Direct Use of Plasma or Milk Vitamin A Specific Activity Data to Model Retinol Kinetics and Predict Vitamin A Stores in Theoretical Lactating Women.

BACKGROUND: Many applications of the Simulation, Analysis and Modeling software use data on the fraction of an orally administered tracer dose (FD) in plasma; thus, researchers must scale-up measured analyte concentration to the total plasma pool. For studies in lactating women, estimating breast milk pool size is challenging. OBJECTIVES: The objectives were to determine whether the standard vitamin A modeling approach using FD data could be modified to use vitamin A specific activity in milk (SAm) and/or plasma (SAp) for compartmental analysis of vitamin A kinetics and status in theoretical lactating women. METHODS: Using 12 previously studied theoretical subjects with a wide range of assigned values for vitamin A total body stores (TBS) and the coefficient ("FaS") needed to predict TBS using a retinol isotope dilution equation, we simulated data for SAp and SAm for 49 d after oral administration of labeled vitamin A. Then we modeled datasets for SAp and SAm, as well as only SAp or SAm, incorporating a linear scaling factor to automatically convert SA to FD and including several physiologically reasonable constraints as input data. As outcomes, we compared model-predicted TBS and FaS to assigned values. RESULTS: Scaling factors effectively adjusted SA data to adequately predict vitamin A mass in plasma and breast milk pools. Data for SAp and SAm provided model predictions of TBS that were comparable to assigned values (range: 85-107%); using only SAp, ratios ranged from 92% to 108% and for SAm from 85% to 108%. Parallel results were obtained for simulated FaS. CONCLUSIONS: Results show that SA data from plasma and/or milk can be used directly for modeling vitamin A during lactation in theoretical subjects, providing accurate estimates of TBS and FaS. Results suggest that, in free-living lactating women, researchers might measure only SAp or only SAm and adequately describe whole-body vitamin A metabolism and status.

Prediction of Vitamin A Stores in Young Children Provides Insights into the Adequacy of Current Dietary Reference Intakes.

BACKGROUND: Limited data were available in infants and children when vitamin A (VA) DRIs were established; recommendations were developed based on average breast milk VA intake and extrapolation of data from adults. OBJECTIVES: Our objective was to evaluate whether DRIs and reported intakes, with and without VA from intervention programs, would be sufficient to develop adequate VA stores from birth to age 5 y in Bangladeshi, Filipino, Guatemalan, and Mexican children. METHODS: A mathematical relationship was established, defined by a series of equations, to predict VA total body stores (TBS) as a function of age based on VA intake and utilization. TBS calculated using reported VA intakes, with and without additional VA from intervention programs, were compared to those predicted using DRIs (specifically, Adequate Intake and RDA). Liver VA concentrations were also estimated. RESULTS: Our predictions showed that for these 4 groups, DRIs were sufficient to attain liver VA concentrations >0.07 µmol/g by 1 wk of age and sustain positive VA balance for 5 y. Using reported intakes, which were lowest in Bangladeshis from 1 y on and highest in Guatemalans, predicted VA stores in Bangladeshi and Filipino children increased until ∼2-3 y, then TBS stabilized and liver VA concentrations decreased with age. When VA interventions were included, stores exceeded those predicted using DRIs by 12-18 mo. In contrast, reported intakes alone in Guatemalan and Mexican children resulted in VA stores that surpassed those calculated using DRIs. For all populations, reported intakes were sufficient to build liver concentrations >0.07 µmol/g by 3 mo. CONCLUSIONS: Although more information is needed to better define dietary VA requirements in children, our results suggest that for an average, generally healthy child in a low- or middle-income country, current DRIs are sufficient to maintain positive VA balance during the first 5 y of life.

The "Super-Child" Approach Is Applied To Estimate Retinol Kinetics and Vitamin A Total Body Stores in Mexican Preschoolers.

BACKGROUND: Retinol isotope dilution (RID) and model-based compartmental analysis are recognized techniques for assessing vitamin A (VA) status. Recent studies have shown that RID predictions of VA total body stores (TBS) can be improved by using modeling and that VA kinetics and TBS in children can be effectively studied by applying population modeling ("super-child" approach) to a composite data set. OBJECTIVES: The objectives were to model whole-body retinol kinetics and predict VA TBS in a group of Mexican preschoolers using the super-child approach and to use model predictions of RID coefficients to estimate TBS by RID in individuals. METHODS: Twenty-four healthy Mexican children (aged 3-6 y) received an oral dose (2.96 µmol) of [13C10]retinyl acetate in corn oil. Blood samples were collected from 8 h to 21 d after dosing, with each child sampled at 4 d and at 1 other time. Composite data for plasma labeled retinol compared with time were analyzed using a 6-component model to obtain group retinol kinetic parameters and pool sizes. Model-predicted TBS was compared with mean RID predictions at 4 d; RID estimates at 4 d were compared with those calculated at 7-21 d. RESULTS: Model-predicted TBS was 1097 µmol, equivalent to ∼2.4 y-worth of VA; using model-derived coefficients, group mean RID-predicted TBS was 1096 µmol (IQR: 836-1492 µmol). TBS at 4 d compared with a later time was similar (P = 0.33). The model predicted that retinol spent 1.5 h in plasma during each transit and recycled to plasma 13 times before utilization. CONCLUSIONS: The super-child modeling approach provides information on whole-body VA kinetics and can be used with RID to estimate TBS at any time between 4 and 21 d postdose. The high TBS predicted for these children suggests positive VA balance, likely due to large-dose VA supplements, and warrants further investigation.

A Population-Based (Super-Child) Approach for Predicting Vitamin A Total Body Stores and Retinol Kinetics in Children Is Validated by the Application of Model-Based Compartmental Analysis to Theoretical Data.

BACKGROUND: Public health nutritionists need accurate and feasible methods to assess vitamin A status and to evaluate efficacy of interventions, especially in children. The application of population-based designs to tracer kinetic data is an effective approach that reduces sample burden for each child. OBJECTIVES: Objectives of the study were to use theoretical data to validate a population-based (super-child) approach for estimating group mean vitamin A total body stores (TBS) and retinol kinetics in children and to use population-based data to improve individual TBS predictions using retinol isotope dilution (RID). METHODS: We generated plasma retinol kinetic data from 6 h to 56 d for 50 theoretical children with high vitamin A intakes, assigning values within physiologically reasonable ranges for state variables and kinetic parameters ("known values"). Mean data sets for all subjects at extensive (n = 36) and reduced (n = 11) sampling times, plus 5 data sets for reduced numbers (5/time, except all at 4 d) and times, were analyzed using Simulation, Analysis and Modeling software. Results were compared with known values; population RID coefficients were used to calculate TBS for individuals. RESULTS: For extensive and reduced data sets including all subjects, population TBS predictions were within 1% of the known value. For 5 data sets reflecting numbers and times being used in ongoing super-child studies, predictions were within 1-17% of the known group value. Using RID equation coefficients from population modeling, TBS predictions at 4 d were within 25% of the known value for 66-80% of subjects and reflected the range of assigned values; when ranked, predicted and assigned values were significantly correlated (Rs  = 0.93, P < 0.0001). Results indicate that 7 d may be better than 4 d for applying RID in children. For all data sets, predictions for kinetic parameters reflected the range of known values. CONCLUSION: The population-based (super-child) approach provides a feasible experimental design for quantifying retinol kinetics, accurately estimating group mean TBS, and predicting TBS for individuals reasonably well.

Evaluation of the "“Olson equation"”, an isotope dilution method for estimating vitamin A stores.

Isotope dilution methods have been successfully used to estimate vitamin A status in human populations as well as to evaluate the impact of vitamin A interventions. The most commonly applied isotope dilution method is the retinol isotope dilution technique, which is based on the 1989 "“Olson equation"” for estimating total body vitamin A stores (sometimes equated to liver vitamin A) after an oral dose of labeled vitamin A. The equation relies on several factors related to absorption and retention of the dose, the equilibration of label in plasma vs. liver, and timing of a blood sample for measurement of labeled vitamin A. Here, the assumptions underlying these factors are discussed, and new results based on applying model-based compartmental analysis [specifically, the Simulation, Analysis and Modeling software (WinSAAM)] to data on retinol kinetics in humans are summarized. A simplification of the Olson equation, in which plasma tracer is measured 3 days after administration of the oral dose and several factors are eliminated, is presented. The potential usefulness of the retinol isotope dilution technique for setting vitamin A requirements and assessing vitamin A status in children, as well as the confounding effects of inflammation and likely variability in vitamin A absorption, are also discussed.