Incidence and Severity in Relation to Magnitude of Intake above the ADI or TDI: Use of Critical Effect Data

Noncancer effects are considered to show thresholds, such that no effect would be produced when the intake is below the threshold. Application of a 100-fold uncertainty factor to the no-observed-adverse-effect level (NOAEL) for the critical effect in animal studies provides an estimate of an intake for sensitive humans (the acceptable daily intake or ADI) without significant adverse health effects. The risks of intakes by humans above the ADI theoretically move the most sensitive subjects from negligible risk to possible risk. An increase in intake above the ADI would move the population distribution of internal dose toward the dose–response curve for sensitive subjects. The proportion of a population affected depends on the magnitude of the excess intake, the relationship of the NOAEL and the biological threshold in animals, and the coefficient of variation for the kinetic parameters (e.g., clearance and bioavailability) which determine the internal dose in humans. The severity of any effect in sensitive and high-intake individuals depends on the magnitude of the excess intake, the nature of the critical effect, and the slope of the dose–response relationship.     

Is the acceptable daily intake as presently used an axiom or a dogma?

International scientific committees, regional scientific committees such as those of the European Union, and national regulatory agencies generally use the uncertainly factor approach for establishing acceptable or tolerable intakes of substances that exhibit thresholds of toxicity. No observed adverse effect levels (NOAELs) are identified in the critical studies to which appropriate uncertainly factors are applied to allocate acceptable daily intake (ADI). This paper discusses the different steps of the risk assessment process considered for decades worldwide a pragmatic approach to allocate safe doses, yet in need of improvements during the extrapolation phase which could increase the confidence level of the work performed by risk assessors.     

Comparison of estimated daily intakes of flavouring substances with no-observed-effect levels.

This study was conducted to determine the margins of safety between no-observed-effect levels (NOELs) and estimates of daily intake for 809 flavouring substances evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) between 2000 and 2004. Estimates of daily intake were calculated using two methods, the maximized survey-derived daily intake (MSDI) and the possible average daily intake (PADI). The MSDI estimates were based on the production volume of flavouring agents as reported by industry, whereas the higher more conservative PADI estimates were derived by multiplying the anticipated average use level of a flavouring substance in each of 33 food categories by the average amount of food consumed daily from that food category and summing the intake over all 33 food categories. These intake estimates were used to calculate the margins of safety for the flavouring agents to determine whether adequate margins of safety would still exist in the event that the MSDIs used by JECFA to evaluate the safety of flavouring substances underestimated daily intakes. Based on the calculation of the margins of safety using the MSDI values, 99.9% of the 809 flavouring substances evaluated by JECFA have margins of safety of greater than 100. In comparison, 98% of flavouring substances have margins of safety of greater than 100 when the margins of safety were calculated from PADI values. The results indicate that if the MSDI estimates used by JECFA for the evaluation of the safety of flavouring substances were underestimated, a wide margin of safety exists for all but a few of the flavouring substances even when intakes were estimated from PADI values.     

The application of in vitro data in the derivation of the Acceptable Daily Intake of food additives

The acceptable daily intake (ADI) for food additives is commonly derived from the NOAEL (no-observed-adverse-effect level) in long-term animal in vivo studies. To derive an ADI a safety or uncertainty factor (commonly 100) is applied to the NOAEL in the most sensitive test species. The 100-fold safety factor is considered to be the product of both species and inter-individual differences in toxicokinetics and toxicodynamics. Although in vitro data have previously been considered during the risk assessment of food additives, they have generally had no direct influence on the calculation of ADI values. In this review 18 food additives are evaluated for the availability of in vitro toxicity data which might be used for the derivation of a specific data-derived uncertainty factor. For the majority of the food additives reviewed, additional in vitro tests have been conducted which supplement and support the short- and long-term in vivo toxicity studies. However, it was recognized that these in vitro studies could not be used in isolation to derive an ADI; only when sufficient in vivo mechanistic data are available can such information be used in a regulatory context. Additional short-term studies are proposed for the food additives which, if conducted, would provide data that could then be used for the calculation of data-derived uncertainty factors.     

Estimated intake levels for Finnish children of methylmercury from fish

Methylmercury (MeHg) is a well-known neurotoxic agent, and consumption of contaminated fish is the principal environmental source of MeHg exposure in humans. Children are more susceptible to adverse effects than adults. No previous specific data exist for intake by Finnish children of methylmercury from fish. We estimated fish consumption and MeHg intakes from species most commonly consumed by Finnish children aged 1–6 years. The total mercury concentrations were determined in fish species consumed, and age-specific methylmercury intakes were derived. We also examined safety margins and the proportion of children exceeding the tolerable daily intakes set by international expert bodies. The daily intake of MeHg ranged from 0 to 0.33 μg/kg bw. The strictest reference value 0.1 μg/kg bw/day for MeHg, proposed by USEPA, was exceeded by 1–15% of the study population, and FAO/WHO JECFA provisional tolerable weekly intake of 1.6 μg/kg bw was exceeded by 1% of boys and 2.5% of girls aged 6 years. Intakes of 1-year old girls were higher than of boys, whereas for 3-year olds they were the opposite. The highest intakes were observed for 6-year-old boys and girls. There was great variation in the estimated MeHg intakes among Finnish children.     

Safety assessment of hydroxypropyl methylcellulose as a food ingredient

Hydroxypropyl methyl cellulose (HPMC; CAS No. 9004-65-3) is an odorless and tasteless, white to slightly off-white, fibrous or granular, free-flowing powder that is a synthetic modification of the natural polymer, cellulose. It is used in the food industry as a multipurpose food ingredient. HPMC is approved by FDA as both a direct and an indirect food additive, and is approved for use as a food additive by the EU. The JECFA has evaluated the food uses of HPMC and established an acceptable daily intake (ADI) of ‘not specified’ for such uses. Based on the no-observed-adverse-effect level (NOAEL) of 5000 mg/kg body weight/day from a 90-day feeding study in rats, a tolerable intake for ingestion of HPMC by humans of 5 mg/kg body weight/day is posited and, as such, is more than 100-fold greater than the estimated current consumption of 0.047 mg/kg body weight/day.     

Precision of Estimates of an ADI (or TDI or PTWI)

Factors influencing the precision of an acceptable daily intake (ADI) are discussed in this paper. As the same principles apply to tolerable daily intake (TDI) or provisional tolerable weekly intake (PTWI), although not specifically mentioned, this paper also refers to TDI and PTWI. The allocation of an ADI is in principle based on the most critical (many times the lowest) no-observed (adverse)-effect level [NO(A)EL] established in toxicological studies in experimental animals or in humans by applying a uncertainty factor for extrapolation from animals or humans to the general human population (and for the extrapolation from high to low intake levels). As the ADI predicts a virtual safe intake level for a life span exposure, to establish a NO(A)EL in general the toxicological database should include long-term studies, otherwise only a provisional ADI will be allocated for which a higher uncertainty factor is applied. The validity of an ADI greatly depends on the precision of the toxicological studies considered for the safety of a food additive or contaminant. The precision of the ADI is also inversely related to the uncertainty factors applied, although these uncertainty factors are not totally independent of the completeness and precision of the toxicological data from which a NO(A)EL is derived. This paper focuses on the precision of the toxicological data and the established NO(A)EL. Human data on the toxicity of a chemical which are preferred for the safety evaluation or hazard assessment are frequently not available or incomplete with respect to a quantitative dose–response assessment. Epidemiological studies will have inherent difficulties for hazard assessment such as possible confounders, restricted number of toxicological end points which can be studied, and limited quantitative data on oral exposure levels. Case report studies include the same limitations but in addition the exposure data are usually very imprecise due to reconstruction of the possible dose level(s). Case reports of intoxication are mainly restricted to acute and at best subacute effects. Controlled human exposure studies (human volunteer studies) are restricted in their experimental design such as the level of the dose and the toxicological end points due to medical ethical reasons. Therefore, quite rarely a safety evaluation of a food chemical will be solely based on human data. In the practice of hazard assessment of chemicals in foods the experimental animal studies will be totally or partly the basis for establishing an ADI. In these toxicological studies in animals there are many experimental variables which can affect the precision of an ADI, such as (1) duration of the experiment, dose ranges, identity, and purity of the substance; (2) the parameters and toxicological end points studied; (3) the species and strain used; (4) the gut microflora of the test animals; (5) dietary composition; (6) statistics performed; and (7) knowledge about the kinetic behavior and metabolism (e.g., elimination half-life and bioavailability of the chemical and its main metabolites) of the chemical considered. How these factors can influence the precision of a NO(A)EL, respectively the ADI, is illustrated by several examples. In relation to the question of incidental excursions of an ADI, it can be concluded that due to the variation in precision of experiments slight incidental excursions would not lead to an increased risk. However, to answer in general the question of how often and/or how much the total intake of a chemical in food may exceed the ADI is not possible. This should be considered case by case. To answer such a question, the precision for those studies representative for incidental excursions should be considered. Other factors which should be considered are (1) type of effect on which the ADI was based, (2) mechanism of toxicity, (3) toxicokinetics and metabolism, and (4) difference in NO(A)ELs from short-term toxicity studies with the NO(A)EL on which the ADI was based. Nevertheless, slight excursions of the intake above the ADI for a substance should always trigger additional consideration and if possible additional studies with high precision.     

Inter-ethnic differences in xenobiotic metabolism

The aim of safety assurance procedures is to determine a level of intake (the acceptable daily intake (ADI) or tolerable daily intake (TDI)) that is without adverse health effects in the human population. The majority of studies on inter-ethnic differences in xenobiotic metabolism have concentrated in the incidence of expression of the poor metaboliser phenotype for a number of drug metabolising enzymes. Such ethnic differences can result in different incidences of individuals at higher risk, but this would not affect the safety assurance/risk assessment outcome unless poor metaboliser status was not recognised in the database used for the initial assessment and calculation of ADI or TDI. Of far greater importance are ethnic differences which result in population differences in the mean values, and/or the extent of variability within the population, for key kinetic parameters such as the internal dose or area under the plasma concentration time curve (AUC). There are few studies on inter-ethnic differences in sensitivity and most of these relate to in vivo differences for therapeutic/pharmacological agents, so that the reported data reflect both kinetic and dynamic variability. Inter-ethnic differences are limited in extent and well within the uncertainty factor of 10 used for human variability.     

The Role of the World Health Organization in the Evaluation of Pesticides

The International Programme on Chemical Safety (IPCS), which is a cooperative program of the World Health Organization (WHO). United Nations Environment Programme (UNEP), and International Labour Organisation (ILO), directs a number of pesticide activities, including the WHO component of the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) and the preparation of Environmental Health Criteria (EHC) documents and Health and Safety Guides (HSGs) on pesticides. The intake of pesticide residues is being predicted at the international level, which is based upon the maximum residue limits (MRLs) that are estimated by JMPR. Acceptance of the MRLs is increased when the prediction does not exceed the acceptable daily intake (ADI). IPCS is active in developing new methodologies and in developing scientific consensus documents on the assessment of health risks from exposure to chemicals. Two new initiatives are a project to obtain agreement among important national institutions on the approaches to be taken for the interpretation of data relating to specific effects and the development of a "Joint Meeting on Pesticides," which will provide comprehensive reviews of pesticide safety and use.     

Risk assessment of micronutrients

Risk assessment of micronutrients has to take into account two different intake-response relationships; the risk of deficiency, which decreases with increase in intake, and the risk of toxicity, which increases with increase in intake. The available databases on micronutrients tend to focus on benefits at low intakes, and there are usually few reliable data on hazard identification and characterisation at high intakes. Application of the usual default uncertainty factors for species differences, human variability and database inadequacy could result in "recommended" upper intake levels that would cause deficiency. There have been a number of comprehensive reviews that have used low, and largely arbitrary, uncertainty factors to establish tolerable upper intake levels for vitamins and minerals. A recent FAO/WHO Workshop developed a structured approach to the application of a single composite uncertainty factor. Risk-benefit approaches have been developed recently that balance the risk of toxicity against the risk of deficiency, and offer the potential for more scientifically based methods.     

Regulatory history and experimental support of uncertainty (safety) factors

A synthesis of available literature on uncertainty (safety) factors which are used to estimate acceptable daily intakes (ADIs) for toxicants is presented. This synthesis reveals reasonable qualitative biological premises, as well as specific biological data that support both the use and choice of these factors. A suggestion is made in order to derive a range of ADI. Research needs in various areas of uncertainty are also identified.     

A procedure for the safety evaluation of flavouring substances. Joint FAO/WHO Expert Committee on Food Additives.

This review describes a procedure for the safety evaluation of flavouring substances. Over 2500 flavouring substances are currently in use in food. While toxicity data do not exist on all flavouring substances currently in use, within structurally related groups of flavouring substances many do have toxicity data and this information along with knowledge of structure-activity relationships and data on the daily intake provides a framework for safety evaluation. The safety evaluation procedure provides a scientifically based practical method of integrating data on intake, structure-activity relationships, metabolism and toxicity to evaluate flavouring substances in a timely manner. The procedure has been used recently by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) to evaluate a total of 263 flavouring substances.     

The JFFMA assessment of flavoring substances structurally related to menthol and uniquely used in Japan

Using the procedure devised by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), we performed safety evaluations on four flavoring substances structurally related to menthol (l-menthyl 2-methylbutyrate, dl-menthyl octanoate, dl-menthyl palmitate, and dl-menthyl stearate) uniquely used in Japan. While no genotoxicity study data were available in the literature, all four substances had no chemical structural alerts predictive of genotoxicity. Moreover, they all four are esters consisting of menthol and simple carboxylic acids that were assumed to be immediately hydrolyzed after ingestion and metabolized into innocuous substances for excretion. As menthol and carboxylic acids have no known genotoxicity, it was judged that the JECFA procedure could be applied to these four substances. According to Cramer’s classification, these substances were categorized as class I based on their chemical structures. The estimated daily intakes for all four substances were within the range of 1.54–4.71 μg/person/day and 60–1250 μg/person/day, using the methods of Maximized Survey-Derived Intake and Single Portion Exposure Technique, respectively, based on the annual usage data of 2001, 2005, and 2010 in Japan. As the daily intakes of these substances were below the threshold of concern applied to class I substances viz., 1800 μg/person/day, it was concluded that all four substances raise no safety concerns when used for flavoring foods under the currently estimated intake levels.     

Comparison of estimated daily per capita intakes of flavouring substances with no-observed-effect levels from animal studies.

A study was conducted to determine the margins of safety between no-observed-effect levels (NOELs) and daily per capita intake of flavouring substances evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) using the safety evaluation procedure for flavouring substances. The safety evaluation procedure provides a practical method for integrating data on intake, structure-activity relationships, metabolism and toxicity to evaluate flavouring substances. The comparison of NOELs to intake reinforces the fact that the margins of safety between intake of flavouring substances and their representative NOELs is very large. 98% of flavouring substances have margins of safety greater than 1000, illustrating that even if intake was underestimated by several fold, in almost every case, a wide margin of safety would still exist.     

Excursions of Intake above ADI: Case Study on Cadmium

High oral intake of cadmium via food or drink in a single dose by humans gives rise to vomiting, abdominal pain, and diarrhea. Concentrations of cadmium in drinks giving rise to such symptoms have been 16 mg/liter and higher corresponding to doses of 3 mg and higher. Longer term intakes of food (rice) with concentrations around 1 mg/kg corresponding to daily intakes of 600 μg have given rise to some less pronounced symptoms including signs of malabsorption. Reproductive and developmental effects have been observed in animal experiments at oral and other exposures. The present provisional tolerable weekly intake (PTWI) for Cd is 500 μg (a weekly intake of 7 μg/kg body wt), corresponding to a daily intake of 70 μg or 1 μg per kg body wt. Recent data demonstrating renal dysfunction in humans at even lower lifelong oral exposures indicate that the PTWI needs to be lowered in the future. An estimated lowest-observed-adverse-effect level (LOAEL) for symptoms from the gastrointestinal tract in humans after intake of a single oral dose is 43 μg/kg body wt. If a safety factor of 3–10 is used based on LOAEL, a tolerable single dose would be 0.3–1 mg (4 to 14 μg/kg body wt). For longer time exposures (months–a few years) daily intakes of 200 μg (3 μg/kg body wt) may be tolerated without obvious gastrointestinal symptoms or signs. At present, there is no convincing human evidence that such doses can cause reproductive or developmental effects, but since such effects have been reported in animals, it may be advisable not to exceed a daily intake of 1 μg/kg body wt for such potentially sensitive subsections of the population as children and women who are pregnant or lactating. Any excursions above the PTWI need to be compensated for by a corresponding period with intake below the PTWI in order for the cumulative dose to be low enough to avoid the long-term effects of cadmium on the kidney.     

The joint food and agriculture organization of the united nations/world health organization expert committee on food additives and its role in the evaluation of the safety of veterinary drug residues in foods

The Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) recommended the evaluation of food additives at the international level through the establishment of an expert committee or committees. These committees evaluated the safety of food additives present as residues resulting from the use of pesticides or veterinary pharmaceuticals. The results of these meetings include international harmonization on acceptable daily intake of these compounds and the maximum residue limit that is permitted to be present within any food of animal or plant origin. The decisions rendered by these committees provide a key element in the elimination of international trade barriers associated with products intended for human consumption.     

Assessment of safety/risk of chemicals: inception and evolution of the ADI and dose-response modeling procedures.

This article reviews the procedures for the assessment of safety/risk of chemicals to human health. Because the nature and severity of toxicity and the extent of the database vary from chemical to chemical, the assessment is done on a case by case basis. Essentially 5 steps are involved in the assessment: (a) identification of hazards based on appropriate human and animal data; (b) determination of the dose-response relationship of the adverse effects of the chemical; (c) extrapolation of the dose-response data from test subjects to human populations; (d) estimation of the exposure; and (e) assessment of the safety/risk of the chemical under a specified exposure. Emphasis in this article, however, is placed on the extrapolation of the dose-response data to the human situation. The extrapolation is done by the identification of a no-observed-adverse-effect level (NOAEL) and the application of a safety factor, thereby arriving at an acceptable daily intake (ADI). The safety factor is selected on the basis of, inter alia, the severity of the adverse effect and the adequacy of the database. On the other hand, with genotoxic carcinogens, mathematical modeling is used for extrapolation. This is because the effects of genotoxic carcinogens are generally believed to have no threshold. The ADI approach, which involves the identification of a NOAEL, is therefore not applicable. A number of mathematical models have been developed to assess, from the dose-response data, either the risks that may be associated with a specified dose, or the 'virtually safe dose' at a specified risk level. The evolution, application and shortcomings of these procedures and the potential improvements in the ADI approach and in the dose-response characterization based on these mathematical models are also discussed.     

Assessment of dietary intake of flavouring substances within the procedure for their safety evaluation: advantages and limitations of estimates obtained by means of a per capita method.

The procedure for the safety evaluation of flavourings adopted by the European Commission in order to establish a positive list of these substances is a stepwise approach which was developed by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and amended by the Scientific Committee on Food. Within this procedure, a per capita amount based on industrial poundage data of flavourings, is calculated to estimate the dietary intake by means of the maximised survey-derived daily intake (MSDI) method. This paper reviews the MSDI method in order to check if it can provide conservative intake estimates as needed at the first steps of a stepwise procedure. Scientific papers and opinions dealing with the MSDI method were reviewed. Concentration levels reported by the industry were compared with estimates obtained with the MSDI method. It appeared that, in some cases, these estimates could be orders of magnitude (up to 5) lower than those calculated considering concentration levels provided by the industry and regular consumption of flavoured foods and beverages. A critical review of two studies which had been used to support the statement that MSDI is a conservative method for assessing exposure to flavourings among high consumers was performed. Special attention was given to the factors that affect exposure at high percentiles, such as brand loyalty and portion sizes. It is concluded that these studies may not be suitable to validate the MSDI method used to assess intakes of flavours by European consumers due to shortcomings in the assumptions made and in the data used. Exposure assessment is an essential component of risk assessment. The present paper suggests that the MSDI method is not sufficiently conservative. There is therefore a clear need for either using an alternative method to estimate exposure to flavourings in the procedure or for limiting intakes to the levels at which the safety was assessed.     

Codex Committee on Pesticide Residues--a plan for improved participation by governments.

The Codex Committee on Pesticide Residues (CCPR), which is responsible for establishing maximum residue limits (MRLs) for pesticides on food, has a vital role in protecting the public health and facilitating international trade. Codex MRLs are based on scientific evaluations by expert panels that constitute the Joint FAO/WHO Meeting on Pesticide Residues (JMPR). These panelists estimate an acceptable daily intake for a pesticide and expected level of residue remaining in food when the pesticide is used according to good agricultural practice. The goals of the CCPR are not being fully achieved. Governments are generally not accepting Codex MRLs; instead, technical and procedural aspects of the JMPR and CCPR process are being criticized. The CCPR is responding to valid criticisms of the process; however, governments may still lack the will to seek harmonization of pesticide limits for food in international trade. Overcoming this problem will be difficult, but not impossible. A plan of action is proposed that allows countries to selectively accept Codex MRLs, increase the number of chemicals in the JMPR/CCPR system for evaluation, and be responsive to both their consumers and their food producers without compromising national health and safety standards and competitive trade advantages.     

Assessment of Extreme Levels of Chronic Food Intakes

Acceptable daily intake (ADI) of food constituents refers to “daily ingestion over a lifetime.” There is a need to determine mean and extreme daily intakes of defined constituents, in order to compare them with their ADI. The significance of overstepping the ADI during long periods must be discussed in relation with the definition of chronic toxicity. It is seldom possible to obtain original data on the intakes of food constituents, which must be evaluated from data on food intakes. Such data issued mainly from the French Observatoire des Consommations Alimentaires are used to present and discuss the choice of cut-off points (percentiles) to determine unacceptable high-level intakes. When distributions of individual intakes of food are available, the estimation of extreme levels of food intakes from mean intakes is possible with precautions. The characterization of extreme consumers is helpful to define target groups for informative or preventive actions. Foresight of extreme consumptions is made difficult due to time-related and generation effects.