December 2022 • our1al o) E18,ro1me1tal Healt+ 21 interaction is with iron. Similar to calcium, iron deficiencies in children are associated with higher BLLs (Marcus & Schwartz, 1987; Schell et al., 2004; Wolf et al., 2003) and animal studies have shown that lead competes with iron absorption in the intestines (Bannon et al., 2003; Morrison & Quarterman, 1987). Thus, more lead is absorbed when a child is iron deficient, when lead replaces iron in the receptors and/or binding proteins found in the intestines. With regard to individual dierences, there are at least two inherited conditions that directly impact iron metabolism: hemochromatosis and transferrin genes (Hopkins et al., 2008), both of which have been associated with higher BLLs in children. With regard to four clinically recommended nutrients to reduce lead absorption (calcium, iron, vitamin C, and zinc), there is limited evidence that the supplementation of these nutrients prevents lead absorption in nutritionally robust children (Kordas, 2017). Post-Absorption Mechanisms and Potential for Re-Release Once in the bloodstream, lead is passed between blood and organs via carrier-mediated transportation (active transport) and diusion (Leggett, 1993; O’Flaherty, 1998). Absorbed lead is transported via RBCs to soft tissue organs (liver, kidneys, lungs, brain, spleen, muscles, and heart) and exchanged, filtered, and/or trapped to diering degrees, depending on the organ. Ultimately, lead that is not excreted is stored in mineralized tissues (bone and teeth). The amount of lead that remains in the blood rather than transferring to organ tissues depends on multiple shifting factors. Lead elimination occurs primarily via the kidneys (Lentini et al., 2017). The remaining lead, referred to as total lead body burden, is transported back and forth between the blood system, soft tissue, and mineralizing tissues in a continual process of lead concentration equilibrium (Marcus, 1985; Rabinowitz et al., 1973; Smith et al., 1996). Total lead body burden is dependent on the frequency of lead exposure, concentration, distribution, metabolism, and ability to eliminate lead from the body through urine or feces, as well as developmental and individual dierences in the implicated body systems of children. Furthermore, several mechanisms facilitate or oppose the distribution of lead into tissues. Simple diusion and carrier proteins for calcium facilitate the transfer of lead into soft tissues (Rădulescu & Lundgren, 2019). In contrast, plasma proteins such as albumin, transferrin, globulin, and lipoproteins oppose and limit distribution by binding to lead molecules (Gonick, 2011). Unbound lead passes through capillary endothelial cells into the extravascular space for tissue storage. Of note, the immaturity of this mechanism in young children does not allow tissue absorption and reabsorption, leaving greater amounts of lead in circulating blood. Site-specific proteins and interstitial conditions can also contribute to BLLs (Table 1). Two mechanisms in the liver act simultaneously to remove lead from blood and retain lead in hepatocytes (Braet & Wisse, 2002). Inorganic lead, the most common form absorbed by children, is stored in the liver via the fenestrate, a layer of endothelial cells with scattered small and large pores lining the liver sinusoids (ATSDR, 2017; Beath, 2003). A second retention mechanism involves metallothionein, an intracellular protein that, once bound to lead, ensures that the lead does not exit hepatocytes (Gonick, 2011). The hepatocytes, submucosal and mucosal layers, and bile duct size do not mature in young children until the age of 2 years (Gow et al., 2001; Wells, 2017); the transition to a single cell wall of hepatocytes is not complete until age 5 years (Morgan & Hartroft, 1961). Thus, depending on the age of the child and individual dierences in development, these mechanisms might or might not be mature enough to consistently metabolize, detoxify, and/or excrete lead, contributing to increased or fluctuating BLLs (Allegaert et al., 2007; Gow et al., 2001; Wells, 2017). Reabsorption of lead into the kidney is another mechanism that influences BLLs. Lead is reabsorbed through active or passive transport mechanisms along three main sections of the nephron: the proximal convoluted tubule (via both passive and active transportation), predominately in the ascending limb of the loop of Henle (mainly via active transportation), and the distal convoluted tubule (mainly via passive transportation) (Fowler & DuVal, 1991; Kwon et al., 2015). When lead binds to metallothionein, it is retained in the cell wall of the nephron (Fowler & DuVal, 1991). Another pathway for reabsorption of lead is by erythrophagocytosis eected via macrophages in the epithelial cells that line the proximal convoluted tubule (Kwon et al., 2015). Thus, lead in degrading RBCs is engulfed and removed; reabsorbed lead is then transported to the peritubular capillary network, eventually leading into the bloodstream. Lead that is not reabsorbed exits the nephron as urine. The mechanisms responsible for kidney filtration and excretion mature at dierent ages. Nephrons and tubular structures continue to grow until approximately 1 year; kidney excretion mechanisms (via the parenchyma) mature when the child is approximately 7 months (Čukuranović & Vlajković, 2005; Weinstein & Anderson, 2010). Kidney perfusion and glomerular filtration rates reach full capacity by approximately 2 years; urine concentration capacity matures by 18 months; and renal blood flow by 1 year. Importantly however, full renal function is not complete until young adulthood (approximately 25 years) (Čukuranović & Vlajković, 2005; Davies & Shock, 1950; Levey et al., 2003; Weinstein & Anderson, 2010). The kidneys do not reach maximum functional capacity until early to middle adulthood (between 20 and 30 years) (Blane et al., 1985; Čukuranović & Vlajković, 2005). These age-related factors necessarily influence the amount of lead detectable in circulating whole blood. Individual dierences in children are also important to consider. For example, lead can be stored in body fat. While lead concentrations in fat might be lower than in other types of tissues initially, with chronic exposure they can begin to equal BLL concentrations (Mikalsen et al., 2019; Riedt et al., 2009). Lead stored in fat can be re-released into the bloodstream when fat reserves are mobilized, such as during fasting, hunger, starvation, or exercise (Mikalsen et al., 2019; Riedt et al., 2009). Thus, children with insecure food access or irregular eating habits, who are likely to be at highest environmental risk of lead exposure, might mobilize fat stores more frequently (Dhurandhar, 2016; Pan et al., 2012; Tester et al., 2020). Approximately one half of the lead that the body absorbs is stored in bone/mineralized tissues, accounting for an estimated 74% of the total lead body burden in children (Barry, 1975, 1981). The storage is relatively temporary, however, because bone tissue re-releases lead via dierent types of biological processes. Depending on the type and duration of expo-
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