Folate fortification for the prevention of birth defects: case study.
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Decision Making↗
Biomedical subjects
J I Rader
Publications and source records attributed to J I Rader.
Iron and folate in fortified cereals.
BACKGROUND: Fortification of cereal-grain products was introduced in 1941 when iron and three vitamins were added to flour and bread. Ready-to-eat cereals were fortified at about the same time. These fortifications have contributed to increased dietary iron intake and reductions in iron deficiency anemia in the US. In 1996, FDA finalized rules for fortification of specific enriched cereal-grain products with folic acid. This measure was instituted to increase the folate intakes of women of child-bearing age and thereby reduce the risk of having a pregnancy affected with a neural tube birth defect. However, with recent increases in fortification, public health officials in the US are concemed that excess intake of specific nutrients such as iron and folic acid may result in toxic manifestations. OBJECTIVE: Our objective was to measure iron and total folate content in breakfast cereals and compare assay to label values for % Daily Value. We also determined by weight the amount of a ready-to-eat breakfast cereal adults would eat and compared this to the labeled serving size, for which the reference amount for this cereal per eating occasion was 1 cup or 30 g. DESIGN: Twenty-nine breakfast cereals were analyzed for iron content using the bathophenanthroline reaction. Twenty-eight cereals were analyzed for total folate, utilizing a microbiological assay with tri-enzyme digestion. Serving size quantities were estimated in seventy-two adults who regularly ate breakfast cereal and were asked to fill a 16 or 22 cm round bowl with the amount of cereal that they would consume for breakfast. RESULTS: When the labeled value was compared to the assayed value for iron content 21 of the 29 breakfast cereals were 120% or more of the label value and 8 cereals were 150% or more of the label value. Overall, analyzed values for iron ranged from 80% to 190% of label values. Analyzed values for folate ranged from 98% to 320% of label values. For 14 of 28 cereals, analyzed values exceeded label declarations by more than 150%. Bran-containing cereals contained the highest amounts of folate relative to their label declarations. The median analyzed serving size for the breakfast cereal was 47 g for females, 61 g for males with a combined median of 56 g as compared to the label value of 30 g. CONCLUSIONS: Analyzed values of iron and folic acid in breakfast cereals were considerably higher than labeled values. For adults, the amount of cereal actually consumed was approximately 200% of the labeled serving size. When the quantity of cereal consumed is more than the labeled serving size and when the levels of iron and folate are higher than declared, the intake of both will be significantly greater than the labeled values. It will be important to continue monitoring serum ferritin and folate levels in NHANES IV, since daily consumption of breakfast cereals may contribute to excessive intakes of iron and folate.
Edible Grain↗
Oil-soluble vitamin content of new reduced-fat and fat-free margarines. Potential implications for vitamin E intake.
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Fats↗
Interactions in indices of vitamin A, zinc and copper status when these nutrients are fed to rats at adequate and increased levels.
The purpose of the present study was to determine the effects of feeding nutritionally adequate and increased levels of vitamin A (retinyl acetate at 1.4, 34.4, and 206.4 mg/kg diet) in combination with adequate or increased Zn (12 and 240 mg/kg) and Cu (5 and 50 mg/kg) on serum and tissue concentrations of retinol and retinyl palmitate and on indices of Cu and Zn status in female Sprague-Dawley rats, and to measure interactive effects of such nutrient imbalances. Rats fed on diets containing 34.4 and 206.4 mg vitamin A/kg had higher feed intakes and relative liver weights than those fed on diets containing 1.4 mg vitamin A/kg. An interaction between dietary Cu and Zn and an independent effect of vitamin A affected serum ceruloplasmin oxidase (EC 1.16.3.1) activity. Rats fed on high Zn, adequate-Cu diets (240 and 5 mg Zn and Cu/kg respectively) had lower serum ceruloplasmin oxidase levels than rats fed on adequate-Zn, adequate-Cu diets (12 and 5 mg Zn and Cu/kg respectively). This effect was not observed in rats fed on high-Zn, high-Cu diets (240 and 50 mg Zn and Cu/kg respectively). Alterations in dietary levels of Cu and vitamin A independently affected haemoglobin levels. Serum cholesterol concentration was affected by interactions between Zn and vitamin A and Cu and vitamin A. Levels of retinol and retinyl palmitate in liver and kidney were significantly higher in rats fed on diets with increased dietary vitamin A than in those fed on diets with adequate vitamin A. Three-way interactions among Cu, Zn, and vitamin A affected levels of retinol in serum and liver. Two-way interactions between Cu and vitamin A affected liver retinyl palmitate and the sum of liver retinol+retinyl palmitate. An independent effect of dietary Zn on these variables was also observed. Interactions between Cu and vitamin A affected levels of Cu in liver and kidney, while Fe and Zn in kidney were affected by interactions between Cu and Zn. This study demonstrates that differing interactions among variables of vitamin A metabolism and mineral status occur with higher dietary levels of vitamin A, Zn and Cu in the rat.
Animals↗
The challenge of regulating health claims and food fortification.
The Food and Drug Administration has several options that will assist the Public Health Service in implementing its September 1992 recommendation that all women of childbearing age consume 0.4 mg folic acid daily to reduce their risk of having a pregnancy affected with a neural tube defect. The FDA can authorize the use of a health claim on labels and in the labeling of foods that characterizes the relationship between a nutrient and a health-related condition. Fortification of cereal-grain products with folic acid is a second option that has the potential for reaching most women of childbearing age without requiring them to change their food selection patterns. Consideration of these options has been intertwined with rapid developments in the scientific database that is the foundation of the health claim, by conflicting opinions regarding the effectiveness for women in the target population of FDA's proposed level of cereal-grain fortification, by lack of systematic safety data regarding the impact of fortification on persons in the general population and by changes in the regulatory environment in which the agency acts.
Female↗
Evaluating food fortification options: general principles revisited with folic acid.
OBJECTIVES: This article uses folic acid as an example to illustrate some of the complex issues and general principles that emerge when evaluating fortification of the food supply as one possible means to address a public health recommendation. METHODS: Distributions of current daily folate intakes from conventional foods and dietary supplements were estimated. Intakes that might result from fortification of cereal-grain products and ready-to-eat cereals at various levels for eight age-gender groups were also estimated by using the US Department of Agriculture's 1987-1988 Nationwide Food Consumption Survey. RESULTS: The results illustrate that fortification of the US food supply tends to increase folate intakes of consumers at the high end of the intake distribution curves in the general population to a greater extent than it affects consumers at the low end of the intake distribution curves in the target population. CONCLUSIONS: The effectiveness of food fortification options for a target population and the safety for the general population impose conflicting challenges that must be considered concurrently when making decisions about fortifying the US food supply.
Adolescent↗
Pathological and immunological effects of ingesting L-tryptophan and 1,1'-ethylidenebis (L-tryptophan) in Lewis rats.
The eosinophilia-myalgia syndrome (EMS) has been associated with ingestion of L-tryptophan (L-TRP) produced by a single manufacturer. Epidemiological data implicated 1,1'-ethylidenebis (L-tryptophan) (EBT) (peak 97 or peak E) as a possible etiologic agent. We showed previously that Lewis rats treated with the L-TRP implicated in EMS develop fasciitis and perimyositis similar to those seen in human EMS. We now report the pathology associated with the treatment of Lewis rats with synthetic EBT and/or L-TRP. All animals treated for 6 wk with case-associated L-TRP or EBT developed significant myofascial thickening, compared with animals in the vehicle control and control L-TRP groups. However, even those animals receiving the control L-TRP showed a mild but significant increase in the thickness of the myofascia, compared with vehicle-treated control animals. All animals except vehicle controls also exhibited significant pancreatic pathology, including fibrosis and acinar changes. Only animals treated with case-associated L-TRP for 6 wk showed evidence of immune activation with increased frequency of CD8, Ia, and IL-2 receptor-positive cells in the peripheral blood. Animals receiving L-TRP or EBT for < 6 wk did not show significant differences in myofascial thickness, although these animals did show pancreatic acinar changes. Although these results demonstrate for the first time the pathological effects of EBT, they do not rule out the possibility that other impurities in the EMS-case-associated L-TRP may also contribute to some of the features of EMS.
Animals↗
Hepatic toxicity of unmodified and time-release preparations of niacin.
Niacin (nicotinic acid) is used frequently in the treatment of hypercholesteremia. It is available in both unmodified and time-release preparations. The latter were developed in attempts to minimize the skin-flushing reaction that affects virtually all users and may limit acceptance. Adverse effects on the liver from both unmodified and time-release preparations have been recognized for many years. We reviewed the literature on the hepatic toxicity of both types of niacin preparations. Adverse reactions in six patients resulted from the exclusive use of unmodified niacin and in two patients from the exclusive use of time-release preparations. In 10 additional patients, adverse reactions developed after an abrupt change from unmodified to time-release preparations. Many of these patients were ingesting time-release niacin at doses well above the usual therapeutic doses currently recommended. Signs of liver toxicity developed in less than 7 days in four of these 10 patients. In doses that achieve equivalent reductions in serum lipids, hepatic toxicity occurred more frequently with time-release preparations than with unmodified preparations. An awareness of toxicity associated with ingestion of high doses of time-release niacin preparations is important because of their widespread availability and the potential for self-prescribed, unmonitored use.
Chemical and Drug Induced Liver Injury↗
Anti-nutritive effects of dietary tin.
Tin is usually present in foods at levels of less than 4 micrograms/g. Higher levels may be found in some processed foods due to the addition of tin-based preservatives and stabilizers or to corrosion and leaching of the metal from unlacquered cans or from tin foils used in packaging. Estimates of dietary intake range from about 0.2 to greater than 5 mg Sn/day. Diets including a high proportion of canned vegetables and fish could supply greater than 30 mg Sn/day. Although intakes from dietary sources are generally considered to be harmless, a variety of adverse effects of tin have been reported, including effects on serum and bone alkaline phosphatase, lactic dehydrogenase, heme oxygenase, and 5-aminolevulinic acid dehydratase. Perturbations in glutathione metabolism have been reported, as have adverse effects on metabolism of essential trace minerals such as copper, zinc, and iron. Specific effects on calcium content of bone, serum, and kidney have also been described. Reported effects vary with the chemical form, dose of tin, and route and frequency of administration. Effects of tin in animal systems and on essential trace mineral absorption and excretion in human volunteers are reviewed. A summary of recent investigations on dietary tin-copper interactions and effects of tin on rat hepatocellular antioxidant protection are also presented.
Animals↗
Use of the Hildebrand grid nebulizer for inductively coupled plasma atomic emission spectrometric analysis of foodware leach solutions and rodent soft tissues and femurs.
The Hildebrand grid nebulizer (HGN) was used for the inductively coupled plasma atomic emission spectrometric determination of major, minor and trace elements in perchloric acid digests of rodent femurs, sulphuric acid digests of rodent soft tissues and in solutions leached from foodware using acetic acid. The HGN performed well when the signal-to-background ratio was optimized for each acid solution by adjusting the injector gas flow, solution uptake rate and observation height. Three problems were overcome while using the HGN: (i) nebulizer wash-out time was reduced by rinsing at high uptake rate with the solution to be analysed; (ii) clogging of the injector tip of the torch during femur analysis was minimized by extensive rinsing; and (iii) errors due to the suppression of the Cu, Fe, Mn and Zn signal intensities by matrix elements Ca and P in femur digests were eliminated by calibrating the spectrometer with matched matrix standard solutions. Overall, the precision of analysis for the leach and tissue solutions analysed in this study ranged from 0.5 to 2.9% relative standard deviation.
Acetates↗
Environmental pathology. Mast cell and eosinophil infiltration in intestinal mucosa of Lewis rats treated with L-tryptophan implicated in human eosinophilia myalgia syndrome.
A recently developed animal model for the L-tryptophan-associated eosinophilia myalgia syndrome was used to examine the small intestine and colon, because there is clinical involvement at these sites in patients. Increased perivascular inflammatory infiltrates rich in degranulating mast cells, eosinophils, and monocytes were seen in the lamina propria of experimental animals when compared with controls. L-Tryptophan-associated disease also shares many clinical features with idiopathic scleroderma/eosinophilic fasciitis, in which there is gastrointestinal involvement as well. These features are similar to those found in the recently described animal model. The apparent morphologic and clinical similarities between these entities suggest that the animal model is suitable for further studying the pathogenesis of the gastrointestinal involvement in all these diseases.
Animals↗
Developmental effects and mineral interactions in rats fed textured vegetable protein.
The teratogenic effects of feeding a diet based on textured vegetable protein to Long-Evans rats were studied along with maternal and fetal mineral interactions and their relationship to diet composition. Pregnant rats were fed purified diets containing 18% protein as casein (CAS), textured vegetable protein (TVP, from defatted soy flour) with 18 mg Zn/kg, or TVP diet with 100 mg Zn/kg. A fourth group was fed diet NIH-31. The animals received their diets throughout pregnancy and were sacrificed on day 20 of gestation. Fetuses were examined for developmental effects, and mineral levels were determined in maternal and fetal tissues by inductively coupled argon plasma-atomic emission spectrometry. Females fed the casein diet or diet NIH-31 had normal weight gains throughout pregnancy and their progeny exhibited normal development. The animals on the TVP-containing diet with 18 mg Zn/kg had decreased food consumption and body weights, and their fetuses exhibited developmental anomalies as well as reductions in size and weight. These developmental alterations may be the result of decreased zinc levels in the fetal tissues, caused by reduced bioavailability of the trace element in the maternal diet. Significant increases in tissue iron accompanied the low zinc levels. No developmental effects were found in animals receiving the high Zn-TVP diet, and mineral data from these animals were not significantly different from the casein group.
Animals↗
L-tryptophan implicated in human eosinophilia-myalgia syndrome causes fasciitis and perimyositis in the Lewis rat.
Tryptophan-associated eosinophilia-myalgia syndrome (L-TRP-EMS) is a newly described syndrome which occurred in epidemic fashion in the United States in the summer and fall of 1989. Epidemiologic data has linked the syndrome to intake of L-tryptophan (L-TRP) from one specific manufacturer, but the precise etiologic compound(s) must be established by replication of the syndrome in an appropriate animal model. In this study, implicated L-TRP, United States Pharmacopeia (USP) grade L-TRP, or vehicle was administered by gavage in a blinded fashion for 38 d to female Lewis rats at doses comparable with those ingested by patients who developed the eosinophilia-myalgia syndrome. Animals receiving implicated L-TRP, but not those receiving USP grade L-TRP or vehicle, developed histologic signs consistent with fasciitis and perimyositis, specific pathologic features of human L-TRP-EMS. Peripheral blood eosinophilia was not observed. Hypothalamic corticotropin releasing hormone mRNA levels were lower and plasma corticosterone levels tended to be lower in the animals that received implicated L-TRP. Plasma L-kynurenine was higher in both L-TRP-treated groups compared to the vehicle-treated animals. The female Lewis rat is known to be susceptible to a wide variety of inflammatory diseases. Identification of specific inflammatory changes in this rat following exposure to implicated L-TRP indicates that this animal model will be important in subsequent investigations into the etiology, pathogenesis, and treatment of human L-TRP-EMS.
Animals↗
Effects of dietary tin and copper on rat hepatocellular antioxidant protection.
The effects of dietary tin on copper status and on enzymes and metabolites involved in hepatocellular antioxidant protection were measured in rats fed copper-adequate or copper-deficient diets with glucose or fructose. Rats became copper-depleted after 4 weeks on diets containing less than 0.5 micrograms of copper/g as evidenced by significant decreases in liver copper and serum ceruloplasmin. Signs of copper deficiency occurred in copper-depleted rats fed diets containing 100 micrograms of tin/g. Significant effects of tin on liver glutathione peroxidase and superoxide dismutase activities and on liver iron and total glutathione concentrations were observed. Interactions between copper and tin on liver copper and iron and on liver superoxide dismutase and malondialdehyde production are reported. Adverse effects of feeding diets containing 100 micrograms of tin/g include (i) copper depletion in rats fed copper-adequate diets, (ii) accelerated development of copper deficiency in rats fed copper-deficient diets, and (iii) reduction in hepatocellular antioxidant protection.
Animals↗
Purified reference diets for weanling rats: effects of biotin and cellulose.
Standardized purified diets limited to required nutrients are needed for nutritional and toxicological studies. In the present study, we formulated a biotin- and cellulose-free diet of reproducible mineral composition (diet A), based on diet AIN-76, and fed it to weanling Long-Evans rats for 3 wk. Inductively coupled argon plasma atomic emission spectrometry was used to determine Ca, Cu, Fe, K, Mg, Mn, Na, P and Zn in liver, duodenum, kidney, spleen and femur. Results were compared with those obtained with rats fed biotin- and/or cellulose-supplemented variations of diet A, diet AIN-76 and diet NIH-31 (an open-formula stock diet). Weanling rats grew slowly and steadily on purified diet A. Growth rates increased when diet A was supplemented with biotin and cellulose. In general, differences among tissue mineral levels in rats fed diet NIH-31 and those fed diet AIN-76 were more pronounced than those among groups fed our purified diets. Values for hemoglobin and hematocrit were significantly lower in rats fed all purified diets than in those fed diet NIH-31. Diets A + biotin, A + cellulose and A + cellulose + biotin appear satisfactory as reference diets for measuring mineral interactions at near-requirement levels as well as effects of fiber on mineral utilization or for studies on vitamins whose endogenous synthesis may be influenced by dietary fiber.
Animal Feed↗
Trace element studies in weanling rats: maternal diets and baseline tissue mineral values.
The initial nutritional status of experimental animals can influence their response to subsequent dietary regimens. In the present study, we determined the variations in minerals in diet NIH-31, a breeding colony stock diet, and in tissues of weanling rats nursed by dams fed this diet. Inductively coupled plasma-atomic emission spectrometry (ICP-AES) was used to determine nine elements (Ca, Cu, Fe, K, Mg, Mn, Na, P and Zn) in diet and in liver, kidney, spleen, duodenum and femur from 22- to 26-day-old rats. Wet digestions were performed in mixtures of nitric, perchloric, and sulfuric acids (diets and soft tissues) or nitric and perchloric acids (femur). Solution concentrations ranged from less than 25 ng/ml for the trace elements to greater than 100 micrograms/ml for the major elements. Large variations in mineral content were found between batches of commercially prepared NIH-31 diet; relative amounts of Cu, Fe, Mn and Zn varied markedly. Significant differences in concentrations of major and trace minerals in liver, kidney, spleen and duodenal tissue were found among groups of weanling rats obtained from the same supplier at different times. Mn was readily quantitated in all tissues except spleen, where it was below detection limits. The precision obtained with the ICP-AES methodology has significant advantages for establishing variations in tissue mineral levels.
Animal Nutritional Physiological Phenomena↗
Retention of lead acetate in weanling and adult rats.
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Age Factors↗