Assessing Adverse Health Effects of Long-Term Exposure to Low Levels of Ambient Air Pollution: The HEI Experience and What's Next?

Although concentrations of ambient air pollution continue to decline in high-income regions, epidemiological studies document adverse health effects at levels below current standards in many countries. The Health Effects Institute (HEI) recently completed a comprehensive research initiative to investigate the health effects of long-term exposure to low levels of air pollution in the United States (U.S.), Canada, and Europe. We provide an overview and synthesis of the results of this initiative along with other key research, the strengths and limitations of the research, and remaining research needs. The three studies funded through the HEI initiative estimated the effects of long-term ambient exposure to fine particulate matter (PM2.5), nitrogen dioxide, ozone, and other pollutants on a broad range of health outcomes, including cause-specific mortality and cardiovascular and respiratory morbidity. To ensure high quality research and comparability across studies, HEI worked actively with the study teams and engaged independent expert panels for project oversight and review. All three studies documented positive associations between mortality and exposure to PM2.5 below the U.S. National Ambient Air Quality Standards and current and proposed European Union limit values. Furthermore, the studies observed nonthreshold linear (U.S.), or supra-linear (Canada and Europe) exposure-response functions for PM2.5 and mortality. Heterogeneity was found in both the magnitude and shape of this association within and across studies. Strengths of the studies included the large populations (7-69 million), state-of-the-art exposure assessment methods, and thorough statistical analyses that applied novel methods. Future work is needed to better understand potential sources of heterogeneity in the findings across studies and regions. Other areas of future work include the changing and evolving nature of PM components and sources, including wildfires, and the role of indoor environments. This research initiative provided important new evidence of the adverse effects of long-term exposures to low levels of air pollution at and below current standards, suggesting that further reductions could yield larger benefits than previously anticipated.

Do Interactions Between Environmental Chemicals and the Human Microbiome Need to Be Considered in Risk Assessments?

One of the most dynamic and fruitful areas of current health-related research concerns the various roles of the human microbiome in disease. Evidence is accumulating that interactions between substances in the environment and the microbiome can affect risks of disease, in both beneficial and adverse ways. Although most of the research has concerned the roles of diet and certain pharmaceutical agents, there is increasing interest in the possible roles of environmental chemicals. Chemical risk assessment has, to date, not included consideration of the influence of the microbiome. We suggest that failure to consider the possible roles of the microbiome could lead to significant error in risk assessment results. Our purpose in this commentary is to summarize some of the evidence supporting our hypothesis and to urge the risk assessment community to begin considering and influencing how results from microbiome-related research could be incorporated into chemical risk assessments. An additional emphasis in our commentary concerns the distinct possibility that research on chemical-microbiome interactions will also reduce some of the significant uncertainties that accompany current risk assessments. Of particular interest is evidence suggesting that the microbiome has an influence on variability in disease risk across populations and (of particular interest to chemical risk) in animal and human responses to chemical exposure. The possible explanatory power of the microbiome regarding sources of variability could reduce what might be the most significant source of uncertainty in chemical risk assessment.

Advancing human health risk assessment.

The current/traditional human health risk assessment paradigm is challenged by recent scientific and technical advances, and ethical demands. The current approach is considered too resource intensive, is not always reliable, can raise issues of reproducibility, is mostly animal based and does not necessarily provide an understanding of the underlying mechanisms of toxicity. From an ethical and scientific viewpoint, a paradigm shift is required to deliver testing strategies that enable reliable, animal-free hazard and risk assessments, which are based on a mechanistic understanding of chemical toxicity and make use of exposure science and epidemiological data. This shift will require a new philosophy, new data, multidisciplinary expertise and more flexible regulations. Re-engineering of available data is also deemed necessary as data should be accessible, readable, interpretable and usable. Dedicated training to build the capacity in terms of expertise is necessary, together with practical resources allocated to education. The dialogue between risk assessors, risk managers, academia and stakeholders should be promoted further to understand scientific and societal needs. Genuine interest in taking risk assessment forward should drive the change and should be supported by flexible funding. This publication builds upon presentations made and discussions held during the break-out session 'Advancing risk assessment science - Human health' at EFSA's third Scientific Conference 'Science, Food and Society' (Parma, Italy, 18-21 September 2018).

Polybrominated diphenyl ether (PBDE) neurotoxicity: a systematic review and meta-analysis of animal evidence.

A recent systematic review (SR) and meta-analysis of human studies found an association between prenatal serum polybrominated diphenyl ethers (PBDE) concentrations and a decrease in the IQ of children. A SR of experimental developmental animal PBDE-mediated neurotoxicity studies was performed in the present study. Outcomes assessed included measures related to learning, memory, and attention, which parallel the intelligence-related outcomes evaluated in the human studies SR. PubMed, Embase, and Toxline were searched for relevant experimental non-human mammalian studies. Evaluation of risk of bias (RoB) and overall body of evidence followed guidance developed by the National Toxicology Program. Animal studies using varying designs and outcomes were available for BDEs 47, 99, 153, 203, 206, and 209 and the technical mixture DE-71. Study reporting of methods and results was often incomplete leading to concerns regarding RoB. A meta-analysis of 6 Morris water maze studies showed evidence of a significant increase in last trial latency (effect size of 25.8 [CI, 20.3 to 31.2]) in PBDE-exposed animals with low heterogeneity. For most endpoints, there were unexplained inconsistencies across studies and no consistent evidence of a dose-response relationship. There is a "moderate" level of evidence that exposure to BDEs 47, 99, and 209 affects learning. For other PBDEs and other endpoints, the level of evidence was "low" or "very low". The meta-analysis led to stronger conclusions than that based upon a qualitative review of the evidence. The SR also identified RoB concerns that might be remedied by better study reporting.

Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance.

Male reproductive alterations found in animals and humans following in utero phthalate exposure include decreased anogenital distance (AGD) and other reproductive-tract malformations. The aim of this investigation was to conduct systematic reviews of human and animal evidence of the effect of in utero exposure to diethylhexyl phthalate (DEHP) on anogenital distance (AGD) in males. PubMed, Embase, and Toxline were searched for relevant human and experimental animal studies on August 15, 2016. Search results were screened for relevance, and studies that met the inclusion criteria were evaluated for quality and data extracted for analysis. Confidence in the human and animal bodies of evidence was assessed and hazard conclusions reached by integrating evidence streams. The search yielded 6 relevant human studies and 19 animal studies. Meta-analysis of 5 human observational prospective cohort studies showed that increased maternal urinary concentrations of DEHP metabolites were associated with decreased AGD in boys (-4.07 [CI, -6.49 to -1.66] % decrease per log10 rise in DEHP metabolites). Meta-analysis and meta-regression of the 19 experimental animal studies found reduced AGD with DEHP treatment, with a dose-response gradient, and with heterogeneity explained by species and strain. There is a moderate level of evidence from human investigations and a high level of data from animal studies that in utero exposure to DEHP decreases AGD. Based upon the available human and animal evidence, and consideration of mechanistic data, DEHP is presumed to be a reproductive hazard to humans on the basis of effects on AGD.

Toxicity testing in the 21st century: implications for human health risk assessment.

At the request of the Environmental Protection Agency, the National Research Council (NRC) recently completed a major report entitled Toxicity Testing in the 21st Century: A Vision and a Strategy. The terms of reference for this report were to develop a long-range vision and strategic plan to advance the practices of toxicity testing and human health assessment of environmental agents. The report describes how current and anticipated scientific advances can be expected to transform toxicity testing to permit broader coverage of the universe of potentially toxic chemicals to which humans may be exposed, using more timely and more cost-effective methods for toxicity testing. The report envisages greatly expanded use of high- and medium-throughput in vitro screening assays, computational toxicology, and systems biology, along with other emerging high-content testing methodologies, such as functional genomics and transcriptomics. When fully implemented, the vision will transform the ways toxicity testing and chemical risk assessment are conducted, moving away from measuring apical health endpoints in experimental animals toward identification of significant perturbations of toxicity pathways using in vitro tests in human cells and cell lines. Population-based studies incorporating relevant biomarkers will also be useful in identifying pathway perturbations directly in humans and in interpreting the results of in vitro tests in the context of human health risk assessment. The present article summarizes and extends the NRC report and examines its implications for risk assessment practice.