December 2022 • our1al o) E18,ro1me1tal Healt+ 19 instability in child BLLs over time. Tables 1 and 2 provide an overview of the detailed information discussed in this special report. Absorption of Inhaled Lead Inhaled lead particles follow respiratory system pathways that are relatively well defined. Approximately 30–50% of inhaled lead is retained in the lungs (Chamberlain, 1983; Geiser & Kreyling, 2010) and the duration of respiratory exposure appears to increase absorption (Kastury et al., 2019). Inhaled lead particles are drawn into the windpipe and bronchi, which have mucusproducing cells where cilia attempt to move dust-laden mucus upward and out of the lungs (Bailey et al., 2007). When trapping fails, dust is absorbed directly by the lung alveoli, a thin barrier of cells between air and blood capillaries (Bailey et al., 2007). In the alveoli, activated macrophages can engulf dust particles, preventing dust from reaching the bloodstream (Hamilton et al., 2008; James et al., 1994). Absorption of remaining dust depends on particle size and shape; the distribution of particles is determined by air direction and air force. Ultrafine particles (<100 nm) quickly enter the bloodstream via alveoli. Mechanisms by which larger lead particles enter the bloodstream are not well understood, however, particularly in children. Larger lead particles (100 nm–5 µm) are deposited and can remain in dierent regions of the lungs from months to years before they are eventually absorbed, filtrating from the lungs to the heart and into the bloodstream, or expelled from the lungs and then ingested (Bailey et al., 2007; James et al., 1994; Kastury et al., 2019). During development, absorption is also influenced by lung growth rate and maturity of alveoli. Lungs of children develop throughout childhood up until age 18 (Ahlfeld & Conway, 2014; Narayanan et al., 2012). It is estimated that by age 8 years, only 63% of alveoli have developed (Ahlfeld & Conway, 2014; Dunnill, 1962; Ochs et al., 2004). Fewer alveoli would be expected to result in poorer filtering capacity and higher absorbed lead. Coupled with relatively high respiratory rates, children at dierent ages have the potential to retain substantial amounts of inhaled lead, especially in the tracheobronchial and alveolar regions (Asgharian et al., 2004). Individual dierences in lung development further complicate how and when lead absorption occurs at dierent ages. Absorption of Ingested Lead Compared with inhalation, ingested lead is influenced by relatively more complex and interacting factors including, for example, the bioaccessibility of the lead source, particulate size, site of absorption, individual dierences in physiological and molecular lead-uptake processes, lead–nutrient interactions, whether ingestion occurs in an empty or full gut, and developmental and individual dierences in the maturity of the gastrointestinal (GI) tract. The bioaccessibility of a given lead source depends on its chemical form (Deshommes & Prévost, 2012); the chemical form determines the rate of absorption in the GI tract by altering how digestive proteins, gastric fluid pH, and other ions interact with lead (Deshommes et al., 2012). The chemical forms of lead that exist in non-nutritive substances—such as in leaded paint chips, paint dust, and in some contaminated soils—are far more bioaccessible than Summary of Developmental Influences on Lead Absorption and Re-Release Variability Throughout Childhood Body System Mechanism Source of Variability Respiratory (lungs) Lead in gases and particles <100 nm enters via diffusion in alveoli (limited evidence for absorption of particles >100 nm); particles not expelled or ingested are absorbed into the bloodstream Alveoli densities reach 93% by age 8 (Ahlfeld & Conway, 2014; Dunnill, 1962); full density not reached until approximately age 18 (Narayanan et al., 2012) Digestive (liver) Soluble and insoluble lead stored in hepatocytes via metallothionein binding reduces lead in blood Decreased capacity to metabolize, detoxify, and excrete lead in newborns (Beath, 2003; Gow et al., 2001; Wells, 2017); liver does not fully mature until age 5 Circulatory (red blood cells) Blood nutrient deficiencies allow lead binding to calcium, iron, and zinc sites Malnutrition and genetic polymorphisms (ALAD) directly impact lead absorption by red blood cells, suggesting variability in lead absorption during childhood (Sobin et al., 2009, 2011, 2015) Excretory (kidneys) Metallothionein-bound lead is retained in nephron cell walls; active or passive transport along the nephron can rerelease lead into the bloodstream Mechanisms for filtration and excretion mature at age 2, while full kidney function is not reached until young adulthood (Blane et al., 1985; Čukuranović & Vlajković, 2005) Endocrine (fat cells) Initial evidence that lead is stored in fat; fasting, starvation, and exercise can trigger fat metabolism and re-release lead Initial data suggest insecure food access, irregular eating habits, and/or empty gut can increase vulnerability to lead re-release Skeletal (bone) Accumulation in the inert and labile components of cortical and trabecular bone via binding to hydroxyapatite; low calcium blood levels break down hydroxyapatite and lead is re-released from bone into bloodstream Broken bones, growth spurts during puberty, and deficiencies in bone nutrients can re-release lead into the bloodstream (Janz, 2002; Jones, 2011) Central nervous system (brain) Mimics calcium and activates calciumdependent protein kinase (CDPK), crossing the blood-brain barrier (BBB), possibly disrupting the cohesiveness of the BBB and ability for astrocytes to maintain BBB integrity; inability to regulate the integrity of the BBB may allow for lead to be exchanged more easily between the brain and bloodstream Nutrient deficiencies and stress can affect BBB integrity (Kadry et al., 2020), suggesting fluctuations in lead absorption through childhood TABLE 1
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