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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.

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.sub.3]), in this association. It is accepted that physiological adaptation involving the respiratory system occurs with repeated exposures to [O.sub.3]. We hypothesize that adaptation to PM and [O.sub.3] varies among different inbred mouse strains, and cardiopulmonary adaptation to [O.sub.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: C57B1/6J (B6), C3H/HeJ (HeJ), and C3H/HeOuJ (OuJ). Physiological responses were assessed during dual exposures to filtered air (FA), [O.sub.3] (576 [+ or -] 32 parts/billion), and/or carbon black (CB; 556 [+ or -] 34 [micro]g/[m.sup.3]). Exposures were repeated for 3 consecutive days. While each strain showed significant reductions in HR during CB with [O.sub.3] preexposure ([O.sub.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.sub.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.sub.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.sub.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. air pollution; toll-like receptor 4; heart rate variability; cardiopulmonary regulation; echocardiography

ABSTRACT The goal of this study was to test the following hypotheses: (1) exposure to mobile emissions from mobile sources close to a heavily trafficked roadway will exacerbate airway inflammation [...]

A new method of moment-based formulation for the solution of the telegraphist's equations in nonuniform transmission lines is presented. Entire domain basis functions that build in a frequency variation are used to cover wider frequency and physical dimension ranges. The results obtained using the proposed formulation are validated by comparison to those obtained by a CAD package and to measured data. Different nonuniform lines in microstrip and coplanar technologies on monolithic microwave/millimeter wave integrated circuit (MMIC) and miniaturized hybrid microwave integrated circuit (MHMIC) substrates are investigated with an application to the design a matched taper transition in a MMIC coplanar line.

This study aims to obtain knowledge of how ASD individuals differ from their normally developed equals in terms of physical literacy and quality of life on a stage of early adolescents. Data have been collected from two samples: 18 males with autism spectrum disorders (ASD) aged 11-13 years (main group) and 30 males aged 11-12 years without ASD diagnosis (control group, CG). Canadian Assessment of Physical Literacy - second edition (CAPL-2) has been applied for assessing the level of physical literacy. Pediatric Quality of Life Inventory (PedsQL™4.0) has been used to assess the quality of life. Children with ASD have the most significant lag in static strength endurance of muscles (84%), coordination, dynamic, and static balance lag behind the standard (by 67% to 45%). The quality of life following the Emotional Functioning scale is relatively low both in children with ASD (58.42 ± 19.51 points) and healthy respondents (69.50 ± 17.04 points). Respondents with ASD indicate that it is hard to establish good relationships with other children (47.37%), had complaints about bullying (21.05%), and maintain the required pace of the game (68.43%). Physical education programs should focus more on coping with disabled children in the integration environment and better preparation of ASD children for physical activity which requires social interaction like playing sports games. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (O3) and carbon black (CB) at two ages, (5 months, 12 months), for 3 consecutive days, to either filtered air (FA), CB particles, or O3 and CB sequentially (O3CB) (CB, 550 µg/m3; O3, 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 O3CB exposure in each strain, relative to FA exposure for both age groups. Each mouse strain showed distinct adaptation profiles to repeated acute exposures to O3. 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 O3CB exposures albeit with patterns differing by age or exposure. Discussion/conclusion: Our results suggest that age considerably attenuates physiological responses to O3 and O3CB exposures. Age-related physiological changes such as increased oxidative stress in mouse tissue may be involved in this attenuation. [ABSTRACT FROM AUTHOR]

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., >106 particles/cm3) 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. [ABSTRACT FROM AUTHOR]

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... [ABSTRACT FROM AUTHOR]

Motor vehicle exhaust emissions are known to exacerbate asthma and other respiratory diseases. Several studies have demonstrated significant associations between living near highly trafficked roadways and increased incidence of asthma and increased severity of asthma-related symptoms, medication usage, and physician visits. This study tested the hypotheses that (1) exposure to particulate matter (PM) near a heavily trafficked Los Angeles freeway would enhance inflammatory and allergic responses in ovalbumin (OVA)-sensitized BALB/c mice compared to sensitized, clean air controls, and (2) there would be differences in response at two distances downwind of heavily traveled freeways because of greater toxicity of PM closest to the freeway. An ambient particle concentrator was used to expose ovalbumin (OVA)-treated BALB/c mice to purified air, to concentrated fine ambient particles, and to concentrated ultrafine airborne particles (CAPs) at 2 distances, 50 m and 150 m, downwind of a roadway that is impacted by emissions from both heavy-duty diesel and light duty gasoline vehicles. Tissues and biological fluids from the mice were analyzed after exposures for 5 days/wk in 2 consecutive weeks. The biomarkers of allergic or inflammatory responses that were assessed included cytokines released by Type 2 T-helper cells (interleukin [IL]-5 and IL-13), OVA-specific immunoglobulin E (IgE), OVA-specific immunoglobulin G1 (IgG1), and pulmonary infiltration of polymorphonuclear leukocytes and eosinophils. IL-5 and IgG1 were significantly increased in mice exposed to CAPs 50 m downwind of the road, compared to responses in mice exposed to purified air, providing evidence of allergic response. No significant increases in allergy-related responses were observed in mice exposed to CAPs 150 m downwind of the road. The biological responses at the 50-m site were significantly associated with organic and elemental carbon components of fine and ultrafine particles (p ≤ .05). The primary source of these contaminants at the roadway sites was motor vehicle emissions, suggesting that particulate matter from motor vehicle fuel combustion could exert adjuvant effects and promote the development of allergic airway diseases. [ABSTRACT FROM AUTHOR]

Most animal genotoxicity studies have used exposures to single chemicals; humans, however, are potentially exposed to mixtures of genotoxins. Cancer and developmental toxicity risks associated with genotoxins in mixture are generally estimated by assuming additivity of the components. Two or more genotoxins acting sequentially or simultaneously may present a greater or lesser hazard than that predicted by simple addition of their potencies. Previously, we studied the effect of one genotoxin on the binding of a second genotoxin to DNA in an in vitro system and demonstrated that consecutive binding of the two toxins was not additive. In the present study, the effect of one genotoxin on the mutagenicity of another was evaluated for two well-known genotoxins using the Salmonella assay. Pretreatment of frameshift strains TA98 and TA1538 with AFB1-8.9-epoxide (17.3 ng/plate) enhanced the mutagenicity induced by subsequent exposure to N-acetoxy-acetylaminofluorene (N-AcO-AAF) ∼2-3 times above theoretical values for additivity. Pretreatment of base-substitution strain TA100 with N-AcO-AAF (0.1 μg/plate) inhibited the mutagenicity following subsequent exposure to AFB1-8,9-epoxide by 3 times below the theoretical additive value. Concentration-response relationships for these enhancing or inhibitory effects were demonstrated using increasing concentrations of the first genotoxin during pretreatment. These results demonstrate effects, other than additive, of sequential exposures to two genotoxins on the induction of mutations in a bacterial system. [ABSTRACT FROM PUBLISHER]

A new method of moment-based formulation for the analysis of nonuniform transmission lines is presented. Subdomain complex basis functions are used to simulate different structures over a wide range of frequencies. The results obtained using the proposed formulation are validated by comparison to those obtained by CAD packages. Strip-line and microstrip-line transitions are investigated with an application to the design of a matched microstrip taper with width and dielectric height variations. [ABSTRACT FROM AUTHOR]

O3 is a principal pollutant that coexists with PM in urban ambient air. Studies associate O3 and PM exposure with adverse health effects; however the mechanisms of action remain unclear. We implanted radiometers to measure HR, and then exposed two mouse strains (i.e. C3H/HeJ, C3 and C57Bl/6J, B6 [n=3/ strain]) to three different protocols for 3 consecutive days as follows: 1) 2 hr-filtered air (FA) + 3 hr-FA; 2) 2 hr-FA + 3 hr-carbon black (CB); and 3) 2 hr-ozone (O3, 550 ppb) + 3 hr-CB HR and VO2 were collected simultaneously on the mornings before and after exposure. We observed relative increases in O2-pulse,(VO2/HR) with FACB (4.9%±2.4), and O3CB (7.5%±6) independent of HR changes in the B6 mice. Correlations between HR and VO2 were also examined. The C3 mice did not exhibit obvious coupling of HR and VO2 (r²=0.16±0.06) at baseline or with treatment. The B6 animals, however, appear to inherently possess a high association between HR and VO2 (r²= 0.40±0.08) and this association changed dramatically with exposure: i.e., FACB (r²=0.13±0.06) and O3CB (r²=0.60±0.01) exposures. Thus, these results suggest that HR and VO2 coupling varies between inbred strains and among different pollutants. In terms of hemodynamic control, HR regulation is altered by air pollutant exposures such that a greater O2 delivery is required with each stroke of the heart. Future studies will aim to elucidate genetic factors that may modify individual responses and susceptibility to these air pollutants. [ABSTRACT FROM AUTHOR]

Background: High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy characterized by resistance to chemotherapy and high rates of recurrence. HGSC tumors display a high prevalence of tumor suppressor gene loss. Given the type 1 interferon regulatory function of BRCA1 and PTEN genes and their associated contrasting T-cell infiltrated and non-infiltrated tumor immune microenvironment (TIME) states, respectively, in this study we investigated the potential of stimulator of interferon genes (STING) pathway activation in improving overall survival via enhancing chemotherapy response, specifically in tumors with PTEN deficiency., Methods: Expression of PTEN protein was evaluated in tissue microarrays generated using pretreatment tumors collected from a cohort of 110 patients with HGSC. Multiplex immunofluorescence staining was performed to determine spatial profiles and density of selected lymphoid and myeloid cells. In vivo studies using the syngeneic murine HGSC cell lines, ID8- Trp53 -/- ; Pten -/- and ID8- Trp53 -/- ; Brca1 -/- , were conducted to characterize the TIME and response to carboplatin chemotherapy in combination with exogenous STING activation therapy., Results: Patient tumors with absence of PTEN protein exhibited a significantly decreased disease specific survival and intraepithelial CD68+ macrophage infiltration as compared with intact PTEN expression. In vivo studies demonstrated that Pten -deficient ovarian cancer cells establish an immunosuppressed TIME characterized by increased proportions of M2-like macrophages, GR1+MDSCs in the ascites, and reduced effector CD8+ cytotoxic T-cell function compared with Brca1 -deficient cells; further, tumors from mice injected with Pten -deficient ID8 cells exhibited an aggressive behavior due to suppressive macrophage dominance in the malignant ascites. In combination with chemotherapy, exogenous STING activation resulted in longer overall survival in mice injected with Pten -deficient ID8 cells, reprogrammed intraperitoneal M2-like macrophages derived from Pten -deficient ascites to M1-like phenotype and rescued CD8+ cytotoxic T-cell activation., Conclusions: This study reveals the importance of considering the influence of cancer cell intrinsic genetic alterations on the TIME for therapeutic selection. We establish the rationale for the optimal incorporation of interferon activating therapies as a novel combination strategy in PTEN-deficient HGSC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Early epidural steroid injections are currently widely used for patients experiencing lumbago. However, there is uncertainty about their efficacy, such as the limitation of continuous drug infusion and the need for well-trained physicians on this technique. The main objective of this study was to evaluate the effectiveness of early epidural steroid injections in treating patients with acute sciatica in the lower back in terms of symptom relief and recurrence rate. Methods A case series was conducted in Lebanon from 2015 to 2019. We recruited 98 patients suffering from sciatica due to disc disease over three-time intervals: two weeks, one, and three months. The immediate results accounted for the intensity of various symptoms (numerical rating scale (NRS) for pain) and the assessment of patient satisfaction (Macnab criteria). Results The clinical results showed at least a three-point pain relief according to Numerical Rating Scale (NRS) and a good grade according to MacNab (P <0.001), with only 10.4% of the total population having a positive leg raise test post-injection. The maximum benefit was noted after two weeks from the injection with a 5.7 mean change in NRS (p<0.001) with a good/excellent response in MacNab and a 4.9 change with only a good response after one month. This study noticed a rebound phenomenon where around half of the patients needed two steroid injections after three months (39.6 % after three months and 17.9 % after six months). Conclusion Even though current guidelines worldwide may suggest the use of conservative treatment for low back pain with acute sciatica, our study has demonstrated the effectiveness of epidural steroid injections in the Lebanese population with a significant outcome., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Chemeisani et al.)

Background: Preventing child falls from windows is easily accomplished by installing inexpensive window-limiting devices but window falls remain a common cause of child injuries. This article describes the history and evolution of the New York City (NYC) window guard rule,which requires building owners to install window guards in apartments housing children aged ≤10 years. The NYC window guard rule was the first directive of its kind in the USA when it was adopted in 1976, and it has led to a dramatic and long-lasting reduction in child window fall-related injuries and deaths., Methods: Data about the history of the window guard rule were obtained by reviewing programmatic records, correspondence, legal decisions and the published literature. In addition, key informant interviews were conducted with programme staff., Results and Discussion: This article describes each stage of policy development, starting with epidemiological studies defining the scope of the problem in the 1960s and pilot-testing of the window guard intervention. We describe the adoption, implementation and enforcement of the rule. In addition, we show how the rule was modified over time and document the rule's impact on window fall incidence in NYC. We describe litigation that challenged the rule's constitutionality and discuss the legal arguments used by opponents of the rule. Finally, we discuss criminal and tort liability as drivers of compliance and summarise lessons learnt., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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.

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).