Dietary supplements: what is in the public's best interest?
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Consumer Advocacy↗
Biomedical subjects
J N Hathcock
Publications and source records attributed to J N Hathcock.
Over-the-counter chromium and renal failure.
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Food, Fortified↗
Vitamins and minerals: efficacy and safety.
Safety and efficacy are crucial but separate issues for vitamin and mineral supplements. Misinterpretation of "safe and adequate" to mean "safety limit" would impose restrictions on vitamin and mineral intakes that are not needed to ensure safety. Substantial evidence indicates that intakes greater than the recommended dietary allowances (RDAs) of certain vitamins and minerals such as calcium, folic acid, vitamin E, selenium, and chromium reduce the risk of certain diseases for some people. Limitation of intakes to the RDAs would preclude reductions in disease risk from these nutrients. The margin of safety between the usual dietary intake and the intake that would produce adverse effects varies greatly among the different nutrients. Very high intakes of vitamins A and D, niacin, pyridoxine, and selenium have produced adverse effects. Many widely discussed putative adverse effects of vitamin C, vitamin E, and trivalent chromium have little factual basis. There is no evidence of adverse effects from beta-carotene supplements except in current heavy smokers.
Heart Diseases↗
Safety limits for nutrients.
The occurrence of adverse health effects from ingestion of any substance depends on its inherent toxic potential, the amount of intake, and the biological characteristics of the exposed individual. A safe intake is one that provides an acceptable margin of safety below the intake that carries risk of adverse effects. If appropriate data are available, applying fixed safety factors, systematically varying safety factors or using other methods to identify reasonable limits for safe intakes. A crucial factor in understanding the margin of safety that a particular intake is likely to provide is the adequacy of the data to estimate the likely frequency of the adverse response among persons with that intake. For a few nutrients there are sufficient numbers of reports of adverse effects over a sufficiently wide range of exposures to allow estimation of lowest adverse effect levels; for other nutrients the reports of adverse effects are too infrequent or inconsistent to support estimations that are meaningful.
Adult↗
Applications of antioxidants in physiologically functional foods: safety aspects.
Intense public and scientific debate exists over whether the intake of some nutrients above the recommended dietary allowances may provide benefits beyond their traditional functions. However, excessive intakes of nutrients are well documented to cause adverse effects. This review focuses on methods that may be useful for identifying chronic intakes that result in adverse effects and for identifying intakes that provide a reasonable margin of safety from these effects. Groups responsible for nutrition and health policy must establish effective criteria for establishing safety limits, for validating end points, and determination of data acceptability. These criteria are needed to minimize toxicity while maximizing potential health benefits of exaggerated nutrient intake.
Antioxidants↗
Marginal zinc status does not exacerbate pancreatic carcinogenesis associated with dietary soybean trypsin inhibitor concentrate in rats.
Although the etiology of pancreatic cancer is largely unknown, diet-associated factors may play a role. Male Sprague-Dawley rats (14 d of age) were given a single injection of either saline or azaserine and were weaned (21 d) to diets with either adequate (30 micrograms/g) or low (9 micrograms/g) zinc, with or without 1.0 g/100 g active trypsin inhibitor in the form of soybean trypsin inhibitor concentrate. Experimental diets were fed for 14 wk. Regardless of dietary zinc status, diets with soybean trypsin inhibitor concentrate caused hyperplasia and/or hypertrophy of the pancreas. Pancreatic zinc content was not different among groups. Low dietary zinc levels did not affect total body growth rate or serum zinc concentration. Tibia zinc was also used as an indicator of zinc status. Tibia zinc concentration was lower in rats fed diets low in zinc relative to adequate zinc diets. Azaserine-induced acidophilic foci were larger and more numerous when soybean trypsin inhibitor concentrate was present in the diet regardless of dietary zinc level. Thus, low zinc does not exacerbate the soybean trypsin inhibitor concentrate effects that promote pancreatic cancer.
Animals↗
Safety limits for nutrient intakes: concepts and data requirements.
The possible quantitative methods calculating safety limits for nutrient intakes are related conceptually to those used to calculate safe limits for exposure to environmental chemicals and to the therapeutic index used to assess the relative safety of drugs. The impact of using a fixed SF has been compared with the use of variable SFs. Of the methods identified, the SRM gives lower limits than does the MPM. However, neither of these methods calculates safety limits below the RDA, even for nutrients with narrow margins of safety. The acceptability criteria for toxicity data for use in identifying safety limits are an issue of major importance and must be resolved before calculated limits may be used to support policy or regulatory decisions. An advantage of adopting a standard formula involving systematically varying SFs to calculate safety limits is that the margin of safety below the expected range of toxicity for each nutrient would be systematic, without having the safety limit for any nutrient regress below its RDA. Once the data acceptability criteria were met, the safety limit would be identified objectively. The confidence in and reasonableness of safety limits, regardless of the method used to define them, will be enhanced if the objectives, data criteria, and the quantitative method have been agreed upon ahead of time by groups responsible for nutrition and health policy. Even with such agreement, the confidence in using such procedures to support policy decisions will be improved by the extent and quality of the data base on toxicity and adverse reactions associated with consumption of excessive levels of the nutrients under consideration.
Adult↗
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↗
Prolonged acetaminophen ingestion by mice fed a methionine-limited diet does not affect iron-induced liver lipid peroxidation or S-adenosylmethionine.
This study determined whether acetaminophen (ACAP)-induced glutathione depletion was associated with liver lipid peroxide formation, or the concentrations of liver S-adenosylmethionine and S-adenosylhomocysteine in mice fed diets with L-methionine below or at the requirement level (0.25 or 0.5%) for 7 wk. Iron dextran (281 mg/kg body wt) or saline was administered for 2 d before measurement of lipid peroxide formation. Chronic dietary ACAP (0.5%) in mice fed 0.25% methionine caused a failure to maintain body weight even though food intake was similar to intake by all other treatment groups. Liver GSH (measured as nonprotein sulfhydryl concentration) and cysteine concentrations were depleted by ACAP and by ACAP plus iron. Liver lipid peroxide formation was increased by iron but was not altered additionally by ACAP ingestion. Liver glutathione peroxidase activity was increased by methionine in controls, whereas glutathione S-transferase activity was increased by ACAP ingestion in mice fed 0.5% methionine compared with controls. Liver S-adenosylmethionine and nuclear 5-methyldeoxycytidine concentrations were not affected by dietary ACAP or methionine. Liver S-adenosylhomocysteine levels were lower in mice fed ACAP and 0.25% methionine compared with mice fed ACAP and 0.5% methionine. In conclusion, chronic ACAP did not increase the susceptibility of mice to liver lipid peroxidation or alter the availability of methyl groups for methylation reactions.
Acetaminophen↗
Oral cobalamin for treatment of pernicious anemia?
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Administration, Oral↗
Residue trypsin inhibitor: data needs for risk assessment.
Trypsin inhibitor (TI) occurs naturally in many foods from plants, notably soybean protein products. Heat treatment inactivates TI and improves nutritional quality, but residual TI activity of 5 to 20% remains after typical commercial treatments. Chronic feeding of TI or products that contain TI can inhibit trypsin and chymotrypsin, stimulate their secretion, cause hypertrophy and hyperplasia of the pancreas, and lead to adenomas and carcinomas of the exocrine pancreas. In the rat, TI promotes pancreatic carcinogenesis initiated by azaserine. Data needed for possible risk assessment on TI would include 2-year bioassays from animals treated with TI and fed diets carefully controlled for type and amount of fat (which also promotes pancreatic carcinogenesis). The effects of TI on protein nutrition would have to be considered when identifying the maximum tolerated dose. Major reductions in human dietary TI exposure may not be feasible because of the multiple sources of TI, the substantial promotion by other factors such as fat, and the adverse effects of excessive heat on food products. For risk assessment of TI in a particular food, other promotors and the feasibility of decreasing TI intake must be considered.
Animals↗
Nutritional toxicology: basic principles and actual problems.
Nutritional toxicology is a specialty that combines the backgrounds and research approaches of nutrition and toxicology. Many problems of substantial importance to health and food safety involve interactions of nutrition process and requirement with the effects of toxicological impact. Solution of these problems requires research that meets the procedural and design criteria of experimental nutrition and these of experimental toxicology. The relationships may be described in three basic categories: (1) influence of nutrition on toxicities; (2) influence of toxicants on nutrition; and (3) toxicities of nutrients. Trypsin inhibitor research, an example of diet impacting on toxicological response, illustrates the necessity of controlling nutritional composition aspects that can confound the results. Prolonged acetaminophen administration provides an example of the effects of toxicants on nutritional requirement and function which could be important for persons with marginal sulphur amino acid intake.
Animals↗
Evaluation of vitamin A toxicity.
Toxicity has been associated with abuse of vitamin A supplements and with diets extremely high in preformed vitamin A. Consumption of 25,000-50,000 IU/d for periods of several months or more can produce multiple adverse effects. The lowest reported intakes causing toxicity have occurred in persons with liver function compromised by drugs, viral hepatitis, or protein-energy malnutrition. Certain drugs or other chemicals may markedly potentiate vitamin A toxicity in animals. Especially vulnerable groups include children, with adverse effects occurring with intakes as low as 1,500 IU.kg-1.d-1, and pregnant women, with birth defects being associated with maternal intakes as low as approximately 25,000 IU/d. The maternal dose threshold for birth defects cannot be identified from present data. An identifiable fraction of the population surveyed consumes vitamin A supplements at 25,000 IU/d and a few individuals consume much more. beta-Carotene is much less toxic than vitamin A.
Abnormalities, Drug-Induced↗
Prolonged acetaminophen ingestion in mice: effects on the availability of methionine for metabolic functions.
The objective of this study was to determine the effect of prolonged ingestion of acetaminophen (ACAP) on the availability of methionine for its metabolic functions in mice. ACAP was fed to weanling mice at levels of 0.0, 0.3, 0.5 or 0.8% of the diet, with methionine provided at requirement (0.5%) or at twice the requirement (1.0%) level, for 2 wk to assess its effect on the availability of methionine for growth. In another study, ACAP was fed to adult mice at levels of 0.0, 0.4, or 0.6% of the diet, with methionine at 0.5 or 1.0% of the diet, for 2 wk to assess its effect on the availability of methionine for protein synthesis and methylation reactions. The growth rate of weanling mice decreased with increasing dietary ACAP in mice fed 0.5% methionine, but not in those fed 1.0%. Hepatic reduced glutathione (GSH) decreased and plasma glutamic-pyruvic transaminase activity increased in an ACAP dose-dependent manner in weanling mice fed 0.5% methionine. Protein synthesizing ability decreased in adult mice fed 0.5% methionine and 0.6% ACAP. Relative liver weight and liver lipid decreased with increasing dietary ACAP in mice fed methionine at or above requirement. Neither plasma creatinine or muscle creatine was affected by variations in dietary methionine or ACAP. Ingestion of ACAP for a prolonged period of time increased the methionine requirement for growth, maintenance of hepatic GSH level and protein synthesis, but did not affect the methionine requirement for methylation reactions.
Acetaminophen↗
High nutrient intakes--the toxicologist's view.
At sufficiently high intake all substances, including essential nutrients, can be toxic. Toxicity may be described by characteristics of the symptoms (identity, severity and degree of persistence) and by the dose-response relationship (threshold, slope, limit, susceptibility to modulation by other substances and tendency to bioaccumulate). Some nutrient toxicities are deleterious exaggerations of essential functions, whereas others are not. The therapeutic indices for nutrients should be defined as the ratio of the lowest toxic dose to the recommended intake, the ratio of the medians of the effective and the toxic doses commonly used in pharmacology. For infant formulas, a ratio of the lowest toxic concentration to the maximum concentration allowed is an analogous ratio. Nutrients with low therapeutic indices and small physical size of a toxic dose require special caution to avoid excessive intake. Modulation of absorption, metabolism or excretion, as well as the physiological state of the exposed individual, may alter the minimum toxic intake of a nutrient and hence alter the risk of toxicity. Extrapolation to estimate the toxic dose can be made on the basis of body weight, body surface area or food intake. Nutrient minimums and maximums in infant formula are set on a 100-kcal basis and thus are related to heat loss and surface area. Evaluation of vitamin A toxicity cases on a dose per 100-kcal basis suggest that the current maximum in infant formula is appropriate. Extrapolation from toxicity data in adults can be made on the dose per 100-kcal basis to estimate appropriate infant formula maximums for nutrients for which maximums have not been set.
Adult↗
Effects of methionine and other sulfur compounds on drug conjugations.
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Amino Acids, Sulfur↗
Effects of prolonged acetaminophen ingestion and dietary methionine on mouse liver glutathione.
Acetaminophen (ACAP) was fed to adult Swiss-Webster mice for 4 weeks to examine the effect of prolonged ACAP ingestion on hepatic reduced glutathione (GSH) concentrations. In the first experiment, male and female mice were pair-fed diets containing ACAP at levels of 0.0 (control), 0.3, 0.6, and 1.0% of diet on a dry weight basis with the total sulfur-amino acids provided at 0.5% of the diet. Hepatic GSH was depleted, and the percentage of dose excreted as the urinary ACAP-GSH-derived conjugate increased in a dose-dependent manner with increasing ACAP. Serum glutamic-pyruvic transaminase activity, relative liver weight, and hepatic microsomal protein content increased in the group given 1.0% ACAP, but microsomal aniline hydroxylation decreased. In the second experiment, adult male mice were fed ad libitum diets containing 0.0 or 0.6% ACAP with total L-methionine provided at 0.25, 0.5 (requirement level), or 1.0%. Hepatic GSH was markedly depleted 1 week after initiation of ACAP treatment in all groups except those receiving 1.0% methionine. This reduction persisted throughout the 4-week treatment period. After 4 weeks, liver cysteine was also reduced as a result of ACAP ingestion and methionine deficiency, whereas serum inorganic sulfate concentration was not changed. Reduction in hepatic cysteine levels was also prevented by 1.0% dietary methionine. The dose-dependent depletion of GSH, the trend toward an increase in ACAP-GSH-derived conjugate excretion, and the prevention of GSH depletion by providing dietary methionine in excess of requirement indicate that prolonged ingestion of ACAP may increase the requirement for sulfur-containing amino acids and limit the availability of methionine and cysteine for protein synthesis, methylation reactions, and drug detoxification.
Acetaminophen↗