Application of adverse outcome pathway networks to integrate mechanistic data informing the choice of a point of departure for hydrogen sulfide exposure limits.

Acute exposure to hydrogen sulfide initiates a series of hallmark biological effects that occur progressively at increasing exposure levels: odor perception, conjunctivitis, olfactory paralysis, "knockdown," pulmonary edema, and apnea. Although effects of exposure to high concentrations of hydrogen sulfide are clear, effects associated with chronic, low-level exposure in humans is under debate, leading to uncertainty in the critical effect used in regulatory risk assessments addressing low dose exposures. This study integrates experimental animal, observational epidemiology, and occupational exposure evidence by applying a pathway-based approach. A hypothesized adverse outcome pathway (AOP) network was developed from 34 studies, composed of 4 AOPs sharing 1 molecular initiating events (MIE) and culminating in 4 adverse outcomes. A comparative assessment of effect levels and weight of evidence identified an AOP leading to a biologically-plausible, low-dose outcome relative to the other outcomes (nasal lesions, 30 ppm versus olfactory paralysis, >100 ppm; neurological effects, >80 ppm; pulmonary edema, >80 ppm). This AOP (i.e. AOP1) consists of the following key events: cytochrome oxidase inhibition (>10 ppm), neuronal cell loss (>30 ppm), and olfactory nasal lesions (defined as both neuronal cell loss and basal cell hyperplasia; >30 ppm) in rodents. The key event relationships in this pathway were supported by moderate empirical evidence and have high biological plausibility due to known mechanistic understanding and consistency in observations for diverse chemicals.

The shape of low-concentration dose-response functions for benzene: implications for human health risk assessment.

Are dose-response relationships for benzene and health effects such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) supra-linear, with disproportionately high risks at low concentrations, e.g. below 1 ppm? To investigate this hypothesis, we apply recent mode of action (MoA) and mechanistic information and modern data science techniques to quantify air benzene-urinary metabolite relationships in a previously studied data set for Tianjin, China factory workers. We find that physiologically based pharmacokinetics (PBPK) models and data for Tianjin workers show approximately linear production of benzene metabolites for air benzene (AB) concentrations below about 15 ppm, with modest sublinearity at low concentrations (e.g. below 5 ppm). Analysis of the Tianjin worker data using partial dependence plots reveals that production of metabolites increases disproportionately with increases in air benzene (AB) concentrations above 10 ppm, exhibiting steep sublinearity (J shape) before becoming saturated. As a consequence, estimated cumulative exposure is not an adequate basis for predicting risk. Risk assessments must consider the variability of exposure concentrations around estimated exposure concentrations to avoid over-estimating risks at low concentrations. The same average concentration for a specified duration is disproportionately risky if it has higher variance. Conversely, if chronic inflammation via activation of inflammasomes is a critical event for induction of MDS and other health effects, then sufficiently low concentrations of benzene are predicted not to cause increased risks of inflammasome-mediated diseases, no matter how long the duration of exposure. Thus, we find no evidence that the dose-response relationship is supra-linear at low doses; instead sublinear or zero excess risk at low concentrations is more consistent with the data. A combination of physiologically based pharmacokinetic (PBPK) modeling, Bayesian network (BN) analysis and inference, and partial dependence plots appears a promising and practical approach for applying current data science methods to advance benzene risk assessment.

Facilitation of risk assessment with evidence-based methods - A framework for use of systematic mapping and systematic reviews in determining hazard, developing toxicity values, and characterizing uncertainty.

Systematic review tools and approaches developed for clinical medicine are often difficult to apply "off the shelf" in order to meet the needs of chemical risk assessments. To address such, we propose an approach that can be used by practitioners for using evidence-based methods to facilitate the risk assessment process. The framework builds on and combines efforts conducted to date by a number of agencies and researchers; the novelty is in combining these efforts with a practical understanding of risk assessment, and translating such into a 'step-by-step' guide. The approach relies on three key components: problem formulation, systematic evidence mapping, and systematic review, applied using a stepwise approach. Unique to this framework is the consideration of exposure in selecting, prioritizing, and evaluating data (e.g., dose-relevance, routes of exposure, etc.). Using the proposed step-by-step process, critical appraisal of individual studies (e.g., formal and structured assessment of both relevance and reliability) and integration efforts are considered in context of specified risk assessment objectives (e.g., mode of action, dose-response) as well as chemical-specific considerations. The resulting framework provides a logical approach of how evidence-based methods can be used to facilitate risk assessment, and elevates the use of systematic methods beyond hazard identification to directly facilitating transparent and objective selection of candidate studies and/or datasets used to quantitatively characterize risk, and to better use the underlying process to inform the approaches used to develop toxicity values.

The Practical Significance of Measurement Error in Pulmonary Function Testing Conducted in Research Settings.

Conventional spirometry produces measurement error by using repeatability criteria (RC) to discard acceptable data and terminating tests early when RC are met. These practices also implicitly assume that there is no variation across maneuvers within each test. This has implications for air pollution regulations that rely on pulmonary function tests to determine adverse effects or set standards. We perform a Monte Carlo simulation of 20,902 tests of forced expiratory volume in 1 second (FEV1 ), each with eight maneuvers, for an individual with empirically obtained, plausibly normal pulmonary function. Default coefficients of variation for inter- and intratest variability (3% and 6%, respectively) are employed. Measurement error is defined as the difference between results from the conventional protocol and an unconstrained, eight-maneuver alternative. In the default model, average measurement error is shown to be ∼5%. The minimum difference necessary for statistical significance at p < 0.05 for a before/after comparison is shown to be 16%. Meanwhile, the U.S. Environmental Protection Agency has deemed single-digit percentage decrements in FEV1 sufficient to justify more stringent national ambient air quality standards. Sensitivity analysis reveals that results are insensitive to intertest variability but highly sensitive to intratest variability. Halving the latter to 3% reduces measurement error by 55%. Increasing it to 9% or 12% increases measurement error by 65% or 125%, respectively. Within-day FEV1 differences ≤5% among normal subjects are believed to be clinically insignificant. Therefore, many differences reported as statistically significant are likely to be artifactual. Reliable data are needed to estimate intratest variability for the general population, subpopulations of interest, and research samples. Sensitive subpopulations (e.g., chronic obstructive pulmonary disease or COPD patients, asthmatics, children) are likely to have higher intratest variability, making it more difficult to derive valid statistical inferences about differences observed after treatment or exposure.

Evaluating the MoA/human relevance framework for F-344 rat liver epithelioid granulomas with mineral oil hydrocarbons.

Toxicology feeding studies of mineral oil hydrocarbons (MOHs), within the carbon number range C22-C28, results in species-specific epithelioid granulomas in the liver of F-344 rats but not in other rat strains, or species. While MOH has been detected, and some pathological effects have been shown to occur in other organs/tissues of F-344 rats and other rat strains/species, it is generally accepted that the effect of toxicological concern is species-specific inflammatory liver granuloma. As oil retention and other MOH-related nontoxic pathological changes in the liver are observed in humans, some have hypothesized that the potential for oil accumulation over a lifetime, through dietary sources, may predispose humans to similar liver effects as observed in F-344 rats. To address this concern, a mode of action/human relevance framework (MoA/HRF) analysis for MOH-induced epithelioid granuloma in the F-344 rat model was developed. The key events for the development of liver epithelioid granulomas were identified as increased MOH intestinal absorption, preferential tissue retention and ultimately formation of necrotic granulomas encased by infiltrating inflammatory lymphocytes. The hypothesized MoA was evaluated using the modified Bradford Hill considerations for causality and was considered to be established in the F-344 rodent model. However, key strain/species differences in the rate of intestinal absorption, tissue retention of MOH and inflammatory response to MOH in the liver were identified. Overall, the F-344 rat MoA was not considered to be relevant to humans, consistent with data showing no evidence for the formation of epithelioid granulomas with humans even in cases of massive ingestion of MOHs.

Chronic low-level hydrogen sulfide exposure and potential effects on human health: a review of the epidemiological evidence.

The effects of exposure to high concentrations of hydrogen sulfide (H2S) on human health are well known. However, the potential human health hazards posed by low-level chronic environmental H2S exposure are being debated. Accordingly, we reviewed the literature regarding the effects of chronic, environmentally-relevant H2S exposures on human health. All human observational studies using an analytical study design (e.g. cohort, cross-sectional, case-control) to evaluate chronic-duration low-level H2S exposure (approximately ≤ 10 ppm on average, for 1 year or more), were evaluated for a range of health outcomes. Respiratory symptoms in both adults and children were the most consistently reported symptoms on the increase. When reported, such effects appear to be temporary, given that there is no consistent evidence of pulmonary function deficit in either age group, among those chronically exposed to low H2S concentrations. While sparse, some data also suggest potential ocular symptoms and disorders associated with chronic ambient level H2S exposure in adults (not children), but the limited data on H2S exposures, co-exposures and/or strong odor stimulus of H2S, temper interpretation. Neurological symptoms and deficits have been reported in some studies, but the highest quality evidence, obtained using objective outcome measures and a reasonably detailed assessment of exposure, does not support a neurological-related risk in adults (only one study in children). For the other endpoints assessed (cardiovascular, reproductive and developmental, and carcinogenicity), the results were mixed and/or conflicting, but did not indicate a potential health hazard, although this literature has several major limitations, particularly with regard to exposure estimation and the ability to assess exposure-response.

A framework for fit-for-purpose dose response assessment.

The NRC report Science and Decisions: Advancing Risk Assessment made several recommendations to improve chemical risk assessment, with a focus on in-depth chronic dose-response assessments conducted by the U.S. Environmental Protection Agency. The recommendations addressed two broad elements: improving technical analysis and utility for decision making. To advance the discussions in the NRC report, in three multi-stakeholder workshops organized by the Alliance for Risk Assessment, available and evolving risk assessment methodologies were considered through the development and application of case studies. A key product was a framework (http://www.allianceforrisk.org/Workshop/Framework/ProblemFormulation.html) to guide risk assessors and managers to various dose-response assessment methods relevant to a range of decision contexts ranging from priority setting to full assessment, as illustrated by case studies. It is designed to facilitate selection of appropriate methodology for a variety of problem formulations and includes a variety of methods with supporting case studies, for areas flagged specifically by the NRC committee for consideration--e.g., susceptible sub-populations, population variability and background. The framewok contributes to organization and communication about methodologies for incorporating increasingly biologically informed and chemical specific knowledge into dose-response analysis, which is considered critical in evolving fit-for-purpose assessment to address relevant problem formulations.

Scoping Review of Employer-Led Research Using Employee Health Claims Data.

Employers may evaluate employee claims data for various reasons, including assessment of medical insurance and wellness plan efficacy, monitoring employee health trends, and identifying focus areas for wellness measures. The objective of this scoping review (ScR) is to describe the available literature reporting the use, applications, and outcomes of employee health claims data by self-insured employers. The ScR was conducted in a stepwise manner using an established framework: identifying the research question, identifying and selecting relevant studies, charting the data, and collating and reporting results. Literature searches were conducted in PubMed and Embase. Studies of self-insured employee populations that were conducted by the employer/s through May 2022 were identified using predefined criteria. Forty-one studies were included. The majority (90%) were cohort study designs; most employers (51%) were in industries such as aluminum production and health insurance providers. Twenty-four (59%) studies supplemented claims data with other sources such as human resource data to evaluate programs and/or health outcomes. A range of exposures (eg, chronic conditions, wellness program participation) and outcomes (eg, rates or costs of conditions, program effectiveness) were considered. Among the 25 studies that reported on patient confidentiality and privacy, 68% indicated institutional review board approval and 48% reported use of deidentified data. Many self-insured employers have used employee health claims data to gain insights into their employees' needs and health care utilization. These data can be used to identify potential improvements for wellness and other targeted programs to improve employee health and decrease absenteeism.

Lung cancer incidence in Canadian petroleum workers.

OBJECTIVES: This study's purpose was to conduct a more in-depth analysis of the potential association between lung cancer, occupational exposures and smoking using data on cohort members from a Canadian petroleum company and refined statistical analyses. METHODS: Information on various exposures including asbestos and petroleum coke dust, as well as job type and operating segment were collected via manual and computerised company records. We performed life-table analyses, Poisson regression and restricted cubic splines to model exposure-response patterns while controlling for smoking status and age. Model diagnostics included the assessment of dispersion and offset parameters. RESULTS: These analyses show that lung cancer risk is strongly related to age and smoking, and to a lesser extent to province of last residence. When controlling for these covariates, there is suggestive evidence that maintenance work may also be related to lung cancer risk. Some analyses also indicate that asbestos exposure may be associated with lung cancer risk, although a clear exposure-response trend is not seen. Other exposures, including petroleum coke dust, were not strongly related to lung cancer risk, particularly when expressed as a continuous measure. CONCLUSIONS: These data suggest that maintenance work may be associated with lung cancer incidence, although exposures to the single agents studied did not emerge as strong predictors of lung cancer incidence. Maintenance work may be a surrogate for general exposures to several agents (eg, polycyclic aromatic hydrocarbons, metals, welding fumes, radiation, etc), although these results may be affected by residual confounding due to smoking or other socio-demographic factors.

Preliminary evaluation of the human relevance of respiratory tumors observed in rodents exposed to naphthalene.

Inhalation bioassays in mice and rats exposed to naphthalene (NA) show incidences of lung and nasal cancer, respectively. This paper describes a preliminary mode of action (MOA)/human relevance (HR) framework for NA. Species differences in both carcinogenic and cytotoxic responses between the rodent and human have been noted based on qualitative and quantitative differences in metabolism. Some occur at the initial oxidation of NA in the rat through CYP2F, versus CYP2A13 metabolism in the human respiratory system and which results in a difference in the specific naphthoquinone formed. Normally, subsequent reactive metabolites are then conjugated through glutathione, but high dose exposures, as in the rat bioassay, result in glutathione depletion, and the availability of 1,2-naphthoquinone for other conjugation. In the rat nose, it is proposed that a naphthoquinone imine is formed via a species and site-specific aryl amidase acting on an amino acid conjugate of the quinone. Such a quinone imine is believed to be the active agent in Alachlor and phenacetin, resulting in the same profile of respiratory tumors in the rat as NA. Based on the MOA and the limited epidemiological data indicating no human evidence of nasal or lung tumor risk, the carcinogenic response observed in rats does not appear relevant to the human.

Mortality of 196,826 Men and Women Working in U.S.-Based Petrochemical and Refinery Operations: Update 1979 to 2010.

OBJECTIVE: To describe mortality trends of men and women working in various petrochemical and refinery operations of a U.S.-based company. METHODS: The cohort consists of full-time employees with at least 1 day of service during 1979 through 2010. Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) were calculated for 111 possible causes of death studied. RESULTS: SMRs for malignant mesothelioma and asbestosis were highest for the 1940s decade of hire. Increased SMRs were observed for malignant melanoma and motor neuron disease with no obvious work patterns. Decreasing mortality patterns were observed for aplastic anemia and acute nonlymphocytic leukemia. CONCLUSIONS: Mortality surveillance of this large established cohort aids in assessing the chronic health status of the workforce. Identifying methods for incorporating job-exposure matrices and nonoccupational risk factors could further enhance interpretations for some findings such as motor neuron disease.

Development of an Evidence-Based Risk Assessment Framework.

Assessment of potential human health risks associated with environmental and other agents requires careful evaluation of all available and relevant evidence for the agent of interest, including both data-rich and data-poor agents. With the advent of new approach methodologies in toxicological risk assessment, guidance on integrating evidence from mul-tiple evidence streams is needed to ensure that all available data is given due consideration in both qualitative and quantitative risk assessment. The present report summarizes the discussions among academic, government, and private sector participants from North America and Europe in an international workshop convened to explore the development of an evidence-based risk assessment framework, taking into account all available evidence in an appropriate manner in order to arrive at the best possible characterization of potential human health risks and associated uncertainty. Although consensus among workshop participants was not a specific goal, there was general agreement on the key consider-ations involved in evidence-based risk assessment incorporating 21st century science into human health risk assessment. These considerations have been embodied into an overarching prototype framework for evidence integration that will be explored in more depth in a follow-up meeting.

A weight of evidence approach for selecting exposure biomarkers for biomonitoring.

CONTEXT: It is known that there are usually several biomarkers and/or medium combinations that can be applied to answer a specific exposure question. To help determine an appropriate combination for the specific question, we have developed a weight-of-evidence Framework that provides a relative appropriateness score for competing combinations. METHODS: The Framework is based on an expert assessor's evaluation of the relevance and suitability of the biomarker and medium for the question based on a set of criteria. We provide a computer based modeling tool to guide the researcher through the process. RESULTS: We present an example with six biomarkers of benzene exposure in one matrix; the six are either the most commonly used biomarkers and/or have recent widespread usage. The example clearly demonstrates the usefulness of the Framework for scoring the choices, as well as the transparency of the method that provides the basis for discussion. CONCLUSIONS: The Framework provides for the first time a method to transparently document the rationale behind selecting, from among a set of alternatives, the most scientifically supportable exposure biomarker to address a specific biomonitoring question, thus providing a reproducible account of expert opinions on the suitability of a biomarker.

Environmental epidemiology and risk assessment: Exploring a path to increased confidence in public health decision-making.

Throughout history, environmental epidemiology has proven crucial to identify certain threats to human health and to provide a basis for the development of life-saving public health policies. However, epidemiologists are facing challenges when studying tenuous threats such as environmental exposure to chemicals, whose association with adverse health effects may be difficult to characterize. As a result, epidemiological data can seldom be fully leveraged for quantitative risk assessment and decision-making. Despite two decades of efforts to improve a more systematic integration of human data to evaluate human health risks, assessors still heavily rely on animal data to do so, while epidemiology plays more of a secondary role. Although the need for more and better collaboration between risk assessors and epidemiologists is widely recognized, both fields tend to remain siloed. In 2017, the Health and Environmental Sciences Institute initiated a project engaging the epidemiology, exposure science, and regulatory communities with tripartite representation from regulators, industry, and academia in a dialogue on the use of environmental epidemiology for regulatory decision-making. Several focus groups attended by epidemiology, exposure science, and risk assessment experts were organized to explore incentives and barriers to collaboration, to ultimately bridge the gap between the various disciplines, and to realize the full potential of epidemiological data in risk assessment. Various ideas that have emerged from these meetings could help ensure the better integration of epidemiological data in quantitative risk assessment and contribute to building confidence in a robust and science-based regulatory decision-making process.

Systematic Review and Meta-Analysis of Selected Cancers in Petroleum Refinery Workers.

OBJECTIVE: We studied the risk of 11 cancers of a priori interest in petroleum refinery workers. METHODS: Iterative searches identified 36 studies for the 11 cancer sites. Statistical heterogeneity and publication bias were assessed to enhance interpretation of meta-relative risks. RESULTS: Statistical heterogeneity was marked for mesothelioma, but was largely due to study quality. Higher quality studies showed a meta-relative risk (RR) of 3.22, (95% prediction interval 1.45 to 7.23). Melanoma (meta-RR = 1.23) and acute lymphoid leukemia (meta-RR = 1.51), showed results consistent with higher risk, but both were driven by one or two studies. Eight other cancer outcomes showed summary meta-RR's consistent with unity. CONCLUSIONS: Most cancer outcomes are consistent with background risk in refinery workers. This work has clarified an excess mesothelioma risk, conditional on study quality stratification. Continued surveillance is warranted for melanoma and ALL.

Future directions in butadiene risk assessment and the role of cross-species internal dosimetry.

The 2005 International Symposium on the evaluation of butadiene and chloroprene health risks provided the opportunity to consider the past, present and future state of research issues for 1,3-butadiene. Considerable advancements have been made in our knowledge of exposure, metabolism, biomarkers of exposure and effect, and epidemiology. Despite this, uncertainties remain which will impact the human health risk assessment for current worker and environmental exposures. This paper reviews key aspects of recent studies and the role that biomarkers of internal dosimetry can play in addressing low to high exposure, gender, and cross-species differences in butadiene toxicity and metabolism. Considerable information is now available on the detection and quantification of protein adducts formed from the mono-, di- and dihydroxy-epoxide metabolites of butadiene. The diepoxide metabolite appears to play a key role in mutagenesis. Species differences in production of this critical metabolite are reflected by the diepoxybutane-specific hemoglobin adduct, pry-Val. To date, the pry-Val adduct has not been quantifiable in human blood samples from workers with cumulative occupational exposures up to 6.3 ppm-weeks; whereas, the pry-Val was quantifiable in the blood of mice and rats with similar cumulative exposures. Levels in mice were much higher than in rats. Further improvements in analytical sensitivity for the pyr-Val adduct are on the horizon. Epidemiology studies are also described and ongoing efforts promise to help bridge our understanding of past and future risks.

International Symposium on the Evaluation of Butadiene and Chloroprene Health Risks.

These proceedings represent nearly all the platform and poster presentations given during the International Symposium on Evaluation of Butadiene and Chloroprene Health Risks, held in Charleston, South Carolina, USA, on September 20-22, 2005. The Symposium was attended by 78 participants representing private industry (37), academia (21), government (11), not-for-profit organizations (5), and consulting (4). The program followed the format of previous symposia on butadiene, chloroprene, and isoprene in London UK (2000) and butadiene and isoprene in Blaine, Washington USA (1995). This format enabled the exchange of significant new scientific results and discussion of future research needs. Isoprene was not evaluated during the 2005 Symposium because of lack of new data. For background information, the reader is referred to the proceedings of the London 2000 meeting for a thorough historical perspective and overview of scientific and regulatory issues concerning butadiene, chloroprene, and isoprene [Chem.-Biol. Interact. (2001) 135-136:1-7]. The Symposium consisted of seven sessions: (1) Introduction and Opening Remarks, (2) Butadiene/styrene-butadiene rubber (SBR)--Process Overview, Exposure and Health Effects/Human Studies; (3) Chloroprene--Process Overview, Exposure and Health Effects/Human Studies; (4) Mode of Action/Key Events; (5) Risk Assessment; (6) Poster Presentations; and (7) Panel Discussion and Future Directions. The Symposium concluded with a discussion by all participants of issues that arose throughout the course of the Symposium. The Proceedings of the Symposium published in this Special Issue are organized according to the Sessions outlined above. The purpose of this foreword is to summarize the presentations and their key findings and recommend future research directions for each chemical.

Guidance on assessing the methodological and reporting quality of toxicologically relevant studies: A scoping review.

Assessments of methodological and reporting quality are critical to adequately judging the credibility of a study's conclusions and to gauging its potential reproducibility. To aid those seeking to assess the methodological or reporting quality of studies relevant to toxicology, we conducted a scoping review of the available guidance with respect to four types of studies: in vivo and in vitro, (quantitative) structure-activity relationships ([Q]SARs), physico-chemical, and human observational studies. Our aims were to identify the available guidance in this diverse literature, briefly summarize each document, and distill the common elements of these documents for each study type. In general, we found considerable guidance for in vivo and human studies, but only one paper addressed in vitro studies exclusively. The guidance for (Q)SAR studies and physico-chemical studies was scant but authoritative. There was substantial overlap across guidance documents in the proposed criteria for both methodological and reporting quality. Some guidance documents address toxicology research directly, whereas others address preclinical research generally or clinical research and therefore may not be fully applicable to the toxicology context without some translation. Another challenge is the degree to which assessments of methodological quality in toxicology should focus on risk of bias - as in clinical medicine and healthcare - or be broadened to include other quality measures, such as confirming the identity of test substances prior to exposure. Our review is intended primarily for those in toxicology and risk assessment seeking an entry point into the extensive and diverse literature on methodological and reporting quality applicable to their work.

Reliability and validity of an occupational health history questionnaire.

This study determined the reliability and validity of a self-administered occupational health history questionnaire. Reliability was evaluated using a test-retest study design based on 123 volunteers (56% participation rate) who were administered the questionnaire approximately 1 month apart. Validity and general acceptability was evaluated in a clinical setting through in-depth clinician interviews of 25 patients. The interviews assessed patients' understanding of and sensitivities to questions and degree of adherence to initial responses after discussing questions with clinicians. All but one question related to repetitive motion exposures showed 84% or higher agreement. Clinician interviews of patients indicated that most questions were well understood, although some patients misinterpreted questions regarding pregnancy history, repetitive motion, and immunization history. Overall, our results suggest that the questionnaire is highly reliable, valid, and acceptable to both clinicians and employees.

Extreme sensitivity and the practical implications of risk assessment thresholds.

Traditional risk-assessment theory assumes the existence of a threshold for non-cancer health effects. However, a recent trend in environmental regulation rejects this assumption in favor of non-threshold linearity for these endpoints. This trend is driven largely by two related concepts: (1) a theoretical assumption of wide-ranging human sensitivity, and (2) inability to detect thresholds in epidemiologic models. Wide-ranging sensitivity assumes a subpopulation with extreme background vulnerability, so that even trivial environmental exposures are hazardous to someone somewhere. We use examples from the real world of clinical medicine to show that this theoretical assumption is inconsistent with the biology of mammalian systems and the realities of patient care. Using examples from particulate-matter air-pollution research, we further show that failure to reject linearity is usually driven by statistical rather than biological considerations, and that nonlinear/threshold models often have a similar or better fit than their linear counterparts. This evidence suggests the existence of practical, real-world thresholds for most chemical exposures.