, which suggests its conservative nature. In order to test how variations in input data influence the obtained results, probabilistic Monte Carlo sensitivity analysis was applied to demonstrate that the model performs in stable manner.     

A retrospective analysis of Acute Reference Doses for pesticides evaluated in the European Union

This retrospective analysis of Acute Reference Doses (ARfD) values is based on pesticides that have been evaluated and peer-reviewed in Europe between 2000 and 2008. The published database of the 198 ARfDs was analysed. For 48% of all substances, no ARfD was considered necessary because of the low acute toxicity of these pesticides. The majority of ARfDs were based on studies that were required for pesticides and conducted for regulatory purposes and in which specific acute alerts were investigated. In less than 10% of cases, conservatively established ARfDs were based on repeated-dose toxicity or multigeneration studies. For 4 of these 198 pesticides, a refinement of a conservative ARfD using an additional toxicity study would be justifiable because a more realistic calculation of the exposure component was not sufficient to eliminate any health concern. In the analysed database, special studies for ARfD refinement were submitted for 8 of the 198 pesticides. They were mostly performed in addition to the basic acute toxicity data requirements, in cases in which it was apparent that the acute intake estimation exceeded a conservatively established ARfD. However, several studies were not accepted by regulatory authorities because of quality deficiencies. The results of this analysis indicate that the development of a harmonised study design that produces consistent and robust toxicological data on the occurrence of acute effects and their dose response would be valuable for setting ARfDs. Such a protocol, plus additional research on the mode of action for acute effects observed in relevant targets for ARfD derivation, is considered as an important prerequisite for an improved acute risk assessment for pesticides.     

Setting occupational exposure limits for unstudied pharmaceutical intermediates using an in vitro parallelogram approach

Occupational exposure limits for unstudied pharmaceutical synthetic intermediates are often established under the assumption that penultimate and near-ultimate intermediates have the same structure-activity and dose-response as the ultimate active pharmaceutical ingredient (API). This is seldom the case because moieties that render biological activity to the API are often protected or modified for synthetic purposes. Incorrectly assuming that intermediates have biological activity similar to the API may lead to excessive exposure controls that in turn impose unnecessary ergonomic hazards on workers and greatly reduces the scale and efficiency of production. Instead of assuming intermediates have the same toxicity profile as the API, it is feasible to use a parallelogram approach to establish exposure limits for synthetic intermediates using low-cost in vitro data. By comparing in vitro responses of intermediates to structurally similar data-rich molecules such as the API, occupational exposure categories can be established for unstudied intermediates. In this contribution (1) methods for setting occupational exposure limits for data-poor compounds are reviewed; (2) applications and limitations of in vitro assays are discussed; (3) two exposure categorization examples are presented that rely on an in vitro parallelogram approach; and (4) inherent safeguards for uncertainties in pharmaceutical risk assessment are identified. In vitro hazard and dose-response information for unstudied intermediates that are structurally similar to well-studied APIs can greatly enhance the basis for setting occupational exposure limits for unstudied synthetic intermediates.     

Risk assessment of engineered nanomaterials: a review of available data and approaches from a regulatory perspective

Abstract

It has been largely recognised that substantial limitations and uncertainties make the conventional risk assessment (RA) of chemicals unfeasible to apply to engineered nanomaterials (ENMs) today, which leaves the regulators with little support in the near term. The aim of this paper is to discuss the state of the art in the area of the RA of nanomaterials, focusing on the available data and approaches. There is a paucity of reliable information in the online safety databases and the literature is dominated by (eco)toxicity studies, while the nano-exposure research lags behind. Most of the reviewed nano-RA approaches are designed to serve as preliminary risk screening and/or research prioritisation tools and are not intended to support regulatory decision making. In this context, we recommend to further study the possibilities to apply complementary/alternative tools for near-term RA of ENMs in order to facilitate their timely regulation, using the data that are currently available in the literature.     

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.     

Derivation of an occupational exposure limit for inorganic borates using a weight of evidence approach

Inorganic borates are encountered in many settings worldwide, spurring international efforts to develop exposure guidance (US EPA, 2004; WHO, 2009; ATSDR, 2010) and occupational exposure limits (OEL) (ACGIH, 2005; MAK, 2011). We derived an updated OEL to reflect new data and current international risk assessment frameworks. We assessed toxicity and epidemiology data on inorganic borates to identify relevant adverse effects. International risk assessment frameworks (IPCS, 2005, 2007) were used to evaluate endpoint candidates: reproductive toxicity, developmental toxicity, and sensory irritation. For each endpoint, a preliminary OEL was derived and adjusted based on consideration of toxicokinetics, toxicodynamics, and other uncertainties. Selection of the endpoint point of departures (PODs) is supported by dose–response modeling. Developmental toxicity was the most sensitive systemic effect. An OEL of 1.6 mg B/m³ was estimated for this effect based on a POD of 63 mg B/m³ with an uncertainty factor (UF) of 40. Sensory irritation was considered to be the most sensitive effect for the portal of entry. An OEL of 1.4 mg B/m³ was estimated for this effect based on the identified POD and an UF of 1. An OEL of 1.4 mg B/m³ as an 8-h time-weighted average (TWA) is recommended.     

Exposure Assessment of Multiple Mycotoxins and Cumulative Health Risk Assessment: A Biomonitoring-Based Study in the Yangtze River Delta,China

The extensive exposure to multiple mycotoxins has been demonstrated in many countries; however, realistic assessments of the risks related to cumulative exposure are limited. This biomonitoring study was conducted to investigate exposure to 23 mycotoxins/metabolites and their determinants in 227 adults (aged 20–88 years) in the Yangtze River Delta, China. Eight mycotoxins were detected in 110 urine samples, and multiple mycotoxins co-occurred in 51/227 (22.47%) of urine samples, with deoxynivalenol (DON), fumonisin B1 (FB1), and zearalenone (ZEN) being the most frequently occurring. For single mycotoxin risk assessment, FB1, ZEN, aflatoxin B1 (AFB1), and ochratoxin A (OTA) all showed potential adverse effects. However, for the 12 samples containing DON and ZEN, in which none had a hazard risk, the combination of both mycotoxins in two samples was considered to pose potential endocrine disrupting risks to humans by hazard index (HI) method. The combined margin of exposure (MOE_T) for AFB1 and FB1 could constitute a potential health concern, and AFB1 was the main contributor. Our approach provides a blueprint for evaluating the cumulative risks related to different types of mycotoxins and opens a new horizon for the accurate interpretation of epidemiological health outcomes related to multi-mycotoxin exposure.     

Pediatric susceptibility to 18 industrial chemicals: a comparative analysis of newborn with young animals

We comprehensively re-analyzed the toxicity data for 18 industrial chemicals from repeated oral exposures in newborn and young rats, which were previously published. Two new toxicity endpoints specific to this comparative analysis were identified, the first, the presumed no observed adverse effect level (pNOAEL) was estimated based on results of both main and dose-finding studies, and the second, the presumed unequivocally toxic level (pUETL) was defined as a clear toxic dose giving similar severity in both newborn and young rats. Based on the analyses of both pNOAEL and pUETL ratios between the different ages, newborn rats demonstrated greater susceptibility (at most 8-fold) to nearly two thirds of these 18 chemicals (mostly phenolic substances), and less or nearly equal sensitivity to the other chemicals. Exceptionally one chemical only showed toxicity in newborn rats. In addition, Benchmark Dose Lower Bound (BMDL) estimates were calculated as an alternative endpoint. Most BMDLs were comparable to their corresponding pNOAELs and the overall correlation coefficient was 0.904. We discussed how our results can be incorporated into chemical risk assessment approaches to protect pediatric health from direct oral exposure to chemicals.     

Critical analysis of literature on low-dose synergy for use in screening chemical mixtures for risk assessment

There is increasing interest in the use of tiered approaches in risk assessment of mixtures or co-exposures to chemicals for prioritization. One possible screening-level risk assessment approach is the threshold of toxicological concern (TTC). To date, default assumptions of dose or response additivity have been used to characterize the toxicity of chemical mixtures. Before a screening-level approach could be used, it is essential to know whether synergistic interactions can occur at low, environmentally relevant exposure levels. Studies demonstrating synergism in mammalian test systems were identified from the literature, with emphasis on studies performed at doses close to the points of departure (PODs) for individual chemicals. This search identified 90 studies on mixtures. Few included quantitative estimates of low-dose synergy; calculations of the magnitude of interaction were included in only 11 papers. Quantitative methodology varied across studies in terms of the null hypothesis, response measured, POD used to test for synergy, and consideration of the slope of the dose-response curve. It was concluded that consistent approaches should be applied for quantification of synergy, including that synergy be defined in terms of departure from dose additivity; uniform procedures be developed for assessing synergy at low exposures; and the method for determining the POD for calculating synergy be standardized. After evaluation of the six studies that provided useful quantitative estimates of synergy, the magnitude of synergy at low doses did not exceed the levels predicted by additive models by more than a factor of 4.     

Benchmark dose of cadmium concentration in rice for renal effects in a cadmium‐polluted area in Japan

The aim of this study was to estimate the reference level of cadmium in rice as the benchmark doses (BMD) and their 95% lower confidence limits (BMDL) for various renal effects by applying an updated hybrid approach. The participants were 1120 men and 1274 women aged 50 years or older who lived in the environmentally exposed Kakehashi river basin for at least 30 years. As indicators of renal dysfunction, glucose, protein, aminonitrogen, metallothionein and β₂‐microgrobulin in urine were measured. Cadmium concentration was determined for rice samples stored in warehouses of the farmers in all of the polluted hamlets. The BMD and BMDL that corresponded to an additional risk of 5% were calculated with background risk at a zero exposure set at 5%. The obtained BMDLs were 0.39 (aminonitrogen), 0.26 (metallothionein), 0.25 (β₂‐microgrobulin) mg kg^–1 in men and 0.44 (glucose), 0.32 (protein), 0.33 (aminonitrogen), 0.28 (metallothionein) and 0.24 (β₂‐microgrobulin) mg kg^–1 in women. The lowest BMDL was 0.25 and 0.24 mg kg^–1 (β₂‐microgrobulin) in men and women respectively. These values were lower than the maximum level (0.4 mg kg^–1) determined by the Codex Alimentarius Commission, indicating that these BMDLs may contribute to further discussion on the health risk assessment of cadmium exposure. Copyright © 2014 John Wiley & Sons, Ltd.     

Towards quantitative uncertainty assessment for cancer risks: central estimates and probability distributions of risk in dose-response modeling

Regulatory agencies and the scientific community have been engaged in a long-term effort to strengthen health risk assessment procedures. Recently the momentum of this effort has accelerated to increasing biological information for a variety of toxic compounds and emphasis on the policy goal of broader characterization of scientific uncertainty (in contrast to providing only a single risk estimate). For example, the OMB Regulatory Analysis Guidelines [OMB, 2003. Office of Management and Budget. Circular A-4. Available from: ] suggest that a formal quantitative uncertainty analysis be performed for economic assessments in support of major regulatory analyses, a process that can utilize both expected values and probability distributions for risk estimates. Some efforts have been made in the past to provide probability distributions of risk estimates. In this article, we examine a procedure for constructing probability distributions and expected values of risk estimates using a Bayesian framework. This approach has the advantage of mathematical soundness and computational feasibility, given the Markov chain Monte Carlo software tools that are available today. Importantly, the Bayesian framework can serve as a unifying platform for uncertainty analysis in cancer risk assessment. This paper provides some initial applications of Bayesian methods in quantitative analysis of uncertainty in cancer risk assessment, including implementation with cancer dose-response data sets for two chemicals. The Bayesian expected risk calculations provide an approach to generating a central estimate of risk that does not have the instability problems that have often limited utility of MLE risk estimates.