Extended Analysis and Evidence Integration of Chloroprene as a Human Carcinogen.

ß-Chloroprene is used in the production of polychloroprene, a synthetic rubber. In 2010, Environmental Protection Agency (EPA) published the Integrated Risk Information System "Toxicological Review of Chloroprene," concluding that chloroprene was "likely to be carcinogenic to humans." This was based on findings from a 1998 National Toxicology Program (NTP) study showing multiple tumors within and across animal species; results from occupational epidemiological studies; a proposed mutagenic mode of action; and structural similarities with 1,3-butadiene and vinyl chloride. Using mouse data from the NTP study and assuming a mutagenic mode of action, EPA calculated an inhalation unit risk (IUR) for chloroprene of 5 × 10-4 per µg/m3 . This is among the highest IURs for chemicals classified by IARC or EPA as known or probable human carcinogens and orders of magnitude higher than the IURs for carcinogens such as vinyl chloride, benzene, and 1,3-butadiene. Due to differences in pharmacokinetics, mice appear to be uniquely responsive to chloroprene exposure compared to other animals, including humans, which is consistent with the lack of evidence of carcinogenicity in robust occupational epidemiological studies. We evaluated and integrated all lines of evidence for chloroprene carcinogenicity to assess whether the 2010 EPA IUR could be scientifically substantiated. Due to clear interspecies differences in carcinogenic response to chloroprene, we applied a physiologically based pharmacokinetic model for chloroprene to calculate a species-specific internal dose (amount metabolized/gram of lung tissue) and derived an IUR that is over 100-fold lower than the 2010 EPA IUR. Therefore, we recommend that EPA's IUR be updated.

Cancer Risk Associated With Exposure to Bitumen and Bitumen Fumes: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate whether cancer risks are increased among bitumen (asphalt) workers. METHODS: Systematic review and meta-analysis of cancer risks (lung, upper aerodigestive tract (UADT), esophagus, bladder, kidney, stomach, and skin) and bitumen exposure. Certainty in the epidemiological evidence that bitumen-exposed workers experience increased cancer risks was rated using Grading of Recommendations Assessment, Development and Evaluation criteria. RESULTS: After excluding lower-quality studies, lung cancer risks were not increased among bitumen-exposed workers (meta-relative risk [RR] 0.94, 95% CI 0.74 to 1.20, eight studies). Increased risks of UADT and stomach cancers were observed (meta-RR 1.31, 95% CI 1.03 to 1.67, 10 studies and meta-RR 1.29, 95% CI 1.03 to 1.62, seven studies, respectively). CONCLUSIONS: Except for lung cancer, evidence for increased cancer risks among bitumen-exposed workers was judged to be of low certainty, due to inadequate exposure characterization and unmeasured confounders (coal tar exposure, smoking, and alcohol consumption).

Short-term ozone exposure and asthma severity: Weight-of-evidence analysis.

To determine whether evidence indicates that short-term exposure to ambient concentrations of ozone in the United States can affect asthma severity, we systematically reviewed published controlled human exposure, epidemiology, and animal toxicity studies. The strongest evidence for a potential causal relationship came from epidemiology studies reporting increased emergency department visits and hospital admissions for asthma following elevated ambient ozone concentrations. However, while controlled exposure studies reported lung function decrements and increased asthma symptoms following high ozone exposures 160-400 parts per billion [ppb]), epidemiology studies evaluating similar outcomes reported less consistent results. Animal studies showed changes in pulmonary function at high ozone concentrations (> 500ppb), although there is substantial uncertainty regarding the relevance of these animal models to human asthma. Taken together, the weight of evidence indicates that there is at least an equal likelihood that either explanation is true, i.e., the strength of the evidence for a causal relationship between short-term exposure to ambient ozone concentrations and asthma severity is "equipoise and above."

Particle size distributions of lead measured in battery manufacturing and secondary smelter facilities and implications in setting workplace lead exposure limits.

Inhalation plays an important role in exposures to lead in airborne particulate matter in occupational settings, and particle size determines where and how much of airborne lead is deposited in the respiratory tract and how much is subsequently absorbed into the body. Although some occupational airborne lead particle size data have been published, limited information is available reflecting current workplace conditions in the U.S. To address this data gap, the Battery Council International (BCI) conducted workplace monitoring studies at nine lead acid battery manufacturing facilities (BMFs) and five secondary smelter facilities (SSFs) across the U.S. This article presents the results of the BCI studies focusing on the particle size distributions calculated from Personal Marple Impactor sampling data and particle deposition estimates in each of the three major respiratory tract regions derived using the Multiple-Path Particle Dosimetry model. The BCI data showed the presence of predominantly larger-sized particles in the work environments evaluated, with average mass median aerodynamic diameters (MMADs) ranging from 21-32 µm for the three BMF job categories and from 15-25 µm for the five SSF job categories tested. The BCI data also indicated that the percentage of lead mass measured at the sampled facilities in the submicron range (i.e., <1 µm, a particle size range associated with enhanced absorption of associated lead) was generally small. The estimated average percentages of lead mass in the submicron range for the tested job categories ranged from 0.8-3.3% at the BMFs and from 0.44-6.1% at the SSFs. Variability was observed in the particle size distributions across job categories and facilities, and sensitivity analyses were conducted to explore this variability. The BCI results were compared with results reported in the scientific literature. Screening-level analyses were also conducted to explore the overall degree of lead absorption potentially associated with the observed particle size distributions and to identify key issues associated with applying such data to set occupational exposure limits for lead.

Ozone exposure and systemic biomarkers: Evaluation of evidence for adverse cardiovascular health impacts.

The US Environmental Protection Agency (EPA) recently concluded that there is likely to be a causal relationship between short-term (< 30 days) ozone exposure and cardiovascular (CV) effects; however, biological mechanisms to link transient effects with chronic cardiovascular disease (CVD) have not been established. Some studies assessed changes in circulating levels of biomarkers associated with inflammation, oxidative stress, coagulation, vasoreactivity, lipidology, and glucose metabolism after ozone exposure to elucidate a biological mechanism. We conducted a weight-of-evidence (WoE) analysis to determine if there is evidence supporting an association between changes in these biomarkers and short-term ozone exposure that would indicate a biological mechanism for CVD below the ozone National Ambient Air Quality Standard (NAAQS) of 75 parts per billion (ppb). Epidemiology findings were mixed for all biomarker categories, with only a few studies reporting statistically significant changes and with no consistency in the direction of the reported effects. Controlled human exposure studies of 2 to 5 hours conducted at ozone concentrations above 75 ppb reported small elevations in biomarkers for inflammation and oxidative stress that were of uncertain clinical relevance. Experimental animal studies reported more consistent results among certain biomarkers, although these were also conducted at ozone exposures well above 75 ppb and provided limited information on ozone exposure-response relationships. Overall, the current WoE does not provide a convincing case for a causal relationship between short-term ozone exposure below the NAAQS and adverse changes in levels of biomarkers within and across categories, but, because of study limitations, they cannot not provide definitive evidence of a lack of causation.

Rethinking Meta-Analysis: Applications for Air Pollution Data and Beyond.

Meta-analyses offer a rigorous and transparent systematic framework for synthesizing data that can be used for a wide range of research areas, study designs, and data types. Both the outcome of meta-analyses and the meta-analysis process itself can yield useful insights for answering scientific questions and making policy decisions. Development of the National Ambient Air Quality Standards illustrates many potential applications of meta-analysis. These applications demonstrate the strengths and limitations of meta-analysis, issues that arise in various data realms, how meta-analysis design choices can influence interpretation of results, and how meta-analysis can be used to address bias and heterogeneity. Reviewing available data from a meta-analysis perspective can provide a useful framework and impetus for identifying and refining strategies for future research. Moreover, increased pervasiveness of a meta-analysis mindset-focusing on how the pieces of the research puzzle fit together-would benefit scientific research and data syntheses regardless of whether or not a quantitative meta-analysis is undertaken. While an individual meta-analysis can only synthesize studies addressing the same research question, the results of separate meta-analyses can be combined to address a question encompassing multiple data types. This observation applies to any scientific or policy area where information from a variety of disciplines must be considered to address a broader research question.

Are the elements of the proposed ozone National Ambient Air Quality Standards informed by the best available science?

The United States Environmental Protection Agency (US EPA) issues National Ambient Air Quality Standards (NAAQS) for six criteria pollutants, including ozone. Each standard has four elements: an indicator, level, averaging time, and form. Ozone levels (i.e., air concentrations) alone in scientific studies are not directly comparable to the "level" element of the NAAQS because the standard considers the level in the context of its relation to the remaining elements. Failure to appreciate this has led to misunderstandings regarding NAAQS that would be health-protective. This can be seen with controlled human ozone exposure studies, which often involved small numbers of people exercising quasi-continuously for a long duration at an intensity not common in the general population (and unlikely achievable by most sensitive individuals), under worst-case exposure profiles. In addition, epidemiology studies have used different averaging times and have had methodological limitations that may have biased results. Such considerations can make it difficult to compare ozone levels and results across studies and to appropriately apply them in a NAAQS evaluation. Relating patterns and circumstances of exposure, and exposure measurements, to all elements of the NAAQS can be challenging, but if US EPA fully undertook this, it would be evident that available evidence does not indicate that proposed lower ozone standards would be more health protective than the current one.

Providing perspective for interpreting cardiovascular mortality risks associated with ozone exposures.

When identifying standards for air pollutants based on uncertain evidence, both science and policy judgments play critical roles. Consequently, critical contextual factors are important for understanding the strengths, limitations, and appropriate interpretation of available science, and potential benefits of risk mitigation alternatives. These factors include the relative magnitude and certainty of the risks posed by various factors and the impacts of other risk factors on air pollutant epidemiology study findings. This commentary explores ozone's status as a risk factor for cardiovascular mortality in contrast with decades of strong and consistent evidence for other established risk factors. By comparison, the ozone evidence is less conclusive, more heterogeneous, and subject to substantial uncertainty; ozone's potential effects, if any, are small and challenging to discern. Moreover, the absence of a demonstrated causal relationship calls into question efforts to quantify cardiovascular mortality risks attributed to ozone exposures on a population level and highlights the need to explicitly acknowledge this uncertainty if such calculations are performed. These concerns are relevant for other similar policy contexts - where multiple established risk factors contribute to the health impact of interest; exposure-effect associations are relatively small, weak, and uncertain; and a causal relationship has not been clearly established.

Weight-of-evidence evaluation of short-term ozone exposure and cardiovascular effects.

There is a relatively large body of research on the potential cardiovascular (CV) effects associated with short-term ozone exposure (defined by EPA as less than 30 days in duration). We conducted a weight-of-evidence (WoE) analysis to assess whether it supports a causal relationship using a novel WoE framework adapted from the US EPA's National Ambient Air Quality Standards causality framework. Specifically, we synthesized and critically evaluated the relevant epidemiology, controlled human exposure, and experimental animal data and made a causal determination using the same categories proposed by the Institute of Medicine report Improving the Presumptive Disability Decision-making Process for Veterans ( IOM 2008). We found that the totality of the data indicates that the results for CV effects are largely null across human and experimental animal studies. The few statistically significant associations reported in epidemiology studies of CV morbidity and mortality are very small in magnitude and likely attributable to confounding, bias, or chance. In experimental animal studies, the reported statistically significant effects at high exposures are not observed at lower exposures and thus not likely relevant to current ambient ozone exposures in humans. The available data also do not support a biologically plausible mechanism for CV effects of ozone. Overall, the current WoE provides no convincing case for a causal relationship between short-term exposure to ambient ozone and adverse effects on the CV system in humans, but the limitations of the available studies preclude definitive conclusions regarding a lack of causation. Thus, we categorize the strength of evidence for a causal relationship between short-term exposure to ozone and CV effects as "below equipoise."

Weight-of-evidence evaluation of long-term ozone exposure and cardiovascular effects.

We conducted a weight-of-evidence (WoE) analysis to assess whether the current body of research supports a causal relationship between long-term ozone exposure (defined by EPA as at least 30 days in duration) at ambient levels and cardiovascular (CV) effects. We used a novel WoE framework based on the United States Environmental Protection Agency's National Ambient Air Quality Standards causal framework for this analysis. Specifically, we critically evaluated and integrated the relevant epidemiology and experimental animal data and classified a causal determination based on categories proposed by the Institute of Medicine's 2008 report, Improving the Presumptive Disability Decision-making Process for Veterans. We found that the risks of CV effects are largely null across human and experimental animal studies. The few positive associations reported in studies of CV morbidity and mortality are very small in magnitude, mainly reported in single-pollutant models, and likely attributable to bias, chance, or confounding. The few positive effects in experimental animal studies were observed mainly in ex vivo studies at high exposures, and even the in vivo findings are not likely relevant to humans. The available data also do not support a biologically plausible mechanism for the effects of ozone on the CV system. Overall, the current WoE provides no convincing case for a causal relationship between long-term exposure to ambient ozone and adverse effects on the CV system in humans, but the limitations of the available studies preclude definitive conclusions regarding a lack of causation; thus, we categorize the strength of evidence for a causal relationship between long-term exposure to ozone and CV effects as "below equipoise."

Evaluation of adverse human lung function effects in controlled ozone exposure studies.

The US EPA is evaluating controlled human ozone exposure studies to determine the adequacy of the current ozone National Ambient Air Quality Standard of 75 ppb. These studies have shown that ozone exposures of 80 ppb and greater are associated with lung function decrements. Here, we critically review studies with exposures below 80 ppb to determine the lowest ozone concentration at which decrements are causally associated with ozone exposure and could be considered adverse using the Adverse Effects/Causation Framework. Regarding causation, the framework includes consideration of whether exposure-related effects are primary or secondary, statistically significant, isolated or independent, or due to study limitations. Regarding adversity, the framework indicates one should consider whether effects are adaptive, compensatory, precursors to an apical effect, severe, transient and/or reversible. We found that, at exposures below 72 ppb ozone, lung function effects are primary effects, but are isolated, independent and not statistically different compared to effects observed during filtered air exposure, indicating a lack of causation. Up to 72 ppb, lung function effects may be precursors to an apical effect, but are not likely adverse because they are transient, reversible, of low severity, do not interfere with normal activity and do not result in permanent respiratory injury or progressive respiratory dysfunction. Overall, these studies do not demonstrate a causal association between ozone concentrations in the range of the current National Ambient Air Quality Standard and adverse effects on lung function.

Evaluation of the causal framework used for setting national ambient air quality standards.

Abstract A scientifically sound assessment of the potential hazards associated with a substance requires a systematic, objective and transparent evaluation of the weight of evidence (WoE) for causality of health effects. We critically evaluated the current WoE framework for causal determination used in the United States Environmental Protection Agency's (EPA's) assessments of the scientific data on air pollutants for the National Ambient Air Quality Standards (NAAQS) review process, including its methods for literature searches; study selection, evaluation and integration; and causal judgments. The causal framework used in recent NAAQS evaluations has many valuable features, but it could be more explicit in some cases, and some features are missing that should be included in every WoE evaluation. Because of this, it has not always been applied consistently in evaluations of causality, leading to conclusions that are not always supported by the overall WoE, as we demonstrate using EPA's ozone Integrated Science Assessment as a case study. We propose additions to the NAAQS causal framework based on best practices gleaned from a previously conducted survey of available WoE frameworks. A revision of the NAAQS causal framework so that it more closely aligns with these best practices and the full and consistent application of the framework will improve future assessments of the potential health effects of criteria air pollutants by making the assessments more thorough, transparent, and scientifically sound.

Particulate matter in new technology diesel exhaust (NTDE) is quantitatively and qualitatively very different from that found in traditional diesel exhaust (TDE).

Diesel exhaust (DE) characteristic of pre-1988 engines is classified as a "probable" human carcinogen (Group 2A) by the International Agency for Research on Cancer (IARC), and the U.S. Environmental Protection Agency has classified DE as "likely to be carcinogenic to humans." These classifications were based on the large body of health effect studies conducted on DE over the past 30 or so years. However, increasingly stringent U.S. emissions standards (1988-2010) for particulate matter (PM) and nitrogen oxides (NOx) in diesel exhaust have helped stimulate major technological advances in diesel engine technology and diesel fuel/lubricant composition, resulting in the emergence of what has been termed New Technology Diesel Exhaust, or NTDE. NTDE is defined as DE from post-2006 and older retrofit diesel engines that incorporate a variety of technological advancements, including electronic controls, ultra-low-sulfur diesel fuel, oxidation catalysts, and wall-flow diesel particulate filters (DPFs). As discussed in a prior review (T. W. Hesterberg et al.; Environ. Sci. Technol. 2008, 42, 6437-6445), numerous emissions characterization studies have demonstrated marked differences in regulated and unregulated emissions between NTDE and "traditional diesel exhaust" (TDE) from pre-1988 diesel engines. Now there exist even more data demonstrating significant chemical and physical distinctions between the diesel exhaust particulate (DEP) in NTDE versus DEP from pre-2007 diesel technology, and its greater resemblance to particulate emissions from compressed natural gas (CNG) or gasoline engines. Furthermore, preliminary toxicological data suggest that the changes to the physical and chemical composition of NTDE lead to differences in biological responses between NTDE versus TDE exposure. Ongoing studies are expected to address some of the remaining data gaps in the understanding of possible NTDE health effects, but there is now sufficient evidence to conclude that health effects studies of pre-2007 DE likely have little relevance in assessing the potential health risks of NTDE exposures.

Non-chemical stressors and cumulative risk assessment: an overview of current initiatives and potential air pollutant interactions.

Regulatory agencies are under increased pressure to consider broader public health concerns that extend to multiple pollutant exposures, multiple exposure pathways, and vulnerable populations. Specifically, cumulative risk assessment initiatives have stressed the importance of considering both chemical and non-chemical stressors, such as socioeconomic status (SES) and related psychosocial stress, in evaluating health risks. The integration of non-chemical stressors into a cumulative risk assessment framework has been largely driven by evidence of health disparities across different segments of society that may also bear a disproportionate risk from chemical exposures. This review will discuss current efforts to advance the field of cumulative risk assessment, highlighting some of the major challenges, discussed within the construct of the traditional risk assessment paradigm. Additionally, we present a summary of studies of potential interactions between social stressors and air pollutants on health as an example of current research that supports the incorporation of non-chemical stressors into risk assessment. The results from these studies, while suggestive of possible interactions, are mixed and hindered by inconsistent application of social stress indicators. Overall, while there have been significant advances, further developments across all of the risk assessment stages (i.e., hazard identification, exposure assessment, dose-response, and risk characterization) are necessary to provide a scientific basis for regulatory actions and effective community interventions, particularly when considering non-chemical stressors. A better understanding of the biological underpinnings of social stress on disease and implications for chemical-based dose-response relationships is needed. Furthermore, when considering non-chemical stressors, an appropriate metric, or series of metrics, for risk characterization is also needed. Cumulative risk assessment research will benefit from coordination of information from several different scientific disciplines, including, for example, toxicology, epidemiology, nutrition, neurotoxicology, and the social sciences.

Non-cancer health effects of diesel exhaust: a critical assessment of recent human and animal toxicological literature.

We reviewed laboratory and clinical studies bearing on the non-cancer health effects of diesel exhaust (DE) published since the 2002 release of the US EPA Health Assessment Document for Diesel Engine Exhaust. We critically evaluated over 100 published articles on experimental research, focusing on their value for predicting the risk of non-cancer health effects in humans exposed to DE. Human controlled-exposure studies provide new evidence of lung inflammatory effects and thrombogenic and ischemic effects of inhaled DE, albeit for older-model diesel engines and concentrations that are much higher (approximately 300 microg/m(3)) than typical ambient or even occupational levels. Recent animal studies provide insight into the potential mechanisms underlying observed respiratory and cardiovascular health responses; however, because of unrealistically high DE concentrations, the mechanisms elucidated in these studies may not be relevant at lower DE exposure levels. Although larger in number, and suggestive of possible mechanisms for non-cancer health effects at elevated DE levels, interpretation of this recent group of clinical-study findings and laboratory-animal results remains hindered by inconsistencies and variability in outcomes, potentially irrelevant DE-exposure compositions, limitations in exposure protocols and pathways, and uncertainties in extrapolation and generalization. A mechanism of action that allows reliable prediction of adverse health effects at DE-exposure levels typical of the present-day ambient and occupational environment has not emerged. Because of changing diesel-engine technology, inhalation studies using realistic environmental and occupational exposures of new-technology diesel exhaust are of critical importance.

Measurement of particle concentrations in a dental office.

Particles in a dental office can be generated by a number of instruments, such as air-turbine handpieces, low-speed handpieces, ultrasonic scalers, bicarbonate polishers, polishing cups, as well as drilling and air sprays inside the oral cavity. This study examined the generation of particles during dental drilling and measured particle size, mass, and trace elements. The air sampling techniques included both continuous and integrated methods. The following particle continuous measurements were taken every minute: (1) size-selective particle number concentration (Climet); (2) total particle number concentration (PTRAK), and; (3) particle mass concentration (DustTrak). Integrated particle samples were collected for about 5 h on each of five sampling days, using a PM(2.5) sampler (ChemComb) for elemental/organic carbon analysis, and a PM(10) sampler (Harvard Impactor) for mass and elemental analyses. There was strong evidence that these procedures result in particle concentrations above background. The dental procedures produced number concentrations of relatively small particles (<0.5 microm) that were much higher than concentrations produced for the relatively larger particles (>0.5 microm). Also, these dental procedures caused significant elevation above background of certain trace elements (measured by X-ray fluorescence) but did not cause any elevation of elemental carbon (measured by thermal optical reflectance). Dental drilling procedures aerosolize saliva and products of drilling, producing particles small enough to penetrate deep into the lungs. The potential health impacts of the exposure of dental personnel to such particles need to be evaluated. Increased ventilation and personal breathing protection could be used to minimize harmful effects.

Trends in the elemental composition of fine particulate matter in Santiago, Chile, from 1998 to 2003.

Santiago, Chile, is one of the most polluted cities in South America. As a response, over the past 15 yr, numerous pollution reduction programs have been implemented by the environmental authority, Comisión Nacional del Medio Ambiente. This paper assesses the effectiveness of these interventions by examining the trends of fine particulate matter (PM(2.5)) and its associated elements. Daily fine particle filter samples were collected in Santiago at a downtown location from April 1998 through March 2003. Additionally, meteorological variables were measured continuously. Annual average concentrations of PM(2.5) decreased only marginally, from 41.8 microg/m3 for the 1998-1999 period to 35.4 microg/m3 for the 2002-2003 period. PM(2.5) concentrations exceeded the annual U.S. Environmental Protection Agency standard of 15 microg/m3. Also, approximately 20% of the daily samples exceeded the old standard of 65 microg/m3, whereas approximately half of the samples exceeded the new standard of 35 microg/m3 (effective in 2006). Mean PM(2.5) levels measured during the cold season (April through September) were three times higher than those measured in the warm season (October through March). Particulate mass and elemental concentration trends were investigated using regression models, controlling for year, month, weekday, wind speed, temperature, and relative humidity. The results showed significant decreases for Pb, Br, and S concentrations and minor but still significant decreases for Ni, Al, Si, Ca, and Fe. The larger decreases were associated with specific remediation policies implemented, including the removal of lead from gasoline, the reduction of sulfur levels in diesel fuel, and the introduction of natural gas. These results suggest that the pollution reduction programs, especially the ones related to transport, have been effective in reducing various important components of PM(2.5). However, particle mass and other associated element levels remain high, and it is thus imperative to continue the efforts to improve air quality, particularly focusing on industrial sources.