A systematic evidence map for the evaluation of noncancer health effects and exposures to polychlorinated biphenyl mixtures

Abstract

Assessing health outcomes associated with exposure to polychlorinated biphenyls (PCBs) is important given their persistent and ubiquitous nature. PCBs are classified as a Group 1 carcinogen, but the full range of potential noncancer health effects from exposure to PCBs has not been systematically summarized and evaluated. We used systematic review methods to identify and screen the literature using combined manual review and machine learning approaches. A protocol was developed that describes the literature search strategy and Populations, Exposures, Comparators, and Outcomes (PECO) criteria used to facilitate subsequent screening and categorization of literature into a systematic evidence map of PCB exposure and noncancer health endpoints across 15 organs/systems. A comprehensive literature search yielded 62,599 records. After electronic prioritization steps, 17,037 studies were manually screened at the title and abstract level. An additional 900 studies identified by experts or supplemental searches were also included. After full-text screening of 3889 references, 1586 studies met the PECO criteria. Relevant study details such as the endpoints assessed, exposure duration, and species were extracted into literature summary tables. This review compiles and organizes the human and mammalian studies from these tables into an evidence map for noncancer health endpoints and PCB mixture exposure to identify areas of robust research as well as areas of uncertainty that would benefit from future investigation. Summary data are available online as interactive visuals with downloadable metadata. Sufficient research is available to inform PCB hazard assessments for most organs/systems, but the amount of data to inform associations with specific endpoints differs. Furthermore, despite many years of research, sparse data exist for inhalation and dermal exposures, which are highly relevant human exposure routes. This evidence map provides a foundation for future systematic reviews and noncancer hazard assessments of PCB mixtures and for strategic planning of research to inform areas of greater uncertainty.

Keywords: Evidence map; Hazard identification; Polychlorinated biphenyl; Risk assessment; Systematic review.

Fig. 1.. Illustration of electronic prioritization approaches.

1 A. Schematic illustration of electronic prioritization of literature depicting references clustered by similarity using natural language processing. 1 B. Illustration depicting clusters containing relevant seed references (circled blue clusters). Clusters were ranked by the number of seed studies included. 1C. Visualization of identified clusters. Clusters were organized into groups (A–F) on the basis of the number of approaches that identified the cluster such that Group A contains clusters harboring seed references identified by six approaches and Group F contains clusters harboring seed references identified by a single approach. All references in the top four groups (A–D) were manually screened for inclusion based on PECO criteria. Low scoring groups (E, F) were subjected to additional machine learning approaches to capture relevant references for manual screening. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2.. Chronology of prioritization approaches applied to PCB literature search results.

The initial 2015 literature search used DoCTER, an electronic prioritization approach described in Section 2.2 and in ICF (2019). The literature updates from 2017 to 2021 utilized SWIFT-Active Screener, another electronic prioritization program and fully described in Sciome (2021).

Fig. 3.. Literature search flow diagram for PCBs.

Searches were conducted up to August 31, 2021, in PubMed, Web of Science, and, prior to 2019, also Toxline. References were identified by technical experts or through supplemental searches, including seed references (records identified through other sources). During screening, records were prioritized using machine learning tools (DoCTER for references identified in 2015–2016 database searches and SWIFT-Active Screener for 2017–2021). Excluded records are those studies not meeting PECO criteria. Records tagged as supplemental includes potentially relevant supplemental material such as conference abstracts, reviews, and non-English studies that met PECO and studies on PECO-related topics (e.g., toxicokinetic or mechanistic studies). Some studies examined health endpoints in both humans and other mammals.

Fig. 4.. Overview of Human and Other Mammalian Studies Across Organs/Systems.

Summary of the database of studies evaluating exposures to PCB mixtures and health endpoints organized by system. Lists of studies included in each count can be accessed via the online interactive version of this figure (https://hawc.epa.gov/summary/visual/assessment/100500282/OverviewAllStudies/). The online figure can be expanded to include information by endpoint category. Shading intensity corresponds with the number of studies in each category, from 1 to 357, which is the maximum number of studies in any category.

Fig. 5.. Overview of Human Studies by Organ/System and Population.

Summary of the database of human studies evaluating exposures to PCB mixtures and health endpoints organized by system and population. Lists of studies included in each count can be accessed via the online interactive version of this figure (https://hawc.epa.gov/summary/visual/assessment/100500282/OverviewHumanStudies/). The online figure can be expanded to include information by endpoint category and can be filtered by organ/system (options: cardiovascular, dermal, developmental, endocrine, gastrointestinal, hematopoietic, hepatobiliary, immune system, metabolic, musculoskeletal, nervous system, ocular, reproductive, respiratory, urinary system), study design (options: case-control, cohort, cross-sectional, other), population (options: accidental, contaminated schools and other buildings, fish/marine mammal (diet), general population, occupational, residents in contaminated area, Yusho/Yu-Cheng), sex (relevant only for reproductive endpoints; options: couple, female, male), and exposure metric (options: adipose tissue, blood, breast milk, child blood, cord blood, dietary estimates, fish consumption, maternal blood, occupational/JEM, other metric [includes dust and modeled estimates], other tissue). Shading intensity corresponds with the number of studies in each category, from 1 to 167, which is the maximum number of studies in any category. JEM = job exposure matrix.

Fig. 6.. Overview of Human Studies by Organ/System and Study Design.

Summary of the database of human studies evaluating exposures to PCB mixtures and health endpoints organized by system and study design. Lists of studies included in each count can be accessed via the online interactive version of this figure (https://hawc.epa.gov/summary/visual/assessment/100500282/OverviewHumanStudies/). The online figure can be expanded to include information by endpoint category and can be filtered by organ/system (options: cardiovascular, dermal, developmental, endocrine, gastrointestinal, hematopoietic, hepatobiliary, immune system, metabolic, musculoskeletal, nervous system, ocular, reproductive, respiratory, urinary system), study design (options: case-control, cohort, cross-sectional, other), population (options: accidental, contaminated schools and other buildings, fish/marine mammal (diet), general population, occupational, residents in contaminated area, Yusho/Yu-Cheng), sex (relevant only for reproductive endpoints; options: couple, female, male), and exposure metric (options: adipose tissue, blood, breast milk, child blood, cord blood, dietary estimates, fish consumption, maternal blood, occupational/JEM, other metric [includes dust and modeled estimates], other tissue). Shading intensity corresponds with the number of studies in each category, from 1 to 155, which is the maximum number of studies in any category. JEM = job exposure matrix.

Fig. 7.

Overview of Human Studies by Organ/System and Exposure Metric. Summary of the database of human studies evaluating exposures to PCB mixtures and health endpoints organized by system and exposure metric. Lists of studies included in each count can be accessed via the online interactive version of this figure (https://hawc.epa.gov/summary/visual/assessment/100500282/OverviewHumanStudies/). The online figure can be expanded to include information by endpoint category and can be filtered by organ/system (options: cardiovascular, dermal, developmental, endocrine, gastrointestinal, hematopoietic, hepatobiliary, immune system, metabolic, musculoskeletal, nervous system, ocular, reproductive, respiratory, urinary system), study design (options: case-control, cohort, cross-sectional, other), population (options: accidental, contaminated schools and other buildings, fish/marine mammal (diet), general population, occupational, residents in contaminated area, Yusho/Yu-Cheng), sex (relevant only for reproductive endpoints; options: couple, female, male), and exposure metric (options: adipose tissue, blood, breast milk, child blood, cord blood, dietary estimates, fish consumption, maternal blood, occupational/JEM, other metric [includes dust and modeled estimates], other tissue). Shading intensity corresponds with the number of studies in each category, from 1 to 144, which is the maximum number of studies in any category. JEM = job exposure matrix.

Fig. 8.

Overview of Nonhuman Mammalian Studies by Organ/System and Species. Summary of the database of studies in nonhuman mammals evaluating exposures to PCB mixtures and health endpoints organized by system and species. Lists of studies included in each count can be accessed via the online interactive version of this figure (https://hawc.epa.gov/summary/visual/assessment/100500282/OverviewNonhumanMammalStudies/). The online figure can be expanded to include information by endpoint category and can be filtered by organ/system (options: cardiovascular, dermal, developmental, endocrine, gastrointestinal, hematopoietic, hepatobiliary, immune system, metabolic, musculoskeletal, nervous system, ocular, reproductive, respiratory, urinary system), exposure duration/life stage (options: acute [single dose], chronic, developmental, NR, short-term, subchronic), species (options: cat, cow, dog, ferret, gerbil, goat, guinea pig, hamster, mink, mouse, nonhuman primate, rabbit, rat, sheep, swine, vole), sex (relevant only for reproductive endpoints; options: female, male, pair), and exposure route (options: dermal, inhalation, injection, oral). Shading intensity corresponds with the number of studies in each category, from 1 to 239, which is the maximum number of studies in any category. NR = not reported.

Fig. 9.

Overview of Nonhuman Mammalian Studies by Organ/System and Exposure Route. Summary of the database of studies in nonhuman mammals evaluating exposures to PCB mixtures and health endpoints organized by system and exposure route. Lists of studies included in each count can be accessed via the online interactive version of this figure (https://hawc.epa.gov/summary/visual/assessment/100500282/OverviewNonhumanMammalStudies/).The online figure can be expanded to include information by endpoint category and can be filtered by organ/system (options: cardiovascular, dermal, developmental, endocrine, gastrointestinal, hematopoietic, hepatobiliary, immune system, metabolic, musculoskeletal, nervous system, ocular, reproductive, respiratory, urinary system), exposure duration/life stage (options: acute [single dose], chronic, developmental, NR, short-term, subchronic), species (options: cat, cow, dog, ferret, gerbil, goat, guinea pig, hamster, mink, mouse, nonhuman primate, rabbit, rat, sheep, swine, vole), sex (relevant only for reproductive endpoints; options: female, male, pair), and exposure route (options: dermal, inhalation, injection, oral). Shading intensity corresponds with the number of studies in each category, from 1 to 293, which is the maximum number of studies in any category. NR = not reported.

Fig. 10.

Overview of Nonhuman Mammalian Studies by Organ/System and Exposure Duration/Lifestage. Summary of the database of studies in nonhuman mammals evaluating exposures to PCB mixtures and health endpoints organized by system and exposure duration/lifestage. Lists of studies included in each count can be accessed via the online interactive version of this figure (https://hawc.epa.gov/summary/visual/assessment/100500282/OverviewNonh umanMammalStudies/). The online figure can be expanded to include information by endpoint category and can be filtered by organ/system (options: cardiovascular, dermal, developmental, endocrine, gastrointestinal, hematopoietic, hepatobiliary, immune system, metabolic, musculoskeletal, nervous system, ocular, reproductive, respiratory, urinary system), exposure duration/life stage (options: acute [single dose], chronic, developmental, NR, short-term, subchronic), species (options: cat, cow, dog, ferret, gerbil, goat, guinea pig, hamster, mink, mouse, nonhuman primate, rabbit, rat, sheep, swine, vole), sex (relevant only for reproductive endpoints; options: female, male, pair), and exposure route (options: dermal, inhalation, injection, oral). Shading intensity corresponds with the number of studies in each category, from 1 to 170, which is the maximum number of studies in any category. NR = not reported.