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Section of Nutrition, Department of Pediatrics University of Colorado Health Sciences Center Denver, CO 80262
Dear Editor:
We have read with interest the recent report from Shames et al. (1
) evaluating techniques for estimating fractional zinc absorption (FZA) in humans. Although the report makes an important contribution to the nutrition research methodology literature, we feel it is necessary to bring to attention several shortcomings of the method and results. In particular, the evaluation of the fecal monitoring technique with the "English correction" (2
) is misleading because it does not reflect the method as it is actually used in practice, at least in our laboratory. We have routinely used the method for a number of years after determining to our satisfaction that it produces a sufficiently accurate estimate of fractional absorption.
In light of the findings of Shames et al., we elected to simulate the corrected fecal monitoring method as it is implemented in our laboratory using the model of Lowe et al. (3
) as Shames has done. We simulated cumulative daily fecal collections out to 10 and 14 d after tracer administration because our standard sampling protocol typically results in collection periods within that range. We then plotted the cumulative data as fraction of tracer dose vs. time and performed a series of linear regressions beginning with the final three data points and sequentially adding the preceding data, point by point, until the r2 of the regression line exhibited a notable decrease (accompanied by a larger shift in the slope and intercept of the line). With these simulated data, the rejection threshold tended to coincide with the r2 dropping below 0.9. Because the simulated data do not exhibit the well-defined "breakpoint" change in slope that we usually observe with actual data (further discussion below), selection of the best regression line was not so unequivocal. Nonetheless, we obtained by consensus an FZA value of 0.282 (overestimating the actual FZA of 0.279 by 1.1%) when sampling out to 10 d and a value of 0.273 (2.2% underestimate) when going to 14 d. This small error indicates the performance of our fecal monitoring method to be sufficiently accurate.
We also point out that the fecal monitoring method is not based on the assumption that the rate of excretion of absorbed-then-secreted zinc is constant, as the authors have stated, but that within certain time intervals it can be adequately approximated as a constant rate (4
).
The consequences of variable and prolonged colon transit times are not adequately evaluated by Shames’ use of the Lowe model. We feel that the model’s use of a mixing compartment for the colon produces a time course of fecal tracer excretion that is unrealistic. It is our experience that it is more accurately modeled by representing the colon with a delay compartment (5
). The apparent inaccuracy resulting from using the mixing compartment is more pronounced when the output rate constant, k(0,6), is decreased to simulate longer transit times, as we assume Shames has done. When we decreased k(0,6) to 0.399 to simulate a doubled mean intestinal transit time, the shape of the resulting cumulative tracer excretion curve deviated even more from our observations of actual data. As a result, the difficulty with applying our normal analysis method was exacerbated. Nonetheless, when we extended the collection period to 20 d and applied the method of starting with regression analysis of the later data and sequentially adding preceding data points until the r2 of the regression was about to decrease below 0.9, we obtained an FZA value of 0.280 (0.4% overestimate).
Review of our practical experience with simultaneous application of the fecal monitoring and the double isotope tracer ratio (DITR) technique indicates that the results are consistent with these theoretical calculations. These data have been derived from seven studies that have included from 5 to 20 subjects per study and a total of 87 subjects. The mean difference in FZA for each of these studies (DITR method minus fecal monitoring method) ranged from -1.80 to + 2.2% of the mean FZA derived from the two methods. The overall mean difference was only 1.03% ± 0.39% (P = 0.038). Although the result is statistically significant, the actual amount of the difference, 
1%, is too small to be of clinical importance.
It is true that the fecal excretion method is vulnerable to incomplete sample collection. However, this is not reason enough to discard this method which, in contrast to the double isotope tracer ratio technique (DITR), does not require the administration of a tracer intravenously. This not only has implications for acceptability, e.g., in infant studies, but frees an additional tracer for labeling of natural abundance zinc administered orally, for example, in different test meals. Moreover, the challenge of achieving complete fecal collections is unavoidable in studies of zinc homeostasis because of the importance of measurements of excretion of endogenous zinc via the intestine.
LITERATURE CITED
1.
Shames, D. M., Woodhouse, L. R., Lowe, N. M. & King, J. C. (2001) Accuracy of simple techniques for estimating fractional zinc absorption in humans. J. Nutr. 131:1854-1861.
2. English, J. L., Fennessey, P. V., Miller, L. V. & Hambidge, K. M. (1989) Use of a dual isotope technique to measure zinc absorption. FASEB J 4:A4956(abs.).
3.
Lowe, N. M., Shames, D. M., Woodhouse, L. R., Matel, J. S., Roehl, R., Saccomani, M. P., Toffolo, G., Cobelli, C. & King, J. C. (1997) A compartmental model of zinc metabolism in healthy women using oral and intravenous stable isotope tracers. Am. J. Clin. Nutr. 65:1810-1819.
4. Krebs, N. F., Miller, L. V., Naake, V. L., Lei, S., Westcott, J. E., Fennessey, P. V. & Hambidge, K. M. (1995) The use of stable isotope techniques to assess zinc metabolism. J. Nutr. Biochem. 6:292-301.
5.
Miller, L. V., Krebs, N. F. & Hambidge, K. M. (2000) Development of a compartmental model of human zinc metabolism: identifiability and multiple studies analyses. Am. J. Physiol. 279:R1671-R1684.
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