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Department of Nutritional Physiology and * Department of Food and Food Supplement Analysis, TNO Nutrition and Food Research, Zeist, The Netherlands
2To whom correspondence should be addressed. E-mail: T.vanVliet{at}voeding.tno.nl.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • retinoic acid • vitamin A • humans • single intake • safety
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,2
). The vitamin A metabolites responsible for the teratogenic effects are retinoic acid (RA) and its metabolites, i.e., all-trans-retinoic acid (all-trans-RA), 13-cis-retinoic acid (13-cis-RA), and 13-cis-4-oxo-retinoic acid (13-cis-4-oxo-RA) (3
). Because RA and its metabolites reach the embryo by direct transfer across the placenta, the teratogenic potential of vitamin A–containing products may be assessed by measuring the amounts of RA and its metabolites in maternal plasma. In addition to the absorption of RE from the gastrointestinal tract, the pharmacokinetic properties of RA and its metabolites, including their elimination from the blood (half-life), also influence exposure of the embryo. Thus, the area under the time-response curve (AUC) of a metabolite in plasma may show higher correlation with teratogenicity than its maximal concentration in maternal plasma and is therefore often used to estimate exposure risk (3
).
Current recommendations on safe vitamin A intakes are based on studies that have evaluated birth defects associated with chronic exposure to vitamin A, showing that with intakes higher than 7.5 mg/d, teratogenicity cannot be excluded (4
). Little is known about the dose of vitamin A that may have an acute teratogenic effect; only one case has been reported in which a woman gave birth to a malformed baby after a single oral dose of 150 mg vitamin A during her pregnancy (5
). Similarly, no limit is available below which a single intake of vitamin A can be considered safe for pregnant women. For long-term intake, amounts up to 3 mg vitamin A/d have shown no risk of inducing abnormalities in the developing embryo and are therefore considered "safe" (6
,7
).
For a more complete risk evaluation, bioavailability of vitamin A from various sources should be considered. Buss et al. (8
) provided evidence for a lower availability of vitamin A from liver compared with vitamin A–containing supplements after intakes of single dosages of 50 or 150 mg vitamin A. Also, the absolute amounts of the major RA metabolites were lower after intake of liver. Other studies reported the response after intakes of either liver (9
) or supplements (10
–13
). The main limitation of these studies was the relatively high dosages, which were above nutritional levels (i.e., 15–150 mg). Plasma responses of RA and metabolites after a large range of vitamin A dosages (0.4–15 mg) with normal meals were demonstrated by Chen et al. (14
), but the sources of vitamin A were not reported.
The aim of the present study was to compare the bioavailability of vitamin A and formation of RA and its metabolites from liver paste and from a vitamin A supplement at three nutritionally relevant levels of intake, to evaluate the current level of safe intake of vitamin A for supplements and liver products.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The study was conducted according to good clinical practice guidelines at TNO Nutrition and Food Research (Zeist, The Netherlands). The protocol was approved by the TNO Medical Ethics Committee. Subjects were recruited from the pool of volunteers of TNO Nutrition and Food Research.
Healthy women (n = 36; aged 19–47 y) entered the study after giving their written, informed consent. All volunteers underwent a screening procedure that included a health and lifestyle questionnaire, a physical examination and a routine blood clinical chemistry profile. They had no history of medical or surgical events that may have affected the results, including chronic gastrointestinal complaints or indication of fat malabsorption. Pregnant or lactating women were excluded and a pregnancy test was done before each treatment. Subjects did not use supplements containing vitamin A, D, E or carotenoids before (1 mo) and during the study.
Study design.
The study was an open, randomized study, using a crossover approach for two sources of vitamin A (i.e., liver paste and retinyl palmitate containing oil) and a parallel approach for three dose levels of vitamin A (i.e., 3.0, 7.5, and 15 mg vitamin A).
The subjects were stratified by age and body mass index (BMI) and then randomly assigned to three groups of 12 subjects. Within each group, half of the subjects started with a vitamin A supplement and the other half started with liver paste. Each subject received two study meals 15 d apart, one with supplement and one with liver paste in random order. Both meals of each subject contained the same dosage of vitamin A. All subjects were instructed not to consume liver or liver products 3 d before each test day.
On d 1 of the study, a blood sample was collected from fasting subjects; they then consumed a study meal consisting of 2 slices of brown bread with either test substance or reference substance, skimmed or butter milk, and unsweetened coffee or tea without cream. The test substance was liver paste (Ter Beke, Waarschoot, Belgium) given in dosages of 32, 80 or 160 g, which was equivalent to 3.0, 7.5 or 15 mg of total vitamin A, respectively. The reference substance was retinyl palmitate in arachis oil (van Lennep Pharmacy, Zeist, The Netherlands) given in dosages equivalent to 3.0, 7.3 or 14.6 mg vitamin A in combination with salami (local butcher) in dosages equivalent to the amount of fat in the applied dosage of liver paste. The concentration of vitamin A in the salami was very low (12 µg/100 g) and contributed <0.1% of the intake of vitamin A with the supplement. Concentrations of vitamin A in the supplement, liver paste and salami were measured after saponification, taking into account a bioavailability of 75% for 13-cis retinol relative to all-trans retinol (= 100%).
Subsequently, blood samples were collected either by venipuncture or by an indwelling canula (obturator locked) from the antecubital vein in Vacutainer tubes containing heparin. Blood samples were taken at 2, 3, 4, 5, 6, 8 and 10 h after the study meal. After collection of the sample at t = 5 h and t = 10 h, a lunch and a dinner were served, respectively; they were low in fat and almost free of vitamin A. After dinner, the subjects left the institute and returned the next morning in a fasting state for collection of the 24-h sample. At d 15 and 16 of the study, the same procedures were followed as for d 1 and 2, except that consumption of vitamin A supplement and liver paste with a study meal was reversed for each subject.
Analytical methods.
Contents of retinol and RE were determined in liver paste and plasma according to a modified version of an HPLC method described previously (15
) using a Hyperchrome stainless steel column (125 x 4.6 mm) filled with Hypersil ODS, 3 µm (Shandon HPLC, Runcorn, Cheshire, UK). A mobile phase of acetonitrile/methanol/methylene chloride/water (70:15:10:5, v/v/v/v) was used.
The retinoids all-trans-RA, 13-cis-RA, all-trans-4-oxo-RA and 13-cis-4-oxo-RA were determined using HPLC according to a method described by Wyss and Bucheli (16
). In brief, 1 mL plasma was deproteinated by adding 3 mL ethanol containing 2 µg/L acitretin as the internal standard. The supernatant (2 mL) was injected onto a precolumn (Hypersil BDS C18 All Guard cartridge, 5 µm, 7.5 x 4.6 mm) and eluted with a mobile phase consisting of water/100% ethanol/10% ammonium acetate/100% acetic acid (690:200:100:10, v/v/v/v) at a flow rate of 0.7 mL/min. The retained components were transferred to the analytical column (Hypersil BDS C18, 5 µm, 250 x 4.6 mm) in the back flush mode and separated at a flow rate of 1.25 mL/min by gradient elution consisting of one solution similar to the precolumn mobile phase, and solutions of acetonitrile/2.5% ammonium acetate/acetic acid (960:20:20, v/v/v), actonitrile, and 1.0% ammonium acetate (pH 5.5), respectively. Components were detected using a diode array detector (Waters 996; Etten-Leur, The Netherlands) in a wavelength range of 280–420 nm. In plasma, RE, all-trans-RA, 13-cis-RA, 13-cis-4-oxo-RA and all-trans-4-oxo-RA were quantified. The percentages of recovery and coefficients of variations are given in Table 1
.
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Results are expressed as means ± SD. The AUC was calculated for 0–24 h after subtraction of the baseline values, using trapezoidal approximation. In addition, the maximal increase in plasma concentration (Cmax) and the time of the maximal plasma concentration (Tmax) were calculated. Differences between the sources of vitamin A and between dosing levels were evaluated by regression analysis (General Linear Models Procedure). Statistical analyses were carried out with SAS statistical software package SAS/STAT (version 6, SAS Institute, Cary, NC), using the general linear models procedure (GLM). Differences with P < 0.05 were considered significant. Because the study was designed as a combination of a crossover and parallel approach, when a significant source effect was present, individual sources within each dose level were compared using paired t tests, and when an overall significant dose effect was found, individual doses were compared using unpaired t tests.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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After consumption of liver paste and the vitamin A supplement, RE, all-trans-RA, 13-cis-RA, 13-cis-4-oxo-RA and all-trans-4-oxo-RA were detected in plasma.
For RE (the sum of retinyl palmitate and retinyl stearate), clear response curves were obtained for all treatments (Fig. 1
). The average response curve showed a first peak at 3 h and a second peak at 6 h after consumption of both the supplement and the liver paste. At 24 h, plasma concentrations had returned to baseline. For RE, the AUC was significantly affected by the dosage, but not by the source (liver paste or supplement). Cmax and Tmax were not significantly affected by dose or source (Table 2
).
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). The two lowest dosages induced only small increases in plasma concentrations with a maximum at 3–4 h after dosing. Thereafter, concentrations gradually decreased to levels below baseline at 6–10 h before returning to baseline at 24 h after the meal. Only after consumption of liver paste containing 15 mg was the mean response substantially higher than after consumption of 3.0 and 7.5 mg, and the concentration did not decrease below baseline. The AUC after the highest dose of liver paste was significantly higher compared with after the supplement. The Cmax increased significantly with dose and was significantly higher for 15 mg liver paste compared with the supplement (Table 2)
.
|
). The average curves showed maximum concentrations 
5 h with a second, smaller peak at 10 h. Although the concentrations gradually decreased thereafter, baseline values were not reached within 24 h. The AUC and Cmax were significantly affected by both dose and source. Differences between the sources were demonstrated at all three dose levels. Tmax was significantly higher after intake of the 15-mg dose compared with the lower dosages. A linear increase in AUC was demonstrated with dose. Dose response relationships were significantly different between sources, with a higher increase with dose after intake of liver paste (Table 2)
.
|
). No maximum concentrations were reached within 10 h after dosing although at 5 h some curves showed a first, small peak. The curves did not return to baseline within 24 h. Responses were significantly higher after consumption of liver paste at 7.5 and 15 mg compared with the supplement. The AUC increased with dose for both sources, but the increase was greater for liver paste than for the supplement. Both Cmax and Tmax increased significantly with dose, whereas only Cmax was significantly influenced by source (Table 2)
.
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Retinol concentrations were not significantly affected by the treatments (data not shown). Moreover, long-term baseline concentrations were not affected by a single intake of vitamin A; retinol concentrations at t = 0 h for all treatment groups did not differ between d 1 (2.30 ± 0.53 µmol/L) and d 15 (2.26 ± 0.49 µmol/L) of the study.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Bioavailability of vitamin A.
In this study, we compared single intake of vitamin A by consumption of liver paste and a supplement. RE were the main compounds measured in plasma after consumption of a meal containing liver paste or supplement. Because no differences in AUC were found for RE after intake of liver paste or supplement, we concluded that the bioavailability of vitamin A was comparable for both sources. In contrast, Buss et al. (8
) found that the maximum concentration of RE after intake of a vitamin A supplement was 1.5-fold higher than the maximum RE concentration after intake of fried liver containing the same amount of vitamin A. Using a 2.3-fold higher vitamin A dose (50 vs. 15 mg), they demonstrated a RE response 3–4 times our response after supplement, and 1.5–2 times our response after liver. Differences can be explained in part by the use of higher dosages of vitamin A and the use of different sources of vitamin A. In our study, retinyl palmitate in oil was used in combination with a test meal, whereas in the study by Buss et al. (8
), a water-soluble retinyl palmitate supplement (Arovit) was used without a meal. Moreover, the liver paste was provided with bread whereas fried liver used in the study of Buss et al. (8
) was provided with a light meal.
Arnhold et al. (9
) reported a fourfold higher response of RE after a single dose of fried liver containing 80 mg vitamin A, which corresponded to the RE response after intake of the 15-mg dose of vitamin A as liver paste in our study. Consumption of a supplement containing 23 mg vitamin A has been demonstrated to result in a twofold higher response of RE compared with intake of the 15-mg vitamin A supplement in our study (13
). Other studies investigating plasma levels and metabolism of vitamin A after intake of vitamin A supplements (10
,11
) or unspecified meals rich in vitamin A (14
) did not provide data on RE.
Plasma responses of RA metabolites.
In the present study, the main RA metabolites were 13-cis-RA and 13-cis-4-oxo-RA, whereas all-trans-RA was present in lower amounts. These findings were in accordance with other studies (8
–11
). In addition, other metabolites have been reported in plasma such as 9-cis-RA, 9,13-di-cis-RA and 14-hydroxy-4,14-retro-retinol (9
). However, the concentrations of these metabolites have been reported to be relatively low, and may be considered of minor importance for the overall RA responses in plasma. In our study, intake of liver paste resulted at all dosages in about two times higher responses of 13-cis-RA and 13-cis-4-oxo-RA compared with intake of the corresponding dosages of supplement. In contrast, Buss et al. (8
) reported higher responses after intake of the supplement compared with liver consumption, i.e., about twofold higher for 13-cis-RA and 13-cis-4-oxo-RA, 20-fold higher for all-trans-RA and about fourfold higher for all-trans-4-oxo-RA. Direct comparison of AUC between the study of Buss et al. (8
) and our study is difficult because they estimated AUC until infinity, whereas we measured in a fixed time period of 24 h postdosing. Only for all-trans-RA was comparison of AUC possible because the concentrations returned to baseline values within 24 h. We demonstrated that intake of 15 mg vitamin A with liver paste resulted in a higher response than intake of 50 mg vitamin A with liver in the study by Buss et al. (8
), i.e., AUC of 59 vs. 18 (nmol · L-1) · h, whereas the response after supplement intake in our study was much lower, i.e., AUC of 4 vs. 286 (nmol · L-1) · h. Cmax values for 13-cis-RA and 13-cis-4-oxo-RA after liver consumption were comparable between the two studies taking into account the differences in dosage of liver paste; our study used dosages of 30%, resulting in responses of 33–40% compared with the study of Buss. However, Cmax values for 13-cis-RA and 13-cis-4-oxo-RA in our study were only 7–11% after supplement intake compared with Buss.
After intake of 80 mg vitamin A in the form of liver (9
), 1.3-fold higher responses were observed for 13-cis-RA and 5.8-fold higher responses for 13-cis-4-oxo-RA compared with the response after intake of 15 mg liver paste in our study; AUC of 680 vs. 291 (nmol · L-1) · h and AUC of 1384 vs. 203 (nmol · L-1) · h, respectively. The AUC for all-trans-RA was comparable between the two studies.
Data on RE responses are not always presented and because information about actual RE exposure is lacking in these studies, it is difficult to compare overall plasma responses of RA. Peiker et al. (10
) used a single intake of a 15-mg vitamin A supplement and reported 50% lower AUC for 13-cis-RA [54 vs. 121 (nmol · L-1) · h] and for 13-cis-4-oxo-RA [60 vs. 101 (nmol · L-1) · h] compared with the 15-mg vitamin A supplement in our study. Also the study by Eckhoff et al. (11
), in which the subjects were provided with a 20-mg vitamin A supplement, demonstrated 60% lower values of AUC for these RA metabolites. A low dose of 3 mg vitamin A supplement was given in a study by Tang and Russell (12
), but they reported only the response of 13-cis-RA relative to that of all-trans-RA, i.e., 9.6.
In summary, comparison of our data with data reported in the literature concerning RA and metabolites demonstrated that the absolute responses after consumption of liver compared quite well between our study and the studies of Buss et al. (8
) and Arnhold et al. (9
), whereas for supplement intake, our responses were much lower compared with the data of Buss et al. (8
), but were higher than the results given by Peiker et al. (10
) and Eckhoff et al. (11
). Differences in dose and formulation may likely explain these different outcomes because administration of a water-soluble preparation without a meal was reported (8
), as well as an oil-soluble preparation without a meal (12
), with the habitual diet (10
,11
) or with unspecified test meals (14
). In rat studies, absorption of vitamin A from water-soluble solutions has been shown to be higher compared with oil-based preparations (17
). Also differences in doses may explain differences in responses. On the one hand, after high dosages, the presence of excess vitamin A may lead to an increase in the formation of RA in the intestine. On the other hand, RA and/or its metabolites might inhibit formation of RA through feedback mechanisms.
"Safe" levels of vitamin A intake from liver.
In conformity with the current regulations, over-the-counter vitamin A supplements may contain up to 1.2 mg vitamin A per recommended number of capsules to be used daily. Liver products contain 1–10 mg vitamin A/100 g (18
). For liver, amounts of 10–100 mg vitamin A/100 g have been reported (19
).
A study by Rothman et al. (20
) demonstrated that women who consumed >3.0 mg vitamin A/d from supplements already had an increased risk of an infant with malformities. Other studies have been published showing that high exposure to vitamin A during pregnancy could induce birth defects, but dose threshold levels were difficult to establish (21
,22
). Although the study by Rothman et al. (20
) was one of the few studies presenting dose levels, other observational data and studies in nonhuman primates have shown no teratogenicity at doses <10 mg/d (4
).
In 1994, the Dutch Health Council/Food and Nutrition Council (6
) accepted a daily intake of up to 3.0 mg vitamin A as a "safe" upper level, irrespective of the source of the vitamin. It is more than adequate to provide for good nutrition but is likely low enough to avoid toxicity. It was recognized, however, that daily intakes up to 7.5 mg, except for one case, have never been connected with increased teratogenic risk. Yet, to meet adequate levels of vitamin A in the body, Recommended Dietary Intake for vitamin A for women ranges between 0.5 (23
) and 0.8 mg (24
,25
), depending on the country.
As a consequence of the complex absorption process of RE, storage in the liver and metabolism, it may be more appropriate to use plasma concentrations to estimate the teratogenic potency of a vitamin A–containing product rather than the intake of vitamin A. Information on endogenous plasma levels of the retinoids is important to assess to what extent a single or multiple doses of vitamin A cause a disturbance of the steady-state levels. In this respect "safe" intake implies the intake for which physiologic ranges of plasma retinoids are not exceeded. Both the maximum concentration reached as well as the AUC of RA and its metabolites in plasma are therefore considered of relevance to estimate "safe" levels of intake of vitamin A (3
).
At present, no definite threshold value can be established above which teratogenic effects will occur. However, values can be estimated on the basis of levels reported in healthy individuals, levels measured in pregnant women with uncomplicated pregnancies and dosages that were not related to a specific risk.
In our study, measured basal values were close to other reference values (11
,26
,27
), i.e., 2.86–8.12 (3.79 ± 0.17) nmoL/L for 13-cis-RA, and 3.12–16.5 (8.09 ± 0.32) nmoL/L for 13-cis-4-oxo-RA. Concentrations of all-trans-RA, i.e., 4.39–10.65 (7.02 ± 0.17) nmoL/L were higher, but within the range of reported physiologic concentrations (15
). For pregnant women, reported concentrations ranged between 2.70 and 7.99 (4
) and 2.26 and 7.26 (28
) nmoL/L for all-trans-RA, 2.70 and 16.31 and 2.40 and 14.21 nmoL/L for 13-cis-RA, and 3.08 and 24.99 and 2.67 and 25.70 nmoL/L for 13-cis-4-oxo-RA. Because all pregnant women gave birth to healthy babies, these plasma retinoid levels were considered nonteratogenic.
After intake of liver paste or supplement, peak concentrations of 13-cis-RA (4.93–15.18 nmol/L) stayed within the range of endogenous concentrations found in pregnant women at all dosages. Peak concentrations of 13-cis-4-oxo-RA did not exceed physiologic ranges reported in pregnant women both at a dosage of 3 mg/L (5.76–15.74 nmol/L) and 7.5 mg/L (7.38–20.79 nmol/L). No statement can be made on this point based on peak levels of all-trans-RA because basal levels were already higher than those reported by Miller et al. (4
) and Wiegand et al. (28
).
Although the teratogenicity of vitamin A itself has not yet been clearly established, 13-cis-RA, in particular, has been shown to induce a disturbed differentiation of the embryo (4
). Our data showed a clear, dose-dependent increase in both Cmax and AUC for 13-cis-RA (and 13-cis-4-oxo-RA) that was higher for the liver paste than for the supplement for all three dose levels.
In conclusion, the data presented in our study showed that the bioavailability of vitamin A from liver paste and from a vitamin A supplement was not significantly different after single intake of nutritional dosages of 3.0, 7.5 and 15 mg vitamin A. Nevertheless, the formation of 13-cis-RA, 13-cis-4-oxo-RA and to a lesser extent of all-trans-RA was higher after consumption of liver paste compared with the supplement, especially at higher dosages. This study provided no evidence to deviate from the current safety recommendations on vitamin A intake, and pregnant women should limit the intake of vitamin A from liver products or excess vitamin A supplements during pregnancy.
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FOOTNOTES |
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3 Abbreviations used: AUC, area under the time-response curve; BMI, body mass index; Cmax, maximal increase in plasma concentration; RA, retinoic acid; RE, retinyl esters; Tmax, time of the maximal plasma concentration.
Manuscript received April 23, 2001. Initial review completed June 21, 2001. Revision accepted August 27, 2001.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Underwood, B. A. (1989) Teratogenicity of vitamin A. Int. J. Vitam. Nutr. Res. 30(suppl.):42-53.
2. Biesalski, H. K. (1989) Comparative assessment of the toxicology of vitamin A and retinoids in man. Toxicology 57:117-161.[Medline]
3. Armstrong, R. B., Ashenfelter, K. O., Eckhoff, C., Levin, A. A. & Shapiro, S. S. (1994) General and reproductive toxicology of retinoids. Sporn, M. B. Roberts, A. B. Goodman, D. S. eds. The Retinoids: Biology, Chemistry, and Medicine 1994 Raven Pres New York, NY. .
4. Miller, R. K., Hendricks, A. G., Mills, J. L., Hummler, H. & Wiegand, U.-W. (1998) Periconceptional vitamin A use: how much is teratogenic?. Reprod. Toxicol. 12:75-88.[Medline]
5. Mounoud, R., Klein, D. & Weber, F. (1975) A propos d’un cas de syndrome de Goldenhar: intoxication aigue a la vitamine A chez la mere opendant la grossesse. J. Genet. Hum. 23:135-154.[Medline]
6. Dutch Health Council/Food and Nutrition Council (1994) Vitamin A and teratogenicity 1994 The Hague The Netherlands. .
7. Bauernfeind, J. C. (1980) The safe use of vitamin A. A report of the International Vitamin A Consultative Group (IVACG) 1980 Nutrition Foundation Washington, DC. .
8.
Buss, N. E., Tembe, E. A., Prendergast, B. D., Renwick, A. G. & George, C. F. (1994) The teratogenic metabolites of vitamin A in women following supplements and liver. Hum. Exp. Toxicol. 13:33-43.
9. Arnhold, T., Tzimas, G., Wittfoht, W., Plonait, S. & Nau, H. (1996) Identification of 9-cis-retinoic acid, 9,13-di-cis-retinoic acid, and 14-hydroxy-4,14-retro-retinol in human plasma after liver consumption. Life Sci 59:L169-PL177.
10. Peiker, G., Eckhoff, & Ch. & Nau, H. (1991) Untersuchungen über Plasmaspiegel und Metabolismus von Vitamin A (Vitadral®) bei Frauen im fertilen Alter. Zent. bl. Gynäkol. 113:1100-1106.
11. Eckhoff, C., Collins, M. D. & Nau, H. (1991) Human plasma all-trans-, 13-cis- and 13-cis-4-oxoretinoic acid profiles during subchronic vitamin A supplementation: comparison to retinol and retinyl ester plasma levels. J. Nutr. 121:1016-1025.
12. Tang, G. & Russell, R. M. (1991) Formation of all-trans-retinoic acid and 13-cis-retinoic acid from all-trans-retinyl palmitate in humans. J. Nutr. Biochem. 2:210-213.
13. Borel, P., Mekki, N., Boirie, Y., Partier, A., Alexandre-Gouabau, M.-C., Grolier, P., Beaufrere, B., Portugal, H., Lairon, D. & Azais-Braesco, V. (1998) Comparison of the postprandial plasma vitamin A response in young and older adults. J. Gerontol. 53A:B133-B140.
14. Chen, C., Mistry, G., Jensen, B., Heizmann, P., Timm, U., Vanbrummelen, P. & Rakhit, A. K. (1996) Pharmacokinetics of retinoids in women after meal consumption or vitamin A supplementation. J. Clin. Pharmacol. 36:799-808.[Abstract]
15. van Vliet, T., van Schaik, F., van Schoonhoven, J. & Schrijver, J. (1991) Determination of several retinoids, carotenoids and vitamin E vitamers by high-performance liquid chromatography. Application to plasma and tissues of rats fed a diet rich in either B-carotene or canthaxanthin. J. Chromatogr. 553:179-186.[Medline]
16. Wyss, R. & Bucheli, F. (1997) Determination of endogenous levels of 13-cis-retinoic acid (isotretinoin), all-trans-retinoic acid (tretinoin) and their 4-oxo metabolites in human and animal plasma by high-performance liquid chromatography with automated column switching and ultraviolet detection. J. Chromatogr. B. 700:31-47.
17. Grolier, P., Agoudavi, S. & Azais-Braesco, V. (1995) Comparative bioavailability of diet, oil- and emulsion-based preparations of vitamin A and beta-carotene in rats. Nutr. Res. 10:1507-1516.
18. van den Berg, H., Hulshof, K.F.A.M. & Deslypere, J. P. (1996) Evaluation of the effect of the use of vitamin supplements on vitamin A intake among (potentially) pregnant women in relation to the consumption of liver and liver products. Eur. J. Obstet. Gynecol. Reprod. Biol. 66:17-21.[Medline]
19. Howells, L. C. & Livesey, C. T. (1998) A survey of vitamin A concentrations in the liver of food-producing animals. Food Addit. Contam. 15:10-18.[Medline]
20.
Rothman, K. J., Moore, L. L., Singer, M. R., Nguyen, U.D.T., Mannino, S. & Milunsky, A. (1995) Teratogenicity of high vitamin A intake. N. Engl. J. Med. 333:1369-1373.
21. Martinez-Frias, M. L. & Salvador, J. (1990) Epidemiological aspects of prenatal exposure to high doses of vitamin A in Spain. Eur. J. Epidemiol. 6:118-123.[Medline]
22. Werler, M. M., Lammer, E. J., Rosenberg, L. & Mitchell, A. A. (1990) Maternal vitamin A supplementation in relation to selected birth defects. Teratology 42:497-503.[Medline]
23. FAO/WHO (1988) Requirements of vitamin A, iron, folate and vitamin B12. FAO Food and Nutrition Series 23 Rome, Italy FAO .
24. Netherlands Nutrition Council (1989) Recommended Dietary Allowances 1989 in The Netherlands 1989 Voorlichtingsbureau voor de Voeding Den Haag, Netherlands .
25. National Research Council (1989) Recommended Daily Allowances 10th ed. 1989 National Academy of Sciences Press Washington, DC. .
26. Tang, G. W. & Russell, R. M. (1990) 13-cis-Retinoic acid is an endogenous compound in human serum. J. Lipid. Res. 31:175-182.[Abstract]
27. Eckhoff, C. & Nau, H. (1990) Identification and quantitation of all-trans- and 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid in human plasma. J. Lipid Res. 31:1445-1454.[Abstract]
28. Wiegand, U.-W., Hartmann, S. & Hummler, H. (1998) Safety of vitamin A: recent results. Int. J. Vitam. Nutr. Res. 68:411-416.[Medline]
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 L. E. Mitchell, J. C. Murray, S. O'Brien, and K. Christensen Retinoic Acid Receptor Alpha Gene Variants, Multivitamin Use, and Liver Intake as Risk Factors for Oral Clefts: A Population-based Case-Control Study in Denmark, 1991-1994 Am. J. Epidemiol., July 1, 2003; 158(1): 69 - 76. [Abstract] [Full Text] [PDF]
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