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.     

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.     

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.     

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.     

New trends in the development of occupational exposure limits for airborne chemicals in China

Occupational exposure limits (OELs) are well established in many countries, which serve occupational professionals as benchmarks of industrial hygiene practice at workplaces worldwide. Starting in the mid-1950s, the central government of China began promulgating OELs for hazardous substances at workplaces. This paper discusses the historical basis, philosophical principles and schematic protocols of developing and setting OELs in China. The underlying principles include: (1) protection of human health being the first and the most important criterion; (2) the use of quantitative epidemiological studies in humans being given top priority; (3) integration and full use of all information sources, including animal experimental data for new chemicals or chemicals with new toxicity concerns; (4) considerations of socioeconomic and technological feasibilities in the country; and (5) amending existing standards based on new evidence. The strategy of the World Health Organization's "Two-step Procedure" is applied to convert health-based recommendations to law-based operational OELs, with considerations for national technological and socioeconomic conditions and priorities. As a result of the recent passage of the new law Occupational Diseases Prevention and Control Act of the People's Republic of China (ODPCAct), an official document Occupational Exposure Limits for Hazardous Agents in the Workplace containing a comprehensive list of new and amended OELs has been issued, which has now become one of the most essential regulations affiliated with the ODPCAct. This paper provides a brief summary of the salient features of the new law ODPCAct and the principles and processes of developing or amending OELs. This paper also discusses the challenges that lie ahead in enforcing the new regulations in China.     

Human carcinogenic risk evaluation, part II: contributions of the EUROTOX specialty section for carcinogenesis.

There is growing recognition that carcinogenic risk extrapolation to low doses (and standard setting) should consider the mode of action of a given chemical. So far, there is agreement on distinguishing between genotoxic and nongenotoxic chemicals; yet, further differentiations seem appropriate. For genotoxic carcinogens, case studies of chemicals point to many possibilities for assessing carcinogenic risk. There are numerous, apparently genotoxic carcinogens where practical thresholds are a matter of discussion. For instance, positive data of chromosomal effects only, in the absence of mutagenicity, may support the characterization of a compound that produces carcinogenic effects only at high, toxic doses. There is a wide consensus that for non-DNA-reactive genotoxicants, such as aneugens, thresholds should be defined. Specific mechanisms of clastogenicity have been repeatedly addressed as also having thresholds, such as topoisomerase II poisons, or mechanisms based on reactive oxygen. These and other arguments together lead to the distinction of four groups of carcinogens, which have been introduced (C. Streffer et al., 2004, Springer-Verlag). There are nonthreshold genotoxic carcinogens (for low-dose risk assessment, the linear nonthreshold [LNT] model appears appropriate); genotoxic carcinogens, for which the existence of a threshold cannot be sufficiently supported (in these cases the LNT model is used as a default assumption, based on the scientific uncertainty and backed by the precautionary principle); genotoxic carcinogens for which a practical threshold is supported; and nongenotoxic carcinogens and non-DNA-reactive carcinogens (for these compounds a true [perfect] threshold is associated with a clearly founded no-observed-adverse-effect level).     

Scientific and practical considerations for the development of occupational exposure limits (OELs) for chemical substances

Occupational exposure limits (OELs) serve occupational health professionals as benchmarks for a healthy work environment. OELs are generally developed by manufacturers for substances which are not subject to governmental regulation or which have not been evaluated by consensus organizations such as the American Conference of Governmental Industrial Hygienists. This review is intended to serve as a practical guide to the standard-setting process. The discussion encompasses the evaluation of data, the different methods used for calculating limits, and the application of these limits to the workplace. The need for additional research to enhance the reliability of current methods is also discussed.     

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.     

Procedures for health risk assessment in Europe

This report compares cancer classification systems, health risk assessment approaches, and procedures used for establishing occupational exposure limits (OELs), in various European countries and scientific organizations. The objectives were to highlight and compare key aspects of these processes and to identify the basis for differences in cancer classifications and OELs between various scientific organizations and countries. Differences in cancer classification exist in part due to differences in the ultimate purpose of classification and to the relative importance of different types of data (i.e., animal vs human data, mechanistic data, and data from benign vs malignant tumors). In general, the groups surveyed tend to agree on classification of chemicals with good evidence of carcinogenicity in humans, and agree less on classification of chemicals with positive evidence in animals and inadequate or limited evidence in humans. Most entities surveyed distinguish between genotoxic and nongenotoxic chemicals when conducting risk assessments. Although the risk assessment approach used for nongenotoxic chemicals is fairly similar among groups, risk assessment approaches for genotoxic carcinogens vary widely. In addition to risk assessment approaches, other factors which can affect OELs include selection of the critical effect, use of health-based vs technology-based exposure limits, and consideration of technological feasibility and socioeconomic factors.     

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.     

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.     

Scientific criteria used for the development of occupational exposure limits for metals and other mining-related chemicals

The scientific approaches employed by selected internationally recognized organizations in developing occupational exposure limits (OELs) for metals and other mining-related chemicals were surveyed, and differences and commonalities were identified. The analysis identified an overriding need to increase transparency in current OEL documentation. OEL documentation should adhere to good risk characterization principles and should identify (1) the methodology used and scientific judgments made; (2) the data used as the basis for the OEL calculation; and (3) the uncertainties and overall confidence in the OEL derivation. At least within a single organization, a consistent approach should be used to derive OELs. Opportunities for harmonization of scientific criteria were noted, including (1) consideration of severity in identification of the point of departure; (2) definition of the minimum data set; (3) approaches for interspecies extrapolation; (4) identification of default uncertainty factors for developing OELs; and (5) approaches for consideration of speciation and essentiality of metals. Potential research approaches to provide the fundamental data needed to address each individual scientific criterion are described. Increased harmonization of scientific criteria will ultimately lead to OEL derivation approaches rooted in the best science and will facilitate greater pooling of resources among organizations that establish OELs and improved protection of worker health.     

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.     

Threshold and non-threshold chemical carcinogens: A survey of the present regulatory landscape

For the proper regulation of a carcinogenic material it is necessary to fully understand its mode of action, and in particular whether it demonstrates a threshold of effect. This paper explores our present understanding of carcinogenicity and the mechanisms underlying the carcinogenic response. The concepts of genotoxic and non-genotoxic and threshold and non-threshold carcinogens are fully described. We provide summary tables of the types of cancer considered to be associated with exposure to a number of carcinogens and the available evidence relating to whether carcinogenicity occurs through a threshold or non-threshold mechanism. In light of these observations we consider how different regulatory bodies approach the question of chemical carcinogenesis, looking in particular at the definitions and methodologies used to derive Occupational Exposure Levels (OELs) for carcinogens. We conclude that unless proper differentiation is made between threshold and non-threshold carcinogens, inappropriate risk management measures may be put in place - and lead also to difficulties in translating carcinogenicity research findings into appropriate health policies. We recommend that clear differentiation between threshold and non-threshold carcinogens should be made by all expert groups and regulatory bodies dealing with carcinogen classification and risk assessment.     

Occupational exposure limits for 30 organophosphate pesticides based on inhibition of red blood cell acetylcholinesterase

Toxicity and other relevant data for 30 organophosphate pesticides were evaluated to suggest inhalation occupational exposure limits (OELs), and to support development of a risk assessment strategy for organophosphates in general. Specifically, the value of relative potency analysis and the predictability of inhalation OELs by acute toxicity measures and by repeated oral exposure NOELs was assessed. Suggested OELs are based on the prevention of red blood cell (RBC) acetylcholinesterase (AChE) inhibition and are derived using a weight-of-evidence risk assessment approach. Suggested OEL values range from 0.002 to 2 mg/m³, and in most cases, are less than current permissible exposure levels (PELs) or threshold limit values® (TLVs®). The available data indicate that experimental data for most organophosphates evaluated are limited; most organophosphates are equally potent RBC AChE inhibitors in different mammalian species; NOELs from repeated exposure studies of variable duration are usually equivalent; and, no particular grouping based on organophosphate structure is consistently more potent than another. Further, relative potency analyses have limited usefulness in the risk assessment of organophosphates. The data also indicated that equivalent relative potency relationships do not exist across either exposure duration (acute vs. repeated) or exposure route (oral vs. inhalation). Consideration of all variable duration and exposure route studies are therefore usually desirable in the development of an OEL, especially when data are limited. Also, neither acute measures of toxicity nor repeated oral exposure NOELs are predictive of weight-of-evidence based inhalation OELs. These deviations from what is expected based on the common mechanism of action for organophosphates across exposure duration and route — AChE inhibition — is likely due to the lack of synchrony between the timing of target tissue effective dose and the experimental observation of equivalent response. Thus, comprehensive interpretation of all toxicity data in the context of available toxicokinetic, toxicodynamic and exposure information for each individual organophosphate in a weight-of-evidence based risk assessment is desirable when deriving inhalation OELs.     

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.     

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.     

Derivation of occupational exposure limits based on target blood concentrations in humans

An approach for deriving occupational exposure limits (OEL) for pharmaceutical compounds is the application of safety factors to the most appropriate pre-clinical toxicity endpoint or the lowest therapeutic dose (LTD) in humans. Use of this methodology can be limited when there are inadequate pre-clinical toxicity data or lack of a well-defined therapeutic dose, and does not include pharmacokinetic considerations. Although some methods have been developed that incorporate pharmacokinetics, these methods do not take into consideration variability in response. The purpose of this study was to investigate how application of compartmental pharmacokinetic modeling could be used to assist in the derivation of OELs based on target blood concentrations in humans. Quinidine was used as the sample compound for the development of this methodology though the intent was not to set an OEL for quinidine but rather to develop an alternative approach for the determination of OELs. The parameters for the model include body weight, breathing rate, and chemical-specific pharmacokinetic constants in humans, data typically available for pharmaceutical agents prior to large scale manufacturing. The model is used to simulate exposure concentrations that would result in levels below those that may result in any undesirable pharmacological effect, taking into account the variability in parameters through incorporation of Monte Carlo sampling. Application of this methodology may decrease some uncertainty that is inherent in default approaches by eliminating the use of safety factors and extrapolation from animals to humans. This methodology provides a biologically based approach by taking into consideration the pharmacokinetics in humans and reported therapeutic or toxic blood concentrations to guide in the selection of the internal dose-metric.     

Evaluation of airborne sensory irritants for setting exposure limits or guidelines: A systematic approach

Sensory irritation of eyes and upper airways is an important endpoint for setting occupational exposure limits (OELs) and indoor air guidelines. Sensory irritants cause a painful burning, stinging and itching sensation. Controlled chamber studies are the “golden standard” for evaluations. Well conducted workplace studies offer another possibility. For generalization, the number of participants and their age, smoking, gender, and prior exposure, experience and mood has to be considered. Exposure assessments have to be reliable and exposure duration sufficiently long to establish time-response relationships. A potential confounding by odour has to be assessed. For workplace exposures, mixed exposure and healthy worker effects have to be evaluated. The “Alarie test” is the only validated animal bioassay for prediction of sensory irritation in humans. The mouse bioassay uses the trigeminal reflex-induced decrease in the respiratory rate. The 50% decrease (RD₅₀) has been correlated with OELs set for sensory irritants; predicted OELs for sensory irritants are 0.03xRD₅₀. Evaluation of the bioassay comprises the number of mice and the strain, the reliability of the exposure concentrations and exposure-response relationships, and the similar mode-of-action in mice and humans. These approaches can be used for quality assurance of reported data to set air quality guidelines.