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.     

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.     

Sensory and pulmonary irritation with exposure to methyl isocyanate

Methyl isocyanate (MIC) was tested for its potency as a sensory irritant and as a pulmonary irritant in mice. To evaluate sensory irritation, animals were exposed to MIC at concentrations between 0.5 and 7.6 ppm for a period of 90 min. A characteristic reflex decrease in respiratory rate indicating sensory irritation was observed. The concentration evoking a 50% decrease in respiratory rate (RD50) was found to be 1.3 ppm. To evaluate pulmonary irritation, animals were first anesthetized and fitted with a tracheal cannula. Following recovery from anesthesia, they were exposed to MIC at concentrations between 0.4 and 7.3 ppm for a period of 90 min. A characteristic decrease in respiratory rate indicating pulmonary irritation in tracheally cannulated (TC) mice was observed. The concentration evoking a 50% decrease in respiratory rate (RD50TC) was found to be 1.9 ppm. Thus, MIC was found to be a potent sensory and pulmonary irritant.     

Development of occupational exposure limits for the Hanford tank farms

Production of plutonium for the United States’ nuclear weapons program from the 1940s to the 1980s generated 53 million gallons of radioactive chemical waste, which is stored in 177 underground tanks at the Hanford site in southeastern Washington State. Recent attempts to begin the retrieval and treatment of these wastes require moving the waste to more modern tanks and result in potential exposure of the workers to unfamiliar odors emanating from headspace in the tanks. Given the unknown risks involved, workers were placed on supplied air respiratory protection. CH2MHILL, the managers of the Hanford site tank farms, asked an Independent Toxicology Panel (ITP) to assist them in issues relating to an industrial hygiene and risk assessment problem. The ITP was called upon to help determine the risk of exposure to vapors from the tanks, and in general develop a strategy for solution of the problem. This paper presents the methods used to determine the chemicals of potential concern (COPCs) and the resultant development of screening values and Acceptable Occupational Exposure Limits (AOELs) for these COPCs. A total of 1826 chemicals were inventoried and evaluated. Over 1500 chemicals were identified in the waste tanks headspaces and more than 600 of these were assigned screening values; 72 of these compounds were recommended for AOEL development. Included in this list of 72 were 57 COPCs identified by the ITP and of these 47 were subsequently assigned AOELs. An exhaustive exposure assessment strategy was developed by the CH2MHILL industrial hygiene department to evaluate these COPCs.     

Strategy of the scientific committee on occupational exposure limits (SCOEL) in the derivation of occupational exposure limits for carcinogens and mutagens

Setting standards, such as occupational exposure limits (OELs) for carcinogenic substances must consider modes of action. At the European Union level, the scientific committee on occupational exposure limits (SCOEL) has discussed a number of chemical carcinogens and has issued recommendations. For some carcinogens, health-based OELs were recommended, while quantitative assessments of carcinogenic risks were performed for others. For purposes of setting limits this led to the consideration of the following groups of carcinogens. (A) Non-threshold genotoxic carcinogens; for low-dose assessment of risk, the linear non-threshold (LNT) model appears appropriate. For these chemicals, regulations (risk management) may be based on the ALARA principle ("as low as reasonably achievable"), technical feasibility, and other socio-political considerations. (B) Genotoxic carcinogens, for which the existence of a threshold cannot be sufficiently supported at present. In these cases, the LNT model may be used as a default assumption, based on the scientific uncertainty. (C) Genotoxic carcinogens with a practical threshold, as supported by studies on mechanisms and/or toxicokinetics; health-based exposure limits may be based on an established NOAEL (no observed adverse effect level). (D) Non-genotoxic carcinogens and non-DNA-reactive carcinogens; for these compounds a true ("perfect") threshold is associated with a clearly founded NOAEL. The mechanisms shown by tumour promoters, spindle poisons, topoisomerase II poisons and hormones are typical examples of this category. Health-based OELs are derived for carcinogens of groups C and D, while a risk assessment is carried out for carcinogens of groups A and B. Substantial progress is currently being made in the incorporation of new types of mechanistic data into these regulatory procedures.     

Extensive changes to occupational exposure limits in Korea

Occupational exposure limits (OELs) are used as an important tool to protect workers from adverse chemical exposures and its detrimental effects on their health. The Ministry of Labor (MOL) can establish and publish OELs based on the Industrial Safety and Health Act in Korea. The first set of OELs was announced by the MOL in 1986. At that time, it was identical to the Threshold Limit Values of the American Conference of Governmental Industrial Hygienists. Until 2006, none the first OELs except for those of three chemicals (asbestos, benzene, and 2-bromopropane) were updated during the last twenty years. The Hazardous Agents Review Committee established under the MOL selected 126 chemicals from 698 chemicals covered by OELs using several criteria. From 2005 to 2006, the MOL provided research funds for academic institutions and toxicological laboratories to gather the evidence documenting the need to revise the outdated OELs. Finally, the MOL notified the revised OELs for 126 chemicals from 2007 to 2008. The revised OELs of 58 substances from among these chemicals were lowered to equal or less than half the value of the original OELs. This is the most substantial change in the history of OEL revisions in Korea.     

Awareness and understanding of occupational exposure limits in Sweden

The efficiency of a risk management tool, such as occupational exposure limits (OELs), partly depends on the responsible parties’ awareness and understanding of it. The aim of this study was to measure the awareness and understanding of OELs at Swedish workplaces and to collect opinions on their use and function. Through a web-based questionnaire targeting workers that are exposed to air pollutants or chemicals, and persons working with occupational health and safety or in management at workplaces where workers are exposed to air pollutants or chemicals 1017 responses were collected. The results show that awareness and understanding of Swedish OELs is low among workers, as well as managers and occupational health and safety employees. Statistically significant, but small, differences were found depending on the size of the company and the position in the company. Based on the results, it is recommended that authorities and the social partners target this lack of awareness and understanding regarding OELs. Also, other tools to ascertain a safe working environment with regards to chemicals exposure might be useful for Swedish workplaces.     

Extent of initial corneal injury as a basis for alternative eye irritation tests.

Based on studies that have characterized the extent of injury occurring with irritants of differing type and severity, we have proposed that extent of initial injury is the principal mechanism underlying ocular irritation. We report here our efforts to apply this hypothesis, as a mechanistic basis, to the development of an alternative eye irritation assay using an ex vivo rabbit corneal model. Rabbit eyes were obtained immediately after sacrifice or from an abattoir and 8.5-mm diameter corneal buttons were removed and cultured overnight at an air-liquid interface under serum-free conditions. Buttons were exposed to materials of differing type (surfactant, acid, base, alcohol and aldehyde) and irritancy (slight to severe) that had been previously characterized microscopically in the rabbit low-volume eye test. Exposure was accomplished by applying 1.5 microl of an irritant to a sterile, 3 mm diameter, filter paper disk and then placing the disk on the center of the corneal button for 10 s. After removal of the disk, buttons were washed and cultured for 3, 24 or 48 h. Buttons were then evaluated for extent of injury using a Live/Dead staining kit and fluorescent microscopy to measure cell size of live surface epithelial cells, area of epithelial denudation and depth of stromal injury. Ex vivo exposure to slight irritants generally reduced surface epithelial cell size (i.e. erosion) while exposure to mild irritants produced epithelial denudation with variable injury to the corneal stroma. Severe irritants generally produced extensive epithelial denudation and damaged the corneal stroma and endothelium. Overall, ex vivo extent of injury significantly correlated with in vivo extent of injury as measured in previous animal tests (r=0.81, P<0.001). These findings indicate that extent of corneal injury, as shown to be associated with ocular irritation occurring in vivo, can be applied to the development of a mechanistically-based alternative eye irritation model. We believe that this approach may ultimately lead to an alternative assay to replace the use of animals in ocular irritation testing.     

Human exposure to airborne aniline and formation of methemoglobin: a contribution to occupational exposure limits

Aniline is an important starting material in the manufacture of polyurethane-based plastic materials. Aniline-derived methemoglobinemia (Met-Hb) is well described in exposed workers although information on the dose–response association is limited. We used an experimental design to study the association between aniline in air with the formation of Met-Hb in blood and the elimination of aniline in urine. A 6-h exposure of 2 ppm aniline in 19 non-smoking volunteers resulted in a time-dependent increase in Met-Hb in blood and aniline in urine. The maximum Met-Hb level in blood (mean 1.21 ± 0.29 %, range 0.80–2.07 %) and aniline excretion in urine (mean 168.0 ± 51.8 µg/L, range 79.5–418.3 µg/L) were observed at the end of exposure, with both parameters rapidly decreasing after the end of exposure. After 24 h, the mean level of Met-Hb (0.65 ± 0.18 %) returned to the basal level observed prior to the exposure (0.72 ± 0.19 %); whereas, slightly elevated levels of aniline were still present in urine (means 17.0 ± 17.1 vs. 5.7 ± 3.8 µg/L). No differences between males and females as well as between slow and fast acetylators were found. The results obtained after 6-h exposure were also comparable to those observed in four non-smoking volunteers after 8-h exposure. Maximum levels of Met-Hb and aniline in urine were 1.57 % and 305.6 µg/L, respectively. Overall, our results contribute to the risk assessment of aniline and as a result, the protection of workers from aniline-derived adverse health effects at the workplace.     

The development and regulation of occupational exposure limits in Japan

The Ministry of Health, Labor and Welfare, on an administrative basis, establishes and supervises the Administrative Concentration Level, which can be viewed as an Occupational Exposure Limit (OEL) legally binding employers to maintain a good working environment. The Japan Society for Occupational Health, on a scientific basis, establishes the Recommended OELs, which can be viewed as a reference value for preventing adverse health effects on individual workers. In the case of carcinogens, Reference Values are recommended instead of OELs, corresponding to lifetime excessive risk of 10(-3) and 10(-4). The former is based on monitoring of the ambient working environment (area monitoring) while the latter is based on the monitoring of the individual worker. The two OELs influence each other in the course of establishment.     

The development and regulation of occupational exposure limits in China

Of the 700 million workers in China, approximately 200 million workers are potentially exposed to industrial hazards. Although the promulgation and implementation of occupational exposure limits (OELs) in China began in the mid-1950, a systematic approach was not formalized until the formation of the Subcommittee of Occupational Health Standards Setting (SOHSS) in 1981. More recently, the 2002 Occupational Disease Prevention and Control Act of the People's Republic of China created the legislative framework for the development and enforcement of OELs. The SOHSS, whose members are primarily health professionals, is the organization responsible for the development of recommended standards, under the auspices of the Ministry of Health. The philosophy of OEL development of the SOHSS consists of a two-step approach: (1) an initial health-based recommended standard is established based on scientific data, and (2) a final law-based standard takes into consideration both socioeconomic and technological feasibility. Governmental agencies such as the Centers for Diseases Control and Prevention and the Institutes of Public Health Supervision at the state, provincial or municipal levels are charged with the responsibilities of the enforcement of OELs. The process and challenges in the enforcement of OELs are discussed. A comparison is made between selected Chinese OELs and those in other countries. The OELs for benzene and industrial dusts (including silica) are discussed in some detail.     

The development and regulation of occupational exposure limits in Singapore

Singapore is an island republic in South East Asia with a workforce of about 2.1 million including 0.7 million employed in the manufacturing industry. Singapore's industry is diversified and the main growth sectors include microelectronics, chemical, petrochemical, pharmaceutical, and biomedical sectors. Exposure to chemical hazards is one of the main occupational health problems in the manufacturing sectors. The main roles of government in the protection of workers against safety and health hazards are to set standards and provide a proper infrastructure for industry to self-regulate. The occupation safety and health laws must provide adequate protection of workforce but must not disadvantage local industry in this globally competitive economy. To ensure a level playing field, Singapore's occupational exposure standards are benchmarked against those established in the developed countries. These standards are reviewed regularly to ensure they are realistic and relevant in tandem with worldwide trends. Industry and stakeholders are consulted before any new standards are introduced. In enforcing the laws relating to exposure standards, legal and administrative procedures are followed to ensure fairness and to prevent abuse.     

The development and regulation of occupational exposure limits in Taiwan

The occupational exposure limits (OELs) in Taiwan was promulgated in 1974 and has been revised five times since then. Many of the OELs were adopted from the most recent ACGIH TLVs and US OSHA PELs. A total of 483 chemicals were listed in the current Taiwan OELs Standard. The procedures of OELs development in Taiwan include the IOSH organized a recommended exposure limits (RELs) Committee to select the target chemicals and to recommend the RELs through literature review based on the health effects in the first stage, then, the CLA put policy needs, economical and technical feasibility into consideration and set up the final OELs at the second stage. A standard operation manual of RELs Committee has been developed. Based on our experience, several issues including the participation of representatives from a comprehensive spectrum, communication/education and training/enforcement, continuous collection of the local exposure data and health hazard information, use of health risk assessment, consideration of economic, and technical feasibility, as well as the globalization and information and experience sharing are critical in developing the appropriate OELs. Three examples including benzene, crystalline silica, and 2-methoxy ethanol are given to demonstrate the operation of system.     

The development and regulation of occupational exposure limits in Korea

With the institution of the new chemical regulatory framework in 2003, chemicals at the workplace have been classified into five categories; banned substances, permission-required substances, regulated substances, occupational exposure limit set substances, and other generally controlled substances. Currently, there are 698 substances with OELs. As we have come to gain our own experiences in the study and control of chemical hazards at the workplace such as the 2-bromopropane poisoning, OEL setting process has been streamlined. The OELs in Korea, however, remain merely as a recommendation, which does not require all the substances with OELs to be measured at the workplace. Coordination of whole program for hazardous chemicals including workplace measurement, OEL setting process, and enforcement activities is still needed in Korea.     

Defining occupational and consumer exposure limits for enzyme protein respiratory allergens under REACH

A wide range of substances have been recognized as sensitizing, either to the skin and/or to the respiratory tract. Many of these are useful materials, so to ensure that they can be used safely it is necessary to characterize the hazards and establish appropriate exposure limits. Under new EU legislation (REACH), there is a requirement to define a derived no effect level (DNEL). Where a DNEL cannot be established, e.g. for sensitizing substances, then a derived minimal effect level (DMEL) is recommended. For the bacterial and fungal enzymes which are well recognized respiratory sensitizers and have widespread use industrially as well as in a range of consumer products, a DMEL can be established by thorough retrospective review of occupational and consumer experience. In particular, setting the validated employee medical surveillance data against exposure records generated over an extended period of time is vital in informing the occupational DMEL. This experience shows that a long established limit of 60 ng/m³ for pure enzyme protein has been a successful starting point for the definition of occupational health limits for sensitization in the detergent industry. Application to this of adjustment factors has limited sensitization induction, avoided any meaningful risk of the elicitation of symptoms with known enzymes and provided an appropriate level of security for new enzymes whose potency has not been fully characterized. For example, in the detergent industry, this has led to general use of occupational exposure limits 3–10 times lower than the 60 ng/m³ starting point. In contrast, consumer exposure limits vary because the types of exposure themselves cover a wide range. The highest levels shown to be safe in use, 15 ng/m³, are associated with laundry trigger sprays, but very much lower levels (e.g. 0.01 ng/m³) are commonly associated with other types of safe exposure. Consumer limits typically will lie between these values and depend on the actual exposure associated with product use.     

The development and implementation of occupational exposure limits in Hong Kong

The blooming of economy in Hong Kong started in 1950s. People witnessed the change from a rural town to a modern city. It required the participation of a large number of labours. The development of a list of "practical" hygiene standards for control of airborne contaminants in workplaces is important to protect the well beings of those workers. It follows the pace of economic changes, and it takes quite a long while for the current Code of Practice on Control of Air Impurities in workplace environment to be published. There had been a consultation with stakeholders, professional bodies, representatives of trades, and industries as well as other related parties before it was finalized in 2002. Although the Code of Practice comprises just more than 200 chemicals, its application will be monitored and reviewed. In light of new knowledge, it will be updated to ensure the workers could be well protected.     

Species-specific inhalable exposures in the nickel industry: a new approach for deriving inhalation occupational exposure limits

The American Conference of Governmental Industrial Hygienists (ACGIH) and some regulatory authorities have revised their exposure limits for nickel and nickel compounds in workplaces based upon new sampling standards for inhalable nickel exposures. Others may be in the process of doing so. Safe standards for workplace exposures should utilize the most up-to-date health data on individual nickel species and should incorporate the principles of new sampling conventions that have been developed over the recent decades. The purpose of this paper is to review the basis for setting inhalable occupational exposure standards for the principal inorganic nickel species. It is hoped that this paper will (1) prompt companies in various nickel industry sectors to begin collecting the necessary inhalable aerosol measurements, speciation data, and particle-size information required to implement health-based sampling programs in the future, and (2) encourage regulators to derive species-specific, inhalable-based workplace standards for nickel and its inorganic compounds.     

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.