Impacts of risk assessment data, assumptions, and methods: Considering the evidence for diacetyl and 2,3-pentanedione.

The articles published as part of the Frontiers in Public Health research topic, "Investigating exposures and respiratory health in coffee workers" present research findings that better characterize exposures to diacetyl and 2,3-pentanedione and inform our understanding of the health risks posed by these exposures. Although various research groups and organizations have conducted risk assessments to derive occupational exposure limits (OELs) for diacetyl, differences in the data used and assumptions made in these efforts have resulted in a wide range of recommended OELs designed to protect human health. The primary drivers of these differences include the decision to use data from human or animal studies in conducting a quantitative risk assessment, and the application of uncertainty factors (UF) to derive an OEL. This Perspectives paper will discuss the practical implications of these decisions, and present additional commentary on the potential role that the recent investigation of human exposures to relatively low concentrations of α-diketones, specifically diacetyl and 2,3-pentanedione, may play in supporting qualitative or quantitative human health risk assessments.

NIOSH Risk-Based Model to Resume Field Research and Public Health Service in 2020 During the COVID-19 Pandemic.

In the early months of the COVID-19 pandemic, field research and public health service work conducted by the National Institute for Occupational Safety and Health (NIOSH) was put on hold. During this time, NIOSH developed a risk-based model to resume fieldwork, balancing the public health benefit of such fieldwork with the risks of severe acute respiratory syndrome coronavirus 2 exposure and transmission. We describe our experiences with this model, along with the broader public health significance of the methods used to inform risk management decisions. (Am J Public Health. 2022;112(8):1138-1141. https://doi.org/10.2105/AJPH.2022.306882).

Implications of applying cumulative risk assessment to the workplace.

Multiple changes are influencing work, workplaces and workers in the US including shifts in the main types of work and the rise of the 'gig' economy. Work and workplace changes have coincided with a decline in unions and associated advocacy for improved safety and health conditions. Risk assessment has been the primary method to inform occupational and environmental health policy and management for many types of hazards. Although often focused on one hazard at a time, risk assessment frameworks and methods have advanced toward cumulative risk assessment recognizing that exposure to a single chemical or non-chemical stressor rarely occurs in isolation. We explore how applying cumulative risk approaches may change the roles of workers and employers as they pursue improved health and safety and elucidate some of the challenges and opportunities that might arise. Application of cumulative risk assessment should result in better understanding of complex exposures and health risks with the potential to inform more effective controls and improved safety and health risk management overall. Roles and responsibilities of both employers and workers are anticipated to change with potential for a greater burden of responsibility on workers to address risk factors both inside and outside the workplace that affect health at work. A range of policies, guidance and training have helped develop cumulative risk assessment for the environmental health field and similar approaches are available to foster the practice in occupational safety and health.

Susceptibility of older adults to health effects induced by ambient air pollutants regulated by the European Union and the United States.

Air pollution is a health concern for the general population, but a few subpopulations (e.g., children, individuals with preexisting cardiovascular or respiratory diseases, etc.) are considered more susceptible to the adverse health effects attributed to air pollution. There is sufficient evidence to suggest that older adults (≥65 years old) are more susceptible to air pollution-induced health effects compared to younger adults due to decreased physiological, metabolic and compensatory processes, and a greater incidence of cardiovascular and respiratory disease. This review examines health effects induced by exposures to common ambient air pollutants regulated by the European Union and the United States. Studies were evaluated that examined the potential susceptibility of older adults to air pollutant-induced health effects. This review focuses on epidemiologic studies that directly compared the health effects of older adults to younger adults and/or the general population in order to compare populations within the same study design. Supplementary information is used from controlled human exposure studies, which examined only older adults, and animal toxicological studies, which utilized animal models of senescence, to provide coherence and biological plausibility for the health effects observed in epidemiologic studies. Overall, evidence from available published studies demonstrates that older adults may be more susceptible to air pollution-induced health effects than younger adults and/or the general population. Clinicians and other health professionals should consider advising older adults on pollution-avoiding behaviors in order to decrease the risk of adverse air pollution-related health effects.

Consideration of age-related changes in behavior trends in older adults in assessing risks of environmental exposures.

OBJECTIVE: To explore age-related behavior differences between older and younger adults, and to review how older adult activity patterns are considered in evaluating the potential risk of exposure to environmental pollutants. METHODS: Activity pattern data and their use in risk assessments were analyzed using the U.S. EPA Exposure Factors Handbook (EFH), U.S. EPA Consolidated Human Activity Pattern Database (CHAD), and peer-reviewed literature describing human health risk assessments. RESULTS: The characterization by age of some factors likely to impact older adults' exposures remains limited. We demonstrate that age-related behavior trends vary between younger and older adults, and these differences are rarely explicitly considered in environmental health risk assessment for older adults. DISCUSSION: Incorporating older adult exposure factors into risk assessments may be challenging because of data gaps and difficulty in defining and appropriately binning older adults. Additional data related to older adult exposure factors are warranted for evaluating risk among this susceptible population.

Practical advancement of multipollutant scientific and risk assessment approaches for ambient air pollution.

OBJECTIVES: The U.S. Environmental Protection Agency is working toward gaining a better understanding of the human health impacts of exposure to complex air pollutant mixtures and the key features that drive the toxicity of these mixtures, which can then be used for future scientific and risk assessments. DATA SOURCES: A public workshop was held in Chapel Hill, North Carolina, 22-24 February 2011, to discuss scientific issues and data gaps related to adopting multipollutant science and risk assessment approaches, with a particular focus on the criteria air pollutants. Expert panelists in the fields of epidemiology, toxicology, and atmospheric and exposure sciences led open discussions to encourage workshop participants to think broadly about available and emerging scientific evidence related to multipollutant approaches to evaluating the health effects of air pollution. SYNTHESIS: Although there is clearly a need for novel research and analytical approaches to better characterize the health effects of multipollutant exposures, much progress can be made by using existing scientific information and statistical methods to evaluate the effects of single pollutants in a multipollutant context. This work will have a direct impact on the development of a multipollutant science assessment and a conceptual framework for conducting multipollutant risk assessments. CONCLUSIONS: Transitioning to a multipollutant paradigm can be aided through the adoption of a framework for multipollutant science and risk assessment that encompasses well-studied and ubiquitous air pollutants. Successfully advancing methods for conducting these assessments will require collaborative and parallel efforts between the scientific and environmental regulatory and policy communities.

A review of the genotoxicity of 1,2-dichloroethane (EDC).

1,2-Dichloroethane (EDC, CAS#107-06-2) is a high production volume halogenated aliphatic hydrocarbon that is used mainly in the manufacture of vinyl chloride. EDC has been found in ambient and residential air samples, as well as in groundwater, surface water and drinking water. EDC has been well-studied in a variety of genotoxicity assays, and appears to involve the metabolic activation of the parent compound. We critically evaluated the genotoxicity data of EDC and its metabolites as part of an evaluation of carcinogenic mechanisms of action of EDC. EDC is genotoxic in multiple test systems via multiple routes of exposure. EDC has been shown to induce DNA adduct formation, gene mutations and chromosomal aberrations in the presence of key activation enzymes (including CYP450s and/or GSTs) in laboratory animal and in vitro studies. EDC was negative for clastogenesis as measured by the micronucleus assay in mice. In general, an increased level of DNA damage is observed related to the GSH-dependent bioactivation of EDC. Increased chromosomal aberrations with increased CYP450 expression were suggestive of a role for the oxidative metabolites of EDC in inducing chromosomal damage. Taken together, these studies demonstrate that EDC exposure, in the presence of key enzymes (including CYP450s and/or GSTs), leads to DNA adduct formation, gene mutations and chromosomal aberrations.

A review of controlled human SO2 exposure studies contributing to the US EPA integrated science assessment for sulfur oxides.

Laboratory studies involving intentional and highly controlled exposures to air pollutants among groups of human volunteers provide valuable information related to the potential health effects of pollutants regulated under the US Clean Air Act. These controlled human exposure studies often provide biological plausibility for the associations between air-pollutant concentration and a given health endpoint observed in epidemiologic investigations. In some cases, results from human laboratory studies provide evidence of a relevant health effect at ambient or near-ambient concentrations and thus directly support the selection of air quality standard levels. In the recently completed review of the US National Ambient Air Quality Standards (NAAQS) for sulfur dioxide (SO2), the US Environmental Protection Agency (EPA) concluded that short-term exposures to SO2 are causally associated with an increase in respiratory morbidity. This determination was based in large part on findings from laboratory studies of controlled exposures to SO2 among small groups of asthmatic individuals. The purpose of this review is to concisely present an overview of the evidence from controlled human exposure studies of SO2-induced respiratory health effects following short-term exposures. While the majority of these studies were conducted over 20 years ago, the findings and insights gained from this work continues to play an integral role in evaluating the respiratory effects of ambient exposures to SO2.

Particulate matter-induced health effects: who is susceptible?

BACKGROUND: Epidemiological, controlled human exposure, and toxicological studies have demonstrated a variety of health effects in response to particulate matter (PM) exposure with some of these studies indicating that populations with certain characteristics may be disproportionately affected. OBJECTIVE: To identify populations potentially at greatest risk for PM-related health effects, we evaluated epidemiological studies that examined various characteristics that may influence susceptibility, while using results from controlled human exposure and toxicological studies as supporting evidence. Additionally, we formulated a definition of susceptibility, building from the varied and inconsistent definitions of susceptibility and vulnerability used throughout the literature. DATA SYNTHESIS: We evaluated recent epidemiological studies to identify characteristics of populations potentially susceptible to PM-related health effects. Additionally, we evaluated controlled human exposure and toxicological studies to provide supporting evidence. We conducted a comprehensive review of epidemiological studies that presented stratified results (e.g., < 65 vs. ≥ 65 years of age), controlled human exposure studies that examined individuals with underlying disease, and toxicological studies that used animal models of disease. We evaluated results for consistency across studies, coherence across disciplines, and biological plausibility to assess the potential for increased susceptibility to PM-related health effects in a specific population or life stage. CONCLUSIONS: We identified a diverse group of characteristics that can lead to increased risk of PM-related health effects, including life stage (i.e., children and older adults), preexisting cardiovascular or respiratory diseases, genetic polymorphisms, and low-socioeconomic status. In addition, we crafted a comprehensive definition of susceptibility that can be used to encompass all populations potentially at increased risk of adverse health effects as a consequence of exposure to an air pollutant.

Analysis of the concentration-respiratory response among asthmatics following controlled short-term exposures to sulfur dioxide.

Some of the most compelling evidence of sulfur dioxide (SO(2))-induced respiratory morbidity is derived from a large body of studies involving controlled short-term exposures among groups of asthmatic volunteers. These studies were extensively cited in the recently completed review of the primary National Ambient Air Quality Standards for SO(2). Although it is clear from these investigations that exposure to SO(2) may result in a significant increase in bronchoconstriction, there is uncertainty regarding the range of concentrations over which this respiratory response occurs. The objective of this study was to better characterize the concentration-response relationship between SO(2) and measures of bronchoconstriction using individual subject lung function response data. In reviewing studies of asthmatics exposed to SO(2) during 5- to 10-min periods of elevated ventilation, we observed clear and consistent evidence of an increase in the bronchoconstrictive response to SO(2) with increasing exposure concentrations between 0.2 and 1.0 ppm. In a subsequent analysis of individual subject data, it was found that those asthmatics experiencing SO(2)-induced respiratory effects at relatively high exposure concentrations are also more likely than nonresponders to experience similar effects after exposure to lower SO(2) concentrations (≤0.4 ppm). Although the clinical significance of these effects is unsettled, the findings provide additional support to epidemiologic evidence of an association between ambient SO(2) concentration and various measures of respiratory morbidity in the general population.

Database for physiologically based pharmacokinetic (PBPK) modeling: physiological data for healthy and health-impaired elderly.

Physiologically based pharmacokinetic (PBPK) models have increasingly been employed in chemical health risk assessments. By incorporating individual variability conferred by genetic polymorphisms, health conditions, and physiological changes during development and aging, PBPK models are ideal for predicting chemical disposition in various subpopulations of interest. In order to improve the parameterization of PBPK models for healthy and health-impaired elderly (herein defined as those aged 65 yr and older), physiological parameter values were obtained from the peer-reviewed literature, evaluated, and entered into a Microsoft ACCESS database. Database records include values for key age-specific model inputs such as ventilation rates, organ volumes and blood flows, glomerular filtration rates, and other clearance-related processes. In total, 528 publications were screened for relevant data, resulting in the inclusion of 155 publications comprising 1051 data records for healthy elderly adults and 115 data records for elderly with conditions such as diabetes, chronic obstructive pulmonary disease (COPD), obesity, heart disease, and renal disease. There are no consistent trends across parameters or their associated variance with age; the gross variance in body weight decreased with advancing age, whereas there was no change in variance for brain weight. The database contains some information to inform ethnic and gender differences in parameters; however, the majority of the published data pertain to Asian (mostly Japanese) and Caucasian males. As expected, the number of records tends to decrease with advancing age. In addition to a general lack of data for parameters in the elderly with various health conditions, there is also a dearth of information on blood and tissue composition in all elderly groups. Importantly, there are relatively few records for alveolar ventilation rate; therefore, the relationship between this parameter and cardiac output (usually assumed to be 1:1) in the elderly is not well informed by the database. Despite these limitations, the database represents a potentially useful resource for parameterizing PBPK models for the elderly to facilitate the prediction of dose metrics in older populations for application in risk assessment.

The influence of genetic polymorphisms on population variability in six xenobiotic-metabolizing enzymes.

This review provides variability statistics for polymorphic enzymes that are involved in the metabolism of xenobiotics. Six enzymes were evaluated: cytochrome P-450 (CYP) 2D6, CYP2E1, aldehyde dehydrogenase-2 (ALDH2), paraoxonase (PON1), glutathione transferases (GSTM1, GSTT1, and GSTP1), and N-acetyltransferases (NAT1 and NAT2). The polymorphisms were characterized with respect to (1) number and type of variants, (2) effects of polymorphisms on enzyme function, and (3) frequency of genotypes within specified human populations. This information was incorporated into Monte Carlo simulations to predict the population distribution and describe interindividual variability in enzyme activity. The results were assessed in terms of (1) role of these enzymes in toxicant activation and clearance, (2) molecular epidemiology evidence of health risk, and (3) comparing enzyme variability to that commonly assumed for pharmacokinetics. Overall, the Monte Carlo simulations indicated a large degree of interindividual variability in enzyme function, in some cases characterized by multimodal distributions. This study illustrates that polymorphic metabolizing systems are potentially important sources of pharmacokinetic variability, but there are a number of other factors including blood flow to liver and compensating pathways for clearance that affect how a specific polymorphism will alter internal dose and toxicity. This is best evaluated with the aid of physiologically based pharmacokinetic (PBPK) modeling. The population distribution of enzyme activity presented in this series of articles serves as inputs to such PBPK modeling analyses.

Genetic polymorphism in CYP2E1: Population distribution of CYP2E1 activity.

Cytochrome P-450 2E1 (CYP2E1) is a key enzyme in the metabolic activation of a variety of toxicants including nitrosamines, benzene, vinyl chloride, and halogenated solvents such as trichloroethylene. CYP2E1 is also one of the enzymes that metabolizes ethanol to acetaldehyde, and is induced by recent ethanol ingestion. There is evidence that interindividual variability in the expression and functional activity of this cytochrome (CYP) may be considerable. Genetic polymorphisms in CYP2E1 were identified and linked to altered susceptibility to hepatic cirrhosis induced by ethanol and esophageal and other cancers in some epidemiological studies. Therefore, it is important to evaluate how such polymorphisms affect CYP2E1 function and whether it is possible to construct a population distribution of CYP2E1 activity based upon the known effects of these polymorphisms and their frequency in the population. This analysis is part of the genetic polymorphism database project described in the lead article in this series and followed the approach described in that article (Ginsberg et al., 2009, this issue). Review of the literature found that there are a variety of CYP2E1 variant alleles but the functional significance of these variants is still unclear. Some, but not all, studies suggest that several upstream 5' flanking mutations affect gene expression and response to inducers such as ethanol or obesity. None of the coding-region variants consistently affects enzyme function. Part of the reason for conflicting evidence regarding genotype effect on phenotype may be due to the wide variety of exposures such as ethanol or dietary factors and physiological factors including body weight or diabetes that modulate CYP2E1 expression. In conclusion, evidence is too limited to support the development of a population distribution of CYP2E1 enzyme activity based upon genotypes. Health risk assessments may best rely upon data reporting interindividual variability in CYP2E1 function for input into physiologically based pharmacokinetic (PBPK) models involving CYP2E1 substrates.

Genetic polymorphism in N-Acetyltransferase (NAT): Population distribution of NAT1 and NAT2 activity.

N-Acetyltransferases (NAT) are key enzymes in the conjugation of certain drugs and other xenobiotics with an arylamine structure. Polymorphisms in NAT2 have long been recognized to modulate toxicity produced by the anti-tubercular drug isoniazid, with molecular epidemiologic studies suggesting a link between acetylator phenotype and increased risk for bladder cancer. Recent evidence indicates that the other major NAT isozyme, NAT1, is also polymorphic. The current analysis characterizes the main polymorphisms in both NAT2 and NAT1 in terms of their effect on enzyme activity and frequency in the population. Multiple NAT2 alleles (NAT2*5, *6, *7, and *14) have substantially decreased acetylation activity and are common in Caucasians and populations of African descent. In these groups, most individuals carry at least one copy of a slow acetylator allele, and less than 10% are homozygous for the wild type (fast acetylator) trait. Incorporation of these data into a Monte Carlo modeling framework led to a population distribution of NAT2 activity that was bimodal and associated with considerable variability in each population assessed. The ratio of the median to the first percentile of NAT2 activity ranged from 7 in Caucasians to 18 in the Chinese population. This variability indicates the need for more quantitative approaches (e.g., physiologically based pharmacokinetic [PBPK] modeling) to assess the full distribution of internal dose and adverse responses to aromatic amines and other NAT2 substrates. Polymorphisms in NAT1 are generally associated with relatively minor effects on acetylation function, with Monte Carlo analysis indicating less interindividual variability than seen in NAT2 analysis.

Genetic Polymorphism in Glutathione Transferases (GST): Population distribution of GSTM1, T1, and P1 conjugating activity.

Glutathione transferases (GST) catalyze the conjugation of glutathione (GSH) with electrophiles, many of which may otherwise interact with protein or DNA. In select cases such as halogenated solvents, GST-mediated conjugation may lead to a more toxic or mutagenic metabolite. Polymorphisms that exert substantial effects on GST function were noted in human populations for several isozymes. This analysis focuses on three well-characterized isozymes, GSTM1, T1, and P1, in which polymorphisms were extensively studied with respect to DNA adducts and cancer in molecular epidemiologic studies. The current review and analysis focused upon how polymorphisms in these GST contributed to population variability in GST function. The first step in developing this review was to characterize the influence of genotype on phenotype (enzyme function) and the frequency of the polymorphisms across major population groups for all three GST. This information was then incorporated into Monte Carlo simulations to develop population distributions of enzyme function. These simulations were run separately for GSTM1, T1, and P1, and also for the combination of these isozymes, to assess the possibility of overlapping substrate specificity. Monte Carlo simulations indicated large interindividual variability for GSTM1 and T1 due to the presence of the null (zero activity) genotype, which is common in all populations studied. Even for GSTM1 or T1 non-null individuals, there was considerable interindividual variability with a bimodal distribution of enzyme activity evident. GSTP1 polymorphisms are associated with somewhat less variability due to the absence of null genotypes. However, in all cases simulated, the estimated variability is sufficiently large to warrant consideration of GST function distributions in assessments involving GST-mediated activation or detoxification of xenobiotics. Ideally, such assessments would involve physiologically based toxicokinetic (PBTK) modeling to assess population variability in internal dose.

Genetic polymorphism in paraoxonase 1 (PON1): Population distribution of PON1 activity.

Paraoxonase-1 (PON1) is a serum esterase that hydrolyzes the activated oxon form of several organophosphates. The central role of PON1 in detoxification of organophosphate (OP) pesticides was demonstrated in knockout mouse studies, suggesting that human variability in PON1 needs to be considered in health risk assessments involving exposure to these pesticides. The current analysis focused on two genetic loci in which polymorphisms demonstrated to affect PON1 activity. Detailed kinetic studies and population studies found that the *192Q (wild type) allele is more active toward some substrates (such as sarin, soman, and diazoxon) and less active toward others (such as paraoxon or chlorpyrifos) relative to the variant *192R allele. Another allele that affects activity is *55M; PON1 enzyme quantity, rather than specific activity or substrate preference, is altered. The *192R variant occurs commonly with a frequency of 25-64% across the populations analyzed. The *55M allele is less common, occurring in 5-40% of individuals depending upon the ethnic group studied. These activity and allele frequency data were incorporated into Monte Carlo simulations in which the frequency of both variant alleles was simultaneously modeled in Caucasian, African American, and Japanese populations. The resulting Monte Carlo activity distributions were bimodal for the substrate paraoxon with approximately fourfold differences between low- and high-activity modal medians. Differences in activity between total population median and 1st percentile were five- to sixfold. When sarin metabolic variability was simulated, the population distributions were unimodal. However, there was an even greater degree of interindividual variability (median to 1st percentile difference >20-fold). These results show that the combined effects of two PON1 allelic variants yielded a population distribution that is associated with a considerable degree of interindividual variability in enzyme activity. This indicates that assessments involving PON1 substrates need to evaluate polymorphism-related variability in enzyme activity to display the distribution of internal doses and adverse responses. This may best be achieved via physiologically based pharmacokinetic (PBPK) models that input PON1 activity distributions, such as those generated in this analysis, to simulate the range of oxon internal doses possible across the population.

Ethanol-induced increase in the metabolic clearance of 1,1,1-trichloroethane in human volunteers.

This study evaluated the effect of moderate doses of ethanol over a short period of time on the toxicokinetics of an organic solvent, 1,1,1-trichloroethane. A group of 10 moderate drinkers were recruited and exposed via inhalation for 2 h to a low concentration of 1,1,1-trichloroethane (175 ppm) on two separate occasions. Subjects were administered ethanol (0.35 g/kg body weight) on each of the 7 days preceding one of the exposures. Blood and urine samples were collected during and following each exposure, with blood analyzed for 1,1,1-trichloroethane and urine analyzed for the metabolites of 1,1,1-trichloroethane: trichloroethanol and trichloroacetic acid. Prior ethanol consumption resulted in a significant increase in apparent metabolic clearance of 1,1,1-trichloroethane (mean increase = 25.4%). The results of this study demonstrate that ethanol consumption over time can affect the rate at which an organic solvent is cleared through metabolism in humans. For chemicals with toxic metabolic products, this inductive effect of ethanol consumption on the rate of biotransformation could be potentially harmful to exposed individuals. Metabolic clearance of compounds with high hepatic extraction may not be affected by enzyme induction as it is likely that these compounds are essentially completely metabolized while passing through the liver.

Evaluation of dynamic headspace with gas chromatography/mass spectrometry for the determination of 1,1,1-trichloroethane, trichloroethanol, and trichloroacetic acid in biological samples.

A sensitive and reproducible method is described for the analysis of trichloroacetic acid in urine and 1,1,1-trichloroethane in blood using dynamic headspace GC/MS. Samples were analyzed using the soil module of a modified purge and trap autosampler to facilitate the use of disposable purging vessels. Coefficients of variation were below 3.5% for both analytes, and response was linear in the range of 0.01-7.0 microg/ml for trichloroacetic acid and 0.9 ng/ml-2.2 microg/ml for 1,1,1-trichloroethane. Attempts at using dynamic headspace for the analysis of trichloroethanol in urine were unsuccessful.