Theoretical Background of Occupational-Exposure Models-Report of an Expert Workshop of the ISES Europe Working Group "Exposure Models".

On 20 October 2020, the Working Group "Exposure Models" of the Europe Regional Chapter of the International Society of Exposure Science (ISES Europe) organised an online workshop to discuss the theoretical background of models for the assessment of occupational exposure to chemicals. In this report, participants of the workshop with an active role before and during the workshop summarise the most relevant discussion points and conclusions of this well-attended workshop. ISES Europe has identified exposure modelling as one priority area for the strategic development of exposure science in Europe in the coming years. This specific workshop aimed to discuss the main challenges in developing, validating, and using occupational-exposure models for regulatory purposes. The theoretical background, application domain, and limitations of different modelling approaches were presented and discussed, focusing on empirical "modifying-factor" or "mass-balance-based" approaches. During the discussions, these approaches were compared and analysed. Possibilities to address the discussed challenges could be a validation study involving alternative modelling approaches. The wider discussion touched upon the close relationship between modelling and monitoring and the need for better linkage of the methods and the need for common monitoring databases that include data on model parameters.

Evaluating the Theoretical Background of STOFFENMANAGER® and the Advanced REACH Tool.

STOFFENMANAGER® and the Advanced REACH Tool (ART) are recommended tools by the European Chemical Agency for regulatory chemical safety assessment. The models are widely used and accepted within the scientific community. STOFFENMANAGER® alone has more than 37 000 users globally and more than 310 000 risk assessment have been carried out by 2020. Regardless of their widespread use, this is the first study evaluating the theoretical backgrounds of each model. STOFFENMANAGER® and ART are based on a modified multiplicative model where an exposure base level (mg m-3) is replaced with a dimensionless intrinsic emission score and the exposure modifying factors are replaced with multipliers that are mainly based on subjective categories that are selected by using exposure taxonomy. The intrinsic emission is a unit of concentration to the substance emission potential that represents the concentration generated in a standardized task without local ventilation. Further information or scientific justification for this selection is not provided. The multipliers have mainly discrete values given in natural logarithm steps (…, 0.3, 1, 3, …) that are allocated by expert judgements. The multipliers scientific reasoning or link to physical quantities is not reported. The models calculate a subjective exposure score, which is then translated to an exposure level (mg m-3) by using a calibration factor. The calibration factor is assigned by comparing the measured personal exposure levels with the exposure score that is calculated for the respective exposure scenarios. A mixed effect regression model was used to calculate correlation factors for four exposure group [e.g. dusts, vapors, mists (low-volatiles), and solid object/abrasion] by using ~1000 measurements for STOFFENMANAGER® and 3000 measurements for ART. The measurement data for calibration are collected from different exposure groups. For example, for dusts the calibration data were pooled from exposure measurements sampled from pharmacies, bakeries, construction industry, and so on, which violates the empirical model basic principles. The calibration databases are not publicly available and thus their quality or subjective selections cannot be evaluated. STOFFENMANAGER® and ART can be classified as subjective categorization tools providing qualitative values as their outputs. By definition, STOFFENMANAGER® and ART cannot be classified as mechanistic models or empirical models. This modeling algorithm does not reflect the physical concept originally presented for the STOFFENMANAGER® and ART. A literature review showed that the models have been validated only at the 'operational analysis' level that describes the model usability. This review revealed that the accuracy of STOFFENMANAGER® is in the range of 100 000 and for ART 100. Calibration and validation studies have shown that typical log-transformed predicted exposure concentration and measured exposure levels often exhibit weak Pearson's correlations (r is <0.6) for both STOFFENMANAGER® and ART. Based on these limitations and performance departure from regulatory criteria for risk assessment models, it is recommended that STOFFENMANAGER® and ART regulatory acceptance for chemical safety decision making should be explicitly qualified as to their current deficiencies.

Assessment of exposure determinants and exposure levels by using stationary concentration measurements and a probabilistic near-field/far-field exposure model.

Background: The Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation requires the establishment of Conditions of Use (CoU) for all exposure scenarios to ensure good communication of safe working practices. Setting CoU requires the risk assessment of all relevant Contributing Scenarios (CSs) in the exposure scenario. A new CS has to be created whenever an Operational Condition (OC) is changed, resulting in an excessive number of exposure assessments. An efficient solution is to quantify OC concentrations and to identify reasonable worst-case scenarios with probabilistic exposure modeling. Methods: Here, we appoint CoU for powder pouring during the industrial manufacturing of a paint batch by quantifying OC exposure levels and exposure determinants. The quantification was performed by using stationary measurements and a probabilistic Near-Field/Far-Field (NF/FF) exposure model. Work shift and OC concentration levels were quantified for pouring TiO 2 from big bags and small bags, pouring Micro Mica from small bags, and cleaning. The impact of exposure determinants on NF concentration level was quantified by (1) assessing exposure determinants correlation with the NF exposure level and (2) by performing simulations with different OCs. Results: Emission rate, air mixing between NF and FF and local ventilation were the most relevant exposure determinants affecting NF concentrations. Potentially risky OCs were identified by performing Reasonable Worst Case (RWC) simulations and by comparing the exposure 95 th percentile distribution with 10% of the occupational exposure limit value (OELV). The CS was shown safe except in RWC scenario (ventilation rate from 0.4 to 1.6 1/h, 100 m 3 room, no local ventilation, and NF ventilation of 1.6 m 3/min). Conclusions: The CoU assessment was considered to comply with European Chemicals Agency (ECHA) legislation and EN 689 exposure assessment strategy for testing compliance with OEL values. One RWC scenario would require measurements since the exposure level was 12.5% of the OELV.

Source specific exposure and risk assessment for indoor aerosols.

Poor air quality is a leading contributor to the global disease burden and total number of deaths worldwide. Humans spend most of their time in built environments where the majority of the inhalation exposure occurs. Indoor Air Quality (IAQ) is challenged by outdoor air pollution entering indoors through ventilation and infiltration and by indoor emission sources. The aim of this study was to understand the current knowledge level and gaps regarding effective approaches to improve IAQ. Emission regulations currently focus on outdoor emissions, whereas quantitative understanding of emissions from indoor sources is generally lacking. Therefore, specific indoor sources need to be identified, characterized, and quantified according to their environmental and human health impact. The emission sources should be stored in terms of relevant metrics and statistics in an easily accessible format that is applicable for source specific exposure assessment by using mathematical mass balance modelings. This forms a foundation for comprehensive risk assessment and efficient interventions. For such a general exposure assessment model we need 1) systematic methods for indoor aerosol emission source assessment, 2) source emission documentation in terms of relevant a) aerosol metrics and b) biological metrics, 3) default model parameterization for predictive exposure modeling, 4) other needs related to aerosol characterization techniques and modeling methods. Such a general exposure assessment model can be applicable for private, public, and occupational indoor exposure assessment, making it a valuable tool for public health professionals, product safety designers, industrial hygienists, building scientists, and environmental consultants working in the field of IAQ and health.

Residential inter-zonal ventilation rates for exposure modeling.

Residential inter-zonal (e.g., between rooms) ventilation is comprised of fresh air infiltration in and exfiltration out of the whole house plus the "fresh" air that is entering (and exiting) the room of interest from other rooms or areas within the house. Clearly, the inter-zone ventilation rate in any room of interest will be greater than the infiltration/exfiltration ventilation rate of outdoor air for the whole house. The purpose of this study is to determine how much greater the inter-zonal ventilation rate is in typical U.S. residences compared to the whole house ventilation rate from outdoor air. The data for this statistical analysis came from HouseDB, a 1995 EPA database of residential ventilation rates. Analytical results indicate that a lognormal distribution provides the best fit to the data. Lognormal probability distribution functions (PDFs) are provided for various inter-zonal ventilation rates for comparison to the PDF for the whole house ventilation rates. All ventilation rates are expressed as air change rates per hour (ACH). These PDFs can be used as inputs to exposure models. This analysis suggests that if one were performing a deterministic analysis for unknown housing stocks in the U.S., a default mean and median ACH values of 0.4/hr and 0.3/hr, respectively, for whole house ventilation would be appropriate; and 0.7/hr and 0.6/hr, respectively, for inter-zonal ventilation.

A tiered asthma hazard characterization and exposure assessment approach for evaluation of consumer product ingredients.

Asthma is a complex syndrome with significant consequences for those affected. The number of individuals affected is growing, although the reasons for the increase are uncertain. Ensuring the effective management of potential exposures follows from substantial evidence that exposure to some chemicals can increase the likelihood of asthma responses. We have developed a safety assessment approach tailored to the screening of asthma risks from residential consumer product ingredients as a proactive risk management tool. Several key features of the proposed approach advance the assessment resources often used for asthma issues. First, a quantitative health benchmark for asthma or related endpoints (irritation and sensitization) is provided that extends qualitative hazard classification methods. Second, a parallel structure is employed to include dose-response methods for asthma endpoints and methods for scenario specific exposure estimation. The two parallel tracks are integrated in a risk characterization step. Third, a tiered assessment structure is provided to accommodate different amounts of data for both the dose-response assessment (i.e., use of existing benchmarks, hazard banding, or the threshold of toxicological concern) and exposure estimation (i.e., use of empirical data, model estimates, or exposure categories). Tools building from traditional methods and resources have been adapted to address specific issues pertinent to asthma toxicology (e.g., mode-of-action and dose-response features) and the nature of residential consumer product use scenarios (e.g., product use patterns and exposure durations). A case study for acetic acid as used in various sentinel products and residential cleaning scenarios was developed to test the safety assessment methodology. In particular, the results were used to refine and verify relationships among tiered approaches such that each lower data tier in the approach provides a similar or greater margin of safety for a given scenario.

Exposure Estimation and Interpretation of Occupational Risk: Enhanced Information for the Occupational Risk Manager.

The fundamental goal of this article is to describe, define, and analyze the components of the risk characterization process for occupational exposures. Current methods are described for the probabilistic characterization of exposure, including newer techniques that have increasing applications for assessing data from occupational exposure scenarios. In addition, since the probability of health effects reflects variability in the exposure estimate as well as the dose-response curve-the integrated considerations of variability surrounding both components of the risk characterization provide greater information to the occupational hygienist. Probabilistic tools provide a more informed view of exposure as compared to use of discrete point estimates for these inputs to the risk characterization process. Active use of such tools for exposure and risk assessment will lead to a scientifically supported worker health protection program. Understanding the bases for an occupational risk assessment, focusing on important sources of variability and uncertainty enables characterizing occupational risk in terms of a probability, rather than a binary decision of acceptable risk or unacceptable risk. A critical review of existing methods highlights several conclusions: (1) exposure estimates and the dose-response are impacted by both variability and uncertainty and a well-developed risk characterization reflects and communicates this consideration; (2) occupational risk is probabilistic in nature and most accurately considered as a distribution, not a point estimate; and (3) occupational hygienists have a variety of tools available to incorporate concepts of risk characterization into occupational health and practice.

Modeled comparisons of health risks posed by fluorinated solvents in a workplace spill scenario.

The purpose of this study was to illustrate how available physical-chemical exposure models can be used to compare potential risks and define risk management measures for non-routine exposure events, such as spills, leaks, or process upset conditions. A two-zone physical-chemical model was used to quantify and compare the potential exposure risks from five fluorinated solvents used in the manufacturing of electronic materials during an anticipated spill scenario. A 1-l spill scenario in a room measuring 2.74 m (9 ft) high by 3.66 m (12 ft) wide by 9.14 m (30 ft) long was constructed for modeling exposures using 'The Two-zone Model with An Exponentially Decreasing Contaminant' in available freeware 'IH MOD' (a PC based program available from the American Industrial Hygiene Association). This treatment was followed by using the results from an experimental chamber study in which the evaporation rates and vapor concentrations of the five fluorinated solvents were measured under realistic conditions and then compared to exposure model outputs. The breathing zone concentration/time profiles predicted for the five solvents were compared to their exposure limits to estimate the relative risk. This information was used to help define operationally sufficient risk management options for the safe handling of spills in laboratories, warehouses, or manufacturing facilities. The model indicated that each solvent presented very different risk profiles for the same 1-l liquid spill scenario. Potential exposure concentrations relative to short-term exposure limit (15 min) and Ceiling (C) exposure limit available for some of the solvents are predicted to be exceeded within a few minutes in the area near the spill and in the far field. In addition, the model showed that near-field concentrations for one solvent exceeded the published LC-50 (the concentration predicted to cause 50% mortality in the test animals), which indicates a very high degree of risk for this material in similar scenarios. Given the speed of evaporation during these spills for the materials tested in this study, donning personal protective equipment in the area may not be a viable option and short-term evacuation of the area immediately surrounding the spill would appear to be a practical risk management response.

Using publicly available information to create exposure and risk-based ranking of chemicals used in the workplace and consumer products.

Mandates that require the estimation of exposure and human health risk posed by large numbers of chemicals present regulatory managers with a significant challenge. Although these issues have been around for some time, the estimation of human exposure to chemicals from use of products in the workplace and by the consumer has been generally hindered by the lack of good tools. Logically and in the interest of cost-effective resource allocation and regulation one would typically and naturally first attempt to rank-order or prioritize the chemicals according to the human exposure potential that each might pose. We have developed an approach and systematic modeling construct that accomplishes this critical task by providing a quantitative estimate of human exposure for as many as several hundred chemicals initially; however, it could ultimately do this for any number of regulated chemicals starting only with the identity (Chemical Abstract Service number) for each chemical under consideration. These exposure estimates can then be readily linked to toxicological benchmarks for each item to estimate and rank the human health risk for the chemicals under consideration in a "worst things first" listing. This modeling construct, entitled Complex Exposure Tool (ComET) was developed by The LifeLine Group as a proof of concept under the sponsorship of Health Canada. ComET considers multiple routes of exposure, multiple subpopulations and different possible durations of exposure. A beta-version of ComET was issued and demonstrated in which users can change the assumptions in the model and see the impacts of these changes and the quality of information as they relate to the predicted exposure potential. We have advanced the operational elements of ComET into a tool entitled the Chemical Exposure Priority Setting Tool (CEPST) designed to provide quantitative estimation of the exposure potential of large groups of chemicals with little data and possibly multiple exposure scenarios. A basic feature of this tool is the utilization of an internally consistent approach and assumptions that are completely transparent. It uses publicly available information as critical input and is specifically designed to be continually reviewed, refined, expanded and updated using scientific peer review and stakeholder input.

Available data on naphthalene exposures: strengths and limitations.

Exposures to naphthalene occur from a number of sources. Data on these exposures have been reported by a number of researchers; however, these data have not been organized into a consistent framework. In addition, while naphthalene has been identified as an animal inhalation carcinogen there has been no attempt to define the ranges of long-term average inhalation exposures for the general population or sub populations that are relevant to the assessment of the risk of the occurrence of chronic effects. This paper attempts to organize the available data on naphthalene levels in air and provide ranges for the long-term average concentrations experienced by different populations. The paper also discusses the limitations of available data and identifies areas for future research.

Modeling framework for human exposure assessment.

We are at the dawn of a new era of quantitative consumer exposure and risk assessment of chemicals driven by regulatory mandates. This remarkable development also signals the beginning of a dramatic resurgence in the need for and development of human exposure models. This paper presents some of the philosophical background underlying exposure modeling in the context of human health risk assessment. The basic types of and structure of inhalation exposure models are discussed, as well as the research needed to move us forward into this exciting new period of development.

How much is enough to accept hormesis as the default? or 'At what point, if ever, could/should hormesis be employed as the principal dose-response default assumption in risk assessment?'.

Hormesis as the principal human dose-response default assumption must reasonably await the development of the science of toxicology and molecular biology before this dramatic change can occur. The inherent quality of typical toxicological data is simply too limited to allow for an understanding of what really occurs in human tissues at the relatively low doses generally extant in the environment. Thus, forwarding or asserting the quantitative use of hormesis (or any model of low dose-response) without this reasonable knowledge is simply an argument without data. It is this writer's opinion that any widespread and default acceptance of hormesis will need to look forward to and draw upon the inevitable development and use of tools from the realm of molecular biology and a resulting and distinct change in the entire toxicological testing paradigm.

Uncertainty in exposure estimates made by modeling versus monitoring.

To conduct an initial exposure assessment for an airborne toxicant, industrial hygienists usually prefer air monitoring to mathematical modeling, even if only one exposure value is to be measured. This article argues that mathematical modeling may provide a more accurate (less uncertain) exposure estimate than monitoring if only a few air samples are to be collected, if anticipated exposure variability is high, and if information on exposure determinants is not too uncertain. To explore this idea, a hypothetical "true" distribution of 8-hour time-weighted average airborne exposure values, C, is posited based on an NF exposure model. The C distribution is approximately lognormal. Estimation of the mean value, microC (the long-term average exposure level), is considered. Based on simple random sampling of workdays and use of the sample mean C to estimate microC, accuracy (uncertainty) in the estimate is measured by the mean square error, MSE(C). In the alternative, a modeling estimate can be made using estimates of the mean chemical emission rate microG, the mean room dilution supply air rate microQ, and the mean dilution ventilation rate in the NF of the source mu beta. By positing uniform distributions for the estimates microG, microQ, and mu beta, an equation for the modeling mean square error MSE(microC) is presented. It is shown that for a sample size of three or fewer workdays, mathematical modeling rather than air monitoring should provide a more accurate estimate of microC if the anticipated geometric standard deviation for the C distribution exceeds 2.3.