P 201-252 DEF.qxp 09/08/2006 11:36 Page 249 INORGANIC AND ORGANIC LEAD COMPOUNDS 249 4. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms 4.1 Absorption, distribution, metabolism and excretion 4.1.1 Inorganic lead compounds (a) Humans (i) Absorption Absorption of lead is influenced by the route of exposure, the physicochemical charac- teristics of the lead and the exposure medium, and the age and physiological status of the exposed individual (e.g. fasting, concentration of nutritional elements such as calcium, and iron status). Inorganic lead can be absorbed by inhalation of fine particles, by ingestion and, to a much lesser extent, transdermally. Inhalation exposure Smaller lead particles (< 1 µm) have been shown to have greater deposition and absorption rates in the lungs than larger particles (Hodgkins et al., 1991; ATSDR, 1999). In adult men, approximately 30–50% of lead in inhaled air is deposited in the respiratory tract, depending on the size of the particles and the ventilation rate of the individual. The proportion of lead deposited is independent of the absolute lead burden in the air. The half- life for retention of lead in the lungs is about 15 h (Chamberlain et al., 1978; Morrow et al., 1980). Once deposited in the lower respiratory tract, particulate lead is almost completely absorbed, and different chemical forms of inorganic lead seem to be absorbed equally (Morrow et al., 1980; US EPA, 1986). In two separate experiments, male adult volunteers were exposed to aerosols of lead oxide (prepared by bubbling propane through a solution of tetraethyl lead in dodecane and burning of resulting vapour) containing 3.2 µg/m3 lead (15 subjects) or 10.9 µg/m3 lead (18 subjects) in a room for 23 h/day for up to 18 weeks (Griffin et al., 1975a). Six un- exposed controls were included in each experiment. For those volunteers who remained until the end of the study, blood lead concentrations increased for about 12 weeks and then remained at ∼37 µg/dL and ∼27 µg/dL for the groups with higher and lower exposure, respectively. The concentration in the blood of controls was ∼15 µg/dL. Lead content in blood declined after cessation of exposure, returning to near pre-exposure concentrations after 5 or 2 months for higher and lower exposure, respectively. Chamberlain et al. (1978) P 201-252 DEF.qxp 09/08/2006 11:36 Page 250 250 IARC MONOGRAPHS VOLUME 87 suggested that some residual unburnt tetraethyl lead vapour may have been present in these experiments. Twelve volunteers exposed to 150 µg/m3 lead as lead oxide for 7.5 h per day on 5 days per week for 16–112 weeks exhibited elevated concentrations of lead in blood and urine, with one subject achieving a blood lead concentration of 53 µg/100 g (Kehoe, 1987). An average respiratory intake of 14 µg lead per day was reported for five male volunteers while exposed to an ambient concentration of 0.4–2.1 µg/m3 airborne lead (Rabinowitz et al., 1977). Oral exposure Most data on gastrointestinal absorption of lead are available for adults; there have been very few studies in children. Absorption of lead occurs primarily in the duodenum (reviewed in Mushak, 1991). The mechanisms of absorption have yet to be determined but may involve active transport and/or diffusion through intestinal epithelial cells (transcellular) or between cells (paracellular), and may involve ionized lead (Pb2+) and/or inorganic or organic complexes of lead (Mushak, 1991). The extent and rate of gastrointestinal absorption are influenced by physiological conditions of the exposed individual such as: age, fasting, the presence of nutritional elements including calcium, phosphorus, copper and zinc, iron status, intake of fat and other calories; and physicochemical characteristics of the medium ingested, including particle size, mineral species, solubility and lead species. Studies in adults The experimental studies in adults have mainly employed lead chloride and radio- active tracers (212Pb and later 203Pb). Other evidence, often indirect, comes from stable lead isotope methods and epidemiological studies. Representative studies in adults are summarized in Table 81. The experimental studies generally had small numbers of subjects, ranging from one to 23 and the studies with 203Pb were very short-term, due to the short half-life of the tracer (52 h). There was a wide variation in absorption between individuals in most studies; absorption was up to 96% in subjects who ingested lead with alcohol whilst fasting (Graziano et al., 1996) but was generally less than 10% in subjects who received lead with food. Studies in children Dietary data for very young infants (< 6 months old) are scarce; results of some studies are listed in Table 82. For example, of the eight children investigated by Alexander et al. (1974), only one was aged less than 6 months. In the study by Ziegler et al. (1978), only one infant was studied from 14 days of age, two were studied from 72 and 83 days of age, respectively, and the rest were over 118 days (∼4 months) old. In a study by Gulson et al. (2001a), 15 newborn infants were monitored for at least 6 months postpartum. Infants were breastfed or formula-fed or both and, aged about 91–180 days, usually fed solid foods (baby food called beikost). Daily lead intake ranged from 0.04 to 0.83 µg/kg bw with a geometric mean of 0.23 µg/kg bw and the excretion/intake ratio ranged from 0.7 to 22 with a geometric mean of 2.6. In a stable-isotope study, the mean value of blood P 201-252 DEF.qxp 09/08/2006 11:36 Page 251 INORGANIC AND ORGANIC LEAD COMPOUNDS 251 Table 81. Absorption of lead in adults after ingestion No. and sex Percentage ± SD Exposure conditions Reference of subjects absorption (range) 203 a 203 a Radioactive tracer PbCl2 or PbAc 11 men + 65 Fasting James et al. (1985) 12 women 3.5 Meal with calcium + phosphorus 16 3 h after breakfast 43 5 h after breakfast 10 men 21 ± 16 (10–67) 2 h after meal Blake (1976) 6 men 8 (4–11) Meal Chamberlain et al. 45 ± 17 (24–65) Fasting (1978) 7 men 21 (10–48) 2 h after meal Moore et al. (1979) 4 women 70 (67–74) Fasting Blake & Mann (1983) 17 (7–26) Fasting + 175 mg calcium/250 mg phosphorus 2 (1–5) Fasting + 1750 mg calcium/2500 mg phosphorus 8 men 63 (59–67) Fasting Heard & Chamberlain 6 men 3 (2–5) In liver and kidney of lambb (1982) 2 men 44 (37–56) Fasting Heard et al. (1983) 9 men 5.5 (2–14) In spinachc 8 men 10 (5–15) Normal meal + 200 mg calcium/ 140 mg phosphorus 2 men 14 (3–28) With coffee and tea (and normal meal) (nine tests) 4 men 19.5 (11–23) With beer 10 min before light lunch 9 men 14 ± 3 (8–18) Tracer given 2 h after meal Newton et al. (1992) Stable lead isotopesd 9 men 13.8 ± 3.1 ‘Contaminated’ beer, 0.5 L/d for 5 d Newton et al. (1992) 5 men 10 ± 2.7 (6.5–14) With food: lead nitrate Rabinowitz et al. (1976) 4 men 8.2 ± 2.8 (6–10) With food: lead nitrate/cysteine Rabinowitz et al. (1980) 4 men 35 ± 13 (30–37) Fasting: lead nitrate/sulfide/cysteine 2 men, 76 (46–96) Fasting: Sherry in lead crystal decanter Graziano et al. (1996) 4 women 1 man 34 Fasting: Wine doped with tracer 207Pb Gulson et al. (1998c) 2.3 Wine doped with 207Pb consumed with meal a Volunteers ingested 203Pb as lead chloride or lead acetate in various media, e.g. in water, beverages and meal, with varying amounts of calcium and phosphorus under fasting and non-fasting conditions. Venous blood samples were taken at various times, e.g. 24 and 48 h. Body burden was measured by γ- ray counting, 4–9 days after dosing. b Portions of liver or kidney from lamb injected with 203Pb as lead chloride and butchered after 6 days were cooked and served in meals to volunteers. c The plants of spinach were placed in water containing the 203Pb as lead chloride for 48 h. The tops were then harvested, cooked and eaten with normal meal. d Volunteers ingested non-radioactive enriched lead isotopes 204Pb, 206Pb or 207Pb as lead nitrate, lead cysteine or lead sulfide in various media, e.g. in water, beverages and meal. Lead in samples (blood, urine or faeces) was determined by thermal ionization mass spectrometry. P 201-252DEF.qxp09/08/200611:36Page252 252 Table 82. Daily lead intakes in children and absorption of lead after ingestion Study group Exposure Daily intakes Mean absorptiona (%) Mean Reference (µg/kg bw per day) retentionb mean (range) (%) VOLUME 87 IARC MONOGRAPHS 4 boys and 4 girls, aged 11 balance studies in own 10.6 (5–17) 53 18 Alexander 3 months to 8 years homes. One child was studied et al. (1974) 4 times from 3 months to 1.08 years. 6 boys and 6 girls, aged 2 separate balance studies 11– > 5 42 32 Ziegler et al. 14–746 days 18 days apart in metabolic unit; (1978) 61 studies with variable lead intakes > 5 µg/kg bw per day 9 children in hospital, 104 balance studies with 6.5 [1.5–17] Between –79% and 12% for the Barltrop & aged 3–13 weeks; part 29 children 9 subjects, but high inter- Strehlow of group of 29 children subject variability, some in (1978) aged 3 weeks–14 years negative balance; –40% for all 29 children a Absorption denotes total intake minus faecal excretion b Retention denotes total intake minus total excretion P 253-284 DEF.qxp 09/08/2006 12:01 Page 253 INORGANIC AND ORGANIC LEAD COMPOUNDS 253 lead coming from diet was 50% (Ryu et al., 1983, 1985).