John Vandenberg

Formaldehyde and Leukemia: Epidemiology, Potential Mechanisms and Implications for Risk Assessment

Formaldehyde is widely used in the United States and other countries. Occupational and environmental exposures to formaldehyde may be associated with an increased risk of leukemia in exposed individuals. However, risk assessment of formaldehyde and leukemia has been challenging due to inconsistencies in human and animal studies and the lack of a known mechanism for leukemia induction. Here, we provide a summary of the symposium at the Environmental Mutagen Society Meeting in 2008, which focused on the epidemiology of formaldehyde and leukemia, potential mechanisms, and implication for risk assessment, with emphasis on future directions in multidisciplinary formaldehyde research. Updated results of two of the three largest industrial cohort studies of formaldehyde‐exposed workers have shown positive associations with leukemia, particularly myeloid leukemia, and a recent meta‐analysis of studies to date supports this association. Recent mechanistic studies have shown the formation of formaldehyde‐induced DNA adducts and characterized the essential DNA repair pathways that mitigate formaldehyde toxicity. The implications of the updated findings for the design of future studies to more effectively assess the risk of leukemia arising from formaldehyde exposure were discussed and specific recommendations were made. A toxicogenomic approach in experimental models and human exposure studies, together with the measurement of biomarkers of internal exposure, such as formaldehyde‐DNA and protein adducts, should prove fruitful. It was recognized that increased communication among scientists who perform epidemiology, toxicology, biology, and risk assessment could enhance the design of future studies, which could ultimately reduce uncertainty in the risk assessment of formaldehyde and leukemia. Environ. Mol. Mutagen., 2010. Published 2009 Wiley‐Liss, Inc.

Meeting Report: Moving Upstream—Evaluating Adverse Upstream End Points for Improved Risk Assessment and Decision-Making

Background Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an “adverse effect” in the context of hazard identification and risk assessment. Objectives Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available. Discussion Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects. Conclusions For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population.

Childhood respiratory symptoms, hospital admissions, and long-term exposure to airborne particulate matter.

The effects of long-term exposure to air pollution on respiratory symptoms and respiratory hospitalization (for asthma, bronchitis or pneumonia) were assessed in a cross-sectional study of children (ages 7–11 years, N=667) living in a moderately industrialized city in Central Slovakia. Individual health, residence and family history data obtained through the CESAR study were coupled, using Geographic Information System (GIS) technologies, with total suspended particulate (TSP) exposure estimates derived from dispersion modeling of almost all local stationary sources. These data were used to assess, at the intra-city level and child-specific level, the potential for TSP as a risk factor for respiratory disease in children. TSP, PM10, and PM2.5 monitored ambient concentrations are highly correlated in the study location. Modeled TSP concentrations resulting from local source emissions are dominated by a large wood processing facility, suggesting variation in exposures among children. The prevalence of respiratory non-asthmatic symptoms and hospitalizations was associated with increased TSP. No association between long-term exposure to TSP and asthma diagnosis or wheeze symptoms was found. Logistic regression modeling indicated a significant increase in hospital admissions for asthma, bronchitis or pneumonia associated with increasing air pollution (OR 2.16, CI, 1.01–4.60), doctor-diagnosed bronchitis (OR 1.53, CI, 1.02–2.30), and parent-reported chronic phlegm (OR 3.43, CI, 1.64–7.16), expressed as odds for a 15 μg/m3 increase in estimated TSP exposure, and these increases are not due to differences in socio-economic, health care or other identified factors.

Personal exposure to particles in Banská Bystrica, Slovakia *

Epidemiological studies have associated adverse health impacts with ambient concentrations of particulate matter (PM), though these studies have been limited in their characterization of personal exposure to PM. An exposure study of healthy nonsmoking adults and children was conducted in Banska Bystrica, Slovakia, to characterize the range of personal exposures to air pollutants and to determine the influence of occupation, season, residence location, and outdoor and indoor concentrations on personal exposures. Twenty-four-hour personal, at-home indoor, and ambient measurements of PM10, PM2.5, sulfate (SO42−) and nicotine were obtained for 18 office workers, 16 industrial workers, and 15 high school students in winter and summer. Results showed that outdoor levels of pollutants were modest, with clear seasonal differences: outdoor PM10 summer/winter mean=35/45 µg/m3; PM2.5 summer/winter mean=22/32 µg/m3. SO42− levels were low (4–7 µg/m3) and relatively uniform across the different sample types (personal, indoor, outdoor), areas, and occupational groups. This suggests that SO42− may be a useful marker for combustion mode particles of ambient origin, although the relationship between personal exposures and ambient SO42− levels was more complex than observed in North American settings. During winter especially, the central city area showed higher concentrations than the suburban location for outdoor, personal, and indoor measures of PM10, PM2.5, and to a lesser extent for SO42−, suggesting the importance of local sources. For PM2.5 and PM10, ratios consistent with expectations were found among exposure indices for all three subject groups (personal>indoor>outdoor), and between work type (industrial>students>office workers). The ratio of PM2.5 personal to indoor exposures ranged from 1.0 to 3.9 and of personal to outdoor exposures from 1.6 to 4.2. The ratio of PM10 personal to indoor exposures ranged from 1.1 to 2.9 and the ratio of personal to outdoor exposures from 2.1 to 4.1. For a combined group of office workers and students, personal PM10/PM2.5 levels were predicted by statistically significant multivariate models incorporating indoor (for PM2.5) or outdoor (for PM10) PM levels, and nicotine exposure (for PM10). Small but significant fractions of the overall variability, 15% for PM2.5 and 17% for PM10, were explained by these models. The results indicate that central site monitors underpredict actual human exposures to PM2.5 and PM10. Personal exposure to SO42− was found to be predicted by outdoor or indoor SO42− levels with 23–71% of the overall variability explained by these predictors. We conclude that personal exposure measurements and additional demographic and daily activity data are crucial for accurate evaluation of exposure to particles in this setting.

The Next Generation of Risk Assessment Multi-Year Study—Highlights of Findings, Applications to Risk Assessment, and Future Directions

Background: The Next Generation (NexGen) of Risk Assessment effort is a multi-year collaboration among several organizations evaluating new, potentially more efficient molecular, computational, and systems biology approaches to risk assessment. This article summarizes our findings, suggests applications to risk assessment, and identifies strategic research directions. Objective: Our specific objectives were to test whether advanced biological data and methods could better inform our understanding of public health risks posed by environmental exposures. Methods: New data and methods were applied and evaluated for use in hazard identification and dose–response assessment. Biomarkers of exposure and effect, and risk characterization were also examined. Consideration was given to various decision contexts with increasing regulatory and public health impacts. Data types included transcriptomics, genomics, and proteomics. Methods included molecular epidemiology and clinical studies, bioinformatic knowledge mining, pathway and network analyses, short-duration in vivo and in vitro bioassays, and quantitative structure activity relationship modeling. Discussion: NexGen has advanced our ability to apply new science by more rapidly identifying chemicals and exposures of potential concern, helping characterize mechanisms of action that influence conclusions about causality, exposure–response relationships, susceptibility and cumulative risk, and by elucidating new biomarkers of exposure and effects. Additionally, NexGen has fostered extensive discussion among risk scientists and managers and improved confidence in interpreting and applying new data streams. Conclusions: While considerable uncertainties remain, thoughtful application of new knowledge to risk assessment appears reasonable for augmenting major scope assessments, forming the basis for or augmenting limited scope assessments, and for prioritization and screening of very data limited chemicals. Citation: Cote I, Andersen ME, Ankley GT, Barone S, Birnbaum LS, Boekelheide K, Bois FY, Burgoon LD, Chiu WA, Crawford-Brown D, Crofton KM, DeVito M, Devlin RB, Edwards SW, Guyton KZ, Hattis D, Judson RS, Knight D, Krewski D, Lambert J, Maull EA, Mendrick D, Paoli GM, Patel CJ, Perkins EJ, Poje G, Portier CJ, Rusyn I, Schulte PA, Simeonov A, Smith MT, Thayer KA, Thomas RS, Thomas R, Tice RR, Vandenberg JJ, Villeneuve DL, Wesselkamper S, Whelan M, Whittaker C, White R, Xia M, Yauk C, Zeise L, Zhao J, DeWoskin RS. 2016. The Next Generation of Risk Assessment multiyear study—highlights of findings, applications to risk assessment, and future directions. Environ Health Perspect 124:1671–1682; http://dx.doi.org/10.1289/EHP233

Estimations of historical atmospheric mercury concentrations from mercury refining and present-day soil concentrations of total mercury in Huancavelica, Peru

Detailed Spanish records of cinnabar mining and mercury production during the colonial period in Huancavelica, Peru were examined to estimate historical health risks to the community from exposure to elemental mercury (Hg) vapor resulting from cinnabar refining operations. Between 1564 and 1810, nearly 17,000 metric tons of Hg were released to the atmosphere in Huancavelica from Hg production. AERMOD was used with estimated emissions and source characteristics to approximate historic atmospheric concentrations of mercury vapor. Modeled 1-hour and long-term concentrations were compared with present-day inhalation reference values for elemental Hg. Estimated 1-hour maximum concentrations for the entire community exceeded present-day occupational inhalation reference values, while some areas closest to the smelters exceeded present-day emergency response guideline levels. Estimated long-term maximum concentrations for the entire community exceeded the EPA Reference Concentration (RfC) by a factor of 30 to 100, with areas closest to the smelters exceeding the RfC by a factor of 300 to 1000. Based on the estimated historical concentrations of Hg vapor in the community, the study also measured the extent of present-day contamination throughout the community through soil sampling and analysis. Total Hg in soils sampled from 20 locations ranged from 1.75 to 698 mg/kg and three adobe brick samples ranging from 47.4 to 284 mg/kg, consistent with other sites of mercury mining and use. The results of the soil sampling indicate that the present-day population of Huancavelica is exposed to levels of mercury from legacy contamination which is currently among the highest worldwide, consequently placing them at potential risk of adverse health outcomes.

Perspectives on Air Quality Policy Issues in Europe and North America

This article presents an overview of progress and future directions in air quality management in Europe, the United States, and Canada. The article describes the role of the European Commission, the Clean Air for Europe program, and the World Health Organization (WHO) in devising policies to reduce health risks due to air pollution in Europe. U.S. Environmental Protection Agency (EPA) standards for particulate matter (PM), air quality monitoring programs, and research efforts to support air quality management strategies are discussed. The unique aspects of air quality management in Canada are identified, including the need for a better understanding of the true burden of health effects and improved communication strategies to inform the public and stakeholders.

Residential mercury contamination in adobe brick homes in Huancavelica, Peru.

This is the first study of adobe brick contamination anywhere in the world. Huancavelica, Peru is the site of historic cinnabar refining and one of the most mercury (Hg) contaminated urban areas in the world. Over 80% of homes in Huancavelica are constructed with adobe bricks made from Hg contaminated soil. In this study we measured total Hg concentrations in adobe brick, dirt floor, surface dust, and air samples from the interior of 60 adobe brick houses located in four neighborhoods. Concentrations of total Hg in adobe bricks, dirt floors, and surface dust ranged from 8.00 to 1070 µg/g, 3.06 to 926 µg/g, and 0.02 to 9.69 µg/wipe, respectively, with statistically significant differences between the four neighborhoods. Concentrations of Hg in adobe brick and dirt floor samples in Huancavelica were orders of magnitude higher than in Ayacucho, a non-mining town in Peru. A strong correlation exists between total Hg concentrations in adobe bricks and dirt floors which confirms that adobe bricks were being made on-site and not purchased from an off-site source. A strong correlation between surface dust and adobe bricks and dirt floors indicates that walls and floors serve as indoor sources of Hg contamination. Elemental Hg vapor concentrations were below detection (<0.5 µg/m3) in most homes; however in homes with detectable levels, concentrations up to 5.1 µg/m3 were observed. No statistically significant differences in Hg vapor measurements were observed between neighborhoods. This study demonstrates that building materials used widely in developing communities, such as adobe bricks, may be a substantial source of residential Hg exposure in silver or gold refining communities where Hg is produced or used for amalgamation in artisanal gold production.

Scientific Considerations for Evaluating Cancer Bioassays Conducted by the Ramazzini Institute

Background: The Ramazzini Institute (RI) has completed nearly 400 cancer bioassays on > 200 compounds. The European Food Safety Authority (EFSA) and others have suggested that study design and protocol differences between the RI and other laboratories by may contribute to controversy regarding cancer hazard findings, principally findings on lymphoma/leukemia diagnoses. Objective: We aimed to evaluate RI study design, protocol differences, and accuracy of tumor diagnoses for their impact on carcinogenic hazard characterization. Methods: We analyzed the findings from a recent Pathology Working Group (PWG) review of RI procedures and tumor diagnoses, evaluated consistency of RI and other laboratory findings for chemicals identified by the RI as positive for lymphoma/leukemia, and examined evidence for a number of other issues raised regarding RI bioassays. The RI cancer bioassay design and protocols were evaluated in the context of relevant risk assessment guidance from international authorities. Discussion: Although the PWG identified close agreement with RI diagnoses for most tumor types, it did not find close agreement for lymphoma/leukemia of the respiratory tract or for neoplasms of the inner ear and cranium. Here we discuss a) the implications of the PWG findings, particularly lymphoma diagnostic issues; b) differences between RI studies and those from other laboratories that are relevant to evaluating RI cancer bioassays; and c) future work that may help resolve some concerns. Conclusions: We concluded that a) issues related to respiratory tract infections have complicated diagnoses at that site (i.e., lymphoma/leukemia), as well as for neoplasms of the inner ear and cranium, and b) there is consistency and value in RI studies for identification of other chemical-related neoplasia. Citation: Gift JS, Caldwell JC, Jinot J, Evans MV, Cote I, Vandenberg JJ. 2013. Scientific considerations for evaluating cancer bioassays conducted by the Ramazzini Institute. Environ Health Perspect 121:1253–1263; http://dx.doi.org/10.1289/ehp.1306661

Risk assessment and research : an essential link

Regulatory agencies, such as the U.S. Environmental Protection Agency, use health risk assessment information in developing pollution control regulations and for setting regulatory and research priorities. The risk assessment process, however, is hampered by limitations in test methods, in models for exposure and dose-response, and by chemical-specific data gaps. The research/risk assessment/risk management framework provides opportunities for targeting and coordinating research to address these limitations. Enhanced communication among researchers, risk assessors and risk managers to foster better development and use of scientific information in decision making, and incentives for interdisciplinary research efforts, are needed.