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American Journal of Clinical Nutrition, Vol. 84, No. 2, 389-394, August 2006
© 2006 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Major variables of zinc homeostasis in Chinese toddlers1,2,3

Xiao-Yang Sheng, K Michael Hambidge, Xi-Xiang Zhu, Jun-Xue Ni, Karl B Bailey, Rosalind S Gibson and Nancy F Krebs

1 From the Department of Child and Adolescent Health, Xin-Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (X-YS); the Section of Nutrition, Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO (KMH and NFK); the Yun-Nan Maternal and Children's Hospital, Yun-Nan, China (X-XZ); the Yun-Nan No. 1 People's Hospital, Yun-Nan, China (J-XN); and the Department of Human Nutrition, University of Otago, Dunedin, New Zealand (KBB and RSG)

2 Supported by grants no. PN0312-121 from the Nestle Foundation, 03JC14042 from the Shanghai Science and Technical Foundation, U01 HD40657 (National Institute for Child Health and Development) from the Global Network for Women's and Children's Health Research, and 5P30 DK48520 (Clinical Nutrition Research Unit) from the Bill and Melinda Gates Foundation.

3 Reprints not available. Address correspondence to XY Sheng, Department of Child and Adolescent Health, Xin-Hua Hospital, Shanghai Jiao Tong University, School of Medicine, 1665 Kong-Jiang Road, Shanghai 200092, China. E-mail: xiaoyang.sheng{at}uchsc.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Measurement of the major variables of zinc homeostasis is an essential prerequisite for estimating human zinc requirements, which currently require a factorial approach. The data required for this approach have not been available for toddlers, whose requirements have been estimated by extrapolation from other age groups.

Objective: The objective of the study was to measure key variables of zinc homeostasis in rural and small-town Chinese toddlers.

Design: Zinc stable-isotope tracers were administered intravenously and orally with all meals for 1 d to 43 toddlers. Subsequent metabolic collections in the homes included duplicate diets, quantitative fecal collections, and spot urine sampling. Fractional absorption of zinc (FAZ) was measured by a dual-isotope tracer ratio technique, and endogenous fecal zinc (EFZ) was measured by an isotope dilution technique.

Results: No group or sex differences were found. Therefore, results were combined for 43 toddlers aged 19–25 mo whose major food staple was white rice. Selected results (x± SD) were 1.86 ± 0.55 mg total dietary Zn/d; 0.35 ± 0.12 FAZ; 0.63 ± 0.24 mg total absorbed Zn/d; 0.67 ± 0.23 mg EFZ/d; and 65.0 ± 8.3 µg plasma Zn/dL. The molar ratio of dietary phytate to zinc was 2.7:1.

Conclusions: The mean intake and absorption of zinc in this population are low in comparison with estimated average dietary and physiologic requirements for zinc, and plasma zinc values are consistent with zinc deficiency. Intestinal losses of endogenous zinc exceed previous estimates for toddlers, and only modest evidence exists of conservation in response to low zinc intake and absorption.

Key Words: Toddlers • zinc intake • zinc absorption • intestinal excretion of endogenous zinc • zinc status


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Risk assessment for zinc deficiency remains problematical because it is largely dependent on either indirect or nonspecific indicators (1), imperfect biomarkers (2), or, much more reliably, the results of randomized controlled trials (RCTs) of zinc supplementation in representative subsamples of populations suspected to be at risk of zinc deficiency (3-6). Ideally, a decision on conducting RCTs of zinc supplementation and on the details of their execution should be preceded by measuring dietary intake. Furthermore, studies of zinc homeostasis can provide population-specific estimates of dietary requirements and deficits for zinc and, thus, data on which to base decisions about the most effective intervention strategy for the target population. Unfortunately, initial acquisition of dietary data has not been a characteristic feature of RCTs of zinc supplementation, and preliminary studies of zinc homeostasis have been rare (7). This is despite the fact that the advent and progressive improvement of stable isotope techniques have made it feasible, with adequate care, to undertake detailed studies of zinc homeostasis even in remote rural communities (8-11), poor periurban communities (12), and a busy hospital environment (13).

In 2001, the Dietary Reference Intake Committee of the Food and Nutrition Board (FNB), Institute of Medicine, concluded that a factorial approach is the only means of estimating dietary zinc requirements for which adequate data are available (14). Moreover, the committee concluded that adequate data to permit a reasonably reliable estimate of physiologic requirements, and, thus, estimated average requirements (EARs) and recommended dietary allowances (RDAs) were available at that time only for young adult males (14). For all other age groups except infants and for females, EARs were ascertained by extrapolation from these data. This approach was used subsequently as a model for estimating EARs designed for international use (1). The objectives of this study were to measure the major variables of zinc homeostasis in very young children in rural areas and small towns in southwest China, to evaluate the adequacy of the dietary zinc intake of the population studied, and to compare zinc homeostasis and status (plasma zinc) between the rural and small-town children.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study design
Key variables of zinc homeostasis were measured in toddlers who were consuming their habitual diet in their own homes. All meals for 1 d were extrinsically labeled with a zinc stable isotope, and a second zinc stable isotope was administered intravenously. Isotope ratios were measured in complete fecal collections and timed spot urine samples. Fractional absorption of zinc (FAZ) was measured by a dual-isotope ratio technique (15, 16), and endogenous fecal zinc (EFZ) was measured by an isotope dilution technique (16). Total dietary zinc (TDZ) intake was measured in duplicate diets collected during the metabolic period. Plasma zinc was measured to assess zinc status.

Subjects
Forty-three apparently healthy (ie, no diarrhea, cough, or fever on day 0) children aged 19–25 mo participated in this study. They were {approx}90% of local children in this age range. The locations were the remote small town of Xi-Chou and 2 adjacent rural areas in southern Yun-Nan province, China. Twenty-two subjects (12 girls and 10 boys) were from the town, and 21 subjects (12 girls and 9 boys) were from the adjacent rural areas. Both groups had diets in which rice was the major dietary staple and phytate content was low.

Power calculation was based on the hypothesis that FAZ for the rural group would be lower than that of the small-town group. An assumed SD of 0.095 for variation between subjects (8) meant that 20 subjects per group provided 90% power to detect a difference of 0.10 (P < 0.05) in FAZ between the rural and small-town groups.

All parents gave their written informed consent for their children to participate in the study. The study received ethical approval from Shanghai Second Medical University, Xin-Hua Hospital, Shanghai Children's Medical Center, and the Colorado Multiple Institutional Review Board.

Diet
Baseline 24-h diet records were obtained to derive an approximate estimate of the average quantities of zinc ingested at each meal. These records were analyzed by using nutrient composition values from the NUTRITION DATA SYSTEM FOR RESEARCH (version 4.04_32; Nutrition Coordinating Center, University of Minnesota, Minneapolis, MN). Total diet zinc intake was measured in duplicate diets collected during the metabolic period.

Preparation and administration of tracer
Enriched stable isotopes of zinc were obtained from Trace Science International (Richmond Hill, Canada). Accurately weighed quantities of each isotopically enriched preparation were dissolved in 0.5 mol H2SO4/L and then diluted in thrice-deionized water to prepare a stock solution. For preparation of orally administered doses, the stock solution of enriched 70Zn was diluted and titrated to pH 5.0 with metal-free ammonium hydroxide. This solution was filtered through a 0.22-µm filter to make a sterile solution. For preparation of intravenously administered doses of 68Zn, sterile techniques were used. The stock solution was diluted with 0.45% saline, adjusted to pH 6.0, and then filtered through a 0.22-µm filter to make a sterile solution. The pharmaceutical quality of the sterile solution (ie, the nontoxicity, sterility, and pyrogenicity) was certified by the University of Colorado Hospital pharmacy (the core laboratory of the General Clinical Research Center) and the Shanghai Drug Administration Bureau. Concentrations of zinc in the isotope preparations were measured in triplicate by using atomic absorption spectrophotometry, and concentration measurements were adjusted for the different atomic weights of the preparations.

An accurately weighed quantity of 68Zn ({approx}1 mg) was administered intravenously near 12:00 PM on day 0. The tracer was administered over a 10-min interval via a scalp vein needle in a superficial forearm vein with a 3-way closed stopcock system. This allowed rinsing of the delivery syringe twice with normal saline contained in a second sterile syringe. The average dietary zinc intake, as assessed from the initial 24-h recalls, was almost identical in the 3 main meals of the day; hence, the total oral dose was divided equally between the 3 meals. A few children had a snack that was also labeled with zinc, at a dose approximately one-third of that given with the main meals. A total of {approx}0.2 mg 70Zn (accurately weighted) was administered orally by equal division between all meals on study day 0. The tracer was gradually administered in water during the second half of each meal (17). All isotope administration was supervised by research personnel.

Sample collection
Weighed duplicate meals adjusted for plate waste were collected on days 4–8 for measurement of daily intake of zinc and phytate. All stools were collected for 8 d, starting at the time of the first 70Zn-labeled meal. Feces were collected separately and quantitatively in plastic bags. A clean-void midstream urine sample was collected into a zinc-free plastic container twice daily from day 4 to day 8. The time of each collection was noted on the specimen cup and log sheets. A 1-mL blood sample was collected into a zinc-free heparinized plastic tube before administration of the intravenous tracer, and the plasma was separated within 30 min. All of the specimens were stored at –20 °C until they were transported without processing to the nutrition laboratories of the Department of Pediatrics (University of Colorado Health Science Center).

On days 0 and 30, length and weight were measured (in duplicate) with the use of calibrated equipment and standardized methods while the children were wearing light clothing but no shoes (18). Anthropometric z scores were calculated from the NCHS/CDC/WHO 1977 growth reference data (19) with the use of EPI INFO software (version 6; USD Inc, Stone Mountain, GA).

Sample processing and analyses
Accurately weighed aliquots of homogenized, whole-day duplicate diets and feces were dried separately to constant weight in an electric oven. All samples were prepared in duplicate. The dried samples were ashed in a muffle furnace at 450 °C for 24 h. A few drops of concentrated nitric acid were added to the ash, which was then dried before being heated again at 450 °C for 24 h. Ashed food samples were reconstituted quantitatively in 25 mL of 0.5 mol HCl/L. Ashed fecal samples were reconstituted quantitatively in 50 mL of 6 mol HCL/L. The concentrations of total zinc in these reconstituted food and fecal samples were measured in a diluted aliquot with the use of an atomic absorption spectrophotometer fitted with a deuterium arc background-correction lamp (Perkin-Elmer Corporation, Norwalk, CT.). Total dietary zinc (TDZ) was calculated by multiplying the quantity of zinc in the analyzed aliquot by the weight of the duplicate diet for an entire day divided by the aliquot weight.

Plasma zinc was measured by flame atomic absorption spectrophotometry (20). The precision of the plasma zinc analysis was determined by using the plasma pool. Accuracy was established by analysis of a certified reference material, bovine serum (SRM-1598; National Institute of Standards and Technology, Gaithersburg MD; x ± SD certified value: 890 ± 60 µg/L), and comparison with an analyzed value of 890 ± 17 µg/L.

For the measurements of zinc stable-isotope ratios, the inorganic elements were removed from reconstituted ashed fecal samples by using ion exchange chromatography with AG-1 ion exchange resin (Bio-Rad Laboratories, Richmond, CA). Urine samples were digested by using an MDA-2000 microwave sample preparation system (CEM Corp, Matthews, NC). A 5-mL urine sample was placed into an Advanced Composite Vessel (CEM Corporation, Matthews, NC), combined with 1 mL concentrated HNO3; then the pressure was gradually increased to a maximum of 120 psi. Total digestion time was {approx}90 min. Digested samples were transferred to a 50-mL beaker, evaporated to dryness on a hot plate, and reconstituted in 2 mL ammonia acetate buffer (pH 5.6). Zinc in the sample was purified by its chelation with trifluoroacetylacetone and extraction of the chelate with hexane (21).

Isotope enrichment was determined by measurement of the isotope ratios 68Zn/66Zn and 70Zn/66Zn by using an inductively coupled plasma mass spectrometer (VG Plasma Quad 3; VG Elemental, Thermo Electron Corporation, Waltham, MA). Tracer enrichment was defined as all of the zinc in the sample that was derived from the isotopically enriched tracer preparation divided by the total zinc in the sample.

Ion-pair HPLC with refractive index detection was used to measure hexainositol (IP-6) and pentainositol (IP-5) phosphates (22). Myoinositol phosphates with < 5 phosphate groups were not measured because they do not have a negative effect on zinc absorption (23). The accuracy and precision of this HPLC procedure were assessed by interlaboratory comparison of the IP-5 + IP-6 content of wheat bran and unrefined white maize.

Data processing and statistical analysis
For the measurement of fractional absorption of zinc (FAZ), the ratio of the urinary isotopic enrichment of the intravenously administered 68Zn to the orally administered 70Zn was used in the following equation (16):

Formula 1(1)
Ten urine specimens obtained during study days 4–8 were analyzed, and the calculated FAZs for the specimens were averaged to ascertain each child's FAZ. Total absorbed zinc (TAZ) was calculated by using the following equation:

Formula 2(2)
Endogenous fecal zinc (EFZ) excretion was measured by an isotopic dilution technique in which urine enrichment was substituted for enrichment in solid tissue or plasma (16):

Formula 3(3)
where F is total zinc in each sample (mg), f is intravenous isotope enrichment in each sample, u is average intravenous isotope enrichment in urine during collection, and d is duration of collection (ie, 5 d).

All results are presented as means ± SD. All statistical analyses were performed by using GRAPHPAD PRISM (version 3.01; GraphPad Software Inc, San Diego, CA). Rural versus small-town and sex-specific data were compared by using a 2-sample t test. Differences were considered to be significant at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Forty-three children (24 girls, 19 boys) were enrolled and studied. Data from small-town and rural participants and from the 2 sexes are shown in Table 1Go. No group or sex differences were found. Table 1Go, therefore, also includes combined data for all subjects. No child was underweight or wasted. However, 13 (30.2%) of the participants had a height-for-age z score < –2 and were considered stunted (24).


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  		TABLE 1. Demographic and anthropometric characteristics1

 
The TDZ from duplicate diets and the FAZ, TAZ, EFZ, dietary phytate, and plasma zinc results are shown in Table 2Go. Forty-eight percent of subjects had plasma zinc values below the reference 2.5th percentile (25). The relation between EFZ and TAZ is depicted in Figure 1Go and that between TAZ and TDZ is shown in Figure 2Go.


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  		TABLE 2. Major variables of zinc homeostasis and dietary phytate1

 

Figure 1
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  		FIGURE 1.. Linear regression between endogenous fecal zinc and total absorbed zinc. Regression equation: y = 0.3512x + 0.4496. r2 = 0.1862; P = 0.0048; 95% CIs of slope: 0.1134, 0.5891.

 

Figure 2
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  		FIGURE 2.. Polynomial first-order regression between total absorbed and total ingested zinc. Regression equation: y = 0.3328x. r2 = 0.2329; 95% CIs of slope: 0.2997, 0.3659.

 
The phytate intake was 57.9 ± 30.0 and 42.1 ± 26.3 mg/d in the rural and small-town groups, respectively. The phytate: zinc molar ratio was 3.1:1 in the rural group and 2.3:1 in the small-town group. These values did not differ significantly between groups. The combined value was 2.7:1.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although an approximate estimate from baseline 24-h recall diet histories indicated that the percentage of dietary zinc from flesh foods was significantly higher in the small-town group, the intake of zinc from flesh foods was very low in both groups, and the calculated difference between the groups averaged only 0.3 mg Zn/d. The intake in both groups and in the groups combined (Table 2Go) was significantly lower than the estimated average requirement of the FNB (14).

This study focused on measurements of the major variables of zinc homeostasis that are essential for a factorial approach to the estimation of dietary zinc requirements. These are the quantity of zinc ingested, the quantity of exogenous dietary zinc absorbed—ie, TAZ—and the quantity of endogenous zinc excreted via the intestine—ie, EFZ (14, 26). Together, urine and integumental routes are estimated to account for {approx}20% of losses of endogenous zinc. Also relevant is that, in contrast to EFZ, no evidence exists that urinary zinc varies over a wide range of zinc absorption (27), because it declines only under conditions of extreme dietary zinc restriction (28).

The quantity of zinc absorbed by the participants in this study was essentially the same as the quantity of endogenous zinc excreted via the intestine. When the toddler is retaining sufficient zinc to meet requirements for growth, absorbed zinc would be expected to exceed EFZ by {approx}0.3 mg/d in this age group. This magnitude of difference may not be expected in a study population in which ingested zinc met or exceeded the EAR in only 7% of participants and the average quantity of zinc absorbed was only 80% of the estimated physiologic requirement. However, in previous studies of zinc homeostasis in infants (29) and young children (11), including studies in infants and young children with relatively low zinc intake (10, 13), the quantity of zinc absorbed has, to some extent, exceeded the quantity of endogenous zinc excreted via the intestine. Thus, the possibility of error in zinc intake data cannot be excluded.

Of the major variables of zinc homeostasis, intestinal excretion of endogenous zinc had the most notable values, which were substantially higher than figures used in estimating zinc requirements for toddlers (1, 14). We have no reason to suspect that error contributed to these data. The most likely cause of error for EFZ is incomplete fecal collections, but that would give falsely low rather than falsely high results and therefore would not explain the lack of difference between TAZ and EFZ. Moreover, any (unlikely) error in intravenous tracer dose should not affect the calculation of EFZ. No investigations of gut permeability were undertaken, and the occurrence of environmental enteropathy (30) cannot be completely excluded. However, FAZ was not noticeably depressed, as it was observed to be in young children from a community with a high incidence of impaired gut function (31). Specifically, the mean FAZ, although higher than the estimate of the FNB for this age group (14), was somewhat lower than that more recently calculated for zinc intakes at or slightly below the age-specific EAR (32). These toddlers did not have diarrhea, and the population of this area of China routinely and regularly undergoes prophylactic treatment or early medical intervention for enteric parasitic infection. We conclude, therefore, that it would be inappropriate to dismiss the relatively high EFZs as the result of either error in the measurement of EFZ or undetected environmental enteropathy.

Dietary zinc intake of the participants was low in comparison with current estimates of zinc requirements for toddlers (14). In these circumstances, it is expected that the intestine will conserve endogenous zinc. The mean result for EFZ (Table 2Go) would, therefore, be predicted to be below the EFZ at a level of zinc absorption that just meets physiologic requirements (14). However, even the measured quantity of EFZ (Table 2Go) is 50% more than that used in the estimation of the EAR (14). The latter estimate was derived by extrapolating from adult data, and no previous data on zinc homeostasis from direct measurements at this age are available in the literature for comparison with the current data. Pending the acquisition of further data, it is important not to risk underestimating zinc requirements in young children who are at substantial risk of zinc deficiency–related morbidity and mortality.

Active absorption of zinc is a saturable process (33), and the relation between absorbed and ingested zinc is normally most appropriately fitted by nonlinear saturation kinetic analysis (31, 32, 34). The relation between TAZ and dietary zinc intake in this population has been fitted with a first-order polynomial regression, ie, a linear model (Figure 2Go). The adequacy of fit for this model is similar to that for nonlinear models. This finding is not unexpected when most intakes are below the EAR.

In conclusion, this population of Chinese toddlers, who had a moderately high incidence of stunting and borderline low plasma zinc, had an intake of zinc that was low in comparison with estimated average zinc requirements for this age group (14) and a quantity of absorbed zinc that was lower than estimated physiologic requirements. Intestinal excretion of endogenous zinc was high in comparison with figures that were assumed in estimates of zinc requirements (14), and no apparent explanation was found for the abnormally high losses. Moreover, evidence exists of only modest conservation of endogenous zinc as an adaptive mechanism to maintain zinc homeostasis when zinc intake and absorption were low.


   ACKNOWLEDGMENTS
 
We thank all the subjects who participated in the study and their parents. We gratefully acknowledge Tian-Jian Jiang, the head of Xi-Chou Maternal and Children's Hospital, and her colleagues for their assistance with the conduct of this study. We thank Xiao-Ming Shen, Li-Xiao Shen, and Min-Bo Xue (Shanghai Second Medical University, Xin-Hua Hospital) and Leland V Miller, Jamie E Westcott, and Sian Lei (University of Colorado Health Science Center) for their assistance with study conduct, sample processing, data collection, and data analyses. We also thank Gary Grunwald for statistical advice.

X-YS, KMH, and NFK were responsible for the conceptualization and the design of the study. X-YS, X-XZ, and J-XN conducted the clinical procedures. X-YS conducted the laboratory analyses. KBB and RSG conducted the phytate analyses. X-YS and KMH drafted the manuscript, which was reviewed by all coauthors. None of the authors had any personal or financial conflict of interest.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication October 10, 2005. Accepted for publication April 18, 2006.




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Right arrow Articles by Sheng, X.-Y.
Right arrow Articles by Krebs, N. F

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