This review will follow the Joanna Briggs Institute methodology for scoping reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines [20,21].

We will consider studies conducted on associations between exposure to the 6 VOCs of interest (benzene, toluene, ethylbenzene, xylene, trichloroethylene, and tetrachloroethylene) and/or total VOCs and health effects in pregnant females and on the child from conception through 18 years. Table 1 presents the Population, Exposure, and Outcomes (PEO) framework for this review.

Regardless of the assessment method—whether derived from questionnaires, screenings, biomarkers (including epigenetic markers such as DNA methylation changes), laboratory tests, or clinical diagnoses—any health outcome will be considered for this review. Only the relationship of the VOCs with any health effect will be reported. Studies with total VOC measurement will be included, as this method of exposure assessment represents a proxy for the pollutants considered in this review. These will be reported as their own exposure category. Studies using assessment of exposure to VOCs through biological, environmental matrices, or mathematical or geospatial modeling (eg, exposure estimation based on residential address) will be considered. Exposure and health effects occurring during and throughout adulthood (in the nongravid state) will not be considered.

Studies done in any part of the world and published in English will be included. Both occupational and nonoccupational exposures will be examined.

This scoping review will consider studies that include primary and secondary data, with only peer-reviewed original articles included. All epidemiological research designs such as cross-sectional, retrospective, prospective, bidirectional cohort studies, and case-control studies, and their variations will be explored. Systematic reviews, meta-analyses, and gray literature will not be included in this review (Textbox 1).

The literature search will be conducted to find original research articles with primary or secondary data. A previous rapid literature search with the support of the Sladen Library has been conducted through PubMed MEDLINE to identify reviews (systematic, scoping, and meta-analysis) and original papers to define adequate strategies for the scoping review process. The keywords used are presented in Multimedia Appendix 1. The presearch yielded 265 papers from 1990 to 2024 (June 5), from which 103 papers were eligible for full-text reading and data extraction. As only 1 manuscript (published in 1995) was eligible for the period from 1990 to 2000, we will focus on the period from 2000 to the present for this proposed review.

Literature for the proposed review will be identified by searching Ovid MEDLINE, Embase, and Web of Science. Our literature search will follow the strategy described by Liu et al [22] in their systematic review of indoor VOC exposures and health impacts. The Covidence platform (Covidence systematic review software, Veritas Health Innovation, Melbourne, Victoria, Australia) [23] will be used to screen references, extract data, and track the progress of the work.

After the initial search conducted by the Sladen Library, the citations will be uploaded on the Covidence platform. A total of 2 reviewers will independently conduct a rapid screening based first on the paper’s titles, removing those that are not relevant or do not meet inclusion criteria. Discrepancies will be determined by a third reviewer. Next, 2 reviewers will evaluate the articles’ abstracts and full text for relevance. Each article will be reviewed by 2 reviewers during the full-text review stage. The reviewers will document reasons for the exclusion of any full-text article. Any discrepancies in exclusion or inclusion decisions will be discussed by 2 reviewers and, if necessary, adjudicated by a third reviewer. At the end of this process, the reviewers will examine the bibliographies of the relevant papers (selected for the extraction process) to identify additional articles pertinent to the study objectives. Citations will be managed using EndNote 21 (Clarivate).

Full-text articles must be available to be included in the final analysis of this review. If any publication is unavailable through the Sladen Library resources, we will contact the publication’s corresponding author to request the paper’s full text. For transparency, all details on the results of contacting authors of the unavailable papers will be provided in the methodology section of the final version of the publication resulting from this research. After the data extraction and synthesis, the Sladen Library will conduct a supplementary search to consider any possible new evidence.

The remaining articles will undergo full-text review for further data extraction and synthesis. To define the level of evidence in this scoping review, the following information will be collected as shown in Textbox 2: metadata (authors, country, and year of publication), aims of the study, list of VOCs investigated, methodology (research design, sample size, measures of association, methods to assess VOC exposure and health outcomes, potential confounders), and main conclusion.

A total of 2 reviewers will extract the information separately. In case of discrepancy, both will discuss to reach a consensus. If needed, a third reviewer may intervene. This data extraction instrument may be modified if required according to its efficiency.

This section will address the 2 main review questions. Considering the level of evidence, results will be shown as descriptive data (absolute and relative frequency) of the characteristics of the articles extracted, such as the following:

The goal is to describe the current rigor and depth of previous investigations. We will use a table, chart, or figure to highlight our main findings.

To highlight the current gaps and perspectives for future studies, our results will be presented as a conceptual and thematic map considering the 3 components of our PEO framework (Table 1). The overall goal of the map is to highlight aspects of the associations between VOCs and health in critical windows that have been studied in detail as well as those lacking attention.

We will present a narrative review of the literature describing the similarities and differences in studies conducted on the same topic to highlight possible reasons for contradictory or inconsistent findings. Considering the growing interest in studying exposure to pollutant mixtures, we will present data on the number of studies that evaluated exposure mixtures and those that report mixtures that include at least one of the 6 VOCs of interest, and we will summarize both the associations with health outcomes and the methods used to evaluate mixture effects. Finally, we will comment on and suggest possible implications of this scoping review for future research.

We present the protocol for an ongoing scoping review aimed at evaluating health outcomes associated with 6 VOCs (benzene, toluene, ethylbenzene, xylene, trichloroethylene, and tetrachloroethylene) and total VOCs, which are priorities of an NIEHS-funded Superfund Research Center, CLEAR [19]. This review specifically focuses on pregnant females, fetuses, and individuals ages 0 to 18 years and seeks to address key gaps in knowledge.

To our knowledge, no prior review has provided a comprehensive summary focusing on these VOCs during specific critical life stages. While Liu et al (2022) conducted an extensive systematic review of 8 VOCs, their focus was restricted to indoor exposures and health outcomes at all life stages [22]. Other reviews (systematic, meta-analyses, or narrative) have considered VOCs as part of broader air pollution studies [25-28] or focused narrowly on specific aspects such as (1) individual VOC exposures [6,29-31], (2) specific organ systems [18,31], (3) specific health outcomes such as cancer, respiratory diseases, or allergies [13,26,28,32], or (4) specific populations or geographic regions [16]. In contrast, our review will provide a broader and more inclusive analysis of VOC-related health outcomes in critical stages of human development. Emerging paradigms, such as the life-course perspective [33] and the Developmental Origins of Health and Disease (DOHaD) framework [34], underscore the importance of early prevention. These approaches aim to minimize environmental exposures during key developmental periods, reducing the risk of chronic diseases later in life. Focusing this scoping review on exposures and health outcomes from pregnancy through adolescence will guide future research in this area that could lead to primary prevention efforts.

This review will identify gaps in the current literature and facilitate the development of new research questions. For instance, it may reveal a lack of studies addressing the combined effects of VOCs and other environmental stressors, including chemical and nonchemical factors such as social determinants of health. By highlighting the current evidence and knowledge gaps, we aim to contribute to the dissemination of accurate information, address the limitations of current research, and support efforts to reduce health disparities.

This work has several limitations. First, there is a potential risk of bias, as no formal quality assessment will be conducted, given the nature of scoping reviews. In addition, restricting the language criteria to English limits the inclusion of literature predominantly to Western or English-speaking regions. This approach may exclude valuable evidence from non–English-speaking regions, such as countries in West and Central Africa, Southeast and Central Asia, and Latin America.

This scoping review aims to synthesize evidence from studies conducted since the beginning of the 21st century examining associations of VOC exposures with health outcomes in pregnancy through adolescence. This review is expected to inspire additional research, particularly in these population groups, potentially accelerating the development of policies that promote health equity and protect vulnerable populations.