Considerations towards the better integration of epidemiology into quantitative risk assessment.

Environmental epidemiology has proven critical to study various associations between environmental exposures and adverse human health effects. However, there is a perception that it often does not sufficiently inform quantitative risk assessment. To help address this concern, in 2017, the Health and Environmental Sciences Institute initiated a project engaging the epidemiology, exposure science, and risk assessment communities with tripartite representation from government agencies, industry, and academia, in a dialogue on the use of environmental epidemiology for quantitative risk assessment and public health decision making. As part of this project, four meetings attended by experts in epidemiology, exposure science, toxicology, statistics, and risk assessment, as well as one additional meeting engaging funding agencies, were organized to explore incentives and barriers to realizing the full potential of epidemiological data in quantitative risk assessment. A set of questions was shared with workshop participants prior to the meetings, and two case studies were used to support the discussion. Five key ideas emerged from these meetings as areas of desired improvement to ensure that human data can more consistently become an integral part of quantitative risk assessment: 1) reducing confirmation and publication bias, 2) increasing communication with funding agencies to raise awareness of research needs, 3) developing alternative funding channels targeted to support quantitative risk assessment, 4) making data available for reuse and analysis, and 5) developing cross-disciplinary and cross-sectoral interactions, collaborations, and training. We explored and integrated these themes into a roadmap illustrating the need for a multi-stakeholder effort to ensure that epidemiological data can fully contribute to the quantitative evaluation of human health risks, and to build confidence in a reliable decision-making process that leverages the totality of scientific evidence.

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.

Suspected Palytoxin Inhalation Exposures Associated with Zoanthid Corals in Aquarium Shops and Homes - Alaska, 2012-2014.

On August 12, 2014, an Anchorage hospital notified the Alaska Section of Epidemiology (SOE) that a middle-aged male resident of Anchorage (patient A) had arrived in the emergency department with possible palytoxin exposure. Patient A complained of a bitter metallic taste, fever, weakness, cough, and muscle pain 7-8 hours after introduction of live zoanthid coral into his home aquarium. Palytoxin, a potent toxin known to produce the reported effects, is contained in zoanthid marine corals.

Is exposure to formaldehyde in air causally associated with leukemia?--A hypothesis-based weight-of-evidence analysis.

Recent scientific debate has focused on the potential for inhaled formaldehyde to cause lymphohematopoietic cancers, particularly leukemias, in humans. The concern stems from certain epidemiology studies reporting an association, although particulars of endpoints and dosimetry are inconsistent across studies and several other studies show no such effects. Animal studies generally report neither hematotoxicity nor leukemia associated with formaldehyde inhalation, and hematotoxicity studies in humans are inconsistent. Formaldehyde's reactivity has been thought to preclude systemic exposure following inhalation, and its apparent inability to reach and affect the target tissues attacked by known leukemogens has, heretofore, led to skepticism regarding its potential to cause human lymphohematopoietic cancers. Recently, however, potential modes of action for formaldehyde leukemogenesis have been hypothesized, and it has been suggested that formaldehyde be identified as a known human leukemogen. In this article, we apply our hypothesis-based weight-of-evidence (HBWoE) approach to evaluate the large body of evidence regarding formaldehyde and leukemogenesis, attending to how human, animal, and mode-of-action results inform one another. We trace the logic of inference within and across all studies, and articulate how one could account for the suite of available observations under the various proposed hypotheses. Upon comparison of alternative proposals regarding what causal processes may have led to the array of observations as we see them, we conclude that the case for a causal association is weak and strains biological plausibility. Instead, apparent association between formaldehyde inhalation and leukemia in some human studies is better interpreted as due to chance or confounding.

Age-related changes in cardiac and respiratory adaptation to acute ozone and carbon black exposures: interstrain variation in mice.

CONTEXT: Epidemiological studies show positive associations between increased ambient air pollutant levels and adverse cardiopulmonary effects. These studies suggest that the elderly and those with certain genetic polymorphisms are susceptible to adverse air pollution-associated health events. HYPOTHESIS/OBJECTIVE: We hypothesize that physiological responses to air pollutants vary with age and are genetically influenced. MATERIALS AND METHODS: To test this hypothesis, we exposed mice from three inbred strains (C57BL/6J, B6; C3H/HeJ, HeJ; C3H/HeOuJ, OuJ) to ozone (O(3)) and carbon black (CB) at two ages, (5 months, 12 months), for 3 consecutive days, to either filtered air (FA), CB particles, or O(3) and CB sequentially (O(3)CB) (CB, 550 µg/m(3); O(3), 600 ppb). Heart rate (HR), HR variability (HRV), breathing, and core temperature (Tco) responses were analyzed. RESULTS: We observed time-dependent physiological changes in response to O(3)CB exposure in each strain, relative to FA exposure for both age groups. Each mouse strain showed distinct adaptation profiles to repeated acute exposures to O(3). In younger mice, several time-dependent effects (decreased HR and increased HRV) were prominent in HeJ and OuJ mice but not B6 mice. We also observed variability in adaptation in older mice. However, responses in older mice were generally attenuated when compared to the younger mice. In addition, cardiac-respiratory interactions were affected with CB and O(3)CB exposures albeit with patterns differing by age or exposure. DISCUSSION/CONCLUSION: Our results suggest that age considerably attenuates physiological responses to O(3) and O(3)CB exposures. Age-related physiological changes such as increased oxidative stress in mouse tissue may be involved in this attenuation.

Diesel exhaust particulate (DEP) and nanoparticle exposures: what do DEP human clinical studies tell us about potential human health hazards of nanoparticles?

Engineered nanoparticles (ENPs) are increasingly tested in cellular and laboratory-animal experiments for hazard potential, but there is a lack of health effects data for humans exposed to ENPs. However, human data for another source of nanoparticle (NP) exposure are available, notably for the NPs contained in diesel exhaust particulate (DEP). Studies of human volunteers exposed to diesel exhaust (DE) in research settings report DEP-NP number concentrations (i.e., >10(6) particles/cm(3)) that exceed number concentrations reported for worst-case exposure conditions for workers manufacturing and handling ENPs. Recent human DE exposure studies, using sensitive physiological instrumentation and well-characterized exposure concentrations and durations, suggest that elevated DE exposures from pre-2007 engines may trigger short-term changes in, for example, lung and systemic inflammation, thrombogenesis, vascular function, and brain activity. Considerable uncertainty remains both as to which DE constituents underlie the observed responses (i.e., DEP NPs, DEP mass, DE gases), and as to the implications of the observed short-term changes for the development of disease. Even so, these DE human clinical data do not give evidence of a unique toxicity for NPs as compared to other small particles. Of course, physicochemical properties of toxicological relevance may differ between DEP NPs and other NPs, yet overall, the DE human clinical data do not support the idea that elevated levels of NPs per se (at least in the DEP context) must be acutely toxic by virtue of their nano-sized nature alone.

Critical review of the human data on short-term nitrogen dioxide (NO2) exposures: evidence for NO2 no-effect levels.

Nitrogen dioxide (NO2) is a ubiquitous atmospheric pollutant due to the widespread prevalence of both natural and anthropogenic sources, and it can be a respiratory irritant when inhaled at elevated concentrations. Evidence for health effects of ambient NO2 derives from three types of studies: observational epidemiology, human clinical exposures, and animal toxicology. Our review focuses on the human clinical studies of adverse health effects of short-term NO2 exposures, given the substantial uncertainties and limitations in interpretation of the other lines of evidence. We examined more than 50 experimental studies of humans inhaling NO2, finding notably that the reporting of statistically significant changes in lung function and bronchial sensitivity did not show a consistent trend with increasing NO2 concentrations. Functional changes were generally mild and transient, the reported effects were not uniformly adverse, and they were not usually accompanied by NO2-dependent increases in symptoms. The available human clinical results do not establish a mechanistic pathway leading to adverse health impacts for short-term NO2 exposures at levels typical of maximum 1-h concentrations in the present-day ambient environment (i.e., below 0.2 ppm). Our review of these data indicates that a health-protective, short-term NO2 guideline level for susceptible (and healthy) populations would reflect a policy choice between 0.2 and 0.6 ppm. EXTENDED ABSTRACT: Nitrogen dioxide (NO2) is a ubiquitous atmospheric pollutant due to the widespread prevalence of both natural and anthropogenic sources, and it can be a respiratory irritant when inhaled at elevated concentrations. Natural NO2 sources include volcanic action, forest fires, lightning, and the stratosphere; man-made NO2 emissions derive from fossil fuel combustion and incineration. The current National Ambient Air Quality Standard (NAAQS) for NO2, initially established in 1971, is 0.053 ppm (annual average). Ambient concentrations monitored in urban areas in the United States are approximately 0.015 ppm, as an annual mean, i.e., below the current NAAQS. Short-term (1-h peak) NO2 concentrations outdoors are not likely to exceed 0.2 ppm, and even 1-h periods exceeding 0.1 ppm are infrequent. Inside homes, 1-h NO2 peaks, typically arising from gas cooking, can range between 0.4 and 1.5 ppm. The health effects evidence of relevance to ambient NO2 derives from three lines of investigation: epidemiology studies, human clinical studies, and animal toxicology studies. The NO2 epidemiology remains inconsistent and uncertain due to the potential for exposure misclassification, residual confounding, and co-pollutant effects, whereas animal toxicology findings using high levels of NO2 exposure require extrapolation to humans exposed at low ambient NO2 levels. Given the limitations and uncertainties in the other lines of health effects evidence, our review thus focused on clinical studies where human volunteers (including asthmatics, children, and elderly) inhaled NO2 at levels from 0.1 to 3.5 ppm during short-term ((1/2)-6-h) exposures, often combined with exercise, and occasionally combined with co-pollutants. We examined the reported biological effects and classified them into (a) lung immune responses and inflammation, (b) lung function changes and airway hyperresponsiveness (AHR), and (c) health effects outside the lungs (extrapulmonary). We examined more than 50 experimental studies of humans inhaling NO2, finding that such clinical data on short-term exposure allowed discrimination of NO2 no-effect levels versus lowest-adverse-effects levels. Our conclusions are summarized by these six points: For lung immune responses and inflammation: (1) healthy subjects exposed to NO2 below 1 ppm do not show pulmonary inflammation; (2) at 2 ppm for 4 h, neutrophils and cytokines in lung-lavage fluid can increase, but these changes do not necessarily correlate with significant or sustained changes in lung function; (3) there is no consistent evidence that NO2 concentrations below 2 ppm increase susceptibility to viral infection; (4) for asthmatics and individuals having chronic obstructive pulmonary disease (COPD), NO2-induced lung inflammation is not expected below 0.6 ppm, although one research group reported enhancement of proinflammatory processes at 0.26 ppm. With regard to NO2-induced AHR: (5) studies of responses to specific or nonspecific airway challenges (e.g., ragweed, methacholine) suggest that asthmatic individuals were not affected by NO2 up to about 0.6 ppm, although some sensitive subsets may respond to levels as low as 0.2 ppm. And finally, for extra-pulmonary effects: (6) such effects (e.g., changes in blood chemistry) generally required NO2 concentrations above 1-2 ppm. Overall, our review of data from experiments with humans indicates that a health-protective, short-term-average NO2 guideline level for susceptible populations (and healthy populations) would reflect a policy choice between 0.2 and 0.6 ppm. The available human clinical results do not establish a mechanistic pathway leading to adverse health impacts for short-term NO2 exposures at levels typical of maximum 1-h concentrations in the present-day ambient environment (i.e., below 0.2 ppm).

Interstrain variation in cardiac and respiratory adaptation to repeated ozone and particulate matter exposures.

Increased ambient particulate matter (PM) is associated with adverse cardiovascular and respiratory outcomes, as demonstrated by epidemiology studies. Several studies have investigated the role of copollutants, such as ozone (O(3)), in this association. It is accepted that physiological adaptation involving the respiratory system occurs with repeated exposures to O(3). We hypothesize that adaptation to PM and O(3) varies among different inbred mouse strains, and cardiopulmonary adaptation to O(3) is a synchronized response between the cardiac and respiratory systems. Heart rate (HR), HR variability (HRV), and the magnitude and pattern of breathing were simultaneously measured by implanted telemeters and by plethysmography in three inbred mouse strains: C57Bl/6J (B6), C3H/HeJ (HeJ), and C3H/HeOuJ (OuJ). Physiological responses were assessed during dual exposures to filtered air (FA), O(3) (576 +/- 32 parts/billion), and/or carbon black (CB; 556 +/- 34 mug/m(3)). Exposures were repeated for 3 consecutive days. While each strain showed significant reductions in HR during CB with O(3) preexposure (O(3)CB) on day 1, prominent HRV responses were observed in only HeJ and OuJ mice. Each strain also differed in their adaptation profile in response to repeated O(3)CB exposures. Whereas B6 mice showed rapid adaptation in HR after day 1, HeJ mice generally showed more moderate HR and HRV adaptation after day 2 of exposure. Unlike either B6 or HeJ strains, OuJ mice showed little evidence of HR or HRV adaptation to repeated O(3)CB exposure. Adaptation profiles between HR regulation and breathing characteristics were strongly correlated, but these associations also varied significantly among strains. These findings suggest that genetic factors determine the responsivity and adaptation of the cardiac and respiratory systems to repeated copollutant exposures. During O(3)CB exposure, adaptation of cardiac and respiratory systems is markedly synchronized, which may explain a potential mechanism for adverse effects of PM on heart function.

Adverse cardiovascular effects with acute particulate matter and ozone exposures: interstrain variation in mice.

OBJECTIVES: Increased ambient particulate matter (PM) levels are associated with cardiovascular morbidity and mortality, as shown by numerous epidemiology studies. Few studies have investigated the role of copollutants, such as ozone, in this association. Furthermore, the mechanisms by which PM affects cardiac function remain uncertain. We hypothesized that PM and O(3) induce adverse cardiovascular effects in mice and that these effects are strain dependent. STUDY DESIGN: After implanting radiotelemeters to measure heart rate (HR) and HR variability (HRV) parameters, we exposed C57Bl/6J (B6), C3H/HeJ (HeJ), and C3H/HeOuJ (OuJ) inbred mouse strains to three different daily exposures of filtered air (FA), carbon black particles (CB), or O(3) and CB sequentially [O(3)CB; for CB, 536 +/- 24 microg/m(3); for O(3), 584 +/- 35 ppb (mean +/- SE)]. RESULTS: We observed significant changes in HR and HRV in all strains due to O(3)CB exposure, but not due to sequential FA and CB exposure (FACB). The data suggest that primarily acute HR and HRV effects occur during O(3)CB exposure, especially in HeJ and OuJ mice. For example, HeJ and OuJ mice demonstrated dramatic increases in HRV parameters associated with marked brady-cardia during O(3)CB exposure. In contrast, depressed HR responses occurred in B6 mice without detectable changes in HRV parameters. CONCLUSIONS: These findings demonstrate that important interstrain differences exist with respect to PM- and O(3)-induced cardiac effects. This interstrain variation suggests that genetic factors may modulate HR regulation in response to and recuperation from acute copollutant exposures.