Juleen Lam

The Navigation guide—evidence-based medicine meets environmental health: Systematic review of human evidence for PFOA effects on fetal growth

Background: In contrast to current methods of expert-based narrative review, the Navigation Guide is a systematic and transparent method for synthesizing environmental health research from multiple evidence streams. The Navigation Guide was developed to effectively and efficiently translate the available scientific evidence into timely prevention-oriented action. Objectives: We applied the Navigation Guide systematic review method to answer the question “Does fetal developmental exposure to perfluorooctanoic acid (PFOA) or its salts affect fetal growth in animals ?” and to rate the strength of the experimental animal evidence. Methods: We conducted a comprehensive search of the literature, applied prespecified criteria to the search results to identify relevant studies, extracted data from studies, obtained additional information from study authors, conducted meta-analyses, and rated the overall quality and strength of the evidence. Results: Twenty-one studies met the inclusion criteria. From the meta-analysis of eight mouse gavage data sets, we estimated that exposure of pregnant mice to increasing concentrations of PFOA was associated with a change in mean pup birth weight of –0.023 g (95% CI: –0.029, –0.016) per 1-unit increase in dose (milligrams per kilogram body weight per day). The evidence, consisting of 15 mammalian and 6 nonmammalian studies, was rated as “moderate” and “low” quality, respectively. Conclusion: Based on this first application of the Navigation Guide methodology, we found sufficient evidence that fetal developmental exposure to PFOA reduces fetal growth in animals. Citation: Koustas E, Lam J, Sutton P, Johnson PI, Atchley DS, Sen S, Robinson KA, Axelrad DA, Woodruff TJ. 2014. The Navigation Guide—evidence-based medicine meets environmental health: systematic review of nonhuman evidence for PFOA effects on fetal growth. Environ Health Perspect 122:1015–1027; http://dx.doi.org/10.1289/ehp.1307177

The Navigation Guide - evidence-based medicine meets environmental health: integration of animal and human evidence for PFOA effects on fetal growth.

Background: The Navigation Guide is a novel systematic review method to synthesize scientific evidence and reach strength of evidence conclusions for environmental health decision making. Objective: Our aim was to integrate scientific findings from human and nonhuman studies to determine the overall strength of evidence for the question “Does developmental exposure to perfluorooctanoic acid (PFOA) affect fetal growth in humans?” Methods: We developed and applied prespecified criteria to systematically and transparently a) rate the quality of the scientific evidence as “high,” “moderate,” or “low”; b) rate the strength of the human and nonhuman evidence separately as “sufficient,” “limited,” “moderate,” or “evidence of lack of toxicity”; and c) integrate the strength of the human and nonhuman evidence ratings into a strength of the evidence conclusion. Results: We identified 18 epidemiology studies and 21 animal toxicology studies relevant to our study question. We rated both the human and nonhuman mammalian evidence as “moderate” quality and “sufficient” strength. Integration of these evidence ratings produced a final strength of evidence rating in which review authors concluded that PFOA is “known to be toxic” to human reproduction and development based on sufficient evidence of decreased fetal growth in both human and nonhuman mammalian species. Conclusion: We concluded that developmental exposure to PFOA adversely affects human health based on sufficient evidence of decreased fetal growth in both human and nonhuman mammalian species. The results of this case study demonstrate the application of a systematic and transparent methodology, via the Navigation Guide, for reaching strength of evidence conclusions in environmental health. Citation: Lam J, Koustas E, Sutton P, Johnson PI, Atchley DS, Sen S, Robinson KA, Axelrad DA, Woodruff TJ. 2014. The Navigation Guide—evidence-based medicine meets environmental health: integration of animal and human evidence for PFOA effects on fetal growth. Environ Health Perspect 122:1040–1051; http://dx.doi.org/10.1289/ehp.1307923

A Systematic Review and Meta-Analysis of Multiple Airborne Pollutants and Autism Spectrum Disorder

Background Exposure to ambient air pollution is widespread and may be detrimental to human brain development and a potential risk factor for Autism Spectrum Disorder (ASD). We conducted a systematic review of the human evidence on the relationship between ASD and exposure to all airborne pollutants, including particulate matter air pollutants and others (e.g. pesticides and metals). Objective To answer the question: “is developmental exposure to air pollution associated with ASD?” Methods We conducted a comprehensive search of the literature, identified relevant studies using inclusion/exclusion criteria pre-specified in our protocol (registered in PROSPERO, CRD # 42015017890), evaluated the potential risk of bias for each included study and identified an appropriate subset of studies to combine in a meta-analysis. We then rated the overall quality and strength of the evidence collectively across all air pollutants. Results Of 1,158 total references identified, 23 human studies met our inclusion criteria (17 case-control, 4 ecological, 2 cohort). Risk of bias was generally low across studies for most domains; study limitations were related to potential confounding and accuracy of exposure assessment methods. We rated the quality of the body of evidence across all air pollutants as “moderate.” From our meta-analysis, we found statistically significant summary odds ratios (ORs) of 1.07 (95% CI: 1.06, 1.08) per 10-μg/m3 increase in PM10 exposure (n = 6 studies) and 2.32 (95% CI: 2.15, 2.51) per 10-μg/m3 increase in PM2.5 exposure (n = 3 studies). For pollutants not included in a meta-analysis, we collectively evaluated evidence from each study in rating the strength and quality of overall evidence considering factors such as inconsistency, imprecision, and evidence of dose-response. All included studies generally showed increased risk of ASD with increasing exposure to air pollution, although not consistently across all chemical components. Conclusion After considering strengths and limitations of the body of research, we concluded that there is “limited evidence of toxicity” for the association between early life exposure to air pollution as a whole and diagnosis of ASD. The strongest evidence was between prenatal exposure to particulate matter and ASD. However, the small number of studies in the meta-analysis and unexplained statistical heterogeneity across the individual study estimates means that the effect could be larger or smaller (including not significant) than these studies estimate. Our research supports the need for health protective public policy to reduce exposures to harmful airborne contaminants among pregnant women and children and suggests opportunities for optimizing future research.

Developmental PBDE Exposure and IQ/ADHD in Childhood: A Systematic Review and Meta-analysis

Background: In the United States, one in six children are affected by neurodevelopmental disorders, and polybrominated diphenyl ethers (PBDEs) in flame-retardant chemicals are measured ubiquitously in children. Objective: We conducted a systematic a systematic review regarding developmental exposure to PBDEs and intelligence or Attention Deficit/Hyperactivity Disorder (ADHD) and attention-related behavioral conditions in humans. Methods: We searched articles published up to 26 September 2016, and included original studies that quantified exposures to PBDEs incurred any time in proximity to conception or during in utero, perinatal, or childhood time periods. We evaluated the risk of bias of individual studies and the overall quality and strength of the evidence according to the Navigation Guide systematic review methodology. We established criteria in advance to identify studies that could be combined using random effects meta-analyses (DerSimonian-Laird method). Results: Fifteen studies met the inclusion criteria; 10 studies met the criteria for intelligence and nine for attention-related problems. We rated studies generally with “low” to “probably low” risk of bias and rated the overall body of evidence as “moderate” quality with “sufficient” evidence for an association between Intelligence Quotient (IQ) and PBDEs. Our meta-analysis of four studies estimated a 10-fold increase (in other words, times 10) in PBDE exposure associated with a decrement of 3.70 IQ points (95% confidence interval: 0.83, 6.56). We concluded the body of evidence was of “moderate” quality for ADHD with “limited” evidence for an association with PBDEs, based on the heterogeneity of association estimates reported by a small number of studies and the fact that chance, bias, and confounding could not be ruled out with reasonable confidence. Conclusion: We concluded there was sufficient evidence supporting an association between developmental PBDE exposure and reduced IQ. Preventing developmental exposure to PBDEs could help prevent loss of human intelligence. https://doi.org/10.1289/EHP1632

Fetal growth and maternal glomerular filtration rate: A systematic review

Abstract Objective: Glomerular filtration rate (GFR) may influence concentrations of biomarkers of exposure and their etiologic significance in observational studies of associations between environmental contaminants and fetal growth. It is unknown whether the size of a developing fetus affects maternal GFR such that a small fetus leads to reduced plasma volume expansion (PVE), reduced GFR and subsequent higher concentrations of biomarkers in maternal serum. Our objective was to answer the question: “Is there an association between fetal growth and maternal GFR in humans?” Methods: We adapted and applied the Navigation Guide systematic review methodology to assess the evidence of an association between fetal growth and GFR, either directly or indirectly via reduction in PVE. Results: We identified 35 relevant studies. We rated 31 human and two non-human observational studies as “low” quality and two experimental non-human studies as “very low” quality. We rated all three evidence streams as “inadequate”. The association between fetal growth and GFR was “not classifiable” according to pre-specified definitions. Conclusions: There is currently insufficient evidence to support the plausibility of a reverse causality hypothesis for associations between exposure to environmental chemicals during pregnancy and fetal growth. Further research would be needed to confirm or disprove this hypothesis.

A Valuable Contribution toward Adopting Systematic Review in Environmental Health

Scientific and regulatory disagreements and debates routinely arise during the determination of which specific environmental agents are of concern and at what exposure levels. Such debates are common during the development of human health assessments by the U.S. Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS). Indeed, IRIS has been the subject of several congressional hearings and National Academy reviews (U.S. EPA 2012; U.S. House of Representatives Committee on Science, Space, and Technology, Subcommittee on Oversight 2011) precisely because it is in the contentious position of assessing chemical hazard. Recently, IRIS has put forth significant effort to enhance and increase the efficiency of its reviews, which includes refining the process by which it selects, evaluates, and integrates scientific evidence (U.S. EPA 2013)—all central elements of systematic review that require transparent and objective criteria or protocols. In “Instruments for Assessing Risk of Bias and Other Methodological Criteria of Published Animal Studies: A Systematic Review,” Krauth et al. (2013) provided a much needed initial overview of various instruments proposed to evaluate animal study quality. In our view, four particularly valuable contributions of the paper will be useful to IRIS and others seeking to adopt systematic review approaches for environmental health. First, the authors systematically identified instruments currently available to assess animal study quality. This is the first review of its kind and is invaluable for the further development of such instruments. Second, the authors highlighted the considerable variability found between instruments with regard to origin, number, and type (e.g., risk of bias, reporting) of evaluation criteria. Clearly, application of these different instruments will lead to different conclusions given this degree of variability. The authors’ discussion of differences between criteria related to risk of bias, reporting, and imprecision provides important insight on how different criteria can affect study estimates and, consequently, how each should be considered in the evaluation of evidence. Third, the authors described serious uncertainties regarding the performance of these instruments that must be considered in their application. Two of the findings by Krauth et al. (2013) were particularly striking: First, of the 30 instruments evaluated, only 1 had been tested for validity; and second, only 6 contained at least one criterion empirically supported to systematically bias effect sizes in animal studies. The possibility that these instruments would be used to assert definitive conclusions of study quality is especially worrisome given the current lack of empirical support for their design. Last, the authors pointed to specific criteria that need additional research to determine whether they introduce systematic bias, such as timing of exposure, sex, and funding sources and financial ties of investigators. Building the evidence base around these criteria would improve the development of future instruments intended to evaluate experimental animal studies. In the clinical field, objective and transparent evidence-based systematic review methods have been used for several decades. These methods have been empirically tested and refined over time for evaluating scientific evidence to assess the effectiveness and potential risks of medical interventions (Guyatt et al. 2011; Higgins and Green 2011). Such standardized review methods are desperately needed for the field of environmental health in order to assess potential human health or environmental impacts of chemical exposures. In their paper, Krauth et al. (2013) provided a critical overview of instruments available for assessing animal study quality and they indicated where additional research is needed to assess and improve these instruments. We believe this review is extremely valuable to entities such as IRIS and the National Toxicology Program Office of Health Assessment and Translation in their current efforts to establish formal systematic review processes when making authoritative determinations of chemical hazard. In particular, it is evident that the differences and uncertainties identified between available instruments assessed by Krauth et al. (2013) must be addressed if public health protective decisions are to be ensured. We strongly believe that the findings of Krauth et al. make apparent the need for a similar review to be conducted on study evaluation instruments and systematic review approaches currently being developed specifically for application to environmental health.

Use of Systematic Review and Meta-Analysis in Environmental Health Epidemiology: a Systematic Review and Comparison with Guidelines

Systematic review (SR) and meta-analysis (MA) have potential to contribute substantially to environmental health (EH) risk assessment and policy-making, provided study questions are clear and methods sound. We undertook a systematic review of the published epidemiological literature for studies using both SR and MA examining associations between chronic low-dose chemical exposures and adverse health outcomes in general populations and compared actual methods and reporting with a checklist based on available published guidelines. We identified 48 EH SRMAs meeting these criteria. Associations were mainly positive and statistically significant, often involving large populations. A majority of studies followed most general SRMA guidance, although we identified weaknesses in problem formulation, study search, selection and data extraction, and integrating policy implications. Fewer studies followed EH-specific SRMA recommendations, particularly regarding exposure heterogeneity and other risks of bias. Development and adoption of EH-specific SRMA guidelines would contribute to strengthening these tools for public health decision-making.

Ambient air pollution epidemiology systematic review and meta-analysis: A review of reporting and methods practice.

BACKGROUND Systematic review and meta-analysis (SRMA) are increasingly employed in environmental health (EH) epidemiology and, provided methods and reporting are sound, contribute to translating science evidence to policy. Ambient air pollution (AAP) is both among the leading environmental causes of mortality and morbidity worldwide, and of growing policy relevance due to health co-benefits associated with greenhouse gas emissions reductions. OBJECTIVES We reviewed the published AAP SRMA literature (2009 to mid-2015), and evaluated the consistency of methods, reporting and evidence evaluation using a 22-point questionnaire developed from available best-practice consensus guidelines and emerging recommendations for EH. Our goal was to contribute to enhancing the utility of AAP SRMAs to EH policy. RESULTS AND DISCUSSION We identified 43 studies that used both SR and MA techniques to examine associations between the AAPs PM2.5, PM10, NO2, SO2, CO and O3, and various health outcomes. On average AAP SRMAs partially or thoroughly addressed 16 of 22 questions (range 10-21), and thoroughly addressed 13 of 22 (range 5-19). We found evidence of an improving trend over the period. However, we observed some weaknesses, particularly infrequent formal reviews of underlying study quality and risk-of-bias that correlated with lower frequency of thorough evaluation for key study quality parameters. Several other areas for enhanced reporting are highlighted. CONCLUSIONS The AAP SRMA literature, in particular more recent studies, indicate broad concordance with current and emerging best practice guidance. Development of an EH-specific SRMA consensus statement including a risk-of-bias evaluation tool, would be a contribution to enhanced reliability and robustness as well as policy utility.