20 Volume 85 • Number 5 A D VANC EME N T O F T H E SCIENCE the forms of lead commonly found in foods. In vitro digestion models have shown that the bioaccessibility of lead-contaminated soil from pottery industries typically ranges from 28% to 73% (Oomen et al., 2003). In contrast, the bioaccessibility of lead-contaminated soil at mining sites ranges from 2% to 33% (Ruby et al., 1992; von Lindern et al., 2016). The bioaccessibility of lead in water ranges broadly from 1.5% to 100% (Deshommes & Prévost, 2012), while the bioaccessibility of lead-contaminated household dust is from 28% to 100% (Sowers et al., 2021; von Lindern et al., 2016). Many chemical forms of ingested lead have been identified and include sulfide, chloride, acetate, carbonate, chromate, monoxide, tetroxide, phosphate, and nitrate, all of which are found in the most common child lead hazard sources, but the bioaccessibility will vary depending on their form (speciation) as well as what matrix they are in (ATSDR, 2017) and goes directly into the stomach where multiple internal mechanisms influence both dissolution and speed of absorption. Gastric acid breaks down lead into more soluble forms. Human intestinal fluid studies and animal models have shown that an interacting complex series of chemical, biological, and biophysicochemical factors directly aect absorption of ingested lead, which creates the potential for broad fluctuation of lead in whole blood samples (Liu et al., 2021; Mushak, 1991). Importantly, lead can transform into dierent lead species in the gut during the digestion process when interactions with native stomach acids increase the lead solubility (Mushak, 1991). Interestingly, the electrical charge associated with lead influences its diusion rate in intestinal cells. Ionized forms of lead have higher anity for intestinal cell junctions that rely on ionic mechanisms for the transport of essential cations including Ca2+, Mg2+, Fe2+, and Na+ (Jaishankar et al., 2014). For example, lead– bile complexes convert to ionized lead and transport lead into intestinal cells—a process not yet well understood (Oomen et al., 2003). Lead absorption in the small intestine occurs primarily in the duodenum (upper first sections) via passive diusion and active transport (Mushak, 1991). In the ileum (third section), micelles form, capture lead in the spaces of the intestines, and are absorbed through the intestinal walls via pinocytosis (Teichmann & Stremmel, 1990). Lead can also pass through the tight spaces between the enterocytes that line the stomach, small intestines, and colon (Kiela & Ghishan, 2016; Mushak, 1991) or can be engulfed by macrophages and/or micelles from the cell membrane of enterocytes. Via these mechanisms, lead can then travel into the bloodstream. While any of these mechanisms can deliver lead into the circulatory system via the liver (Liu et al., 2021; Mushak, 1991), most ingested lead (70–90%) is excreted in urine or feces; sequestered lead can be retained in cells for varying periods of time (Leggett, 1993; O’Flaherty, 1998). Age and maturity of the GI tract influence the functioning of these mechanisms and thus aect lead absorption and excretion. Eating patterns also aect absorption. Absorption is substantially greater when the stomach is empty (Blake et al., 1983; Blake & Mann, 1983; Heard & Chamberlain, 1982; James et al., 1985), thus the timing of meal and dietary nutrient intake can block or enhance lead absorption. In children 3–5 years, those who ate breakfast compared with those who did not had lower BLLs after controlling for nutritional and demographic variables (Liu et al., 2011). If a child’s stomach is near empty, Pb2+ absorption can be as high as 100% (ATSDR, 2017; Heard & Chamberlain, 1982; Rabinowitz et al., 1980). High gut absorption in children has been attributed to developmental and individual dierences in calcium-binding proteins and gut acid (Deren, 1971; Mushak, 1991). Also, the risk of exposure from tap water can be increased when children with empty stomachs drink more due to hunger (Heard & Chamberlain, 1982). Lead in combination with another ion and/ or vitamin can facilitate or block absorption of lead in the GI tract. One obvious critical lead–nutrient interaction is with calcium (Blake & Mann, 1983; Elias et al., 2007; Heard & Chamberlain, 1982; Schell et al., 2004; Ziegler et al., 1978). Another critical Sources of Variability in Key Lead Absorption Mechanisms by Body System Body System Absorption Mechanism Factors Contributing to Blood Lead Level Variability Respiratory • Particles >5.0 µm mainly deposit in the nasopharyngeal region • Particles 2.0–5.0 µm can penetrate the tracheobronchial region • Small particles <0.5 µm and very small particles <1.0 µm can penetrate deep into the alveoli, remaining for months to years • Soluble gases and particles <100 nm enter directly into the bloodstream via diffusion in alveoli • Lead particulate size • Duration of inhalation • Frequency of exposure • Respiratory rate • Alveoli density • Individual respiratory system differences Digestive • Passive and active transport via enterocytes in the gut and small intestine • Bioaccessibility of lead hazard source • Lead particulate size • Lead chemical form • Absorption site • Lead–nutrient interactions and nutrient deficiencies • Maturity of the gastrointestinal tract • Individual differences in physiological and molecular lead uptake • Food intake variability Blood • Active transportation in red blood cells via using calcium- and zinc-activated proteins • Oxidation stage of lead • Concentration of lead • Nutrient deficiencies • Genetic (ALAD) predisposition influencing lead absorption TABLE 2
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