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U.S. Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center and Department of Nutrition, University of California at Davis, Davis, CA
3To whom correspondence should be addressed. E-mail: chawkes{at}whnrc.usda.gov.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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5 mg (63 µmol) going into skeletal muscle. The low selenium group lost only 0.9 mg (11 µmol) of whole-body selenium but lost 3.3 mg (42 µmol) from muscle, indicating that selenium was redistributed from muscle to tissues that have a higher metabolic priority for selenium such as testes. Fecal excretion decreased by half, representing an important but previously underappreciated adaptation to selenium restriction.
KEY WORDS: • selenium absorption • selenium balance • selenium excretion • food selenium • skeletal muscle
Selenium is an essential trace nutrient for humans, animals and bacteria. Klaus Schwartz and colleagues at the National Institutes of Health discovered selenium’s nutritional essentiality in rats in 1957 (1), and similar findings were reported in chicks that same year (2). Selenium’s role as a component of glutathione peroxidase was discovered in 1973 (3), and the form of selenium at the active site was found to be selenocysteine in 1978 (4). Protein-bound selenocysteine is the predominant form of selenium in rats fed sodium selenite (5,6), and many selenocysteine-containing proteins have been reported, including several novel genes identified in silico that also seem to code for selenocysteine proteins (7).
The U.S. recommended dietary allowance (RDA) for selenium is 55 µg/d (697 nmol/d) for adult men (8), and the minimum requirement for men has been estimated at 21 µg/d (266 nmol/d) (9). The U.S. Environmental Protection Agency established an "oral reference dose" of 5 µg (63 nmol)/(kg body weight · d) (10) and the National Academy of Sciences has set the maximum safe dietary intake at 400 µg/d (5.07 µmol/d) (8). The vast majority of nutritional research on selenium has been conducted in rats and mice and usually with sodium selenite, purified selenoamino acids or other small-molecular-weight selenium compounds. Most of the human studies reported in the literature also used these small selenium compounds, rather than selenium in foods. Small-molecular-weight selenium compounds, selenoamino acids and food selenium all have different bioavailabilities and different spectra of biological activities (11,12); different plant foods also seem to have different distributions of selenium compounds (13). Although animals, and presumably humans, are able to efficiently utilize nutritionally adequate levels of selenium from all of these different forms and sources to support selenoprotein synthesis, it is clear that the potencies and biological activities are dependent, sometimes to a very large degree, on the source and chemical form of the selenium administered (11,14–17).
The chemical forms of selenium in the human diet have not been well characterized. Much of the selenium in plants is in small selenoamino acid compounds, with 64–73% of the selenium in wheat and yeast recoverable in the "methyl-selenium" fraction derived from selenomethionine and methylated selenocysteine derivatives (18). Animal-derived food products seem to contain selenium mainly as selenocysteine and selenomethionine in proteins; roughly half of the U.S. selenium intake comes from animal sources and about half from plant sources (19). There have been only a few small metabolic studies of selenium reported in humans, one feeding wheat or meat for 9 wk (20), another feeding sodium selenite for 7 wk (21), and one feeding wheat and tuna for 7 wk (22). We report here our observations on selenium metabolism in healthy men continuously fed conventional foods naturally low or high in selenium for 17 wk while confined in a metabolic research unit.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Healthy male volunteers (n = 12) were recruited for this study from a pool of 148 candidates who passed an initial telephone screening. Exclusion criteria were as follows: weight for height > 125% of ideal (23); use of selenium supplements or selenium-containing shampoos; abnormal electrocardiogram, blood cell counts, clinical chemistries or semen analysis; HIV infection; use of illegal drugs; habitual use of tobacco or alcohol; chronic use of medications; history of psychiatric illness; and history of thyroid or heart disease, syphilis, hepatitis, diabetes, hypertension or hyperlipidemia. It was subsequently determined that one subject in the high selenium group had been a user of selenium-containing shampoo before entering the study; his blood selenium and glutathione peroxidase activities were normal and his hair selenium returned to normal by wk 9, allowing inclusion of his data. One subject in the high selenium group withdrew from the study after 60 d for personal reasons unrelated to the study, and his data are not included. The initial characteristics of the 11 subjects who completed the study are shown in Table 1. There were no significant differences between the groups in these characteristics.
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Experimental diets and treatments.
Study subjects were fed a diet composed of conventional foods, based on beef and rice as staples, with nonfat milk powder as a protein supplement. To ensure an adequate intake of micronutrients, one multivitamin, multimineral supplement tablet, free of selenium ("Unicap M," Upjohn, Kalamazoo, MI), was administered to each subject each day. The total diet (food plus supplements) contained at least 100% of the RDA for all nutrients except magnesium, calcium and selenium (Table 2). The diet was fed in three daily meals and an evening snack, in a repeating cycle of 8 daily menus, using the same quantities of rice, beef and powdered milk every day (Table 3). Foods for each meal were weighed individually to the nearest gram. All meals were consumed completely under the direct observation of staff members. Plates were cleaned with rubber spatulas, cups and glasses were rinsed with distilled water and the residues were consumed.
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The nutrient composition of the experimental diets (Table 2) was analyzed in composite samples representative of the three diets. For each of the three diets, each of the 8 daily menus was prepared for a mock subject on two separate occasions during the study, and that day’s food was homogenized and freeze-dried. Portions of the 16 freeze-dried samples representing each experimental diet were then combined to yield three grand composites, one each for the stabilization diet, the low selenium diet and the high selenium diet. These three grand composite samples were subsequently analyzed for nutrient contents at a commercial laboratory (Corning-Hazelton, Madison, WI) using standard methods (24). Because chemical analysis of the three experimental diets revealed no differences greater than the imprecision of the methods in the amounts of protein, fat, carbohydrate, energy, cystine, methionine, mercury, cadmium, calcium, copper, iron, magnesium, manganese, molybdenum, nickel, phosphorus, potassium, sodium or zinc, only the mean values for all three diets are shown in Table 2. Although iodine was determined in the diet composites, the results in all three diets were below the method’s detection limit; thus Table 2 shows the value calculated from food composition tables, plus the daily supplement. The concentrations of mercury (25,26), cadmium (27), molybdenum (27), nickel (27) and arsenic (28,29) were also below the limits of detection of their respective methods (data not shown). The selenium contents of the three diets were analyzed in-house, as described below.
For the first 21 d (stabilization period), all subjects were fed a diet that provided 47 ± 4 µg/d (595 ± 51 nmol/d) of selenium at the mean energy intake of 11.7 MJ/d to adapt the subjects to the experimental diet and stabilize their body weights. The initial energy requirement of each subject was estimated from the Harris-Benedict equation (30); then the energy intake of each subject was adjusted as needed to maintain a constant body weight. When energy intakes were changed, all components of the diet were changed proportionally such that the relative composition of the diet was constant. Six adjustments were made to subjects’ intake, for a net increase of 0.07–0.08 MJ/d in both groups, similar to the day-to-day SD in diet preparation of ± 0.075 MJ/d (0.6% CV).
On d 22, after blocking into six pairs matched for blood selenium concentrations, the subjects were randomly assigned to receive either 14 ± 2.6 µg/d (177 ± 33 nmol/d, low selenium diet) or 297 ± 26 µg/d (3.8 ± 0.3 µmol/d, high selenium diet) for the remaining 99 d (intervention period), based on an average energy intake of 11.7 MJ/d. The only difference between the experimental diets was the geographic origin of the rice and beef, which were obtained from regions with either very high or very low soil selenium; all other components of the three diets were identical. Subjects and analysts had no knowledge of the diet assignments.
An oral dose of sodium selenite was given on d 110. On this day only, all subjects were fed the low selenium diet and were administered an oral dose of Na274SeO3 with the morning meal as follows: 10 µg selenium (127 nmol) for the low selenium group and 300 µg selenium (3.8 µmol) for the high selenium group. This may have affected the selenium balance at the end of the study. All of the stable isotope samples were lost in the 1997 flood of Grand Forks, ND and were not analyzed.
Specimen collection and laboratory measurements.
Blood samples for selenium and glutathione peroxidase determinations were collected into evacuated 15-mL EDTA tubes at 0700 h after an overnight fast of 12 h and kept on ice. Blood was centrifuged for 10 min at 190 x g at 5°C. The platelet-rich plasma was removed and saved for platelet isolation. The "buffy coat" containing white blood cells was removed and discarded. RBC were washed three times with chilled normal saline and stored at -70°C until analyzed. The platelet-rich plasma was centrifuged for 10 min at 950 x g at 5°C. The overlaying plasma was removed and stored at -70°C. The pelleted platelets were gently resuspended in 1.5 mL chilled HBSS and centrifuged again for 10 min at 950 x g at 5°C. After removal of the overlaying solution, the final platelet pellet was resuspended vigorously in 50 mmol/L Tris-HCl, 0.1% Triton-X100, pH 7.5, and frozen at -70°C until analysis. Blood samples for clinical chemistries were clotted, and the serum was separated by centrifugation and refrigerated until analyzed each night at a reference laboratory ("Chemzyme Plus," Smith-Kline Beecham, Santa Cruz, CA).
Complete collections of urine and feces were obtained throughout the first 42 d of the study, and then twice more for 10 d beginning on day 72 (72–81) and day 110 (110–119). Samples from the first 42 d were collected in 14 x 3-d pools for each subject; the subsequent samples were collected in 4 x 5-d pools. Urine was collected for 24 h in 2.5 L plastic jugs and kept at 4°C until pooled (within 3 d). Aliquots for selenium and nitrogen analyses were acidified by addition of 5 g/L concentrated HCl and stored at –20°C until analyzed. Feces was collected into 15-cm plastic buckets and kept at 4°C, and then stored at –20°C until processed. Frozen daily fecal samples were thawed and quantitatively transferred to a preweighed 2-L stainless steel blender jar using distilled water. After thorough homogenization of the pooled fecal sample to a thin slurry, the blender jar and contents were weighed and the total homogenate weight was calculated. Between 80 and 250 g of homogenized feces was transferred into preweighed plastic jars, weighed and then freeze-dried for subsequent analyses. The rest of the fecal homogenates were discarded. The wet-weight/dry-weight ratio was used to calculate the total dry weight of each fecal pool. This total dry weight was used to calculate total fecal pool contents of selenium and nitrogen from the respective concentrations measured in the freeze-dried specimens.
Selenium was measured by fluorescence-derivatization HPLC (31). Selenium-dependent glutathione peroxidase activity with cumene hydroperoxide and total protein were determined by automated colorimetric methods (32,33). Glutathione peroxidase units were expressed as moles of NADPH oxidized per second by comparison to standards of bovine erythrocyte glutathione peroxidase (Product No. G-6137, Sigma, St. Louis, MO). Nitrogen was analyzed by the dry combustion method (34) on an automated nitrogen analyzer (Model 428, LECO, St. Joseph, MI). Urine creatinine was measured in unacidified urine by a kinetic modification of the Jaffe method (35) on a centrifugal analyzer (Cobas-Fara, Roche Diagnostics, Basel, Switzerland).
Muscle biopsies.
Biopsies were obtained by a licensed physician from the vastus lateralis muscle 15 cm above the patella under local anesthesia with 1% topical lidocaine. After disinfecting the site, a small scalpel incision was made through the skin and deep fascia. The 11-gauge outer cannula of the needle set with a side opening was inserted into the muscle tissue to a depth of 1–2 cm. The sides of the incision were compressed and the inner (sharpened) needle was inserted to cut off the biopsy sample. The biopsy tissue was recovered by washing the needle with saline solution. The incision was closed with a butterfly suture and the subjects’ daily walks were canceled for the next 2 d to minimize discomfort. The baseline biopsy samples were obtained on d 19 of the study, and the repeat biopsy samples were taken at the end of the study on d 117 from the opposite leg. Between 2 and 18 mg of tissue were obtained at each sampling.
Because the biopsies were a heterogeneous mixture of muscle fibers, fascia and fatty tissues, whereas selenium is associated primarily with protein, we based the selenium measurements on the selenium to protein ratio (µg selenium/g protein). The biopsy samples were homogenized thoroughly in 1 mL of 50 mmol/L Tris-HCl, 0.1% Triton-X100, pH 7.5, with a micro rotor-stator grinder (0.7 cm diameter). Protein concentration was determined in a 50-µL aliquot of the homogenate, using the bicinchoninic acid method (36). The entire remainder of each homogenized biopsy sample was analyzed for selenium as described above. However, because the selenium content was near the limit of detection, the cyclohexane extracts were analyzed by HPLC in triplicate. The mean of the triplicate selenium estimates in each sample was divided by the estimated protein content of that sample, and the change in selenium/protein ratio was calculated for each subject.
Statistical analysis.
Effects of dietary selenium were examined using repeated-measures ANOVA, controlling for each subject’s baseline value, or by a t test of the within-subject changes when only a baseline and final measurement were made. The ANOVA calculations were performed with BMDP 7.0 program 2V, Analysis of Variance and Covariance with Repeated Measures (Los Angeles, CA). The ANOVA included a complete model: Selenium, Time, Covariate (baseline value), and Selenium x Time. A two-tailed probability 
0.05 was considered significant. Effects due to dietary selenium were detected as significant Selenium main effects or as significant Selenium x Time interactions, and the Student-Newman-Keuls multiple comparison test was used to identify significant differences between the groups at individual time points. The estimates of data variability are SD, unless otherwise noted.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Plasma selenium concentration was noticeably elevated within 3 d of starting the high selenium diet (Fig. 1) and ended 85% higher than at baseline (Table 4). Plasma selenium took 9 d to decrease noticeably in the low selenium group and ended 34% lower than at baseline. Selenium concentrations in RBC changed more gradually than in plasma, with increases becoming noticeable 17 d after changing the diet and decreases delayed until 65 d after changing the diet (Fig. 2). By the end of the study, RBC selenium had increased by 66% in the high selenium group and decreased by 26% in the low selenium group. Assuming a total blood volume of 6 L, these changes in blood selenium concentrations correspond to an 0.6 mg (7.6 µmol) increase in whole-body selenium in the high selenium group and a 0.25 mg (3.2 µmol) decrease in the low selenium group.
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Selenium levels in skeletal muscle were less affected than in blood. The low selenium diet caused a 19% decline in muscle selenium and the high selenium diet increased it by 38% (Table 4). Assuming that skeletal muscle accounted for 39.5% of the subjects’ body mass (38) and was composed of 12% protein (39), these changes in muscle selenium correspond to a gain of 5 mg (63 µmol) muscle selenium in the high selenium group and a loss of 3.3 mg (42 µmol) muscle selenium in the low selenium group.
After a delay of 3–5 wk, hair selenium concentration began to change (Fig. 3). In the high selenium group, hair selenium rose rapidly to a plateau, but in the low selenium group hair selenium continued to decline gradually throughout the study. By the end of the study hair selenium concentration in the high selenium group was about 2.5 times the concentration in the low selenium group (Table 4). One subject in the high selenium group (#5) had unusually elevated hair selenium concentration at the start of the study, presumably due to prestudy use of selenium-containing antidandruff shampoo. His hair selenium became indistinguishable from the rest of the high selenium group by d 63. Subject #5’s hair selenium data were excluded from Table 4 and his time course is shown separately in Figure 3.
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9 d after the diet change in the high selenium group, but continued to decrease to about half the baseline level in the low selenium group.
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Urinary nitrogen excretion decreased in both groups during the stabilization period, from 10 g/d (714 mmol/d) to 6 g/d (426 mmol/d), where it remained for the rest of the study (data not shown). The initial drop reflected the relatively low 10.6% protein content of the experimental diets, which nevertheless contained adequate amounts of all the essential amino acids. Creatinine excretion did not change or differ between groups (data not shown), indicating that the changes in nitrogen excretion were not due to changes in muscle mass. Furthermore, the clinical chemistry profile of blood serum was normal, showing no signs of muscle catabolism, and all values were within normal ranges (data not shown).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Urinary excretion increased rapidly in the high selenium group, but decreased only slowly with selenium restriction. Such slow adaptation to selenium was observed previously in New Zealand, where from 6 to 12 mo are required for blood selenium levels to adjust in persons traveling to or from this low selenium area (44). This adaptation was attributed to slow changes in the renal metabolism of selenium (45,46) and has led to the concept of life-long selenium exposure to explain the differences in selenium metabolism between populations in high and low selenium areas (21,47). Our novel observation that fecal excretion decreased by half in the low selenium group indicates that it may have an underappreciated role in the metabolic adaptation to low selenium intake.
The slow adaptation of selenium excretion is consistent with the slow turnover of selenium in muscle. Semilogarithmic plots of muscle selenium concentration increases and decreases vs. time showed an apparent biological half-life of 255 ± 39 d. This is close to the apparent biological half-life of 233 ± 58 d estimated from the terminal portion of the plasma selenium vs. time curve of the low selenium group. These estimates are also similar to the whole-body half-life of 245–252 d measured for selenium from selenomethionine (48,49). Much of the selenium in foods is present as selenomethionine; thus, it is not surprising that the kinetics of selenium in food are similar. Because about half of the body’s selenium is in skeletal muscle (50), complete adaptation to a large change in selenium intake may take years, supporting the concept of life-long selenium exposure. The whole-body half-life of selenium from sodium selenite is much shorter, with estimates ranging from 105 to 153 d (21,41,51,52), and selenite exchanges with only 20–40% of the whole-body selenium (53), making results from metabolic studies using selenite difficult to extrapolate to foods.
Metabolic balance was seemingly reached by the end of the 21-d baseline period, suggesting that the newly revised RDA for selenium of 55 µg/d (697 nmol/d) (8) is sufficient to maintain typical body stores in North American men. Selenium losses in blood, hair, sweat, breath, nails, exfoliated skin, semen and saliva were not included in the selenium retention figures in Tables 5, and 6, and these omissions inflate cumulative balance estimates (54). The selenium in sampled blood accounted for a loss of 120 µg (1.5 µmol) in the high selenium group and a loss of 69 µg (874 nmol) in the low selenium group. The high selenium group lost 19.5 µg (247 nmol) in scalp hair, whereas the low selenium group lost 9.5 µg (120 nmol), assuming a typical rate of human hair growth of 0.24 g/d (55). Total integumental losses (scalp hair, body hair, skin and nails) were estimated as 30 µg (380 nmol) in the high selenium group and 15 µg (190 nmol) in the low selenium group (55). Selenium losses in semen were estimated as 1.9 µg (24 nmol) in the high selenium group and 1.4 µg (18 nmol) in the low selenium group. The estimated losses of selenium by these unaccounted routes (152 µg or 1.9 µmol and 85 µg or 1.1 µmol in the high selenium and low selenium groups, respectively) were too small to affect the trends in selenium retention shown in Tables 5, and 6. Excretion of selenium as dimethyl selenide in rat breath is a significant route only at toxic levels of selenium intake (56,57) and has been observed in humans only in response to acute oral doses of selenium (58).
The cumulative retention of selenium between d 22 and 110 in the high selenium group was 15 mg (190 µmol), approximately doubling the whole-body selenium (53). Of the selenium retained by the high selenium group, 5 mg (63 µmol) appeared to be incorporated into muscle. Selenium in rats was also deposited preferentially in skeletal muscle at high selenium intakes (59), which is consistent with the storage role proposed for skeletal muscle selenium. Studies in human cadavers (60) and rats (61) suggest that some of the retained selenium was also deposited in liver, kidney, testes, brain and adrenal glands.
The low selenium group lost only 0.9 mg (11 µmol) of whole-body selenium, even though skeletal muscle lost 3.3 mg (42 µmol) of selenium, suggesting that selenium was redistributed from muscle to other tissues. The rapid decrease and redistribution of muscle selenium during depletion is further evidence for a storage role. Selenium lost from muscle during depletion was probably deposited in testes or other tissues with a higher metabolic priority for selenium. Selenium is preferentially retained in testes, brain and endocrine organs (62), and testes becomes the largest tissue pool in deficient rats (63). Sperm selenium was unchanged in the low selenium group (64), indicating that testes selenium stores were preserved during depletion.
At metabolic balance, apparent absorption was 65–70%, similar to that reported for men in California (22) and North Dakota (40), and was consistently greater from the high selenium diet as previously observed (40). Urinary excretion of selenium stabilized about 18 d after beginning the low selenium diet, slightly longer than reported by Levander et al. (22), but consistent with our lower dietary intake of 14–16 µg/d (177–203 nmol/d) vs. 34 µg/d (431 nmol/d). Urinary excretion of selenium took 12 d to stabilize in the high selenium group, about the same time reported for adaptation to repletion with 200 µg/d (2.5 µmol/d) fed in a formula diet (22).
The dietary intakes of calcium and magnesium were below recommended levels, and subjects may have been in negative balance. However, lower intakes of these minerals may be adequate for many individuals (65), and it is unlikely that low intake of calcium or magnesium affected the absorption, distribution or excretion of selenium in this study. Nutritional interactions between calcium and selenium have not been reported, and a metabolic unit study in adolescent girls found no effects of calcium supplementation on selenium absorption, retention or status (66). The subjects and the diets were not subject to known stressors of calcium nutriture such as extreme exercise or high fiber intakes, and serum calcium and alkaline phosphatase activity remained in the normal range, suggesting that calcium metabolism was normal. Nutritional interactions between selenium and magnesium have similarly not been reported, and we found one study of magnesium deficiency in rats that reported no effect on selenium (67). The dietary ratio of phosphorus to calcium was higher than normal, but serum phosphorus remained in the normal range.
To compare the various selenium parameters for their potential as status indicators, we calculated the t statistics for a comparison of the final parameter values between groups as a measure of selenium response size relative to interindividual variation. Daily urinary selenium excretion was the most discriminating indicator of selenium intake by this criterion (t = 20), but RBC selenium (t = 18) and plasma selenium (t = 13.4) were also quite sensitive, with the practical advantage of requiring only spot blood collections vs. 24-h urine collections. Daily fecal selenium excretion (t = 7.9) was the next most sensitive indicator of selenium intake, followed by muscle selenium (t = 2.5), platelet glutathione peroxidase and hair selenium (t = 1.8), RBC glutathione peroxidase (t = 1.5) and plasma glutathione peroxidase (t = 0.8). The relative responses of these parameters were similar to the responses of selenium status indicators in long-tailed macaques exposed to high levels of L-selenomethionine (68). Plasma selenium initially responds rapidly to changes in selenium intake and subsequently changes at a similar rate to whole-body selenium; it is a simple specimen to collect and analyze, and the response to selenium intake is large compared with the interindividual variation, making it well-suited for assessment of human selenium status.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 U.S. Department of Agriculture Agricultural Research Service Project 5306–51530-010–00D supported this research. Mention of trade name, proprietary product, or specific equipment does not constitute a guarantee or warranty by the U.S. Department of Agriculture, nor does it imply approval to the exclusion of other products that may be suitable. The opinions expressed herein represent those of the authors and do not necessarily represent those of the U.S. Department of Agriculture.
Manuscript received 23 May 2003. Initial review completed 7 July 2003. Revision accepted 21 August 2003.
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LITERATURE CITED |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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