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.     

Derivation of an occupational exposure limit for diacetyl using dose‐response data from a chronic animal inhalation exposure study

Occupational exposure limits (OELs) have been previously proposed for diacetyl; however, most of these values are based on worker cohort studies that are known to have several limitations and confounders. In this analysis, an 8 hour time‐weighted average (TWA) OEL for diacetyl was derived based on data from a chronic, 2 year animal inhalation study recently released by the US National Toxicology Program. In that study, complete histopathology was conducted on male and female mice and rats exposed to 0, 12.5, 25 or 50 ppm diacetyl. Several responses in the lower respiratory tract of rats (the more sensitive species) were chosen as the critical endpoints of interest. Benchmark concentration (BMC) modeling of these endpoints was used to estimate BMC values associated with a 10% extra risk (BMC₁₀) and the associated 95% lower confidence bound (BMCL₁₀), which were subsequently converted to human equivalent concentrations (HECs) using a computational fluid dynamics‐physiologically based pharmacokinetic (CFD‐PBPK) model to account for interspecies dosimetry differences. A composite uncertainty factor of 8.0 was applied to the human equivalent concentration values to yield 8 hour TWA OEL values with a range of 0.16‐0.70 ppm. The recommended 8 hour TWA OEL for diacetyl vapor of 0.2 ppm, based on minimal severity of bronchiolar epithelial hyperplasia in the rat, is practical and health‐protective.     

Workshop report: Strategies for setting occupational exposure limits for engineered nanomaterials

Occupational exposure limits (OELs) are important tools for managing worker exposures to chemicals; however, hazard data for many engineered nanomaterials (ENMs) are insufficient for deriving OELs by traditional methods. Technical challenges and questions about how best to measure worker exposures to ENMs also pose barriers to implementing OELs. New varieties of ENMs are being developed and introduced into commerce at a rapid pace, further compounding the issue of OEL development for ENMs. A Workshop on Strategies for Setting Occupational Exposure Limits for Engineered Nanomaterials, held in September 2012, provided an opportunity for occupational health experts from various stakeholder groups to discuss possible alternative approaches for setting OELs for ENMs and issues related to their implementation. This report summarizes the workshop proceedings and findings, identifies areas for additional research, and suggests potential avenues for further progress on this important topic.     

Evaluation of concentration–response options for diacetyl in support of occupational risk assessment

The current emphasis on occupational exposures to diacetyl has led to new research on its effects. We evaluated whether the data are sufficient to support a transition from a hazard-based risk management approach to a quantitative occupational risk assessment approach, characterized by developing a health-based occupational exposure limit (OEL). Inhalation health effects data were evaluated and issues and uncertainties related to occupational risk assessment needs were identified. A systematic hazard characterization, supported by both the toxicology and epidemiology literature, showed that the respiratory tract effects of diacetyl are the primary end points of relevance for developing an OEL. In an effort to provide a systematic approach for the analysis of the issues that need to be considered in developing an occupational risk assessment for diacetyl, a potential OEL was derived. A concentration–response assessment was completed using tracheobronchial effects in mice as the critical effect. The resulting benchmark concentration (lower bound estimate or BMCL) was adjusted to a human equivalent concentration of 1.8 ppm. A composite uncertainty factor of 10 was recommended to account for extrapolation from an adjusted BMCL from an animal study and for human variability in sensitivity and taking into account other uncertainties in the overall database. The resulting OEL recommendation of 0.2 ppm as a time-weighted average (TWA) was supported by the current occupational epidemiology literature. This evaluation showed that a health-based OEL value can be derived for diacetyl with moderate to high confidence.     

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.     

Use of low-dose clinical pharmacodynamic and pharmacokinetic data to establish an occupational exposure limit for dapagliflozin,a potent inhibitor of the renal sodium glucose co-transporter 2

Classical risk assessment models for setting safe occupational exposure limits (OEL) have used multiple uncertainty factors (UF) applied to a point of departure (POD), e.g., a No Observed Effect Level (NOEL), which in some cases is the pharmacological effect. Dapagliflozin promotes glucosuria by inhibiting the renal sodium–glucose cotransporter-2 transporter. The initial OEL for dapagliflozin (0.002 mg/m³) was calculated when low dose clinical data was not available to identify a NOEL resulting in the need to use excessive UFs. To reduce the UFs from the OEL, a clinical pharmacodynamic [glucosuria and urinary glucose dipstick (UGD)] and pharmacokinetic study was conducted with single oral doses of 0.001, 0.01, 0.1, 0.3, 1.0 or 2.5 mg administered to 36 healthy subjects. Dose-related dapagliflozin systemic exposures were observed at doses ?0.1 mg and glucosuria was observed at doses ?0.3 mg and corroborated by UGD. The NOEL was therefore 0.1 mg for glucosuria. For setting the new OEL, no UFs were required. Dividing the POD by 10 m³ (the volume of air an adult inhales in a workday), the resulting OEL was 0.01 mg/m³. In conclusion, low-dose clinical pharmacodynamic and pharmacokinetic data can allow the OEL to be adjusted to the highest safe level.     

手术室骨科专科护士职业暴露的风险管理与防护

目的探讨手术室骨科专科护士职业暴露的风险管理与防护。方法采集2009年1月-2009年125480例骨科关节置换手术护士职业暴露的例数,进行风险因素评估,制定护理对策,预警干预手术室护士职业暴露的发生。结果通过对480例骨科关节置换手术骨科专科护士职业暴露发生例数分析,其中对照组发生职业暴露22例,职业暴露发生率为8．8％;干预组5例,职业暴露发生率为2．2％,两组间的差异有统计学意义（P〈0．01）。结论通过风险因素评估,干预手术室护士职业暴露的发生,降低手术护士职业暴露发生率。     

Background, approaches and recent trends for setting health-based occupational exposure limits: a minireview

The setting of occupational exposure limits (OELs) are founded in occupational medicine and the predictive toxicological testing, resulting in exposure-response relationships. For compounds where a No-Observed-Adverse-Effect-Level (NOAEL) can be established, health-based OELs are set by dividing the NOAEL of the critical effect by an overall uncertainty factor. Possibly, the approach may also be used for carcinogens if the mechanism is epigenetic or the genetic effect is secondary to effect from reactions with proteins such as topoisomerase inhibitors, and mitotic and meiotic spindle poisons. Additionally, the NOAEL approach may also be used for compounds with weak genotoxic effect, playing no or only a minor role in the development of tumours. No health-based OEL can be set for direct-acting genotoxic compounds where the life-time risks may be estimated from the low-dose linear non-threshold extrapolation, allowing a politically based exposure level to be set. OELs are set by several agencies in the US and Europe, but also in-house in major chemical and pharmaceutical companies. The benchmark dose approach may in the future be used where it has advantage over the NOAEL approach. Also, more attention should be devoted to sensitive groups, toxicological mechanisms and interactions as most workplace exposures are mixtures.     

Fungal spores: A critical review of the toxicological and epidemiological evidence as a basis for occupational exposure limit setting

Fungal spores are ubiquitous in the environment. However, exposure levels in workplaces where mouldy materials are handled are much higher than in common indoor and outdoor environments. Spores of all tested species induced inflammation in experimental studies. The response to mycotoxin-producing and pathogenic species was much stronger. In animal studies, nonallergic responses dominated after a single dose. Allergic responses also occurred, especially to mycotoxin-producing and pathogenic species, and after repeated exposures. Inhalation of a single spore dose by subjects with sick building syndrome indicated no observed effect levels of 4?×?10³ Trichoderma harzianum spores/m³ and 8?×?10³ Penicillium chrysogenum spores/m³ for lung function, respiratory symptoms, and inflammatory cells in the blood. In asthmatic patients allergic to Penicillium sp. or Alternaria alternata, lowest observed effect levels (LOELs) for reduced airway conductance were 1?×?10⁴ and 2?×?10⁴ spores/m³, respectively. In epidemiological studies of highly exposed working populations lung function decline, respiratory symptoms and airway inflammation began to appear at exposure levels of 10⁵ spores/m³. Thus, human challenge and epidemiological studies support fairly consistent LOELs of approximately 10⁵ spores/m³ for diverse fungal species in nonsensitised populations. Mycotoxin-producing and pathogenic species have to be detected specifically, however, because of their higher toxicity.     

Occupational exposure limits: a comparative study

Occupational exposure limits (OELs) are used as an important regulatory instrument to protect workers' health from adverse effects of chemical exposures. The OELs mirror the outcome of the risk assessment and risk management performed by the standard setting actor. In this study we compared the OELs established by 18 different organisations or national regulatory agencies. The OELs were compared with respect to: (1) what chemicals have been selected and (2) the average level of exposure limits for all chemicals. Our database contains OELs for a total of 1341 substances; of these 25 substances have OELs from all 18 organisations while more than one-third of the substances are only regulated by one organisation. The average level of the exposure limits has declined during the past 10 years for 6 of the 8 organisations in our study for which historical data were available; it has increased for Poland and remained nearly unchanged for Sweden. The average level of OELs differs substantially between organisations; the US OSHA exposure limits are (on average) nearly 40 % higher than those of Poland. The scientific or policy-related motivations for these differences remain to be analysed.     

Biomarkers of occupational exposure do anticancer agents: a minireview

The majority of anticancer agents has in common DNA-damaging properties and affects not only target-cells but also non-tumour cells. Its genotoxicity has been demonstrated in experimental models and in cancer patients treated with chemotherapy. Health care personnel involved in the preparation and administration of chemotherapy is therefore at risk for adverse health effects, since most environmental sampling studies demonstrated that there is widespread contamination of work surfaces and equipments with anticancer drugs. Adherence to safety guidelines and proper use of personal protective equipment are insufficient to prevent significant absorption, as evidenced by the presence of detectable amounts of drugs in urine samples and increased frequency of genotoxicity biomarkers. In this minireview, a critical appraisal of the most important biomarkers used for the evaluation of occupational exposure to anticancer agents as well as a summary of the key findings from several studies published in this field is performed.     

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.     

Endpoints as human biomarkers in exposure assessment of triazoles fungicides

Potential endpoint biomarkers were evaluated in the assessment of exposure to triazoles, in the southern region of Minas Gerais, Brazil. Volunteers were divided into three groups: occupationally exposed and rural residents (n = 21), non-occupationally exposed and rural residents (n = 35) and non-occupationally exposed and urban residents (n = 30). Of all endpoints evaluated, plasma concentration of androstenedione (p < 0.001) and glycine-conjugated bile acids presented statistical differences in the three studied groups (p < 0.05). However, our findings concerning oxidative stress and testosterone levels, plus that related to unconjugated and taurine conjugated bile acids, suggested that more studies are necessary to evaluate their potential as biomarkers for triazole exposure, as statistical significance was not attained between the groups. Our human population data contributes to the development of triazole exposure risk assessment with respect to these potential effect biomarkers, in potentially vulnerable groups and individuals.     

Derivation of occupational exposure limits: Differences in methods and protection levels

Frameworks for deriving occupational exposure limits (OELs) and OEL-analogue values (such as derived-no-effect levels [DNELs]) in various regulatory areas in the EU and at national level in Germany were analysed. Reasons for differences between frameworks and possible means of improving transparency and harmonisation were identified. Differences between assessment factors used for deriving exposure limits proved to be one important reason for diverging numerical values. Distributions for exposure time, interspecies and intraspecies extrapolation were combined by probabilistic methods and compared with default values of assessment factors used in the various OEL frameworks in order to investigate protection levels. In a subchronic inhalation study showing local effects in the respiratory tract, the probability that assessment factors were sufficiently high to protect 99% and 95% of the target population (workers) from adverse effects varied considerably from 9% to 71% and 17% to 87%, respectively, between the frameworks. All steps of the derivation process, including the uncertainty associated with the point of departure (POD), were further analysed with two examples of full probabilistic assessments. It is proposed that benchmark modelling should be the method of choice for deriving PODs and that all OEL frameworks should provide detailed guidance documents and clearly define their protection goals by stating the proportion of the exposed population the OEL aims to cover and the probability with which they intend to provide protection from adverse effects. Harmonisation can be achieved by agreeing on the way to perform the methodological steps for deriving OELs and on common protection goals.     

Diazepam influences urinary bioindicator of occupational toluene exposure

In the present study, we investigated the influence of diazepam (DZP) on the excretion of TOL by examining their urinary metabolites, hippuric acid (HA) and ortho-cresol (o-C). Male Wistar rats were exposed to TOL (20 ppm) in a nose-only exposure chamber (6 h/day, 5 days/week for 6 weeks) with simultaneous administration of DZP (10 mg/kg/day). Urinary o-C levels were determined by GC–MS, while HA, creatinine (CR), DZP and its metabolite, nordiazepam, were analysed by HPLC-DAD. The results of a Mann-Whitney U test showed that DZP influenced the urinary excretion of o-C (p < 0.05). This pioneering study revealed that there was an interaction between DZP and TOL, probably by the inhibition of the CYP isoforms (CYP2B6, CYP2C8, CYP2E1, and CYP1A2) involved in the oxidative metabolism of the solvent. This is relevant information to be considered in the biomonitoring of occupational toluene exposure.     

Development of an occupational exposure limit for n-propylbromide using benchmark dose methods

This paper presents the development of an occupational exposure level (OEL) for n-propylbromide (nPB) using benchmark dose methods. nPB is a non-ozone depleting solvent, proposed under the Significant New Alternatives Policy (SNAP) for use as a precision vapor degreaser. OELs have generally been developed on the basis of a NOAEL or LOAEL and application of uncertainty factors; this paper represents a departure from historic methods. Six recently completed toxicological studies were critically reviewed to identify (1) toxicologically significant endpoints, (2) dose-response information on these endpoints, and (3) uncertainties and limitations associated with the studies. Dose-response data were compiled and entered into the USEPA's benchmark dose software for calculation of a benchmark dose (BMD) and a benchmark dose low (BMDL). Once values were estimated for all relevant studies, they were then incorporated into a weight-of-evidence approach to develop a single BMD and BMDL representative of nPB. This approach is similar to that recently taken by USEPA to develop their own recommended OEL for nPB. USEPA's approach is compared and contrasted with ours, particularly in relation to the application of uncertainty factors (UFs) to generate a final OEL. There are no published criteria for application of UFs in developing an OEL. Although USEPA recommends utilizing a UF of 9, based on intraspecies variability and pharmacokinetic differences between rats and humans, to meet the goal of protecting healthy adult in a workplace setting, no uncertainty factor was deemed necessary for nPB in this paper. Therefore, the BMDL was recommended as the OEL.     

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.     

临床护士职业暴露与标准预防的管理探讨

目的了解临床护士的职业暴露现状,职业暴露的危害性因素对护士的影响,探讨职业安全管理的有效方法。方法对全院151名临床护士采用调查问卷随机抽样法,对2007年和2008年发生的职业暴露事件进行回顾性分析。结果加强标准预防教育后,护理人员的职业安全意识明显提高,发生职业暴露事件明显减少。结论临床护士职业暴露发生率高,应强化护理人员的职业安全意识,加强医护人员的职业防护培训,以促进职业安全,使职业暴露的发生率降至最低。     

Derivation of endogenous equivalent values to support risk assessment and risk management decisions for an endogenous carcinogen: Ethylene oxide

An approach is presented for ethylene oxide (EO) to derive endogenous equivalent (EE) values, which are endogenous levels normally found within the body expressed in terms of exogenous exposures. EE values can be used to support risk assessment and risk management decisions for chemicals such as EO that have both endogenous and exogenous exposure pathways. EE values were derived using a meta-analysis of data from the published literature characterizing the distribution for an EO biomarker of exposure, hemoglobin N-(2-hydroxyethyl)-valine (HEV), in unexposed populations. These levels are compared to the those reported in exposed populations (smokers, workers). Correlation between the biomarker of exposure and external exposures of EO were applied to this distribution to determine corresponding EE values, which range from 0.13 to 6.9 ppb for EO in air. These values are orders of magnitude higher than risk-based concentration values derived for EO using default methods, and are provided as a pragmatic, data-driven alternative approach to managing the potential risks from exogenous exposures to EO.     

Influence of occupational styrene exposure on memory and attention

Short-term memory, perceptual speed, attention and psychomotor function were studied in 55 workers professionally exposed to styrene. The subjects were grouped according to their urinary styrene metabolites. Those with higher styrene exposure showed a significant impairment of short-term memory only.