Contribution of Lead from Calcium Supplements to Blood Lead.We conducted a case-control study case-control study, n an investigation employing an epidemiologic approach in which previously existing incidents of a medical condition are used in lieu of gathering new information from a randomized population. to determine the contribution of lead to blood from consumption of calcium supplements approximating the recommended daily intakes over a 6-month period. Subjects were males and females ages 21 to 47 years (geometric mean (mathematics) geometric mean - The Nth root of the product of N numbers. If each number in a list of numbers was replaced with their geometric mean, then multiplying them all together would still give the same result. 32 years) with a geometric mean blood lead concentration of 2.5 [micro]g/dL. They were subdivided into three groups. One treatment group (n = 8) was administered a complex calcium supplement (carbonate/phosphate/citrate) and the other treatment group (n = 7) calcium carbonate calcium carbonate, CaCO3, white chemical compound that is the most common nonsiliceous mineral. It occurs in two crystal forms: calcite, which is hexagonal, and aragonite, which is rhombohedral. . The control group (n = 6) received no supplement. The lead isotopic compositions of the supplements were completely different from those of the blood of the subjects, allowing us easily to estimate contribution from the supplements. The daily lead dose from the supplements at 100% compliance was about 3 [micro]g Pb. Three blood samples were taken at 2-month intervals before treatment to provide background values, and three were taken during treatment. Subjects in the treatment group were thus their own controls. Lead isotopic compositions for the complex supplement showed minimal change during treatment compared with pretreatment pretreatment, n the protocols required before beginning therapy, usually of a diagnostic nature; before treatment. pretreatment estimate, n See predetermination. . Lead isotopic compositions in blood for the calcium carbonate supplement showed increases of up to 0.5% in the [sup.206]Pb/[sup.204]Pb ratio, and for all isotope ratios there was a statistically significant difference between baseline and treatment (p [is less than] 0.005). The change from baseline to treatment for the calcium carbonate supplement differed from that for both the control group and the group administered the complex supplement. Blood lead concentrations, however, showed minimal changes. Variations in blood lead levels over time did not differ significantly between groups. Our results are consistent with earlier investigations using radioactive and stable lead tracers Tracers Refers to investment trusts which are populated by corporate bonds. In October 2001, Morgan Stanley's Tradable Custodial Receipts (Tracers) was launched. Tracers contain a number of coporate bonds and credit default swaps which are selected for liquidity and diversity. , which showed minimal gastrointestinal absorption of lead in the presence of calcium ([+ or -] phosphorus phosphorus (fŏs`fərəs) [Gr.,=light-bearing], nonmetallic chemical element; symbol P; at. no. 15; at. wt. 30.97376; m.p. 44.1°C;; b.p. about 280°C;; sp. gr. 1.82 at 20°C;; valence −3, +3, or +5. ) in adults. Even though there is no discernible increase in blood lead concentration during treatment, there are significant changes in the isotopic composition of lead in blood arising from the calcium carbonate supplement, indicating a limited input of lead from diet into the blood. Because calcium carbonate is overwhelmingly the most popular calcium supplement, the changes we have observed merit further investigation. In addition, this type of study, combined with a duplicate diet, needs to be repeated for children, whose fractional absorption of lead is considerably higher than that of adults. Key words: blood lead, calcium supplements, isotopes, lead. Environ Health Perspect 109:283-288 (2001). [Online 2 March 2001] http://ehpnet1.niehs.nih.gov/docs/2001/ 109p283-288gulson/abstract.html The increasing incidence of fractures related to osteoporosis in both females and males has led to efforts to increase bone mass, especially in young children and adolescents (1). It is recognized, even in developed countries such as the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area. , that daily intakes of calcium among children are below recommended levels (2,3). One approach to increase bone mass has been with vitamin and mineral supplementation; another has been fortification fortification, system of defense structures for protection from enemy attacks. Fortification developed along two general lines: permanent sites built in peacetime, and emplacements and obstacles hastily constructed in the field in time of war. of foodstuffs foodstuffs npl → comestibles mpl foodstuffs npl → denrées fpl alimentaires foodstuffs food npl → such as cereals. In addition to the potential to increase bone mass, calcium supplementation calcium supplementation Metabolism The addition of Ca2+ to the diet, usually in the form of calcium carbonate offers other advantages at various stages of life. For example, calcium supplementation reduces the incidence of pregnancy-induced hypertension pregnancy-induced hypertension A term that encompasses isolated–nonproteinuric HTN, pre-eclampsia or proteinuric HTN, eclampsia; PIH occurs in 5-15% of pregnancies, and is a major cause of obstetric and perinatal M&M Management Low-dose aspirin and preeclampsia preeclampsia /pre·eclamp·sia/ (pre?e-klamp´se-ah) a toxemia of late pregnancy, characterized by hypertension, proteinuria, and edema. pre·e·clamp·si·a n. (4). In addition, Koo et al. (5) showed that supplementation with 2 g calcium per day increased fetal bone density in subjects whose calcium intake was normally [is less than] 600 mg per day. Of relevance to our study is the recognition that lead absorption by the gastrointestinal tract gastrointestinal tract n. The part of the digestive system consisting of the stomach, small intestine, and large intestine. Gastrointestinal tract is increased in calcium-deficient diets (6). Absorption of lead by the gastrointestinal tract is inversely related to the amount of calcium present (6,7). Furthermore, calcium supplements had a protective effect by significantly reducing blood lead levels in pregnant women whose diets were deficient in calcium (8,9). The increased mobilization of skeletal lead during pregnancy and lactation lactation Production of milk by female mammals after giving birth. The milk is discharged by the mammary glands in the breasts. Hormones triggered by delivery of the placenta and by nursing stimulate milk production. was attributed to low calcium intake (10). As people have been encouraged to take calcium supplements, several investigators have drawn attention to their potential lead toxicity (11-15). Furthermore, the lead concentrations in calcium supplements were the subject of California legal action, Proposition 65 (16). Any lead contained in calcium supplements will be introduced in conjunction with the calcium. Lead binds tightly to the same transport proteins used by calcium, but the binding affinity of lead is at least twice that of calcium (17). Because the same transport mechanism is operative for absorption of lead and calcium from the gastrointestinal tract, there is resulting competitive interaction between lead and calcium (18). The agreement reached between the California Attorney General The California Attorney General is the State Attorney General of the government of the state of California in the USA. The officer's duty is to ensure that "the laws of the state are uniformly and adequately enforced" (California Constitution, Article V, Section 13. and supplement manufacturers for Proposition 65 was an acceptable daily intake acceptable daily intake the amount of a drug or chemical residue to which an animal can be exposed daily for a lifetime without suffering a deleterious or injurious effect, on the basis of all of the facts known at the time. of [is less than] 1.5 [micro]g Pb/g Ca for adults (15,16). Even at these levels, however, supplements potentially contribute a significant proportion of the daily intake of lead that is now [is less than] 5 [micro]g/day in the United States (19). We were concerned about the scientific validity of the California judgment in light of earlier investigations from tracer studies in both animals and humans demonstrating limited uptake of lead from the gastrointestinal tract in the presence of calcium ([+ or -] phosphorus; Figure 1) (20-24). These experiments, however, were undertaken at times of considerably higher intakes of lead with small numbers of subjects and mostly over limited time periods. The publicity arising from the California legal action was of concern because we had just begun a clinical trial in which subjects were given calcium supplements to verify the hypothesis that calcium supplementation minimizes the mobilization of skeletal lead during pregnancy and lactation. To satisfy ourselves and participants in our trial of the potential safety of calcium supplements and the minimal contribution to blood lead, we undertook a case-control study in which adults consumed calcium supplements containing lead whose isotopic composition was different from that in their current blood. [GRAPH OMITTED] The question we asked was, does the amount of lead in calcium supplements increase blood lead concentration or change the isotopic composition of lead in blood at the recommended daily intake levels of calcium? Methods Rationale. We demonstrated previously that the lead isotopic composition of multigenerational mul·ti·gen·er·a·tion·al adj. Of or relating to several generations: multigenerational family traditions. Australians was different from that of subjects from most other countries (10). We used this concept, first suggested by Manton (25), in our longitudinal study longitudinal study a chronological study in epidemiology which attempts to establish a relationship between an antecedent cause and a subsequent effect. See also cohort study. of mobilization of lead from the maternal skeleton during pregnancy and lactation. Commercially available Australian calcium supplements, which are typically made from overseas components, were administered to the subjects. Subjects and dosing. Subjects, 8 males and 13 females, ranged in age from 21 to 47 years with a geometric mean of 32 years. We attempted to assign subjects randomly to one of three groups, two treatment and one control group, but two subjects expressed a desire to be in the control group. This does not, however, confound con·found tr.v. con·found·ed, con·found·ing, con·founds 1. To cause to become confused or perplexed. See Synonyms at puzzle. 2. our results, because the treatment subjects formed their own controls by having three baseline measurements. The others were randomly assigned to the treatment groups. Ethics clearance was obtained from Macquarie University Location University publications and material indicate that its campus is located in the suburb of North Ryde, although the Geographical Names Board of NSW indicates it is located in the suburb of Macquarie Park. The University has its own postcode: 2109. . Sampling. A trained phlebotomist phle·bot·o·mist n. 1. One who practices phlebotomy. 2. One who draws blood for analysis or transfusion. obtained 2-3 mL of venous blood venous blood n. Abbr. v Blood that has passed through the capillaries of various tissues other than the lungs, is found in the veins, in the right chambers of the heart, and in pulmonary arteries, and is usually dark red as a result of a from each subject. Three samples were collected at quarterly intervals to establish a background value before treatment. During treatment, samples were collected bimonthly bi·month·ly adj. 1. Happening every two months. 2. Happening twice a month; semimonthly. adv. 1. Once every two months. 2. Twice a month; semimonthly. n. pl. for 6 months of calcium supplementation. Thus, each subject in the treatment group acted as his or her own control. Because of changes observed by the group given the calcium carbonate supplement, an additional blood sample for this group was taken 2 months after the treatment ended to see if there was a trend toward the baseline values. Treatment. We originally intended to use a popular calcium carbonate product, but it was not possible to obtain the required quantity of a single manufacturing batch from the supplier. However, for the two treatment supplements, sufficient product was obtained from the one batch of production to minimize variability in the source of calcium and hence lead. The possibility of supplying the control group with a placebo was investigated but discarded because of production difficulties for such a small batch. The product details are listed in Table 1. The complex supplement was to be taken 3 times daily, with meals and at bedtime, because the fasting state is a time when most parathyroid parathyroid /par·a·thy·roid/ (-thi´roid) 1. situated beside the thyroid gland. 2. see under gland. par·a·thy·roid adj. 1. hormone-mediated bone resorption Bone resorption is the process by which osteoclasts break down bone and release the minerals, resulting in a transfer of calcium from bone fluid to the blood. The osteoclasts are multi-nucleated cells that contain numerous mitochondria and lysosomes. occurs (26). The calcium carbonate was taken twice daily after meals.
Table 1. Product information.
Complex product
Calcium
Calcium Calcium Calcium carbonate
Composition citrate phosphate amino acid (chewable)
Weight Ca compound 300 325 200 1,250
(mg)
Equivalent Ca (mg) 64 126 40 500
Daily total Ca (mg) 920 1,000
Daily dosage 3 times after 2 times
meals; 1 on after
retiring meals
[sup.206]Pb/ 20.14 19.70
[sup.204]Pb
Pb ([micro]g/kg) 293 700
Daily Pb intake 2.8 3.2
([micro]g/day)
Two subjects experienced nauseous nauseous /nau·seous/ (naw´shus) pertaining to or producing nausea. nau·seous adj. 1. Causing nausea. 2. Affected with nausea. reactions which they possibly attributed to the calcium supplements. One subject, given the complex product, had just conceived and was therefore moved to the control group. The other experienced nausea taking the calcium carbonate product; the subject was switched to the alternative supplement and thereafter showed no adverse effects. In this pilot investigation, we did not attempt to undertake a dietary study apart from a questionnaire. However, our previous and ongoing pregnancy research showed that the daily calcium intake of migrant and Australian subjects is low (about 500 mg Ca/day) compared with the recommended levels for subjects participating in U.S. studies on pregnancy and lactation (27-32). In these studies, based on diaries and recall, calcium intake was estimated at 1,200-1,800 mg Ca/day, compared with 300-800 mg Ca/day for our subjects (10). Questionnaire. On one occasion we gave the participants a questionnaire that placed a special emphasis on the intake of potentially calcium-bearing foods. Analyses. All sample preparation was performed in purpose-built low-contamination laboratories (clean rooms) incorporating features such as filtered air intake and laminar flow laminar flow Fluid flow in which the fluid travels smoothly or in regular paths. The velocity, pressure, and other flow properties at each point in the fluid remain constant. hoods. To minimize sample heterogeneity, the total blood sample was predigested pre·di·gest tr.v. pre·di·gest·ed, pre·di·gest·ing, pre·di·gests 1. To subject (food) to partial digestion, usually through an enzymatic or chemical process, before ingestion. 2. in ultrapure concentrated nitric acid nitric acid, chemical compound, HNO3, colorless, highly corrosive, poisonous liquid that gives off choking red or yellow fumes in moist air. It is miscible with water in all proportions. and an aliquot aliquot (al-ee-kwoh) adj. a definite fractional share, usually applied when dividing and distributing a dead person's estate or trust assets. (See: share) of [is less than] 1g removed to a clean Teflon vessel. A [sup.202]Pb spike solution of known isotopic composition and lead concentration (~10 ng/g) was added to the aliquot to obtain the concentration of lead and isotopic composition of the unknown sample in the one analysis (this is known as the isotope dilution method). ([sup.202]Pb is not naturally occurring and is produced in cyclotrons as a by-product by·prod·uct or by-prod·uct n. 1. Something produced in the making of something else. 2. A secondary result; a side effect. by-product Noun 1. of preparation of thallium thallium (thăl`ēəm), metallic chemical element; symbol Tl; at. no. 81; at. wt. 204.383; m.p. 303.5°C;; b.p. about 1,457°C;; sp. gr. 11.85 at 20°C;; valence +1 or +3. used in treatment of thyroid abnormalities; it has a half-life of about 3 x [10.sup.5] years.) We analyzed the calcium supplements for their lead isotopic composition by first spiking with the [sup.202]Pb spike and then dissolving/digesting in ultra-pure nitric acid. An aliquot was removed to a clean Teflon vessel and its pH was adjusted using clean ammonia. We separated lead from the calcium by passing the solution through a chelex filter. We further separated lead from other interfering ions using anion exchange anion exchange n. The process by which an anion in a liquid phase exchanges with another anion previously bound to a solid, positively charged phase. chromatography in a bromide bromide, any of a group of compounds that contain bromine and a more electropositive element or radical. Bromides are formed by the reaction of bromine or a bromide with another substance; they are widely distributed in nature. medium. For isotope ratio measurement, we loaded fractions of the purified lead samples onto a rhenium rhenium (rē`nēəm), metallic chemical element; symbol Re; at. no. 75; at. wt. 186.207; m.p. about 3,180°C;; b.p. about 5,625°C;; sp. gr. 21.02 at 20°C;; valence −1, +2, +3, +4, +5, +6, or +7. filament filament, in astronomy: see chromosphere. using the silica gel silica gel, chemical compound. It is a colloidal form of silica, and usually resembles coarse white sand. It may be prepared by partial dehydration of metasilicic acid, H2SiO3. Because it has many tiny pores, it has great adsorptive power. technique (a mix of dilute phosphoric acid phosphoric acid, any one of three chemical compounds made up of phosphorus, oxygen, and hydrogen (see acids and bases). The most common, orthophosphoric acid, H3PO4, is usually simply called phosphoric acid. and purified silica gel) and analyzed them for lead isotope composition (and lead concentrations by isotope dilution) on a thermal ionization In thermal ionization, also referred to as surface ionization, chemically-purified material loaded onto a filament which is then heated to cause some of the material to be ionized as it boils off the hot filament. mass spectrometer spectrometer Device for detecting and analyzing wavelengths of electromagnetic radiation, commonly used for molecular spectroscopy; more broadly, any of various instruments in which an emission (as of electromagnetic radiation or particles) is spread out according to some (VG-ISO-MASS 54E; VG, Winsford, Cheshire, UK) run in fully automatic mode. Isotopic ratios were measured as [sup.208]Pb/[sup.206]Pb, [sup.207]Pb/[sup.206]Pb, and [sup.206]Pb/[sup.204]Pb. Precision estimates on the isotopic ratios have been defined by a repetition of the digestion/lead separation/mass spectrometry spectrometry /spec·trom·e·try/ (spek-trom´e-tre) determination of the wavelengths or frequencies of the lines in a spectrum. spec·trom·e·try n. stages of the same samples of blood, urine, and water. The precisions we allocate our data are [+ or -] 0.2% (2 [Sigma]) on the [sup.206]Pb/[sup.204]Pb ratio, and [+ or -] 0.1% on the [sup.208]Pb/[sup.206]Pb and [sup.207]Pb/[sup.206]Pb ratios. Data are normalized to the accepted values of the National Institute of Standards and Technology National Institute of Standards and Technology, governmental agency within the U.S. Dept. of Commerce with the mission of "working with industry to develop and apply technology, measurements, and standards" in the national interest. (NIST (National Institute of Standards & Technology, Washington, DC, www.nist.gov) The standards-defining agency of the U.S. government, formerly the National Bureau of Standards. It is one of three agencies that fall under the Technology Administration (www.technology. ) SRM (1) (Storage Resource Management) The management of the storage resources in an organization in order to avoid duplication of files and to determine space utilization across all servers. 981 by applying a correction factor of +0.08% atomic mass units atomic mass unit or amu, in chemistry and physics, unit defined as exactly 1-12 the mass of an atom of carbon-12, the isotope of carbon with six protons and six neutrons in its nucleus. One amu is equal to approximately 1. to allow comparisons between laboratories. We obtained a measurement of the environmental lead acquired by the sample throughout the entire preparation analysis procedure in the form of a lead blank measurement. The amount of contamination detected in blanks Absent limitation or restriction. The term in blank is used in reference to negotiable instruments, such as checks or promissory notes. When such Commercial Paper is endorsed in blank, the designated payee signs his or her name only. was generally around 200 pg for blood and from 300 to 900 pg for the calcium supplements. Because the blanks contributed negligibly to the lead in the sample, no blank corrections to the data were performed. Data treatment. We analyzed the three isotopic ratios ([sup.208]Pb/[sup.206]Pb, [sup.207]Pb/[sup.206]Pb, and [sup.206]Pb/[sup.204]Pb) and lead concentrations using a 2 (baseline and treatment) x 3 (days 1, 2, and 3 of baseline and treatment) x 3 (the control, calcium carbonate, and calcium citrate calcium citrate Cal-Citrate-225, Cal-Citrate-250, Citracal, Citracal Liquitabs, Citrus Calcium Pharmacologic class: Mineral Therapeutic class: Dietary supplement, electrolyte replacement agent groups) factorial factorial For any whole number, the product of all the counting numbers up to and including itself. It is indicated with an exclamation point: 4! (read “four factorial”) is 1 × 2 × 3 × 4 = 24. design. The first two factors were within-subject factors. Results Results are summarized in Table 2, and a comparison of means of the [sup.206]Pb/[sup.204]Pb ratio and blood lead concentrations for each group is shown in Figures 2 and 3. Compliance for the 3 months of the treatment period ranged from 0 to 100% for each month. It was expected that changes in pretreatment blood samples may have been larger because sampling covered the Christmas holidays, a time of increased dietary intake and consumption of unusual foods. We sampled approximately 1 month after Christmas to minimize potential effects of abnormal dietary intakes, because the mean life of lead in blood of adults is approximately 20 days (33, 34). [GRAPHS OMITTED]
Table 2. Changes in lead isotopic composition and blood lead for
subjects.
Changes
during
Pretreatment treatment
PbB PbB
Age ([micro]g/ [sup.206]Pb/ ([micro]g/
Identifier (years) Sex dL) [sup.204]Pb dL)
Calcium
citrate/
phosphate/
chelate
1303 31 M 3.5 17.19 3.2-2.9
1304 38 M 2.1 17.22 2.1-1.4
1309 34 M 1.4 17.21 1.3-1.4
1311 47 F 5.8 16.66 5.2-5.7
1313 21 F 2.5 17.32 2.3-2.6
1314 30 F 3.1 17.49 3.1-3.8
1315 44 F 2.2 17.22 1.5-1.4
1321 27 F 1.8 17.45 1.5-1.5
Calcium
carbonate
1305(b) 39 M 4.5-7.8 16.76-16.39 6.9-4.5
1306(b) 36 F 2.2-3.5 17.36-16.93 2.2-1.9
1308 32 F 3.5-4.3 16.84 5.1-3.3
1312 25 F 2.1 17.39 2.3-2.1
1316 27 F 1.5 17.52 1.4-1.5
1319 33 F 2.1 17.35 2.0-2.6
1320 30 F 1.2 17.28 1.2-1.4
Controls
1302(b) 38 M 3.2-6.7 17.39-17.10 3.8-6.0
1307 32 M 2.3 17.26 2.9-2.1
1317 23 F 1.8 17.37 1.5
1318 39 M 1.7 17.20 1.3-1.5
1322(b) 25 F 2.4 17.24 2.3-1.8
1323(b) 31 M 2.4 17.36 2.6-2.2
Changes
during Posttreatment sample
treatment
PbB Comp-
[sup.206]Pb/ ([micro]g/ [sup.206]Pb/ liance(a)
Identifier [sup.204]Pb dL) [sup.204]Pb (%)
Calcium
citrate/
phosphate/
chelate
1303 17.21-17.25 -- -- 70-100
1304 17.22-17.32 -- -- 87-94
1309 17.19-17.34 -- -- 73-78
1311 16.68-16.70 -- -- 76-90
1313 17.24-17.33 -- -- 0-50
1314 17.42-17.52 -- -- 21-59
1315 17.24-17.28 -- -- 86-92
1321 17.36-17.54 -- -- 29-40
Calcium
carbonate
1305(b) 16.48-16.84 4.1 16.88 94-100
1306(b) 17.25-17.46 1.9 17.53 74-90
1308 17.31-17.42 2.6 17.34 70-89
1312 17.49-17.64 1.6 17.51 84-96
1316 17.63-17.70 1.3 17.58 70-86
1319 17.32-17.47 2.1 17.38 17-62
1320 17.36-17.38 1.0 17.33 29-40
Controls
1302(b) 17.58-17.21 -- -- --
1307 17.23-17.24 -- -- --
1317 17.37-17.38 -- -- --
1318 17.21-17.26 -- -- --
1322(b) 17.54-17.35 -- -- --
1323(b) 17.43-17.35 -- -- --
(a) Compliance each month over the 3 months of treatment.
(b) Possible reasons for the larger variability in isotopic
composition and lead concentration are given in the text.
Blood lead concentrations. We observed a slight downward trend over time in blood lead concentrations (Table 2, Figure 3), which was reflected in a main effect of treatment ([F.sub.(1,14)] = 5.94, p = 0.029) and also in a day main effect ([F.sub.(2,28)] = 4.12, p = 0.027). However, the change over days did not differ for baseline and treatment (for the day-by-treatment interaction, [F.sub.(2,28)] = 0.34, p = 0.717), and, as will be seen below, there was no suggestion of a group-by, treatment interaction. Blood lead isotopic ratios. Apart from the anomalies described below, there were minimal changes in isotopic ratios in the control subjects and those given the complex supplement (Figure 2). In contrast, there were detectable increases in [sup.206]Pb/[sup.204]Pb ratio during administration of the calcium carbonate toward the values in the supplement (Figure 2; p = 0.002). Significant changes in the calcium carbonate group from baseline to treatment also occurred for [.sup.208]Pb/[sup.206]Pb and [sup.207]Pb/[sup.206]Pb (p [is less than] 0.0005 and p = 0.001, respectively). The blood sample taken 2 months after treatment ended showed a decrease toward the baseline values for [sup.206]Pb/[sup.204]Pb in some cases, indicating that the increases toward the supplement noted above were a valid effect. There was also a small decrease in blood lead concentration after cessation of treatment (Figure 3). Anomalies in subjects. As is becoming increasingly evident in human studies, individual susceptibility to toxins or treatments plays a major role in determining impacts on health, as do changes in the environment of subjects. In our study, such problems arose for several subjects. For example, male subject 1305 undertook renovations using unsafe methods to an external garage with lead paint just before the start of treatment. Both he and his wife (subject 1306) experienced a sharp decrease in [sup.206]Pb/[sup.204]Pb ratio in blood Pb and an increase in blood lead (PbB) concentration (Table 2). The low [sup.206]Pb/[sup.204]Pb ratio in their blood is consistent with that of much of the lead in paint used in the past on Australian houses (35). Such changes, especially in isotopic compositions, associated with renovation of leaded paint were documented earlier by Manton (36). Despite the changes associated with renovation, the increases in isotopic composition that occur while taking calcium carbonate are consistent with the increases noted above. One control subject (1302) was a regular firearms shooter, and large changes in PbB and isotopic composition are consistent with lead exposure from this activity. His data were omitted from the discussion and will be documented separately. A husband and wife control pair (1322, 1323) exhibited small changes in PbB and isotopic composition after an 11-day visit to the United States (Table 2). High [sup.206]Pb/[sup.204]Pb ratios are characteristic of U.S. subjects and many environmental and dietary media (39). Statistical analyses. We omitted the data for the anomalous subjects 1302, 1305, and 1306 from the statistical analyses. Significant interactions between group and treatment were found for all blood lead isotopic ratios (p-values for F-ratios with 2 and 14 degrees of freedom ranged from 0.01 for [sup.208]Pb/[sup.206]Pb through 0.023 for [sup.207]Pb/[sup.206]Pb to 0.027 for [sup.206]Pb/[sup.204]Pb). The group-by-treatment interaction was not significant for lead concentrations (p = 0.402). We followed up the significant interactions by testing interaction contrasts to answer the question, does the change between baseline and treatment differ for different pairs of groups? Two contrasts compared the calcium carbonate product and the complex calcium citrate product to the controls. The third contrast compared the complex calcium citrate product to the calcium carbonate product. The results are listed in Table 3. Using an adjusted [Alpha] level of 0.0167 (0.05/3) to allow for the three contrasts, there was a significant difference in the change from baseline and treatment for the calcium carbonate product and the control group for the [sup.208]Pb/[sup.206]Pb ratio (p = 0.008) and close to significant differences for the [sup.207]Pb/[sup.206]Pb and [sup.206]Pb/[sup.204]Pb ratios (p = 0.028 and 0.030, respectively). In contrast, there was no suggestion of significant differences between the control and calcium citrate groups (p [is greater than] 0.5 for each measure). The third contrast showed that the change for calcium carbonate product differed significantly from that for the calcium citrate product for each of the three measures (p [is less than] 0.010 in each case). The overall result was that the change from baseline to treatment for the calcium carbonate group differed from that for both the control and calcium citrate groups.
Table 3. Interaction contrasts.
Analysis Coefficient SE t-Value p-Value
[sup.208]Pb/[sup.206]Pb
Calcium carbonate vs. -0.01692 0.00548 -3.0898 0.00799
control
Calcium citrate vs. -0.00011 0.00465 -0.02456 0.98075
control
Calcium citrate vs. -0.01681 0.00500 3.3618 0.00465
calcium carbonate
[sup.207]Pb/[sup.206]Pb
Calcium carbonate vs. -0.01015 0.00414 -2.4480 0.02815
control
Calcium citrate vs. -0.00155 0.00352 0.4405 0.66631
control
Calcium citrate vs. 0.01169 0.00378 3.0918 0.00796
calcium carbonate
[sup.206]Pb/[sup.204]Pb
Calcium carbonate vs. 0.22127 0.09147 2.4190 0.02977
control
Calcium citrate vs. -0.02776 0.07774 -0.35711 0.72633
control
Calcium citrate vs. -0.24903 0.08350 -2.9823 0.00989
calcium carbonate
Discussion Contribution to blood of lead from supplements. Over the 6-month dosing period, the potential impact on blood lead from the two calcium supplements tested in this pilot study was not detectable in the case of the complex product and only a small contribution was detected in the case of the calcium carbonate product. For the calcium carbonate product, there was little or no change in blood lead concentration but detectable changes in isotopic composition toward the [sup.206]Pb/[sup.204]Pb value of 19.7 in the supplement. Changes in isotopic composition toward the contributing source but not in blood lead concentration were observed in some other studies on newborn infants (37) and percutaneous percutaneous /per·cu·ta·ne·ous/ (per?ku-ta´ne-us) performed through the skin. per·cu·ta·ne·ous adj. Passed, done, or effected through the unbroken skin. absorption of lead (38). This may indicate that the pharmacokinetics of lead in blood need to be reevaluated, as also indicated by the long half-lives of lead in blood of up to 38 months observed in several young infants unnaturally exposed to lead from home renovations (39). With the changes in isotopic composition in blood compared with those in the pretreatment phase of calcium carbonate relative to the values in the product, the maximum contribution to blood lead is [is less than] 0.5%. Indirect evidence supporting the protective effect of calcium (calcium carbonate [+ or -] phosphorous phos·pho·rous adj. Of, relating to, or containing phosphorus, especially with a valence of 3 or a valence lower than that of a comparable phosphoric compound. ) comes from our longitudinal investigation on mobilization of lead from the maternal skeleton during pregnancy and lactation. In four pregnant subjects who were given calcium supplements (calcium carbonate or calcium citrate from the present study), minimal changes in blood lead concentration and isotopic composition were observed during pregnancy and lactation (40). Effect of type of supplement. Given the competition of calcium and lead, an additional factor contributing to the uptake of lead from the gastrointestinal tract is the relative absorption of calcium from different compounds. The absorption of calcium from calcium carbonate and calcium citrate alone is approximately 30% (41). The absorption may be higher for the complex product of calcium citrate/phosphate/chelate, but to our knowledge this has not been rigorously tested using isotopic tracing methods. Effect of state of the gut. Another important factor affecting gastrointestinal absorption is the relative condition of the gut--that is, whether it is in a fasted or nonfasted state. Tracer studies have demonstrated that in the absence of additional calcium, gastrointestinal absorption of lead was greater when lead was ingested in·gest tr.v. in·gest·ed, in·gest·ing, in·gests 1. To take into the body by the mouth for digestion or absorption. See Synonyms at eat. 2. by fasting subjects given soluble lead compounds in distilled water Noun 1. distilled water - water that has been purified by distillation H2O, water - binary compound that occurs at room temperature as a clear colorless odorless tasteless liquid; freezes into ice below 0 degrees centigrade and boils above 100 degrees centigrade; than when lead was ingested in the presence of food. Lead absorption in nonfasted subjects on either a normal diet or a controlled diet, in which nutritional content was known, ranged from approximately 3% to 10%, whereas lead absorption in fasted subjects who received soluble lead in distilled water (with no additional calcium) ranged from approximately 30% to 76% (20-24,33,34). The absence of calcium and other minerals in the gastrointestinal tract at the time of lead ingestion ingestion /in·ges·tion/ (-chun) the taking of food, drugs, etc., into the body by mouth. in·ges·tion n. 1. The act of taking food and drink into the body by the mouth. 2. is a major reason for increased lead absorption in fasting subjects compared with nonfasting subjects (20-24,33,34), although when calcium and other minerals are present, differences seen between fasting and nonfasting subjects essentially disappear (22,23,32). Effect of minerals on absorption. The presence of other minerals than calcium is an important factor in lead absorption from the gastrointestinal tract. For example, lead absorption decreases as calcium ([+ or -] phosphorous) concentrations increase (Figure 1) (20,22). Lead absorption in fasting subjects given lead chloride in drinking water drinking water supply of water available to animals for drinking supplied via nipples, in troughs, dams, ponds and larger natural water sources; an insufficient supply leads to dehydration; it can be the source of infection, e.g. leptospirosis, salmonellosis, or of poisoning, e.g. was reduced by 83% and 97% when the lead was given with calcium and phosphorous at intakes of 200 mg Ca + 140 mg P and 700 mg Ca + 500 mg P, respectively (22). Reductions in lead absorption and retention were noted with both calcium alone (as calcium carbonate) and phosphorous alone (as sodium phosphate sodium phosphate n. Any of various sodium salts of phosphoric acid, especially NaH2PO4, Na2HPO4, and Na3PO4, widely used in pharmaceutical manufacturing, medicine, and chemistry. ), but calcium was much more effective than phosphorous (20,22). The larger decreases in absorption for calcium phosphate calcium phosphate n. 1. A colorless deliquescent powder, Ca(H2PO4)2, used in baking powders, as a plant food, as a plastic stabilizer, and in glass. 2. compared with calcium carbonate observed by Blake and Mann (20) (Figure 1) may explain the absence of any effect of the complex product used in our study. Lead absorption and retention among infants and young children is also influenced by dietary calcium intake. For example, Ziegler et al. (42) observed an inverse relationship A inverse or negative relationship is a mathematical relationship in which one variable decreases as another increases. For example, there is an inverse relationship between education and unemployment — that is, as education increases, the rate of unemployment between dietary calcium and retention and lead absorption in young infants in metabolic balance studies. Dietary calcium and phosphorus were important predictors of blood lead concentrations in children 12-47 months of age from a low-income population in central Washington Central Washington is a region of the United States defined as the western half of Eastern Washington, or those counties lying east of the Cascade Mountains but west of the 119th meridian. , D.C. (43). Likewise, Sorrell et al. (44) and Johnson and Tenuta (45) observed inverse correlations between lead and calcium intake, vitamin D vitamin D Any of a group of fat-soluble alcohols important in calcium metabolism in animals to form strong bones and teeth and prevent rickets and osteoporosis. It is formed by ultraviolet radiation (sunlight) of sterols (see steroid) present in the skin. , and milk-based foods. Reductions in lead absorption were also noted in subjects ingesting different foods, depending on the calcium and mineral content of the ingested meal (24). Animal studies. Studies using fasted and nonfasted laboratory animals, including rats, mice, and monkeys, have produced results similar to those in humans (46-49). For example, Mahaffey-Six and Goyer (46) and Mahaffey et al. (47) reported that rats ingesting a low-calcium diet had blood lead concentrations approximately 4 times higher than rats consuming a normal calcium diet. Later studies showed that gastrointestinal absorption of lead decreases in the presence of a number of minerals (50-52). Increasing calcium concentrations were found to decrease lead retention exponentially as calcium concentrations, increased (49). As in the human studies, administration of phosphorous without calcium did not produce reductions in lead retention as great as that for calcium alone or for calcium with phosphorous (50). Effect of dosing regime. An additional protective effect associated with the complex product may come from its dosing regime. This supplement was to be taken 4 times daily including at bedtime because the fasting state is a time when most parathyroid hormone-mediated bone resorption occurs (26). The calcium carbonate was taken twice daily after meals. Heaney (26) recommended a daily dosing regime of 4 times because, although the amount of a mineral absorbed continues to rise with the intake, the percentage absorbed falls. Matrix effects. The minimal effects observed in our pilot study may also be caused partly by matrix effects of the products. In studies of fasted human subjects, lead was administered as dissolved salts or suspended in solution. Using absorption values for lead in a solution as representative of lead absorption from a complex matrix may produce an overestimate o·ver·es·ti·mate tr.v. o·ver·es·ti·mat·ed, o·ver·es·ti·mat·ing, o·ver·es·ti·mates 1. To estimate too highly. 2. To esteem too greatly. of lead absorption. Before absorption, lead must dissociate dis·so·ci·ate v. dis·so·ci·at·ed, dis·so·ci·at·ing, dis·so·ci·ates v.tr. 1. To remove from association; separate: from the compound to which it is bound. This may explain the difference between the complex calcium citrate and the calcium carbonate; the latter was in a chewable form and more easily absorbed. Effect of duration of investigations. The length of time over which a study is undertaken may also be an important factor in absorption of lead from the gastrointestinal tract. Unlike the investigations by Rabinowitz et al. (23,33), the other studies involving radioactive tracers radioactive tracer, n a molecule to which a radioactive atom has been attached so that it can be followed through a physiologic system with radiation detectors. were only of short duration--less than 7 days. Our treatment period was 6 months, but we were able to detect increases in isotopic composition for calcium carbonate supplement. Because calcium carbonate is the most popular supplement (53), the potential uptake of lead from this product should be verified in a more comprehensive investigation, especially of young children. Daily intake of lead from supplements. The amounts ingested from the two supplements of approximately 3 [micro]g Pb/day are more than half the current daily lead intake of less than 5 [micro]g Pb/day for the United States (19)--despite the temporal decrease in the amount of lead in supplements illustrated by Scelfo and Flegal (15). Lanphear and colleagues recently demonstrated that lead shows detrimental effects in children at blood concentrations as low as 2.5 [micro]g/dL (54). Hence, any source contributing 50% or more to lead exposure--especially in young children, with lead absorption greater than that of adults--requires investigation and monitoring. In conclusion, despite the fact that lead exposure from the calcium supplements tested in this study was approximately half the daily intake of lead, the contribution to blood lead concentration was minimal. However, the same may not apply to calcium-fortified foods. Furthermore, even though there is no discernible increase in blood lead concentration, there are significant changes in the isotopic composition of lead in blood arising from the calcium carbonate supplement, which indicate a limited input of lead from diet into the blood. Because calcium carbonate is the overwhelmingly most popular calcium supplement, the changes we have observed merit further investigation. The small contributions of lead from calcium supplements, however, should not discourage people from their usage given other significant benefits deriving from calcium. REFERENCES AND NOTES (1.) NIH. Osteoporosis and Fractures in Men. NIH Guide, Vol 25, No 39. PA-97-009. Bethesda, MD:National Institutes of Health, 1996. (2.) NIH Consensus Development Panel on Optimal Calcium Uptake. JAMA JAMA abbr. Journal of the American Medical Association 272:1942-1948 (1994). (3.) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes dietary reference intakes (DRIs), n.pl a set of nutritional guidelines concerning the intake of vitamins and minerals from food rather than supplements. . Food and Nutrition Food and Nutrition See also cheese; dining; milk. accubation Rare. the act or habit of reclining at meals. alimentology Medicine. thescience of nutrition. allotriophagy Pathology. Board, Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride fluoride, a salt of hydrofluoric acid; see hydrogen fluoride. See also fluoridation; fluorine. . Washington, DC:National Academic Press, 1997. (4.) Bucher HC, Guyatt GH, Cook RJ, Hatala R, Cook DJ, Lang JD, Hunt D. Effect of calcium supplementation on pregnancy-induced hypertension and preeclampsia. JAMA 275:1113-1117 (1996). (5.) Koo WW, Walters JC, Esterlitz J, Levine RJ, Bush AJ, Sibai B. Maternal calcium supplementation and fetal bone mineralization Mineralization The process by which the body uses minerals to build bone structure. Mentioned in: Rickets mineralization, n the bioprecipitation of an inorganic substance. . Obstet Gynecol 94:577-582 (1999). (6.) Mahaffey KR. Factors modifying susceptibility to lead toxicity. In: Dietary and Environmental Lead: Human Health Effects (Mahaffey KR, ed). Amsterdam:Elsevier, 1985;373-419. (7.) Goyer RA. Nutrition and metal toxicity. Am J Clin Nutr 61(Suppl):646S-650S (1995). (8.) Farias P, Borja-Aburte VH, Rios C, Hertz-Picciotto I, Rojas-Lopez M, Chavez-Ayala R. Blood lead levels in pregnant woman of high and low socioeconomic status socioeconomic status, n the position of an individual on a socio-economic scale that measures such factors as education, income, type of occupation, place of residence, and in some populations, ethnicity and religion. in Mexico City Mexico City Spanish Ciudad de México City (pop., 2000: city, 8,605,239; 2003 metro. area est., 18,660,000), capital of Mexico. Located at an elevation of 7,350 ft (2,240 m), it is officially coterminous with the Federal District, which occupies 571 sq mi . Environ Health Perspect 104:1070-1074 (1996). (9.) Hernandez-Avila M, Gonzalez-Cossio T, Palazuelos E, Romieu I, Aro A, Fishbein E, Peterson KE, Hu H. Dietary and environmental determinants of blood and bone lead levels in lactating lac·tate 1 intr.v. lac·tat·ed, lac·tat·ing, lac·tates To secrete or produce milk. [Latin lact postpartum postpartum /post·par·tum/ (post-pahr´tum) occurring after childbirth, with reference to the mother. post·par·tum adj. Of or occurring in the period shortly after childbirth. women living in Mexico City. Environ Health Perspect 104:1076-1082 (1996). (10.) Gulson BL, Mahaffey KR, Jameson CW, Mizon KJ, Korsch MJ, Cameron MA, Eisman JA. Mobilization of lead from the skeleton during the post-natal Period is larger than during pregnancy. J Lab Clin Med 131:324-329 (1998). (11.) Capar SG, Gould JH. Lead, fluorine fluorine (fl  `ərēn, –rĭn), gaseous chemical element; symbol F; at. no. 9; at. wt. 18.998403; m.p. −219.6°C;; b.p. −188.14°C;; density 1. and other elements in
bonemeal bone´meal`n. 1. ground bones, used as a fertilizer or as a component in animal feed; - it is high in phosphate content. Noun 1. supplements. J Assoc Off Anal Chem 62:1054-1061 (1979). (12.) Boulos BM, Smolinski A. Alert to users of calcium supplements as hypertensive agents hypertensive agents, n.pl the agents that reduce or control blood pressure. due to trace metal contaminants. Am J Hypertens 1:137S-142S (1988). (13.) Bourgoin BP, Evans DR, Cornett For the place in England, see . The cornett, cornetto or zink is an early wind instrument, dating from the Medieval, Renaissance and Baroque periods. It was used in what are now called alta capellas or wind ensembles. JR, Lingard SM, Quattrone AJ. Lead content in 70 brands of dietary calcium supplements. Am J Public Health 83:1155-1160 (1993). (14.) Rogan WJ, Ragan NB, Damokosh AL, Davolie C, Shaffer TR, Jones RL, Wilkens S, Heenehan MC, Ware JW, Henretig F. 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Difference in dietary intake of calcium phosphorus and iron of children having normal and elevated blood lead concentrations [Abstract]. J Nutr 106:7 (1976). (44.) Sorrell M, Rosen JF, Roginsky MR. Interactions of lead, calcium, vitamin D and nutrition in lead-burdened children. Arch Environ Health 32:160-164 (1977). (45.) Johnson NE, Tenuta K. Diets and blood leads of children who practice pica. Environ Res 18:369-376 (1979). (46.) Mahaffey-Six KR, Goyer RA. Experimental enhancement of lead toxicity by low dietary calcium. J Lab Clin Med 76:933-941 (1970). (47.) Mahaffey KR, Haseman JD, Goyer RA. Dose-response to lead ingested in rats fed low dietary calcium. J Lab Clin Med 83:92-100 (1973). (48.) Quarterman J, Morrison NJ, Humphries WR. The influence of high dietary calcium and phosphate on lead uptake and release. Environ Res 17:60-67 (1978). (49.) Meredith PA, Moore MR, Goldberg A. The effect of calcium on lead absorption in rats. Biochem J 16:531-537 (1977). (50.) Barltrop D, Khoo HE. The influence of nutritional factors on lead absorption. Postgrad Med J 51:795-799 (1975) (51.) Ragan HA. Effect of iron deficiency iron deficiency A relative or absolute deficiency of iron which may be due to chelation in the GI tract, loss due to acute or chronic hemorrhage or dietary insufficiency Sources Meat, poultry, eggs, vegetables, cereals, especially if fortified with iron; per the on the absorption and distribution of lead and cadmium cadmium (kăd`mēəm) [from cadmia, Lat. for calamine, with which cadmium is found associated], metallic chemical element; symbol Cd; at. no. 48; at. wt. 112.41; m.p. 321°C;; b.p. 765°C;; sp. gr. 8. in rats. J Lab Clin Med 90:700-706 (1977). (52.) Fine B, Barth A, Sheffet A, Levenhar MA. Influence of magnesium on the intestinal absorption of lead. Environ Res 12:224-227 (1976). (53.) Natural Resources Defense Council The Natural Resources Defense Council (NRDC) is a New York City-based, non-profit non-partisan international environmental advocacy group, with offices in Washington, D.C., San Francisco, Los Angeles, Chicago, and Beijing. Founded in 1970, NRDC today has 1. News Release. NRDC NRDC Natural Resources Defense Council NRDC National Research and Development Centre (Institute of Education, London) NRDC National Realty & Development Corp. reaches legal settlement with largest calcium supplement manufacturer to provide "lead-free" calcium. New York New York, state, United States New York, Middle Atlantic state of the United States. It is bordered by Vermont, Massachusetts, Connecticut, and the Atlantic Ocean (E), New Jersey and Pennsylvania (S), Lakes Erie and Ontario and the Canadian province of :Natural Resources Defense Council, 27 January 1997. (54.) Lanphear BP, Dietrich KN, Auinger P, Cox C. Subclinical subclinical /sub·clin·i·cal/ (sub-klin´i-k'l) without clinical manifestations. sub·clin·i·cal adj. Not manifesting characteristic clinical symptoms. Used of a disease or condition. lead toxicity in U.S. children and adolescents [Abstract]. Pediatr Res 47:894 (Part 2, suppl) (2000). Brian L. Gulson,(1,2) Karen J. Mizon,(1,2) Jacqueline M. Palmer,(2) Michael J. Korsch,(2) and Alan J. Taylor(3) (1) Graduate School of the Environment, Macquarie University, Sydney, Australia; (2) CSIRO/Division of Exploration and Mining, North Ryde, Australia; (3) Department of Psychology, Macquarie University, Sydney, Australia Address correspondence to B.L. Gulson, Graduate School of the Environment, Macquarie University, Sydney NSW NSW New South Wales Noun 1. NSW - the agency that provides units to conduct unconventional and counter-guerilla warfare Naval Special Warfare 2109 Australia. Telephone: 61 2 9850 7983. Fax: 61 2 9850 7972. E-mail: bgulson@gse.mq.edu.au We thank M. Salter salt·er n. 1. One that manufactures or sells salt. 2. One that treats meat, fish, or other foods with salt. Noun 1. for phlebotomy Phlebotomy Definition Phlebotomy is the act of drawing or removing blood from the circulatory system through a cut (incision) or puncture in order to obtain a sample for analysis and diagnosis. , the participants in this study, and R. Setright of Blackmores for supplying one of the products. Received 24 August 2000; accepted 13 October 2000. |
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