Derivation Of Occupational Exposure Limits Research Articles

Exposure limits for indoor volatile substances concerning the general population: The role of population-based differences in sensory irritation of the eyes and airways for assessment factors.

Assessment factors (AFs) are essential in the derivation of occupational exposure limits (OELs) and indoor air quality guidelines. The factors shall accommodate differences in sensitivity between subgroups, i.e., workers, healthy and sick people, and occupational exposure versus life-long exposure for the general population. Derivation of AFs itself is based on empirical knowledge from human and animal exposure studies with immanent uncertainty in the empirical evidence due to knowledge gaps and experimental reliability. Sensory irritation in the eyes and airways constitute about 30-40% of OELs and is an abundant symptom in non-industrial buildings characterizing the indoor air quality and general health. Intraspecies differences between subgroups of the general population should be quantified for the proposal of more 'empirical' based AFs. In this review, we focus on sensitivity differences in sensory irritation about gender, age, health status, and vulnerability in people, based solely on human exposure studies. Females are more sensitive to sensory irritation than males for few volatile substances. Older people appear less sensitive than younger ones. However, impaired defense mechanisms may increase vulnerability in the long term. Empirical evidence of sensory irritation in children is rare and limited to children down to the age of six years. Studies of the nervous system in children compared to adults suggest a higher sensitivity in children; however, some defense mechanisms are more efficient in children than in adults. Usually, exposure studies are performed with healthy subjects. Exposure studies with sick people are not representative due to the deselection of subjects with moderate or severe eye or airway diseases, which likely underestimates the sensitivity of the group of people with diseases. Psychological characterization like personality factors shows that concentrations of volatile substances far below their sensory irritation thresholds may influence the sensitivity, in part biased by odor perception. Thus, the protection of people with extreme personality traits is not feasible by an AF and other mitigation strategies are required. The available empirical evidence comprising age, lifestyle, and health supports an AF of not greater than up to 2 for sensory irritation. Further, general AFs are discouraged for derivation, rather substance-specific derivation of AFs is recommended based on the risk assessment of empirical data, deposition in the airways depending on the substance's water solubility and compensating for knowledge and experimental gaps. Modeling of sensory irritation would be a better 'empirical' starting point for derivation of AFs for children, older, and sick people, as human exposure studies are not possible (due to ethical reasons) or not generalizable (due to self-selection). Dedicated AFs may be derived for environments where dry air, high room temperature, and visually demanding tasks aggravate the eyes or airways than for places in which the workload is balanced, while indoor playgrounds might need other AFs due to physical workload and affected groups of the general population.

The changing outlook of psychedelic drugs: The importance of risk assessment and occupational exposure limits.

Serotonergic psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, dimethyltryptamine (DMT), and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), are currently being investigated for the treatment of psychiatric disorders such as depression and anxiety. Clinical trials with psilocybin and LSD have shown improvement in emotional and psychological scores. Although these drugs are reported to be safe in a controlled environment (such as clinical trials), exposure to low doses of these drugs can result in psychedelic effects, and therefore, occupational safety is an important consideration to prevent adverse effects in the workplace from low daily exposure. This article will discuss the factors involved in the derivation of occupational exposure limits (OELs) and risk assessment of these psychedelic drugs. To support the OEL derivations of psychedelic drugs, information regarding their mechanism of action, adverse effect profiles, pharmacokinetics, clinical effects, and nonclinical toxicity were considered. Additionally, psilocybin and LSD, which are the most extensively researched psychedelic substances, are employed as illustrative examples in case studies. The OELs derived for psilocybin and for LSD are 0.05 and 0.002μg/m3 , respectively, which indicates that these are highly hazardous compounds, and it is important to take into account suitable safety measures and risk-management strategies in order to minimize workplace exposure.

An interdisciplinary framework for derivation of occupational exposure limits.

Protecting the health and safety of workers in industrial operations is a top priority. One of the resources used in industry to ensure worker safety is the occupational exposure limit (OEL). OELs are derived from the assessment and interpretation of empirical data from animal and/or human studies. There are various guidelines for the derivation and implementation of OELs globally, with a range of stakeholders (including regulatory bodies, governmental agencies, expert groups and others). The purpose of this manuscript is to supplement existing guidance with learnings from a multidisciplinary team approach within an industry setting. The framework we present is similar in construct to other risk assessment frameworks and includes: (1) problem formulation, (2) literature review, (3) weight of evidence considerations, (4) point of departure selection/derivation, (5) application of assessment factors, and the final step, (6) derivation of the OEL. Within each step are descriptions and examples to consider when incorporating data from various disciplines such as toxicology, epidemiology, and exposure science. This manuscript describes a technical framework by which available data relevant for occupational exposures is compiled, analyzed, and utilized to inform safety threshold derivation applicable to OELs.

The utility of hERG channel inhibition data in the derivation of occupational exposure limits

Inhibition of the human ether-à-go-go (hERG) channel may lead to QT prolongation and fatal arrhythmia. While pharmaceutical drug candidates that exhibit potent hERG channel inhibition often fail early in development, many drugs with both cardiac and non-cardiac indications proceed to market. In this study, the relationship between in vitro hERG channel inhibition and published occupational exposure limit (OEL) was evaluated. A total of 23 cardiac drugs and 44 drugs with non-cardiac indications with published hERG channel IC50 and published OELs were identified. There was an apparent relationship between hERG IC50 potency and the OEL for cardiac and non-cardiac drugs. Twenty cardiac and non-cardiac drugs were identified that had a potent hERG IC50 (≤25 μM) and a contrastingly large OEL value (≥100 μg/m3). OELs or hazard banding corresponding to ≤100 μg/m3 should be sufficiently protective of effects following occupational exposure to the majority of APIs with hERG IC50 values ≤ 100 μM. It is important to consider hERG IC50 values and possible cardiac effects when deriving OEL values for drugs, regardless of indication. These considerations may be particularly important early in the drug development process for establishing exposure control bands for drugs that do not yet have full clinical safety data.

Arbeitsplatzgrenzwerte für Stoffe mit einer Reiz- und Geruchswirkung

Occupational exposure limits for substances having an irritant and odoriferous effect “Fresh, clean air” is a characteristic of the quality of the air we breathe. The perception of an unpleasant or unexpected odour is often interpreted as an indication of pollution and is associated with concerns about adverse health effects. The frequently asked question is then: Does it only smell, or is it also harmful to health? If hazardous substances are handled at a workplace, the occupational exposure limit protects against a health hazard. In an indoor workplace, e.g. an office, this is the indoor guide value II. Both assessment values are derived on the basis of current toxicological and epidemiological findings from animal and human studies on dose-response relationships from the odour threshold to the irritation threshold. This paper provides an insight into the conceptual considerations and procedures underlying the derivation of occupational exposure limits for substances having an irritant and odoriferous effect. Keywords: odour nuisance – sensory irritation – experimental human studies – limit derivation

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.

Approaches for setting occupational exposure limits in the pharmaceutical industry.

The use of pharmaceutical drugs has provided a cure for many diseases. However, unintended exposure to drugs in the manufacturing workplace can cause significant health hazards to workers. It is important to protect the workforce from these deleterious effects by limiting exposure to an acceptable level, the occupational exposure limit (OEL). OEL is defined as airborne concentrations (expressed as a time-weighted average for a conventional 8-h workday and a 40-h work week) of a substance to which nearly all workers may be repeatedly exposed (for a working lifetime) without adverse effects. Determination of OELs has become very challenging over time, requiring an overall assessment of the preclinical and clinical data of the drug being manufactured. Previously, to derive OEL values, toxicologists used animal no-observed-adverse-effect level (NOAEL) data, which have been replaced with the overall assessment of animal and human data, placing a higher emphasis on human health-based data. A major advantage of working with human pharmaceuticals is that sufficient clinical data are available for them in most cases. The present manuscript reviews the latest knowledge regarding the derivation of occupational exposure limits as health-based exposure limits (HBELs) for pharmaceuticals. We have provided examples of OEL calculations for various drugs including levofloxacin (CAS No. 100986-85-4), dienogest (CAS no. 65928-58-7), and acetylsalicylic acid (ASA, CAS no. 50-78-2) using human data. This report will benefit professionals in the OEL domain in understanding this highly important, growing, and challenging field.

Derivation of occupational exposure limits for multi-walled carbon nanotubes and graphene using subchronic inhalation toxicity data and a multi-path particle dosimetry model.

In this study, we aimed to provide the recommended occupational exposure limits (OELs) for multi-walled carbon nanotubes (MWCNTs) and graphene nanomaterials based on data from a subchronic inhalation toxicity study using a lung dosimetry model. We used a no observed adverse effect level (NOAEL) of 0.98 mg m-3 and 3.02 mg m-3 in rats for MWCNTs and graphene, respectively. The NOAELs were obtained from a 13-week inhalation study in rats. The deposition fractions of MWCNTs and graphene in the respiratory tract of rats and humans were calculated by using the multi-path particle dosimetry model (MPPD model, v3.04). The deposition fraction in the alveolar region was 0.0527 and 0.0984 for MWCNTs and 0.0569 and 0.1043 for graphene in rats and human lungs, respectively. Then, the human equivalent exposure concentrations (HECs) of MWCNTs and graphene were calculated according to the method by the National Institute for Occupational Safety and Health (NIOSH). The HEC was estimated to be 0.17 mg m-3 for MWCNTs and to be 0.54 mg m-3 for graphene, which was relevant to the rat NOAEL of 0.98 mg m-3 and 3.02 mg m-3 for MWCNTs and graphene, respectively. Finally, we estimated the recommended OELs by applying uncertainty factors (UFs) to the HEC as follows: an UF of 3 for species differences (rats to humans), 2 for an experimental duration (subchronic to chronic), and 5 for inter-individual variations among workers. Thus, the OEL was estimated to be 6 μg m-3 for MWCNTs and 18 μg m-3 for graphene. These values could be useful in preventing the adverse health effects of nanoparticles in workers.

Sensory irritation as a basis for setting occupational exposure limits.

There is a need of guidance on how local irritancy data should be incorporated into risk assessment procedures, particularly with respect to the derivation of occupational exposure limits (OELs). Therefore, a board of experts from German committees in charge of the derivation of OELs discussed the major challenges of this particular end point for regulatory toxicology. As a result, this overview deals with the question of integrating results of local toxicity at the eyes and the upper respiratory tract (URT). Part 1 describes the morphology and physiology of the relevant target sites, i.e., the outer eye, nasal cavity, and larynx/pharynx in humans. Special emphasis is placed on sensory innervation, species differences between humans and rodents, and possible effects of obnoxious odor in humans. Based on this physiological basis, Part 2 describes a conceptual model for the causation of adverse health effects at these targets that is composed of two pathways. The first, “sensory irritation” pathway is initiated by the interaction of local irritants with receptors of the nervous system (e.g., trigeminal nerve endings) and a downstream cascade of reflexes and defense mechanisms (e.g., eyeblinks, coughing). While the first stages of this pathway are thought to be completely reversible, high or prolonged exposure can lead to neurogenic inflammation and subsequently tissue damage. The second, “tissue irritation” pathway starts with the interaction of the local irritant with the epithelial cell layers of the eyes and the URT. Adaptive changes are the first response on that pathway followed by inflammation and irreversible damages. Regardless of these initial steps, at high concentrations and prolonged exposures, the two pathways converge to the adverse effect of morphologically and biochemically ascertainable changes. Experimental exposure studies with human volunteers provide the empirical basis for effects along the sensory irritation pathway and thus, “sensory NOAEChuman” can be derived. In contrast, inhalation studies with rodents investigate the second pathway that yields an “irritative NOAECanimal.” Usually the data for both pathways is not available and extrapolation across species is necessary. Part 3 comprises an empirical approach for the derivation of a default factor for interspecies differences. Therefore, from those substances under discussion in German scientific and regulatory bodies, 19 substances were identified known to be human irritants with available human and animal data. The evaluation started with three substances: ethyl acrylate, formaldehyde, and methyl methacrylate. For these substances, appropriate chronic animal and a controlled human exposure studies were available. The comparison of the sensory NOAEChuman with the irritative NOAECanimal (chronic) resulted in an interspecies extrapolation factor (iEF) of 3 for extrapolating animal data concerning local sensory irritating effects. The adequacy of this iEF was confirmed by its application to additional substances with lower data density (acetaldehyde, ammonia, n-butyl acetate, hydrogen sulfide, and 2-ethylhexanol). Thus, extrapolating from animal studies, an iEF of 3 should be applied for local sensory irritants without reliable human data, unless individual data argue for a substance-specific approach.

Guidance on the establishment of acceptable daily exposure limits (ADE) to support Risk-Based Manufacture of Pharmaceutical Products

Health-based limits for active pharmaceutical ingredients (API) referred to as acceptable daily exposures (ADEs) are necessary to the pharmaceutical industry and used to derive acceptance limits for cleaning validation purposes and evaluating cross-carryover. ADEs represent a dose of an API unlikely to cause adverse effects if an individual is exposed, by any route, at or below this dose every day over a lifetime. Derivations of ADEs need to be consistent with ICH Q9 as well as other scientific approaches for the derivation of health-based limits that help to manage risks to both product quality and operator safety during the manufacture of pharmaceutical products. Previous methods for the establishment of acceptance limits in cleaning validation programs are considered arbitrary and have largely ignored the available clinical and toxicological data available for a drug substance. Since the ADE utilizes all available pharmaceutical data and applies scientifically acceptable risk assessment methodology it is more holistic and consistent with other quantitative risk assessments purposes such derivation of occupational exposure limits. Processes for hazard identification, dose response assessment, uncertainty factor analysis and documentation are reviewed.

Multi-walled carbon nanotubes (Baytubes®): Approach for derivation of occupational exposure limit

Carbon nanotubes come in a variety of types, but one of the most common forms is multi-walled carbon nanotubes (MWCNT). This paper focuses on the dose-response and time course of pulmonary toxicity of Baytubes, a more flexible MWCNT type with the tendency to form assemblages of nanotubes. This MWCNT has been examined in previous single and repeated exposure 13-week rat inhalation studies. Kinetic endpoints and the potential to translocate to extrapulmonary organs have been examined during postexposure periods of 3 and 6 months, respectively. The focus of both studies was to compare dosimetric endpoints and the time course of pulmonary inflammation characterized by repeated bronchoalveolar lavage and histopathology during the respective follow-up periods. To better understand the etiopathology of pulmonary inflammation and time-related lung remodeling, two metrics of retained lung dose were compared. The first used the mass metric based on the exposure concentration obtained by filter analyses and aerodynamic particle size of airborne MWCNT. The second was based on calculated volumetric lung burdens of retained MWCNT. Kinetic analyses of lung burdens support the conclusion that Baytubes, in principal, act like poorly soluble agglomerated carbonaceous particulates. However, the difference in pulmonary toxic potency (mass-based) appears to be associated with the low-density (approximately 0.1-0.3g/m(3)) of the MWCNT assemblages. Of note is that assemblages of MWCNT were found predominantly both in the exposure atmosphere and in digested alveolar macrophages. Isolated fibers were not observed in exposure atmospheres or biological specimens. All findings support the conclusion that the low specific density of microstructures was conducive to attaining the volumetric lung overload-related inflammatory response conditions earlier than conventional particles. Evidence of extrapulmonary translocation or toxicity was not found in any study. Thus, pulmonary overload is believed to trigger the cascade of events leading to a stasis of clearance and consequently increased MWCNT doses high enough to trigger sustained pulmonary inflammation. This mechanism served as conceptual basis for the calculation of the human equivalent concentration. Accordingly, multiple interspecies adjustments were necessary which included species-specific differences in alveolar deposition, differences in ventilation, and the time-dependent particle accumulation accounting for the known species-specific differences in particle clearance half-times in rats and humans. Based on this rationale and the NOAEL (no-observed adverse effect level) from the 13-week subchronic inhalation study on rats, an occupational exposure limit (OEL) of 0.05 mg Baytubes/m(3) (time weighted average) is considered to be reasonably protective to prevent lung injury to occur in the workplace environment.

The Concept of “Practical Thresholds” in the Derivation of Occupational Exposure Limits for Carcinogens by the Scientific Committee on Occupational Exposure Limits (SCOEL) of the European Union

In Europe, there has been a scientific discussion on possible thresholds in chemical carcinogens since the late 1990s. Based on this discussion, the Scientific Committee on Occupational Exposure Limits (SCOEL) of the European Union has discussed a number of chemical carcinogens and has issued recommendations. For some carcinogens, health-based Occupational Exposure Limits (OELs) were recommended, while quantitative assessments of carcinogenic risks were performed for others. For purposes of setting OELs the following groups of carcinogens were adopted: (A) Non-threshold genotoxic carcinogens; for low-dose assessment of risk, the linear non-threshold (LNT) model appears appropriate. For these chemicals, the 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, and the ALARA principle may be applied as well. (C) Genotoxic carcinogens with a practical threshold is supported by studies on mechanisms and/or toxicokinetics; health-based exposure limits may be based on an established no-observed adverse effect level (NOAEL). (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 tumor 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. In order to highlight the most important differentiation between Groups B and C, the basic reasoning is given for the six compounds formaldehyde, vinyl acetate, acrylonitrile, acrylamide, trichloroethylene and methylene chloride.

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.

Setting occupational exposure limits in humans: contributions from the field of experimental psychology

Psychophysical methods from the field of experimental psychology are evaluated for their utility in the derivation of occupational exposure limits (OELs) for volatile chemicals based on acute sensory irritation in humans. The lateralization threshold method, which involves the localization of trigeminal vapor to the stimulated nostril, is evaluated for its underlying assumptions, reliability and validity. Whole body exposures, on the other hand, which involve the controlled, ambient exposure of human subjects to the irritant at one or a series of concentrations for an extended period are also discussed. It is concluded that the single-organ psychophysical method is largely resistant to response bias is practical and economical. However, its reliability and validity need further assessment. Whole body exposures, while having enhanced ecological validity, are more prone to demand characteristics, response bias, and subject beliefs than the traditional psychophysical procedures. An approach that involves the exposure of only the most sensitive organs such as the eyes and nose, via a mask or facebox, could facilitate the administration and alternation of odorant/irritant stimuli over a wide range of concentrations while enhancing ecological validity.

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.

The derivation of occupational exposure limits in the pharmaceutical industry.

Many business handle compounds which may have adverse effects upon people but for which no governmental exposure limits exists. There is increasing interest and encouragement in setting ‘in-house’ limits but this is a difficult, imprecise and controversial area. This paper setting out the philosophy and practice of one pharmaceutical company is offered as a contribution to seeking a rational approach to the problem.