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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.

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.

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.

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).

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 < or = .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.