What's an Exposome? Recent Research on Occupational Exposure Limits - 58tinton.win

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Saturday, December 5, 2015

What's an Exposome? Recent Research on Occupational Exposure Limits

This supplemental issue contains nine research articles and two introductory/summary articles detailing recent research in occupational exposure limits (OELs). Members of AIHA and/or ACGIH can log in to their respective member portals to view the research articles referenced below. This blog post is a high-level summary of each of the articles, including best practices that can be used by practicing industrial hygiene and safety professionals.

The Past and Future of Occupational Exposure Limits

This introductory article by Jonathan Borak and Lisa M. Brosseau about �The Past and Future of Occupational Exposure Limits� is a quick history of OELs and analysis of the barriers present in developing new OELs. The authors note that the ten articles �present a systematic approach that begins with an understanding of systems biology, mechanisms of action and the early (i.e., �pre-clinical�) effects of toxic exposures including genetic and epigenetic phenomena.� 

The most obvious barrier to developing OELs is the lack of data available that is relevant to human occupational exposure. Another barrier is the difficulty in establishing global exposure limits � since countries are at different stages of industrialization and the necessary controls may be infeasible. The third barrier mentioned by the authors is the lack of a formal, systematic approach to develop, establish, and update OELs.

Occupational Exposure Limit Derivation and Application

In a summary article titled �State-of-the-Science: The Evolution of Occupational Exposure Limit Derivation and Application� authors A. Maier, T. J. Lentz, K. L. MacMahon, L. T. McKernan, C. Whittaker, and  P. A. Schulte provide a review of the research articles provided in the JOEH supplement. The four-page summary article explains that the research articles in the JOEH supplement are not an exhaustive assessment of OELs, but they explain scientific advances to be considered for risk assessment and management of occupational hazards.

Historical Context for OELs

The first research article in this JOEH supplement is �Historical Context and Recent Advances in Exposure-Response Estimation for Deriving Occupational Exposure Limits� by M.W. Wheeler, R. M. Park, A. J. Bailer, and C. Whittaker. In the abstract of the article, the authors explain that most occupational exposure limits are not based on quantitative risk assessment (QRA), and provide examples of exposure-response modeling methods available for QRA. �The key step in QRA is estimation of the exposure-response relationship,� the authors state, recommending the use of statistical tools to properly characterize the risk.

One of the best takeaways of the article is found in Table 1: �Common Impediments to Inference When Developing an Exposure-Response Relationship from Epidemiological Studies.� This table presents issues such as confounding bias, selection bias, the healthy worker effect, reverse causation, and variable susceptibility, and provides the consequences and fixes for these issues when working on exposure-response relationships. Table 1 is a helpful summary for industrial hygienists or safety professionals who are just starting their education into epidemiology.

Another helpful element of the article is found in Table 7: �OEL Estimation Methods,� which sets forth the data requirements, considerations for use, epidemiological considerations, and caveats for estimation methods such as the no observed adverse effect level (NOAEL), traditional benchmark dose (BMD), and biologically-based methods. In the conclusion of the article, the authors recommend that risk managers select the proper �statistical methodology to estimate risks and quantify relevant uncertainties� in occupational risks.

Dosimetry Modeling for Occupational Risk Assessment

An article by Eileen D. Kuempel, Lisa M. Sweeney, John B. Morris, and Annie M. Jarabek explains the �Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation.� This article introduces the basic concepts of dosimetry, explains the hierarchical model selection criteria, considers agent-specific dosimetry and model selection with agent-specific examples, and discusses challenges to implementing dosimetry models and methods in risk assessment and OEL derivation.

When introducing the basic concepts of dosimetry, the authors explain that dosimetry involves determining the amount, rate, and distribution of a substance in the body. They also introduce the development and use of risk-based exposure estimates including the NOAEL, the lowest observed adverse effect level (LOAEL), and the benchmark dose (BMD), which is �the dose associated with a specified risk (e.g., 10%) of an adverse health effect (or benchmark response) as estimated from modeling the dose-response relationship.�

The authors explain that dosimetry is essential for understanding the relationship between exposure and the body�s response. Dosimetry can improve the accuracy of risk assessment by reducing the level of uncertainty in the calculated estimates. Reliable estimates of the internal dose at the target organ or tissue are accomplished by specific measurements or predictive models. 

The article focuses on inhalation dosimetry since it is a significant route of occupational exposure. Detailed mechanisms and models are provided for the respiratory tract, deposition of particles of fibers, clearance and retention of inhaled particles and fibers (including an interspecies comparison), and gas uptake factors. The interspecies comparisons discuss that similar clearance pathways are used by both humans and laboratory animals, but that extrapolation of animal data for human exposure estimates has changed due to an improved understanding of the differences between animal and human respiration.

Using Systems Biology and Biomarkers

The third research article in this JOEH supplement presents the use of �Systems Biology and Biomarkers of Early Effects for Occupational Exposure Limit Setting� as written by D. Gayle DeBord, Lyle Burgoon, Stephen W. Edwards, Lynne T. Haber, M. Helen Kanitz, Eileen Kuempel, Russell S. Thomas, and Berran Yucesoy. As provided in the abstract of the article, this article discusses �systems biology, biomarkers of effect, and computational toxicology approaches and their relevance to the occupational exposure limit setting process.� In the introduction, the authors mention the dearth of toxicity information known at present about tens of thousands of chemicals in use in industry today.

The authors note that complex exposure scenarios, where workers are �exposed to complex mixtures that may have additive, synergistic, or antagonistic actions� makes it difficult to conduct thorough risk assessments. Useful portions of this article include Table 1: �Glossary of Key Terms.� Table 1 provides definitions for key terms used in the article, including: benchmark dose (BMD), benchmark response (BMR), biomarkers, computational toxicology, metabolomics, proteomics, systems biology, and uncertainty factors.

A biomarker is an �[i]nternal [measure] or [marker] of exposures or effects for a chemical or agent in the body.� Research into biomarkers involves an assessment of which biomarkers can be quantitatively linked to human adverse outcomes from occupational exposure. The authors explain that �[e]nvironmental exposures can directly or indirectly cause alterations in gene expression at either the transcriptional (gene expression) or the translational level (proteomics).� Table 4: �Different Types of Biomarkers� shows the type of biomarker (exposure, effect, or susceptibility), its characteristics, and examples.

In the conclusion, the authors explain the advantages of using biomarkers, since they can be used to �establish more appropriate OELs to protect individuals who are at high risk.� They caution that the �whole field of computational toxicology and systems biology is still evolving and results have not been validated in human populations� and that interpretation of biomarker results is not yet available. These challenges need to be overcome before biomarkers can be used routinely in human occupational risk assessment.

Scientific Basis of Uncertainty Factors

An article by D. A. Dankovic, B. D. Naumann, A. Maier, M. L. Dourson, and L. S. Levy discusses �The Scientific Basis of Uncertainty Factors Used in Setting Occupational Exposure Limits.� The abstract of the research article explains that �[t]he use of uncertainty factors is predicated on the assumption that a sufficient reduction in exposure from those at the boundary for the onset of adverse effects will yield a safe exposure level for at least the great majority of the exposed population, including vulnerable subgroups.�

Of interest to practicing industrial hygienists and safety professionals, Table 1: �UFs Used in OEL-setting, and the Rationale for Their Use� explains the types of uncertainty factors, which area of uncertainty they are used for, and the basic principles when rationalizing their use in risk assessment and OEL setting. For example, UFA is used for animal to human uncertainty, and is used to adjust for differences in sensitivity between animals and the average human (not the occupationally exposed human). Figure 5 shows the hierarchy of approaches that are available when incorporating chemical exposure data into the risk assessment process, in order to improve scientific certainty.

Using Genetic and Epigenetic Information

The fifth article in the JOEH supplement by P. A. Schulte, C. Whittaker, and C. P. Curra is an introductory evaluation of �Considerations for Using Genetic and Epigenetic Information in Occupational Health Risk Assessment and Standard Setting.� The authors note that genetic and epigenetic data have not been widely used in risk assessment for occupational health. However, the authors envision that �genetic and epigenetic data might be used as endpoints in hazard identification, as indicators of exposure, as effect modifiers in exposure assessment and dose-response modeling, as descriptors of mode of action, and to characterize toxicity pathways.�

When evaluating the use of epigenetics in occupational health, the authors mention that using �epigenetics in epidemiologic studies of occupational disease may help explain the relationship between the genome and the work environment; however, other environmental exposures outside of work� also will need to be controlled for. Practicing industrial hygiene and safety professionals may be interested in Table 1: �Guide to Assessing Genetic and Epigenetic Data for Risk Assessment,� which is a 4 � 4 matrix showing the types of risk assessment functions (hazard identification, dose-response modeling, exposure assessment, and risk characterization) and the questions associated with using genetic or epigenetic data (both inherited and acquired) that may be asked.

Table 2: �Framework for use of genetic and epigenetic data in occupational and environmental risk assessment� is also interesting, since it uses the same 4 x 4 matrix and risk assessment functions with the recommended or estimated use of genetic and epigenetic data. For example, for the exposure assessment function, acquired genetic data can show deviations from normal pattern of gene expression, whereas inherited epigenetic data can be used as an indicator of exposure.

In the conclusion, the authors state that: �It is not far-fetched that a worker�s �Right to Know� might someday extend to the worker�s right to know their genetic susceptibility to workplace toxicants.� This is an intriguing idea for future research.

Setting OELs for Chemical Allergens

In an interesting article about �Setting Occupational Exposure Limits for Chemical Allergens�Understanding the Challenges� by G. S. Dotson, A. Maier, P. D. Siegel, S. E. Anderson, B. J. Green, A. B. Stefaniak, C. D. Codispoti, and I. Kimber, the authors discuss establishing exposure limits for low molecular weight (LMW) chemical allergens. The definition of chemical allergy is explained as �immune-mediated adverse health effects, including allergic sensitization and diseases, caused by exposures to chemicals.�

LMW allergens that are recognized occupational hazards include: diisocyanates, organic anhydrides (i.e., maleic anhydride) and some metals (i.e., beryllium and nickel). Table 1: �ACGIH Threshold Limit Values (TLVs) Based on Immune-mediated Health Endpoints� provides a list of chemical allergens with OELs already developed. These chemical allergens include beryllium, flour dust, natural rubber latex, various diisocyanates, and piperazine.

The article also provides an explanation of the biology of chemical allergens, including the difference between sensitization and elicitation, and forms of chemical allergy. The authors note that the two forms of chemical allergy of most interest to occupational health professionals are skin sensitization (resulting in allergic eczema and contact dermatitis) and respiratory tract sensitization (resulting in asthma and rhinitis). Specific challenges associated with development of OELs for chemical allergens are also discussed.

Exposure Estimation and Interpretation of Occupational Risk

The seventh article in the JOEH supplement provides a detailed analysis of �Exposure Estimation and Interpretation of Occupational Risk: Enhanced Information for the Occupational Risk Manager� by Martha Waters, Lauralynn McKernan, Andrew Maier, Michael Jayjock, Val Schaeffer, and Lisa Brosseau. The authors explain the risk characterization process for occupational exposures, including the regulatory basis for OELs, describing exposures and the exposed population(s), intrinsic variability and how to reduce uncertainty in exposure estimation, and methods for estimating exposures.

Table 1: �Occupational Exposure Limits (OELs) Developed by Various Organizations� shows the various OELs, which organization has set them, and whether they were developed based on a health basis, analytical feasibility, economic feasibility, and engineering feasibility. The authors provide an example of the compliance approaches used by the Occupational Safety and Health Administration (OSHA) and National Institute for Occupational Safety and Health (NIOSH). OSHA and NIOSH�s �[approach] include[s] collecting samples from the worst case exposure scenario or randomly from a defined similar exposure group of interest. The measurement is compared to the OEL and is classified into one of three decision categories: clearly below the limit, clearly above the limit, or too close to the limit for an immediate decision.�

The authors also provide an explanation of the AIHA exposure assessment strategy, which �recommended that [time-weighted average (TWA)] OELs be interpreted as upper limits of exposure (e.g., 95th percentile) for each similar exposure group (SEG) and that the exposure distribution profile of each SEG should be controlled so that the 95th percentile exposure is less than the OEL over time.� Following the discussion of SEGs, a short section on Bayesian methods is provided.

Aggregate Exposure and Cumulative Risk Assessment

In this research article about �Aggregate Exposure and Cumulative Risk Assessment�Integrating Occupational and Non-occupational Risk Factors,� T. J. Lentz, G. S. Dotson, P. R.D. Williams, A. Maier, B. Gadagbui, S. P. Pandalai, A. Lamba, F. Hearl, and M. Mumtaz evaluate the benefits of considering non-occupational exposures as part of the occupational risk assessment. The authors debate using a �combined risk from exposure to both chemical and non-chemical stressors, within and beyond the workplace,� with the understanding that �such exposures may cause interactions or modify the toxic effects observed (cumulative risk).�

Like previous articles in this OEL series, the authors provide a glossary of key terms in Table 1, including aggregate risk, exposome, and total worker health. Exposome is defined as �the measure of all the exposures of an individual in a lifetime and how those exposures relate to health.� Exposomics is defined as �the study of the exposome, which relies on the application of internal and external exposure assessment methods.�

Figure 2 of this article will be of special interest to practicing industrial hygienists and safety professionals. It is an illustration of the relationship between the key factors that must be considered in a cumulative risk assessment. The primary factors are divided into three categories: occupational factors, non-occupational factors, and individual factors. The occupational and non-occupational factors are further divided into settings, sources, pathways, dominant exposure routes, key stressors, and effects. Using the illustration in Figure 2, the authors provide an illustrative case study in Figure 3 to assess the cumulative risk for hearing loss.

The Global Landscape of OELs

In this ninth and final research article from the JOEH supplement, �The Global Landscape of Occupational Exposure Limits�Implementation of Harmonization Principles to Guide Limit Selection� is discussed by M. Deveau, C-P Chen, G. Johanson, D. Krewski, A. Maier, K. J. Niven, S. Ripple, P. A. Schulte, J. Silk, J. H. Urbanus, D. M. Zalk, and R. W. Niemeier. The article�s abstract notes that an occupational hygienist seeking to determine the proper OEL to apply in an international setting will encounter a �confusing international landscape for identifying and applying such limits in workplaces.�

Practicing industrial hygienists and safety professionals may be interested in Figure 1, which is a reprint of the hierarchy of risk-based occupational exposure benchmarks as developed by AIHA in their publications on control banding and SEGs. The authors note that the goal of international harmonization for OEL derivation and development has been under much debate and discussion, and explains the existing harmonization initiatives in place.


As occupational health and safety professionals, industrial hygienists can have access to new and exciting research by academic, governmental, and other groups through journals such as JOEH. In their supplemental issue about OELs, JOEH has selected nine research articles that provide the current state of occupational exposure science. This blog post has summarized the contents of each article and provided takeaways and interesting quotes from the articles, to allow practicing industrial hygiene and safety professionals to focus their continuing safety education on the articles that will most interest them.

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