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.

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.

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 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.

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 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.