Polychlorinated biphenyls (PCBs) are a group of 209 halogenated organic pollutants, defined by the number and position of chlorine atoms substituted on biphenyl rings. PCBs were produced as technical mixtures (e.g., Aroclors) for world-wide use in various applications including as dielectric fluids in capacitors and transformers, lubricants, and additives in a variety of other products, including paints and caulk. PCB production was banned in the United States in 1979 (U.S. EPA, 1979) and in most of the world by the time the Stockholm Convention was adopted in 2001 (SCPOP, 2008). However, due to their widespread use, disposal, and resistance to degradation, these chemicals are pervasive in the environment and biota. In addition, industrial processes such as pigment manufacture continue to release PCBs as unintentional by-products (Anh et al., 2021; Vorkamp, 2015). Consequently, humans are exposed to PCBs through the lifespan via multiple routes including diet (Schecter et al., 2010) and inhalation (Lehmann et al., 2015).

Gestation and early life can be particularly sensitive stages for adverse effects from exposure to environmental agents, as they are periods of rapid growth and development that can be perturbed through diverse biological mechanisms. Developmental effects following exposure to PCBs (or other environmental stressors) are critical to consider due to their substantial health and economic costs, which persist across the lifespan. For example, low birth weight and fetal growth restriction are associated with increased risk of infant mortality and morbidity and increased risk for disorders later in life such as metabolic disorders, type II diabetes, obesity, elevated blood pressure, and cardiovascular disease (Barker et al., 2006; Gluckman and Hanson, 2006; Nobili et al., 2008). Relatively small decrements in size at birth for gestational age (even if size is classified in the normal range) caused by an inadequate fetal environment, could have health consequences later in life (Gluckman and Hanson, 2006). Other measures of fetal growth and specific anthropometric parameters (e.g., head circumference) have also been significantly associated with subsequent somatic growth and neurodevelopment (Henrichs et al., 2010; van Batenburg-Eddes et al., 2010). Outcomes at the low end of the distributions (i.e., low birth weight, intrauterine growth restriction, small for gestational age) have been well characterized with regard to associated costs at the time they occur and throughout life. For example, the Organisation for Economic Co-operation and Development (OECD) recently reported the recommended value of a statistical case (VSC) of very low birth weight to be over one million US dollars (USD2022 Purchasing Power Parity (PPP) 1,194,000) (Ščasný et al., 2023). However, extremes at the high end of these distributions (e.g., large for gestational age) might also be harmful and indicative of abnormal fetal development but are less often studied in relation to chemical exposures.

Pregnancy loss and infant mortality, as well as birth defects, are also severe endpoints that are important to evaluate for associations with PCBs. Birth defects are present in approximately 3-5% of births in the United States (Bower et al., 2010; Kirby, 2017; Stallings et al., 2024) and might co-occur with adverse endpoints such as low birth weight and preterm birth (Honein et al., 2009). Major birth defects are associated with significant healthcare costs, lifelong disability, and mortality (Almli et al., 2017; Russo and Elixhauser, 2007; Xu et al., 2016). Birth defects are defined, classified, and counted in different ways, but approaches might rely on medical records or birth certificates, surveillance systems, or parental report. The sensitivity and specificity of different approaches will vary and is also impacted by the type of defect and timing of observation.

In this paper, we describe our systematic approach to identify, evaluate, and synthesize the large body of evidence that has examined associations of developmental exposure to PCB mixtures with body weight and size in early life, offspring mortality, and birth defects, in observational human studies.