The Navigation Guide - evidence-based medicine meets environmental health: systematic review of nonhuman evidence for PFOA effects on fetal growth

Abstract

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.

Figure 1

Flowchart for evaluating risk of bias, quality of evidence, and strength of evidence.

Figure 2

Flowchart of the study-selection process.

Figure 3

Summary of review authors’ risk of bias judgments (low, probably low, probably high, and high risk) for each risk of bias item for each included study (A) and given as percentages across all included studies (B), separated into mammalian (n = 15) and non­mammalian (n = 6) studies.

Figure 4

Meta-analysis results from a two-step mixed-effects model using combined relevant mouse studies in which dams were treated with PFOA via gavage and progeny weight was measured at or soon after birth. Data are presented as the mean (95% CI) change in body weight (g) per 1-unit increase in dose (mg/kg BW/day). Each box represents the dose–response slope estimate for a study; the mid­point of the box is the slope estimated for that study, and the box area is proportional to the weight given to each study in the meta-analysis. The diamond is centered at the overall meta-analysis slope estimate. Wolf (2007) was split into two data sets: a) cross-foster (exposure on GDs 1–17), and b) windows of sensitivity (exposure groups for GDs 7–17, GDs 10–17, GDs 13–17, and GDs 15–17).

Figure 5

Combined scatter plots of response for each tested dose of PFOA for all included mammalian studies. Response was measured as the percentage of weight change for progeny (A) near-term or (B) at birth. Each color represents a different study (separated by dashed lines), and each symbol represents a different species or exposure route category. Multiple symbols of the same color represent responses at multiple tested doses within the same study. Doses are given in mg/kg BW/day unless otherwise specified. For each study, doses decrease as the y-axis increases and are scaled appropriately (i.e., larger vertical gaps indicate larger gaps between doses); the minimum dose for all studies is zero. See Supplemental Material, Tables S46 and S47, for the 95% CIs for the point estimates shown in the figure. ^aStudy split into two data sets: a) cross-foster (exposure on GDs 1–17), and b) windows of sensitivity (exposure groups for GDs 7–17, GDs 10–17, GDs 13–17, and GDs 15–17). *(Within symbols), p < 0.05 compared with the control group.

Figure 6

Combined scatter plots of response for each tested dose of PFOA for all included non­mammalian studies. Response was measured as the percentage of (A) weight change and (B) length change. Each color represents a different study (separated by dashed lines), and each symbol represents a different species or exposure route category. Multiple symbols of the same color represent responses at multiple tested doses within the same study. For each study, doses decrease as the y-axis increases and are scaled appropriately (i.e., larger vertical gaps indicate larger gaps between doses); the minimum dose for all studies is zero. See Supplemental Material, Tables S48 and S49, for the 95% CIs for the point estimates shown in the figure. ^aStudy split into two data sets based on time of outcome measurement: a) embryonic day 19, and b) 16–24 hr posthatching. *(Within symbols), p < 0.05 compared with the control group.