External gamma-ray counting of selected tissues from a Thorotrast patient.

Results of gamma-ray measurements of selected tissues from a patient who was injected with Thorotrast almost 36 y ago are reported. The purposes of this study were: 1) to determine the relative tissue distribution and activities of specific radionuclides in the 232Th decay chain, specifically 228Ra (as measured by 228Ac), 212Pb, and 224Ra (measured directly and as measured by 212Pb), and 2) to evaluate the level of radioactive disequilibrium among the daughter products. The spleen and liver had the highest concentrations of radioactivity. Bone also appears to be a long-term sink for 232Th daughter products based on estimates from a small portion of one rib. Larynx and esophagus contained measurable activity, which may have been due to their proximity to the "Thorotrastoma." Radioactivity in the remaining measured tissues were low, as expected. Secular equilibrium could be demonstrated in bone, pancreas, larynx, esophagus, and breast. Significant disequilibrium was observed for spleen, liver, kidney, and red blood cells. Radioactivity measurements reported here will be useful in estimating radiation doses to selected tissues. Such dose estimates are valuable in refining current risk estimates (e.g., liver) and in identifying tissues at risk for further epidemiologic studies. These results, while consistent with other published studies, should be interpreted with caution since measurements were made on only one patient.

Kinetic analysis of zinc metabolism in humans after simultaneous administration of 65Zn and 70Zn.

Zinc kinetics were studied and compared after oral simultaneous administration of two tracers, radioactive (65Zn) and stable (70Zn) isotope, to four normal human volunteers. Both tracers and zinc concentration were measured in plasma, red blood cells (RBC), urine, and feces for up to 78 days. Radioactive zinc was also measured by external counting over whole body, liver, and thigh. Data from each individual were analyzed using a compartmental model for zinc metabolism. Values calculated for absorption, fractional zinc excretion in urine, exchange with RBC, and secretion into gut using 70Zn data did not differ from values calculated using 65Zn data. Results show that human zinc metabolism can be investigated using stable isotopes as tracers to determine parameters of whole body zinc metabolism, including zinc absorption, excretion, and secretion.

Kinetic analysis of zinc metabolism and its regulation in normal humans.

Zinc metabolism was studied in 32 normal volunteers after oral (n = 25) or intravenous (n = 7) administration of 65Zn. Data were collected from the blood, urine, feces, whole body, and over the liver and thigh regions for 9 mo while the subjects consumed their regular diets (containing 10 mg Zn ion/day) and for an additional 9 mo while the subjects received an exogenous oral supplement of 100 mg Zn ion/day. Data from each subject were fitted by a compartmental model for zinc metabolism that was developed previously for patients with taste and smell dysfunction. These data from normal subjects were used to determine the absorption, distribution, and excretion of zinc and the mass of zinc in erythrocytes, liver, thigh, and whole body. By use of additional data obtained from the present study, the model was refined further such that a large compartment, which was previously determined to contain 90% of the body zinc, was subdivided into two compartments to represent zinc in muscle and bone. When oral zinc intake was increased 11-fold three new sites of regulation of zinc metabolism were identified in addition to the two sites previously defined in patients with taste and smell dysfunction (absorption of zinc from gut and excretion of zinc in urine). The three new sites are exchange of zinc with erythrocytes, release of zinc by muscle, and secretion of zinc into gut. Regulation at these five sites appears to maintain some tissue concentrations of zinc when dietary zinc increases.

Zinc metabolism in adrenal cortical insufficiency: effects of carbohydrate-active steroids.

Detailed studies of zinc kinetics were performed in two patients with adrenal cortical insufficiency to investigate the effects of carbohydrate-active steroids (CAS) on zinc metabolism. Zinc- 69m was administered intravenously to each patient under two conditions: (1) treated with CAS replacement therapy and (2) untreated, ie, without hormone treatment for five to six days. Radioactivity was measured in blood plasma, red blood cells, urine, and stool and by means of external probes placed over liver and thigh. Data were analyzed using a previously developed multicompartmental model, which describes the early phase of zinc metabolism. The results of these studies suggest that CAS promotes the internalization of zinc into red blood cells and liver cells. These results are consistent with previous in vitro and in vivo studies in which CAS was shown to induce the synthesis of metallothionein in liver cells.

Metabolism of human apolipoproteins A-I and A-II: compartmental models.

The metabolism of radioiodinated apolipoproteins (apo) A-I and A-II have been examined using the techniques of compartmental modeling. The model for apoA-I contains two plasma compartments decaying at different rates. One component of apoA-I has a residence time of 3.8 days and the second has a residence time of 6.1 days. In contrast, the apoA-II model has only one plasma component, with a residence time of 5.5 days, which decays through two distinct pathways. Twenty-seven percent of apoA-II decays through a pathway that takes 1.1 days longer to reach the urine than the remaining 73% which decays through the more direct path. These differences in the metabolism exist in both male and female populations. Comparison of fasting and nonfasting concentrations of apoA-I revealed that apoA-I concentration was elevated 0.5 standard deviations in the nonfasting samples while there was no significant difference in the apoA-II concentrations. The fasting apoA-I concentrations were found to be less stable over the study period when compared to fasting apoA-II concentrations. These findings are interpreted as indicating that apoA-I and apoA-II each have a separate metabolism which overlaps when they are present on the same lipoprotein particle. Furthermore, these findings are consistent with the concept that apoA-I metabolism is influenced more by perturbations such as dietary modulation.

Human apolipoprotein A-I and A-II metabolism.

The kinetics of the major apolipoproteins (apo) of plasma high density lipoproteins (HDL), apoA-I and apoA-II, were examined in a total of 44 individual tracer studies in 22 normal male and female subjects. Following the intravenous injection of radioiodinated HDL, the specific radioactivity decay of apoA-I within HDL (residence time, 5.07 +/- 1.53 days), as determined by column chromatography, was significantly (P < 0.01) faster than that of apoA-II (residence time, 5.96 +/- 1.84 days). The specific radioactivity decay of apoA-I within HDL when labeled on HDL or as apoA-I was found to be almost identical. Similar results were obtained for apoA-II. Analysis of simultaneous paired radiolabeled apoA-I and apoA-II studies revealed that the mean apoA-I plasma residence time (4.46 +/- 1.04 days) was significantly (P < 0.01) shorter than that for apoA-II (4.97 +/- 1.06 days). Females had significantly (P < 0.01) higher apoA-I plasma concentrations (124 +/- 24 mg/dl) and apoA-I synthesis rates (13.58 +/- 2.23 mg/kg. day) than did males (108 +/- 16 mg/dl, and 11.12 +/- 1.92 mg/kg. day, respectively). Plasma apoA-I levels were correlated with plasma apoA-I residence times, but not synthesis rates; and apoA-II concentrations were correlated only with apoA-II whole body residence times. ApoA-I and apoA-II plasma residence times were inversely correlated with plasma triglyceride levels. These data are consistent with the following concepts: 1) labeling of apoA-I and apoA-II as apolipoproteins or on HDL does not affect their specific radioactivity decay within HDL; 2) the mean residence time of apoA-I both in plasma and in HDL is significantly shorter than that of apoA-II; 3) the increased apoA-I levels seen in female subjects are due to increased apoA-I synthesis; and 4) the plasma apoA-I residence time, which is inversely correlated with plasma triglyceride levels, is an important determinant of apoA-I concentration in both males and females.-Schaefer, E. J., L. A. Zech, L. L. Jenkins, T. J. Bronzert, E. A. Rubalcaba, F. T. Lindgren, R. L. Aamodt, and H. B. Brewer, Jr. Human apolipoprotein A-I and A-II metabolism.

Effects of oral zinc loading on zinc metabolism in humans--I: Experimental studies.

The effects of oral zinc on distribution, retention and excretion of orally administered 65Zn were studied in 50 patients with taste and smell dysfunction. The study was conducted in three phases. In the first phase all patients were studied for 21 days after receiving 3-18 microCi of 65Zn as ZnCl2 orally after an overnight fast. In the second phase, started after 21 days and continued for 290 to 440 (mean 336) days, all 50 patients received placebo for ZnSO4. In the third phase 14 patients continued on placebo while 36 received ZnSO4 (100 mg/day Zn++) for 112 to 440 (mean 307) days. Phases two and three were a controlled clinical trial of the effects of zinc on retention of 65Zn tracer. Total body retention and activity in plasma and red cells were measured for all patients throughout the study. Ten of the 36 patients treated with ZnSO4 had additional measurements of 65Zn activity in liver and thigh made using external detectors. Total body retention during the second phase placebo period was not significantly different (p greater than 0.25) for the 36 subjects subsequently treated with ZnSO4 (biological half-time (Tb) 378 +/- 12 days) (mean +/- SEM) and the 14 who were continued on placebo through the third phase of the study (Tb = 384 +/- 8 days). During the third phase patients receiving ZnSO4 showed an accelerated loss of total body 65Zn (Tb = 235 +/- 8 days) which was significantly different (p greater than 0.001) from half-time values during placebo treatment. Accelerated loss of 65Zn from the thigh was apparent immediately while that from the liver began after a mean delay of 107 days. There was no apparent effect of zinc on loss of mean 65Zn activity from red blood cells.

Effects of oral zinc loading on zinc metabolism in humans II: in vivo kinetics.

The effects of oral zinc loading on zinc metabolism were studied in 10 patients with taste and smell dysfunction following oral administration of Zn-65 (physical t1/2 = 245 d) and subsequent administration of oral stable zinc. Patients took an ad libitum dietary zinc intake of 8-13 mg daily for 290-440 days (mean, 336) following Zn-65 administration, followed by an intake of an additional 100 mg/day of zinc ion (as ZnSO4) over the next 112-440 days (mean, 307). A previously developed compartmental model, based on five day studies of patients with taste and smell dysfunction, was extended in such a way that it was consistent with both short term and long term kinetics. In this extended model, the turnover of 90% of total body zinc, previously unaccounted for by the kinetics in the short term studies could be explained by a single compartment, as postulated in the short term studies. Using the model, it was found that changes in the rate constants for gastrointestinal absorption and renal excretion of zinc were both necessary and sufficient to explain the changes seen in the kinetic curves following oral zinc loading. Michaelis-Menten type saturation mechanisms were adequate to explain the observed parameter changes. These changes also accounted for the observed mean plasma zinc mass increase of only 37% above pre-load levels in face of an 11-fold increase in zinc intake.

Absorption of orally administered 65Zn by normal human subjects.

Despite studies by several investigators of human gastrointestinal 65Zn absorption, implications of these data for evaluation of functional zinc status are unclear because limited numbers of normal subjects have been studied. To evaluated zinc absorption in normal humans, 75 subjects (31 women, 44 men, ages 18 to 84 yr) were given 10 micro Ci carrier-free 65Zn orally after an overnight fast. Absorption calculated from total body retention measured 7, 14, and 21 days after administration of tracer was 65 +/- 11% (mean +/- 1 SD), range from 40 to 86%. Comparison of these results with those for patients with a variety of diseases indicate that patients exhibit a wider range of absorption and, in four of six studies patients exhibit decreased mean zinc absorption. These results of gastrointestinal zinc absorption in a large number of normal humans offer a basis for a clearer comparison with data from patients who exhibit abnormalities of zinc absorption.

Influence of triiodothyronine withdrawal time on 131I uptake postthyroidectomy for thyroid cancer.

Radioiodine uptake by thyroid remnants and metastases postthyroidectomy for thyroid cancer is increased by withdrawing thyroid hormone, which raises TSH levels. The minimal withdrawal time for maximal uptake is unknown. Therefore, we performed 33 studies in 27 patients after 2 weeks and again after 4 weeks of T3 withdrawal. We examined cervical (or pulmonary) uptake and whole body scanning at 48 h and whole body retention at 48, 72, and 96 h after radioiodine. In 4 studies, only physiological nonthyroidal activity was seen on both scans. Cervical uptake was low in these 4 studies. Of the remaining 29 studies with thyroid activity on both scans, 4 had high cervical uptakes after 2 weeks, which decreased by 4 weeks to less than 50% of the 2 week value. The same trend was seen in whole body retentions. In 2 studies, the uptake increased at 4 weeks compared to that at 2 weeks, but the change was small and was reflected in whole body retention of only 1 of these subjects. In 23 studies, including 6 with metastatic disease, the individual uptakes and whole body retentions were similar after 2 and 4 weeks. The mean uptakes and retentions also did not differ despite significantly higher (P less than 0.001) TSH values at 4 weeks. All definite areas of localization of radioactivity seen on the scans after 4 weeks were seen after 2 weeks. Therefore, radioiodine uptake, scanning, and therapy should be performed after 2 weeks of T3 withdrawal when patients are minimally hypothyroid. Serum TSH should also be measured to identify the rare individual not responding to brief T3 withdrawal.

Zinc metabolism in humans: a kinetic model.

A quantitative model is developed that describes the kinetics of the early phases of zinc metabolism in humans. The model is based on averaged data obtained over 5 days from 17 atients with smell and/or taste dysfunction who were given 69mZn in trace amounts orally and intravenously. A function describing the rate of entry of 69mZn into systemic plasma following ingestion of the isotope is derived showing that about 37% of the ingested zinc enters plasma. Gastrointestinal absorption is essentially completed by 4 h. Sixty-seven percent of the absorbed zinc in the portal circulation is extracted by the liver before being released into the systemic circulation and agrees with the calculated extraction efficiency from the systemic circulation. There are both rapid and slow exchnage phases between plasma and liver and between plasma and red cells. The calculated steady-state zinc values for plasma, red cells, and liver agree with previously reported measured values implying there are no additional zinc pools in these tissues. The tracer data, however, account for only 10% of total body zinc, the remaining 90% in tissues whose kinetics are too slow to be resolved from a 5-day study.

Distribution and excretion in the rat and monkey of [82Br] bromocriptine.

Radiolabeled bromocriptine was administered to rats and monkeys and its tissue distribution, rate of excretion and metabolism were determined. In both species, [82Br]bromocriptine is predominantly concentrated in the liver, metabolized and then excreted through bile. Extractable free drug is undetectable in blood after 30 min. After 2 hr, the estimated concentration of free drug in rat brain is 2 x 10(-8) M. Terminal phase half-lives of radiolabel excretion were 2.9 days for the rat and 27.3 days for the monkey. The retained organically bound 82Br is present in a form more polar than bromocriptine.

Zinc metabolism in humans after oral and intravenous administration of Zn-69m.

Seventeen patients were studied after separate oral and intravenous administration of 50 muCi Zn-69m to determine if Zn-69m is suitable for studying zinc metabolism in humans and to determine if the route of administration affects kinetics. Patients stayed on a metabolic ward for each study. Activity was measured in the total body, urine, feces, blood, plasma, red blood cells, and by detectors over liver and thigh. Five day urine to fecal ratios were 0.44 (intravenous), 0.018 (oral). Most activity went rapidly to liver, then followed two component exponential loss patterns in both cases. Thigh area doubling time was 5.7 days whether the zinc was given orally or intravenously. Plasma activity decreased to less than 2% of that injected by 24 hr after intravenous administration and decreased from a maximum of 1.2% of that ingested, 3 hr after oral administration to 0.7% by 24 hr. Red blood cell activity increased through the 5-day study period to maximum values of 6.4% of that injected after intravenous administration and 2.4% of that ingested after oral administration. Similar metabolic patterns were observed regardless of whether Zn-69m was administered intravenously or orally, suggesting that these patterns were not affected by the mode of administration for the cases studied.

Accidental ingestion of Tc-99m in breast milk by a 10-week-old child.

Ten weeks after the birth of her first child by Caesarian section, a 27-year-old woman was admitted for evaluation of a possible central nervous system lesion. Four hours after i.v. administration of 15 mCi of Tc-99m for a brain scan, the patient breast-fed her infant; then became concerned about the possibility of radioactivity in her breast milk. Total body gamma-ray measurements of the infant indicated ingestion of 82.5 muCi Tc-99m (corrected for effective T 1/2), while ingestion calculated from gamma-ray measurements of serial milk samples was 75.6 muCi. The single organ radiation dose for the thyroid as the critical organ was 300 mRad, whereas that to the total body was 12 mRad (values derived from 82.5 muCi determined by whole body counting). Had breast feeding been continued at 4-hr intervals, the total ingested activity would have been 94.8 muCi giving the infant a dose of 380 mRad to the thyroid and 16 mRad to the whole body. Had the feeding been given 1/2-hr after injection 726 muCi would have been ingested, increasing the dose by a factor of 10.