Metabolism of lead-210 in juvenile and adult rhesus monkeys (Macaca mulatta)

Summary Experiments were conducted measuring the gastrointestinal absorption and elimination of a single dose of lead-210 acetate in infant and adult rhesus monkeys. Urinary and fecal excretion of absorbed lead was followed for 23 days. Infant monkeys eliminated less and absorbed more orally administered lead. Adult animals excreted more absorbed lead in feces, while urinary excretion between adults and infants was similar. Increased absorption of administered lead and reduced fecal excretion of absorbed lead resulted in significantly greater body burden of lead-210 in infant animals. Blood lead values were increased in the infant animals, and were inversely correlated with body burden and percent absorption of ingested lead.     

The effect of milk diet on lead metabolism in rats

The effect of milk on lead absorption and retention was studied in four groups of 6-wk-old female rats after a single oral or intraperitoneal application of lead-203. The animals were fed different diets for 2 wk (1 wk prior and 1 wk after the radiolead application). All animals receiving milk diet or milk additives showed a higher intake of fats and proteins and a lower intake of carbohydrates, vitamin D, and iron than control rats fed on normal diet. The calcium, phosphate, and calorie intake was about the same in all groups.The body retention of the orally applied lead-203 was much higher in animals on milk diet (4 times higher in rats on normal diet and cow's milk; 57 in animals on cow's milk; 33 times in rats on powdered milk) than in controls. The milk diet had only a slight effect on the whole body retention of lead-203 after intraperitoneal application (1.3 and 1.2 times higher in rats on cow's and powdered milk, respectively).This indicates that milk causes considerable enhancement of lead retention in the body mainly by greatly increasing its absorption from the intestinal tract.     

Calculation of zinc absorption in humans using tracers by fecal monitoring and a compartmental approach

Zinc absorption is often determined following oral administration of tracer by fecal monitoring as dose minus tracer excreted in feces. The value obtained for absorption with this method is influenced by excretion of absorbed tracer into feces during the fecal collection period and by any incomplete elimination of unabsorbed tracer. In the present study a published, physiologically based compartmental model of zinc metabolism has been used to calculate, after oral tracer administration, the fecal appearance of unabsorbed and absorbed tracer and the appearance when fractional rates of endogenous excretion and elimination were varied. Absorption was determined by fecal monitoring and compared to the value determined using parameter values of the compartmental model. The value calculated for absorption using fecal monitoring varied with length of fecal collection, rate of excretion of absorbed tracer (secretion) and rate of elimination of unabsorbed tracer. Absorption was determined correctly by fecal monitoring only when the amount of absorbed tracer excreted was equivalent to the amount of unabsorbed tracer remaining in the gut. Fecal monitoring determines a parameter representing the combined processes of absorption, endogenous excretion (or secretion) and fecal elimination.     

Biochemical changes and essential metals concentration in lead-intoxicated rats pre-exposed to ethanol.

The effects of chronic lead exposure on some hematopoietic and hepatic biochemical indices and urine, feces, and tissue essential metal concentration were investigated in rats pre-exposed to different doses of ethanol. Exposure to ethanol (0.5, 1.0, and 2.0 g/kg intraperitoneally, once daily) for 4 weeks produced an inhibition of blood delta-aminolevulinic acid dehydratase (ALAD) activity and a decrease in hepatic glutathione (GSH) concentration. Ethanol ingestion also produced a dose-dependent elevation of hepatic lipid peroxidation. Blood and hepatic calcium and hepatic magnesium contents decreased and urinary Ca and fecal Ca and Mg contents increased significantly following 4-week exposure to ethanol (2 g/kg). Lead administration (10 mg/kg, orally) for 4 weeks in ethanol pre-exposed (2 g/kg) animals produced a more pronounced inhibition of blood ALAD and elevation of urinary delta-aminolevulinic acid (ALA) excretion and hepatic GSH contents. Hepatic GSH contents decreased and hepatic lipid peroxidation increased significantly in rats given lead and pre-exposed to ethanol (2 g/kg). A more pronounced depletion of blood Ca and Mg and hepatic Mg was observed along with significant elevation of urinary Mg and fecal Ca excretion in animals administered lead and pre-exposed to ethanol (2 g/kg). The results suggest that nutritional deficiencies, particularly depletion of body Ca and Mg levels, play an important role in increasing susceptibility to lead intoxication in the rat.     

Oral succimer decreases the gastrointestinal absorption of lead in juvenile monkeys.

Although succimer (Chemet, meso-2,3-dimercaptosuccinic acid, DMSA) is considered to be a safe and effective chelating agent for the treatment of lead poisoning in humans, there is concern that it may increase the gastrointestinal (GI) absorption and retention of Pb from exposures suffered concurrent with treatment. This concern is justified because the availability of Pb-safe housing during outpatient treatment with oral succimer is limited. We used a juvenile nonhuman primate model of moderate childhood Pb intoxication and a sensitive double stable Pb isotope tracer methodology to determine whether oral succimer chelation affects the GI absorption and whole-body retention of Pb. Infant rhesus monkeys (n = 17) were exposed to Pb daily for 1 year postpartum to reach and maintain a target blood lead (BPb) level of 35-40 microg/dL. Animals were administered succimer (n = 9) or vehicle (n = 8) over two successive 19 day succimer treatment regimens beginning at 53 and 65 weeks of age. The present study was conducted over the second chelation regimen only. Animals received a single intravenous (iv) dose of stable (204)Pb tracer (5 microg, 24.5 nmol) followed by a single oral dose of stable (206)Pb tracer (72.6 microg, 352 nmol) immediately before chelation, in order to specifically evaluate GI Pb absorption and whole-body Pb retention with treatment. We collected complete urine and fecal samples over the first 5 days and whole blood over the first 8 days of treatment for analyses of stable Pb isotopes using magnetic sector inductively-coupled plasma mass spectrometry. Results indicate that succimer significantly reduced the GI absorption of Pb (vehicle, 64.9% +/- 5.5; succimer, 37.0% +/- 5.8; mean +/- SEM). Succimer also significantly increased the urinary excretion of endogenous Pb by approximately 4-fold over the vehicle treatment, while endogenous fecal Pb excretion was decreased by approximately 33%. Finally, although succimer reduced the whole-body retention of endogenous Pb by approximately 10% compared to vehicle, the majority (77%) of the administered internal dose of Pb tracer was retained in the body when assessed after 5 days of treatment. These data do not support the concern that succimer treatment increases GI Pb absorption.     

Intestinal absorption and excretion of zinc in streptozotocin-diabetic rats as affected by dietary zinc and protein

65Zn was used to examine the effects of dietary zinc and protein on true zinc absorption and intestinal excretion of endogenous zinc by an isotope dilution technique in streptozotocin-diabetic and control rats. Four groups each of diabetic and control rats were fed diets containing 20 ppm Zn, 20% egg white protein (HMHP); 20 ppm Zn, 10% egg white protein (HMLP); 10 ppm Zn, 20% egg white protein (LMHP); and 10 ppm Zn, 10% egg white protein (LMLP). Measurement of zinc balance was begun 9 d after an i.m. injection of 65Zn. True zinc absorption and the contribution of endogenous zinc to fecal zinc excretion were calculated from the isotopically labeled and unlabeled zinc in the feces, duodenum and kidney. Results from the isotope dilution study indicated that diabetic rats, but not control rats, absorbed more zinc from 20 ppm zinc diets than from 10ppm zinc diets and that all rats absorbed more zinc from 20% protein diets than from 10% protein diets. Furthermore, all rats excreted more endogenous zinc from their intestines when dietary zinc and protein levels resulted in greater zinc absorption. In diabetic and control rats, consuming equivalent amounts of zinc, the amount of zinc absorbed was not significantly different, but the amount of zinc excreted by the intestine was less in the diabetic rats. Decreased intestinal excretion of endogenous zinc may be a homeostatic response to the increased urinary excretion of endogenous zinc in the diabetic rats and may also lead to the elevated zinc concentrations observed in some organs of the diabetic rats.     

EFFECTS OF CALCIUM SODIUM ETHYLENEDIAMINETETRA - ACETATE ON THE KINETICS OF DISTRIBUTION AND EXCRETION OF LEAD IN THE RAT

The effects of calcium sodium ethylenediaminetetra-acetate (CaNa₂EDTA) on the kinetics of distribution and excretion of lead (²¹⁰Pb) have been studied in rats. When the chelant was given intravenously, at 50 mg./rat daily after a single intravenous injection of 100 μg. lead/rat, it greatly increased the urinary excretion of lead but reduced the faecal excretion. The greatest effects occurred in the rats treated with chelant shortly after the lead injection. When the chelant was given seven or more days after the lead the increase in lead excretion was negligible. CaNa₂EDTA mobilized lead from every tissue, but the kinetic analysis of the disappearance of ²¹⁰Pb showed the presence of two elimination phases. Lead ions weakly bound to the cells were rapidly removed by EDTA, whereas the lead fixed to endocellular constituents was only slowly removed. The chelant did not mobilize lead from bone.

Probably CaNa₂EDTA entered the extravascular space but not the cells. Hence it only accelerated the passage of lead from the cells by lowering the concentration of lead outside them.

²¹⁰Pb was also given orally in doses of 500 μg. lead/rat. About 18% of the dose was absorbed through the intestine to be distributed in all tissues. Rats treated orally with CaNa₂EDTA showed an increase in urinary lead excretion and a reduction in lead fixed in the body.

     

Comparative absorption of [13C]glucose and [13C]lactose by premature infants

Oxidation of orally administered [13C]glucose and [13C]lactose and fecal recovery of malabsorbed substrates were determined in two groups of premature infants. Eighteen studies were performed with six infants at Johns Hopkins Hospital (JHH); 24 studies were performed with nine infants at Columbus Children's Hospital (CCH). The two groups differed in that JHH infants had shorter gestations but were older when studied. Fecal 13C loss after [13C]glucose administration did not differ between the two groups. Compared with glucose, the metabolism of lactose appeared to involve more malabsorption and colonic fermentation in JHH infants than in CCH infants and resulted in higher fecal losses of substrate carbon. Maturation appeared to involve increased proximal intestinal absorption and greater retention of absorbed carbohydrate. Simultaneous absorption of substrate from the small and large intestine may limit the usefulness of breath tests for 13C in the premature infant.     

A study on the urinary and fecal excretion of furazolidone in rats by means of mutagenicity assays

The urinary and fecal excretion of furazolidone in rats was studied by means of mutagenicity assays: when animals received a single dose by gavage (1 to 10 mg/100 g body wt) the mutagenic activity recovered in urines accounted for less than 0.1% of the administered dose and quickly disappeared. After prolonged (1 week) treatments, however, some mutagenicity was retained in urine concentrates until the fifth to seventh days. Similarly the fecal excretion of mutagenicity accounted for less than 0.1% of the administered dose and disappeared within the third day. The efficient deactivation of furazolidone observed in vivo was shown to be unaffected by the amount of gut bacteria in treated animals; in in vitro experiments it turned out to be actively performed by a rat intestine homogenate fraction, working more efficiently under hypoxic conditions.     

Dysprosium as a nonabsorbable fecal marker in studies of zinc homeostasis

BACKGROUND: Dysprosium is a nonabsorbable rare earth element that has had successful application as a marker for fecal excretion of unabsorbed zinc. OBJECTIVE: Our goals were 1) to evaluate the efficacy of administering dysprosium with all meals over several days as a method of determining the completeness of fecal collections, 2) to determine the similarity of gastrointestinal transit kinetics and excretion patterns of dysprosium and zinc tracer administered simultaneously over several days, and 3) to evaluate alternative methods of using the data for fecal excretion of orally administered zinc tracer and dysprosium to measure the fractional absorption of zinc. DESIGN: 70Zn and dysprosium were administered orally with all meals for 5 consecutive days to 7 healthy, free-living adults consuming a constant diet based on habitual intake. Additional tracers, 67Zn and 68Zn, were administered intravenously. Urine and fecal samples were collected during tracer administration and for 8 d after the last dose. Isotope ratios were measured in urine and feces, and total zinc and dysprosium were measured in fecal samples. RESULTS: The mean recovery of dysprosium was 101.3 +/- 2.4%. The zinc oral tracer and dysprosium had similar fecal excretory patterns; the correlation coefficient for 70Zn and dysprosium in fecal samples exceeded 0.99 (P < 0.0001) for each subject. Fractional zinc absorption measurements using various dysprosium methods correlated well (r > 0.95) with those from the fecal monitoring and dual-isotope-tracer ratio methods. CONCLUSION: Administration of dysprosium is a useful means of determining the completeness of fecal collections and of measuring zinc absorption.     

Copper absorption in healthy young men: studies with stable isotope 65Cu and neutron activation analysis

1. A method based on Radiochemical Neutron Activation Analysis (RNAA) was developed to measure accurately fecal excretion of both stable isotopes (⁶³Cu, ⁶⁵Cu) of copper in human stools simultaneously. 2. It was shown that analysis of isotopic content of human feces could be carried out with analytical precisions (coefficient of variation) within ±1-2% which is necessary if stable isotopes of copper are to be employed in human metabolic studies. 3. Kinetics of fecal excretion of single or multiple doses of ingested ⁶⁵Cu (enrichment 99.69%) were examined in four healthy young adults and it was shown that re-entry of the absorbed dose into the GI tract could be detected. 4. Limited data on absorption of ⁶⁵CuCl₂ administered in the postabsorptive state were obtained for four healthy young adults and the results were discussed in relation to other reported values of copper absorption.     

The effect of depot parenteral zinc on copper metabolism in the rat

The effect of depot parenteral injections of zinc (110 mg Zn/kg body weight) on copper metabolism in young, male rats was investigated. Individually caged rats, fed known amounts of stock diet and deionized-distilled water, were injected s.c. weekly for the first 4 weeks and biweekly for the next 17 weeks with zinc in sesame oil or the oil vehicle only. No significant differences in body weight, hemoglobin, hematocrit and fecal copper excretions were observed between treatments. However, 2 weeks after the initial injections, urinary copper excretion was elevated in the zinc-injected animals and remained elevated throughout the rest of the study. Plasma copper concentrations were significantly higher in the zinc-injected animals from week 2 to 8 of the study, and plasma zinc concentrations of these injected animals were elevated (P less than 0.05) from week 2 and throughout the remainder of the study. Zinc concentrations were significantly higher in the liver, heart, kidney and spleen (P less than 0.05) and copper concentrations were lower in the liver (P less than 0.07), kidney and spleen (P less than 0.05) of zinc-injected animals compared to the vehicle-treated control animals. The data indicate that when zinc is administered by a non-gastrointestinal route, the fecal excretion of copper, the major route of copper excretion, is not altered. Thus, a negative copper balance is not initiated by high levels of zinc administered by the depot technique, in contrast to the negative copper balance stimulated by the gastrointestinal administration of zinc.     

Excretion of tetramethyllead, trimethyllead, dimethyllead and inorganic lead after injection of tetramethyllead to rabbits

Rabbits were divided to groups of 3, and injected either 9.9 mg of tetramethyllead (Me4Pb)/kg of body weight (7.7 mg Pb/kg) or 39.7 mg/kg (30.8 mg Pb/kg) into the ear vein once only, respectively, and urinary and fecal excretions of lead were studied for chemical species and total lead during the following 7 days. In the group injected 9.9 mg/kg, the urinary total lead excretion was composed of about 73% dimethyllead (Me2Pb2+), about 19% trimethyllead (Me3Pb+), about 6% inorganic lead (Pb2+), and about 2% Me4Pb on the day following the injection, and 100% Me3Pb+ 7 days after the injection. In the group injected 39.7 mg/kg, the urinary total lead excretion was composed of about 67% Me2Pb2+, about 14% Me3Pb+, about 17% Pb2+, and about 2% Me4Pb on the day following the injection, and about 8% Me2Pb2+, about 74% Me3Pb+, about 17% Pb2+, and about 1% Me4Pb 7 days after the injection. In both groups, the fecal total lead excretion during 7 days after the injection was entirely composed of Pb2+. During the 7 days, 1-3% of either administered dose was excreted in the urine, and 7-19% in the feces. The urinary total lead excretion in the rabbits injected Me4Pb was similar to that in the rabbits injected tetraethyllead, but the fecal total lead excretion in the former was extremely smaller. This extremely small fecal excretion of total lead appeared to have resulted from the less elimination of lead into the bile of Me4Pb-injected rabbits.     

Intestinal absorption of cholecalciferol and 25-hydroxycholecalciferol in chronic cholestatic liver disease

We compared the absorption of cholecalciferol and 25-hydroxycholecalciferol in normal subjects and in patients with mild and severe cholestatic liver disease. 3H-cholecalciferol and 3H-25-hydroxycholecalciferol were given orally and serial blood samples were drawn for measurement of the serum level of radiolabeled vitamin. Absorption of 25-hydroxycholecalciferol peaked earlier and was greater than absorption of cholecalciferol at all times in all three groups. Patients with mild cholestasis (normal bilirubin and fecal fat excretion) absorbed both forms of the vitamin normally. Those with severe cholestasis (jaundice and steatorrhea) had minimal absorption of cholecalciferol but relatively preserved absorption of 25-hydroxycholecalciferol. Absorption of cholecalciferol and 25-hydroxycholecalciferol was inversely related to fecal fat excretion. The superior absorption of 25-hydroxycholecalciferol may partly explain its greater efficacy in oral treatment of vitamin D deficiency in patients with severe cholestasis.     

Chlorella accelerates dioxin excretion in rats.

We investigated the effects of Chlorella on fecal excretion of polychlorinated dibenzo-p-dioxin (PCDD) congeners and polychlorinated dibenzofuran (PCDF) congeners in Wistar rats administered the rice oil that caused Yusho disease, as a substitute for purified dioxin. The rats were fed 4 g of a control diet or a 10% Chlorella diet containing 0.2 mL of the rice oil once during the 5-d experimental period. The amounts of PCDD and PCDF congeners excreted in feces from d 1 to 5 in the group fed 10% Chlorella were 0.2-11.3 and 0.3-12.8 times greater (P < 0.05), respectively, than those of the control group. We then investigated the fecal excretion of PCDD and PCDF congeners from d 8 to 35 in rats administered 0.5 mL of the rice oil. Rats consumed the basal diet for 1 wk. After 1 wk, they consumed either the basal diet or the 10% Chorella diet. The fecal excretions of PCDD and PCDF congeners in the group fed 10% Chlorella were 0.3-3.4 and 0.5-2.5 times greater (most, P < 0.05), respectively, than those of the control group. Thus, the fecal excretions of PCDD and PCDF congeners were greater in rats fed Chlorella. These findings suggest that the administration of Chlorella may be useful in preventing gastrointestinal absorption and for promoting the excretion of dioxin already absorbed into tissues. Moreover, these findings suggest that Chlorella might be useful in the treatment of humans exposed to dioxin.     

Calcium metabolism in fed and fasted lead-treated animals.

Calcium metabolism was studied in 5-week-old, fed and fasted female albino rats which received 20 (or 23) mg of lead (as acetate) by gastric intubation daily during 1 week. On the seventh day of the experiment all animals were given 1 μCi of calcium-47, alone or together with lead acetate by the same route. Calcium-47 absorption (i.e., carcass plus total urine activity) was significantly higher and its fecal excretion lower in all fasted than in the fed animals. However, the lead effect appears to be the same for both the fed and the fasted animals. Lead treatment slightly increased calcium absorption (0.05>P>0.02) only in the fed animals which received calcium-47 together with lead acetate, but there was no significant difference in calcium metabolism between the two experimental groups. The method of radiocalcium administration—separately or together with lead acetate—did not affect calcium metabolism.     

Fractional intestinal absorption of magnesium is directly proportional to dietary magnesium intake in rats

The precise mechanisms of intestinal Mg absorption are still unclear and the possibility of an adaptative rise in the fraction of Mg absorbed as Mg intake is lowered is controversial. Mg deficiency has been studied extensively in rats where it is readily produced by dietary depletion. In this study, we investigated the effect of Mg intake on fractional absorption of Mg acutely and after adaptation to graded Mg intake in rats. For this purpose, male Wistar rats (n = 30) were fed a basal semipurified diet containing 600 mg Mg/kg (MgO) for 7 d. Three groups of 10 rats were then formed and fed the basal semipurified diet with 600, 300 or 150 mg Mg/kg, for 28 d. Apparent and true intestinal absorptions and fecal endogenous excretion of Mg were determined at the beginning and end of the experiment. As expected, plasma Mg levels were lower in the deficient groups than in the control by d 4 and differences were more marked at the end of the experiment. Erythrocyte Mg levels were significantly lower at the end of the experiment in the group fed the diet containing 150 mg Mg/kg. The amounts of Mg absorbed were directly proportional to the dietary Mg intakes in all three experimental groups at both testing periods. This indicated that the apparent and true intestinal absorption percentages of Mg were not different in rats fed the three different levels of dietary Mg. These results also show that fecal endogenous excretion of Mg was nearly directly proportional to the dietary Mg intakes. These results argue in favor of a passive diffusional process for intestinal Mg absorption.     

Effect of vitamin D and low dietary calcium on lead uptake and retention in rats

The effects of cholecalciferol (formerly vitamin D-3) supplementation and alterations in dietary calcium levels on intestinal 210Pb absorption and tissue uptake were studied in weanling female Sprague-Dawley rats. Rats were placed in one of three groups: 1) normal dietary calcium with normal cholecalciferol; 2) low dietary calcium with normal cholecalciferol; or 3) normal dietary calcium with cholecalciferol supplementation. Blood 210Pb levels were determined at 3, 6, 12 and 24 hours following the administration of either an oral or an IP dose of 210Pb. Femur and kidney 210Pb activities were subsequently determined for all animals 24 hours after the administration of 210Pb. Cholecalciferol supplementation resulted in increased net intestinal absorption of 210Pb with uptake into femurs and kidneys. The effect of cholecalciferol to increase tissue uptake of 210Pb was shown to be independent of the effect of cholecalciferol on the gastrointestinal absorption of lead. A lowering of dietary calcium was shown to increase lead absorption with uptake into femurs; however, this increased tissue uptake of lead was shown to be dependent upon increased intestinal lead absorption and was not a direct effect of the low calcium diet.     

体内外实验测定淀粉的消化吸收特性

目的　采用体内外实验测定方法比较不同性质的淀粉 ,即可消化淀粉 (DS)和抗性淀粉 (RS)的消化吸收特性。方法　根据Englyst方法采用体外消化实验方法测定了 4种淀粉样品中DS、RS含量 ,再采用十二指肠灌注法直接将DS、RS注入到大鼠十二指肠 ,观察 4h内血糖变化 ,另采用代谢实验方法观察RS对碳水化合物和氮表观吸收率的影响 ,以及对消化酶分泌的影响。结果　体外实验表明 ,4种淀粉样品中以普通市售玉米淀粉DS含量最高 ,而马铃薯淀粉中 76 %为不消化的RS。动物实验表明 ,DS在十二指肠灌注后1 2 0min内血糖达到最大峰值 ;RS吸收相对缓慢 ,但总表观吸收率仍可达 96 %以上。另外RS可促进粪氮排出 ,降低氮表观吸收率 ,并可改变胃液和胃蛋白酶分泌。结论　利用体内外实验方法证明RS吸收缓慢但相对完全 ,部分佐证了Englyst以消化时间 1 2 0min作为界定DS和RS的方法     

Use of mathematical modeling to study copper metabolism in humans

BACKGROUND: An improved understanding of copper metabolism is needed to derive more precise estimates of dietary requirements. OBJECTIVES: The objectives were to validate a method for estimating endogenous losses of copper, test whether a simple model can predict true absorption from the plasma appearance of labeled copper, and develop a compartmental model for copper metabolism by using stable isotopes. DESIGN: A stable isotope of copper was intravenously administered to 6 men, and fecal samples were collected for 14 d. Four weeks later the study was repeated, but with an oral dose, and blood samples were collected for 7 d and fecal samples for 14 d. RESULTS: There was no significant difference (P = 0.48) in the estimated endogenous loss of copper calculated by using either the excreted intravenous dose (x +/- SD: 32 +/- 5%) or the absorbed and excreted oral dose (35 +/- 2%). A simple mathematical model fitted to plasma isotope appearance data estimated true absorption to be 8 +/- 2% compared with 48-49% measured by fecal monitoring. A more complicated compartmental model predicted that, when newly absorbed copper first enters the blood, 74% is removed by the liver and 99% is bound to ceruloplasmin in the plasma. The exchangeable pool of copper was estimated to be 43 +/- 30 mg. Daily endogenous losses were predicted to be 2.4 mg. CONCLUSIONS: The results showed that fecal monitoring is the only method that can reliably measure labeled copper absorption, and it is not necessary to administer an intravenous dose of copper to estimate endogenous losses. The compartmental model provides new insights into human copper metabolism.