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1. Oral levodopa frequently produces an episodic delay in gastric emptying which leads to multiple peak concentrations of the drug in plasma. We have studied the effects of multiple dosing of levodopa on gastric emptying and levodopa absorption in eight healthy young volunteers in a randomised two-way cross-over study. 2. The plasma concentration-time curves for levodopa were measured after three oral doses of 125 mg given at 2 h intervals and compared with the concentration-time curve for levodopa following administration of two doses of placebo and a single oral dose of 125 mg. 3. A low incidence of multiple peak plasma concentrations of levodopa was detected after all doses of levodopa. The area under the plasma concentration-time curves (AUC) for the final dose of levodopa (150.8 +/- 22.0 micrograms ml-1 min) was lower than for the two preceding doses (205.7 +/- 41.8 and 199.5 +/- 51.8 micrograms ml-1 min) but not different from that of the single dose given at the same time of day (141.7 +/- 29.1 micrograms ml-1 min). This indicates that the lower AUC of the final dose of levodopa was related to the time of administration and not a result of the two preceding doses. 4. The absence of any significant effects of preceding doses of levodopa on gastric emptying was confirmed a) by co-administration of soluble paracetamol, as a marker of gastric emptying, with the second dose of levodopa or placebo and b) by co-administration of radiolabelled DTPA and gamma-camera imaging with the final dose of levodopa on the multiple dosing day and the single dose of levodopa on the placebo day.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

1. The effects of adding slow release nifedipine in doses of 20 mg and 40 mg twice daily to atenolol therapy (50 mg twice daily) were assessed in 18 patients with chronic stable angina. 2. The addition of the lower dose of nifedipine to atenolol did not significantly alter the weekly consumption of glyceryl trinitrate or the mean number of anginal attacks as assessed by diary cards. However, 2 h after dosing there was a significant prolongation during stress testing in the time to onset of both 1 mm ST depression on the ECG (by 28%) and to angina (by 37%) compared with atenolol alone, but no benefit was apparent by 12 h after dosing. 3. At a dose of 40 mg twice daily, nifedipine significantly reduced glyceryl trinitrate consumption by 25% and the number of anginal attacks by 36%. The times to onset of ST depression and angina were increased by 37% and 55% respectively at 2 h and by 24% and 26% respectively 12 h after dosing. 4. Analysis of the frequency distribution of anginal attacks showed decreasing efficacy with time after administration of nifedipine. The overall results also suggest a relationship between efficacy and the plasma nifedipine concentration, with a mean 20% improvement in time to development of angina occurring at a nifedipine plasma concentration of approximately 30-40 ng ml-1. 5. In conclusion, the reduction of effort-related angina by nifedipine is related to its plasma concentration and the effective duration of action of the 20 mg slow release formulation is less than 12 h. [ABSTRACT FROM AUTHOR]

1. The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa was investigated in young and elderly healthy volunteers. 2. The plasma clearance of levodopa following intravenous administration of 50 mg was 14.2 +/- 2.8 (s.d.) ml min-1 kg-1 in the elderly compared with 23.4 +/- 4.1 ml min-1 kg-1 in the young (P less than 0.01) which resulted in a 49% greater area under the plasma concentration-time curve (AUC) in the older subjects (P less than 0.01). The volume of distribution (Vss) was lower in the elderly (1.01 +/- 0.29 l kg-1) than in the young (1.65 +/- 0.39 l kg-1) (P less than 0.002). 3. Following oral administration of 250 mg of levodopa the AUC was 2512 +/- 588 ng ml-1h in the elderly compared with 1056 +/- 282 ng ml-1h in the young (P less than 0.002). Cmax was also significantly greater in the elderly (P less than 0.05). The bioavailability of levodopa was significantly greater in the elderly (0.63 +/- 0.12 compared with 0.41 +/- 0.16, P less than 0.01). 4. In the presence of carbidopa, the plasma clearance of intravenous levodopa (50 mg) was reduced in both age groups but remained lower in the elderly (5.8 +/- 0.9 ml min-1 kg-1 compared with 9.3 +/- 1.0 ml min-1 kg-1; P less than 0.01). This resulted in a 54% greater AUC in the older subjects (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

The plasma concentrations of sodium cromoglycate were measured for 4 h following a single dose of 20 mg given by inhalation to six normal volunteers. A series of forced expiratory manoeuvres was performed 2 h after the dose, which resulted in a rapid and marked increase in the plasma concentrations of the drug. A similar increase was found in three volunteers who undertook a single deep inspiration at 4 h. These data indicate that the absorption of cromoglycate from the airways can be affected by manoeuvres used to assess lung function. [ABSTRACT FROM AUTHOR]

1. The pharmacokinetics and metabolism of nifedipine have been studied in a population of 59 young male volunteers following administration of a 10 mg capsule. 2. The area under the plasma concentration-time curves (AUC) for nifedipine demonstrated a skewed but not a bimodal distribution (mean 154 ng ml-1 h; range 54-306 ng ml-1h). 3. Calculation of the ratio of the AUC of nifedipine to the AUC of its nitropyridine metabolite did not separate those individuals with high AUC values of nifedipine from the remainder of the population. 4. Similarly there was no evidence for bimodality in the excretion of the major urinary metabolite. Those subjects with high plasma AUC values for nifedipine excreted similar amounts to the remainder of the population. 5. In contrast to a previous study using a 20 mg oral dose, there was no evidence of polymorphism in the pharmacokinetics or metabolism of nifedipine following a single 10 mg oral dose. [ABSTRACT FROM AUTHOR]

1. The effects of age on the pharmacology of nifedipine were investigated in 11 young and six elderly normotensive volunteers. 2. Following 2.5 mg of nifedipine i.v. the plasma clearance of nifedipine was 348 +/- 83 (s.d.) ml min-1 in the elderly compared with 519 +/- 125 ml min-1 in the young (P less than 0.05) and the AUC in the elderly was significantly greater at 125 +/- 28 ng ml-1 h compared with 83.9 +/- 19 ng ml-1 h (P less than 0.05). The Vss was similar in both age groups. 3. Following 10 mg oral sustained release nifedipine the AUC was 281 +/- 64 ng ml-1 h in the elderly compared with 136 +/- 56 ng ml-1 h in the young (P less than 0.002) and Cmax in the elderly was significantly greater at 36.8 +/- 11.8 ng ml-1 compared with 22.3 +/- 5.8 ng ml-1 (P less than 0.05). The trend towards an increased bioavailability in elderly subjects (36%) was supported by a significantly lower nitropyridine metabolite/nifedipine ratio in the elderly. 4. Absorption rate limited kinetics of the sustained release formulation were indicated by the prolonged t1/2 compared with i.v. administration. In the elderly t1/2 (oral) was significantly greater than in the young (elderly 6.7 +/- 2.2 h, young 3.8 +/- 1.4 h, P less than 0.05). 5. Haemodynamic changes in the young were confined to a tachycardia following i.v. administration. In the elderly, supine BP fell significantly following both oral and i.v. nifedipine while the heart rate remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

1. The trans-hepatic extraction of nifedipine during steady state infusion was studied in six patients undergoing cardiac catheterisation for suspected coronary disease. 2. Mean extraction ratio across the liver was 0.64 but hepatic clearance accounted for a mean of only 65% of total body clearance. 3. These results are consistent with the liver as the major site of metabolism of nifedipine, but also suggest that significant metabolism occurs outside the liver. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of a novel 20 mg biphasic release tablet of nifedipine were compared with the conventional 10 mg capsule and 20 mg sustained release preparations in healthy volunteers. The influence of food and posture on the pharmacokinetics of the biphasic tablet were studied. In the fasting state, the time to peak concentration of nifedipine was not significantly different between the 20 mg biphasic and 20 mg sustained release tablets, but plasma concentrations were higher between 2 and 4 h after the biphasic tablet. The terminal elimination half-lives of the two formulations were similar. In subjects who fed prior to nifedipine administration there was no significant difference between either the peak plasma concentration or terminal half-life of the biphasic tablet and two 10 mg capsules of nifedipine. When the biphasic preparation was given after a standard breakfast, the time to peak plasma concentration was significantly longer and the terminal half-life shorter than when given in the fasting state. The dissolution characteristics of the biphasic tablet were influenced by prior administration of food to an extent which may be of clinical significance during twice daily administration. [ABSTRACT FROM AUTHOR]

1 The pharmacokinetics of isoxicam have been compared in 57 volunteers with an average age of 31.3 years and 48 elderly subjects with an average age of 71.9 years. 2 Isoxicam was given in a single daily dose of 200 mg for up to 22 days. Similar plasma concentrations were obtained in the two age groups, average maximum concentrations being 39.7 mg l-1 in those under 65 and 38.1 mg l-1 in the elderly. There were no significant differences in the half-life which averaged 30.4 and 32.1 h respectively. 3 Approximately 9% of all those studied had half-life values in excess of 50 h. The results are consistent with the possibility of genetic polymorphism of isoxicam hydroxylation. 4 It is concluded that isoxicam is suitable for use in once daily dosage and that there are no clinically significant differences in its pharmacokinetics between young and elderly subjects. [ABSTRACT FROM AUTHOR]

Oral administration of nifedipine (20 and 30 mg tablets) to six volunteers was associated with a bioavailability of 0.43 and the presence of its nitropyridine analogue in the plasma. This metabolite was present in only trace amounts in samples taken from the same volunteers following i.v. administration of nifedipine. The peak plasma concentrations and area under the plasma concentration-time curve suggest that the nitropyridine analogue is a major, first pass, metabolite of nifedipine. [ABSTRACT FROM AUTHOR]

Acebutolol was administered orally in a single dose of 200 mg to 17 individuals whose renal function varied markedly. The plasma half-life and elimination rate constant for acebutolol showed a four-fold variation but these did not correlate with the degree of renal impairment. However, there was a good correlation between the renal clearance of creatinine and that of acebutolol (P less than 0.001). The half-life and elimination rate of the acetyl metabolite, diacetolol, were subject to 10-fold inter-individual variability which correlated significantly with the creatinine clearance and serum creatinine concentration. The AUC for the acetyl metabolite showed a 40-fold individual variation which also correlated with renal function. It is concluded that renal elimination is the principal route of excretion for diacetolol but not the parent compound, acebutolol. [ABSTRACT FROM AUTHOR]

The absorption and elimination of a single 500 mg dose of methyldopa has been studied after oral administration to 10 normal volunteers, 10 patients with coeliac disease, who were on a gluten-free diet, and to five patients with Crohn's disease. In patients with Crohn's disease the percentage of the dose recovered in urine (24%) was about one-half of normal (50%). This decreased absorption was associated with reduced plasma concentrations of both free and conjugated methyldopa and a decreased pharmacological response. In patients with coeliac disease the percentage of dose recovered in urine (43%) was similar to normals, indicating a normal absorption of the drug. However, the plasma concentrations of both free and conjugated methyldopa were significantly higher than normal, although there was no increase in drug-related effects. These findings confirm the importance of using indices other than drug plasma concentrations in the assessment of bioavailability in disease states. [ABSTRACT FROM AUTHOR]

To investigate possible mechanisms of levodopa-induced gastric stasis, we have studied the effect of other amino acids on gastric emptying. The large neutral amino acid tryptophan delays gastric emptying in the dog at molar concentrations below those required to stimulate duodenal osmoreceptors. In healthy volunteers, we have shown that neither tryptophan nor the small neutral amino acid glycine delayed gastric emptying when given in concentrations similar to those of levodopa which produce gastric stasis. The study suggests that levodopa does not inhibit gastric emptying by an effect on duodenal amino acid receptors or via osmoreceptors. [ABSTRACT FROM AUTHOR]

The developmental neurotoxicity of calcium cyclamate was evaluated in Sprague Dawley [Crl:CD(SD)] rats, administered in drinking water, in comparison to a concurrent control group (water) and a positive control group given propylthiouracil (PTU). Calcium cyclamate was administered to F0 females for 4 weeks prior to pairing, throughout mating, gestation and lactation and to F1 offspring from weaning to 12 weeks of age, PTU was administered by gavage to F0 females from Day 6 of gestation up to Day 20 of lactation. Target calcium cyclamate doses were 0, 250, 500 and 1,000 mg/kg bw/day, while the PTU dose was 0.5 mg/kg bw/day. No treatment-related effects of cyclamate were observed in either the F0 or F1 generations on reproductive performance or neurobehavioral development. In comparison, PTU exposure resulted in developmental delays, memory impairment and a number of neuropathological and morphometric outcomes. The results from the unique developmental neurotoxicity study design, corroborate the absence of hyperactivity and any other neurotoxic effects following cyclamate administration at levels up to 878 mg/kg bw/day in F0 females and 784 mg/kg bw/day in F1 animals. This demonstrates the suitability of PTU as a positive control and confirms the safe use of cyclamate as a no-calorie sweetener., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Based on recent research, an upper limit of safe intake (ULSI) for leucine is proposed for healthy adults: 0.53 g/(kg·d). Because leucine has been used as a dietary supplement for many years in people practicing exercise and sport, further study with long-term exposure to leucine in this specific subpopulation should be performed to eventually adjust the ULSI.

The present review explores the interactions between sweeteners and enteroendocrine cells, and consequences for glucose absorption and insulin release. A combination of in vitro, in situ, molecular biology and clinical studies has formed the basis of our knowledge about the taste receptor proteins in the glucose-sensing enteroendocrine cells and the secretion of incretins by these cells. Low-energy (intense) sweeteners have been used as tools to define the role of intestinal sweet-taste receptors in glucose absorption. Recent studies using animal and human cell lines and knockout mice have shown that low-energy sweeteners can stimulate intestinal enteroendocrine cells to release glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. These studies have given rise to major speculations that the ingestion of food and beverages containing low-energy sweeteners may act via these intestinal mechanisms to increase obesity and the metabolic syndrome due to a loss of equilibrium between taste receptor activation, nutrient assimilation and appetite. However, data from numerous publications on the effects of low-energy sweeteners on appetite, insulin and glucose levels, food intake and body weight have shown that there is no consistent evidence that low-energy sweeteners increase appetite or subsequent food intake, cause insulin release or affect blood pressure in normal subjects. Thus, the data from extensive in vivo studies in human subjects show that low-energy sweeteners do not have any of the adverse effects predicted by in vitro, in situ or knockout studies in animals.

This paper presents the work of an expert group established by the International Life Sciences Institute - European branch (ILSI Europe) to follow up the recommendations of an international conference on "Risk Assessment of Compounds that are both Genotoxic and Carcinogenic: New Approaches". Twelve genotoxic and carcinogenic chemicals that can be present in food were selected for calculation of a Margin of Exposure (MOE) between a point of departure on the dose-response for oral carcinogenicity in animal studies and estimates of human dietary exposure. The MOE can be used to support prioritisation of risk management action and, if the MOE is very large, on communication of a low level of human health concern. Depending on the approaches taken in determining the point of departure and the estimation of exposure, it is possible to derive very different values for the MOE. It is therefore essential that the selection of the cancer endpoint and mathematical treatment of the data are clearly described and justified if the results of the MOE approach are to be trusted and of value to risk managers. An outline framework for calculating an MOE is proposed in order to help to ensure transparency in the results., (Copyright 2009 ILSI Europe. Published by Elsevier Ltd.. All rights reserved.)

Extensive discussion sessions were held at the end of each of the 2 d of the workshop. Through the course of the workshop, it became clear that there were different opinions on how to use uncertainty factors to obtain upper levels of intake from no observed adverse effect levels of a particular nutrient and that the selection of an appropriate uncertainty factor would be rather arbitrary. Much of the discussion centered around the potential for using metabolic limits, expressed as the level of intake at which the major pathway of metabolism may approach saturation and at which the amino acid is metabolized by alternative pathways, as a measurable early or surrogate marker for amino acid excess and possible toxicity. After extensive discussion on various conditions that would need to be satisfied for metabolic limits to be used as markers of excessive intake of amino acids, there was a general consensus that methods such as measuring oxidation limits are an attractive approach that merit future investigation. It was noted that there are many data on the clinical use of glutamine, whereas data for proline are very scarce. There was recognition that regardless of the available data, there is regulatory pressure for setting upper levels of intake for amino acids and that much more data are required.

The toxicokinetics and metabolism of rebaudioside A, stevioside, and steviol were examined in rats for comparative purposes to determine whether toxicological studies conducted previously with stevioside would be applicable to the structurally-related glycoside, rebaudioside A. Single, oral doses of the radiolabelled compounds were extensively and rapidly absorbed with plasma concentration-time profiles following similar patterns for stevioside and rebaudioside A. Elimination of radioactivity from plasma was essentially complete within 72h. All plasma samples had similar metabolite profiles; the predominant radioactive component in all samples was steviol, with lower amounts of steviol glucuronide(s) and low levels of one or two other metabolites. Rebaudioside A, stevioside, and steviol were metabolized and excreted rapidly, with the majority of the radioactivity eliminated in the feces within 48h. Urinary excretion accounted for less than 2% of the administered dose for all compounds in both intact and bile duct-cannulated rats, and the majority of the absorbed dose was excreted via the bile. After administration of the compounds to intact and bile duct-cannulated rats, radioactivity in the feces was present primarily as steviol. The predominant radioactive compound detected in the bile of all cannulated rats was steviol glucuronide(s), indicating de-conjugation in the lower intestine. Overall, the data on toxicokinetics and metabolism indicate that rebaudioside A and stevioside are handled in an almost identical manner. These studies support the use of toxicological safety studies conducted with stevioside for the safety assessment of rebaudioside A.

There are more published dietary exposure data for intense sweeteners than for any other group of food additives. Data are available for countries with different patterns of sweetener approvals and also for population groups with high potential intakes, such as children and diabetic subjects. These data provide a secure basis for predicting the potential intakes of a novel intense sweetener by adjustment of the reported intakes of different sweeteners in mg/kg body weight by their relative sweetness intensities. This approach allows the possibility that a novel sweetener attains the same pattern and extent of use as the existing sweeteners. The intakes by high consumers of other sweeteners allows for possible brand loyalty to the novel sweetener. Using this method, the estimated dietary exposures for rebaudioside A in average and high consumers are predicted to be 1.3 and 3.4mg/kg body weight per day for the general population, 2.1 and 5.0mg/kg body weight per day for children and 3.4 and 4.5mg/kg body weight per day for children with diabetes. The temporary ADI defined by the JECFA for steviol glycosides [JECFA, 2005. Steviol glycosides. In: 63rd Meeting of the Joint FAO/WHO Expert Committee on Food Additives. World Health Organization (WHO), Geneva, Switzerland, WHO Technical Report Series 928, pp. 34-39] was set at 0-2mg/kg body weight (expressed as steviol equivalents); after correction for the difference in molecular weights, these estimated intakes of rebaudioside A are equivalent to daily steviol intakes of less than 2mg/kg. In consequence, this analysis shows that the intakes of rebaudioside A would not exceed the JECFA temporary ADI set for steviol glycosides.

A review of the role of gut microbiota in the metabolism of the steviol glycosides, stevioside and rebaudioside A, indicates that they are not absorbed intact but undergo hydrolysis by the intestinal microflora to steviol. Steviol is not metabolized by the intestinal flora and is absorbed from the intestine. The rate of hydrolysis for stevioside is greater than for rebaudioside A. Recent studies using mass spectrometry have shown that steviol-16,17-epoxide is not a microbial metabolite of steviol glycosides. Bacteroides species are primarily responsible for hydrolysis via their beta-glucosidase activity. Fecal incubation studies with both human and animal mixed flora provide similar results, and this indicates that the rat is an appropriate model for studies on steviol glycosides. Given the similarity in the microbial metabolism of stevioside and rebaudioside A with the formation of steviol as the single hydrolysis product that is absorbed from the intestinal tract, the toxicological data on stevioside are relevant to the risk assessment of rebaudioside A.

The threshold of toxicological concern (TTC) has been used for the safety assessment of packaging migrants and flavouring agents that occur in food. The approach compares the estimated oral intake with a TTC value derived from chronic oral toxicity data for structurally-related compounds. Application of the TTC approach to cosmetic ingredients and impurities requires consideration of whether route-dependent differences in first-pass metabolism could affect the applicability of TTC values derived from oral data to the topical route. The physicochemical characteristics of the chemical and the pattern of cosmetic use would affect the long-term average internal dose that is compared with the relevant TTC value. Analysis has shown that the oral TTC values are valid for topical exposures and that the relationship between the external topical dose and the internal dose can be taken into account by conservative default adjustment factors. The TTC approach relates to systemic effects, and use of the proposed procedure would not provide an assessment of any local effects at the site of application. Overall the TTC approach provides a useful additional tool for the safety evaluation of cosmetic ingredients and impurities of known chemical structure in the absence of chemical-specific toxicology data.

Three biodisposition studies with taurine were performed in male and female adult rats at dosages of 30 and 300 mg/kg. A single oral dose of (14)C-taurine was rapidly absorbed, distributed to tissues and excreted unchanged in urine. Elimination of radioactivity from intracellular pools was slow. Pre-treatment of animals for 14 days with unlabelled taurine did not significantly affect the fate of (14)C-taurine. At the higher dose there was more extensive excretion combined with a lower percentage of the dose in the carcass, indicating the possibility of saturation of the tubular reabsorption mechanism for taurine. Daily administration of unlabelled taurine for 14 days did not result in an increase in total taurine in the brain. The data indicate that exogenous taurine rapidly equilibrates with endogenous body pools and that any excess is rapidly eliminated by the kidneys.

The present paper examines the particular difficulties presented by low levels of food-borne DNA-reactive genotoxic carcinogens, some of which may be difficult to eliminate completely from the diet, and proposes a structured approach for the evaluation of such compounds. While the ALARA approach is widely applicable to all substances in food that are both carcinogenic and genotoxic, it does not take carcinogenic potency into account and, therefore, does not permit prioritisation based on potential risk or concern. In the absence of carcinogenicity dose-response data, an assessment based on comparison with an appropriate threshold of toxicological concern may be possible. When carcinogenicity data from animal bioassays are available, a useful analysis is achieved by the calculation of margins of exposure (MOEs), which can be used to compare animal potency data with human exposure scenarios. Two reference points on the dose-response relationship that can be used for MOE calculation were examined; the T25 value, which is derived from linear extrapolation, and the BMDL10, which is derived from mathematical modelling of the dose-response data. The above approaches were applied to selected food-borne genotoxic carcinogens. The proposed approach is applicable to all substances in food that are DNA-reactive genotoxic carcinogens and enables the formulation of appropriate semi-quantitative advice to risk managers.

This review provides an account of recent developments arising from a database that defined human variability in phase I metabolism (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, hydrolysis, alcohol dehydrogenase), phase II metabolism (N-acetyltransferases, glucuronidation, glycine conjugation, sulphation) and renal excretion. This database was used to derive pathway-related uncertainty factors for chemical risk assessment that allow for human variability in toxicokinetics. Probe substrates for each pathway of elimination were selected on the basis that oral absorption was >95% and that the metabolic route was the primary route of elimination of the compound (60-100% of a dose). Intravenous data were used for compounds for which absorption was variable. Human variability in kinetics was quantified for each compound from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups of the population using parameters relating to chronic exposure (metabolic and total clearances, area under the plasma concentration-time curve (AUC)) and acute exposure (Cmax) (data not presented here). The pathway-related uncertainty factors were calculated to cover 95%, 97.5% and 99% of the population of healthy adults and of each subgroup. Pathway-related uncertainty factors allow metabolism data to be incorporated into the derivation of health-based guidance values. They constitute an intermediate approach between the general kinetic default factors (3.16) and a chemical-specific adjustment factor. Applications of pathway-related uncertainty factors for chemical risk assessment and future refinements of the approach are discussed. A knowledge-based framework to predict human variability in kinetics for xenobiotics showing a threshold dose below which toxic effects are not observed, is proposed to move away from default assumptions.

Traditionally, different approaches have been used to determine the recommended dietary allowances for micronutrients, above which there is a low risk of deficiency, and safe upper levels, below which there is a negligible risk of toxicity. The advice given to risk managers has been in the form of point estimates, such as the recommended dietary allowance (RDA) and the tolerable upper level (UL). In future, the gap between the two intake-response curves may become narrower, as more sensitive indicators of deficiency and toxicity are used, and as health benefits above the recommended daily allowance are taken into account. This paper reviews the traditional approaches and proposes a novel approach to compare beneficial and adverse effects across intake levels. This model can provide advice for risk managers in a form that will allow the risk of deficiency or the risk of not experiencing the benefit to be weighed against the risk of toxicity. The model extends the approach used to estimate recommended dietary allowances to make it applicable to both beneficial and adverse effects and to extend the intake-incidence data to provide a range of estimates that can be considered by the risk manager. The data-requirements of the model are the incidence of a response at one or more levels of intake, and a suitable coefficient of variation to represent the person-to-person variations within the human population. A coefficient of variation of 10% or 15% has been used for established recommended dietary allowances and a value of 15% is proposed as default for considerations of benefit. A coefficient of variation of 45% is proposed as default for considerations of toxicity, based on analyses of human variability in the fate and effects of therapeutic drugs. Using this approach risk managers, working closely with risk assessors, will be able to define ranges of intake based on a balance between the risks of deficiency (or lack of benefit) and toxicity.