Tolerable intake

Criteria for setting tolerable intakes and tolerable concentrations... 

According to WHO/IPCS (1994), the critical effect(s) is The adverse effect(s) judged to be most appropriate for determining the tolerable intake. ... 

The approach of deriving a tolerable intake by dividing the N/LOAEL, or alternatively a BMD for the critical effect(s) by an assessment factor has been described and discussed extensively in the scientihc literature. It is beyond the scope of this book to review all these references. This chapter presents an overview of pubhshed extrapolation methods for the derivation of a tolerable intake based on the assessment factor approach, i.e., limited to address effects with threshold characteristics, and is not meant to be exhaustive. The main focus is on the rationale for and the use of the assessment factors. Pertinent guidance documents and reviews for the issues addressed in this chapter include WHO/IPCS (1994, 1996, 1999), US-EPA (2002, 2004), IGHRC (2003), ECETOC (2003), KEMI (2003), Kalberlah and Schneider (1998), Vermeire et al. (1999), and Nielsen et al. (2005). 

Tolerable Intake is Estimated maximum amount of an agent, expressed on a body mass basis, to which each individual in a (sub) population may be exposed over a specified period without appreciable risk. ... 

A tolerable intake may have different units depending on the route of administration upon which it is based, and is generally expressed on a daily or weekly basis. For the oral and dermal routes, a tolerable intake is generally expressed on a body weight basis, e.g., mg/kg body weight per day. Though not strictly an intake, tolerable intakes for inhalation are generally expressed as an airborne concentration, e.g., mg/m. ... 

The term acceptable is used widely to describe safe levels of intake and is apphed for chemicals to be used in food production such as, e.g., food additives, pesticides, and veterinary dmgs. The term tolerable is applied for chemicals unavoidably present in a media such as contaminants in, e.g., drinking water and food. The term PTWI (Provisional Tolerable Weekly Intake) is generally used for contaminants that may accumulate in the body, and the weekly designation is used to stress the importance of limiting intake over a period of time for such substances. The tolerable intake is similar in definition and intent to terms such as Reference Dose and Reference Concentration (RfD/RfC), which are widely used by, e.g., the US-EPA. For some substances, notably pesticides, the ARID (Acute Reference Dose), is also established, often from shorter-term studies than those that would support the ADI. The ARfD is defined as the amount of a substance in food that can be consumed in the course of a day or at a single meal with no adverse effects. 

For systemic effects observed in inhalation smdies, the determining factor for effects to occur at the systemic target is generally the total dose rather than the concentration of the chemical in the air. In such cases, a tolerable intake (expressed as mg/kg body weight per day, or mg/m depending on the standard to be derived, i.e., a tolerable intake in its strict meaning, or a tolerable concentration) is estabhshed from the NOAEC, or LOAEC, derived in the inhalation smdy and adjusted for continuous exposure. 

The overall principles for the derivation of a tolerable intake are equal irrespective of chemical class (e.g., food additives, pesticides, veterinary drags, contaminants) although it should be recognized that the available database for chemicals dehberately added to, e.g., food is generally more... 

The assessment factors generally apphed in the estabhshment of a tolerable intake from the NOAEL, or LOAEL, for the critical effect(s) are apphed in order to compensate for rmcertainties inherent to extrapolation of experimental animals data to a given human situation, and for rmcertainties in the toxicological database, i.e., in cases where the substance-specific knowledge required for risk assessment is not available. As a consequence of the variabihty in the extent and nature of different databases for chemical substances, the range of assessment factors apphed in the establishment of a tolerable intake has been wide (1-10,000), although a value of 100 has been used most often. An overview of different approaches in using assessment factors, historically and currently, is provided in Section 5.2. 

These parameters are parallel to those being considered in the evaluation of the assessment factors to be applied in the establishment of a tolerable intake. 

When appropriate chemical-specific data are available, a CSAF can be used to replace the relevant default sub-factor for example, suitable data defining the difference in target organ exposure in animals and humans could be used to derive a CSAF to replace the uncertainty sub-factor for animal to human differences in toxicokinetics (a factor of 4). The overall UF would then be the value obtained on multiplying the CS AF(s), used to replace default sub-factor(s), by the remaining default sub-factor(s) for which suitable data were not available. In this way, chemical-specific data in one area could be introduced quantitatively into the derivation of a tolerable intake, and data would replace uncertainty. 

In conclusion, the traditional assessment factors (interspecies, intraspecies, subchronic-to-chronic, LOAEL-to-NOAEL, and database-deficiency) are considered to cover the concerns and uncertainties for children adequately, i.e., no children-specific assessment factor is needed when setting tolerable intakes. However, it is recommended to perform children-specific risk assessments for chemical substances in products and foods intended for children, based on specific exposure assessments for children. 

Risk assessments are usually based on data from studies in animals of similar age. In addition, the animals are initially healthy and are fed with the same feed, etc. The NOAEL from animal smdies is extrapolated to a tolerable intake that is considered to be without appreciable health risk for the general population. This raises the questions whether it is possible to generalize to the average human population or whether there is any particular vulnerable subpopulation that should be taken into consideration in the risk assessment. 

Most toxicity studies are performed using oral exposure to the test chemical. However, in some situations, the predominant routes of exposure in humans are via inhalation or dermal contact, e.g., in the working environment. In the case where relevant data are lacking on the exposure route of interest for the derivation of a tolerable intake, a route-to-route extrapolation is used. A route-to-route extrapolation includes an examination of whether knowledge resulting from studies involving one exposure route can be applied to another exposure route. For example, it can be examined whether the internal dose after oral intake is identical to the internal dose following inhalation. 

The most relevant study to base a hazard assessment and derivation of a tolerable intake upon is a study that reflects the human exposure situation as well as possible. In many cases a lifelong exposure is the most relevant exposure scenario for humans and a hfetime animal study (in practice a chronic study) is the most relevant study on which to base the assessment. In other situations where the expected human exposure is of limited duration, for example in seasonal work with plant protection products lasting 2 or 3 months per year, or occasionally, for example use of certain consumer products, the assessment should preferably be based on studies of shorter duration. 

One of the most evident limitations in the NOAEL approach in the derivation of tolerable intakes is that it does not take into account the slope of the dose-response curve for the particular response of interest (Section 4.2.4). The NOAEL is by definition one of the doses tested, and apart from ensuring that the number and spacing of data points are adequate to provide a reasonable estimate of the NOAEL, all other data points are ignored. Although the NOAEL could be considered an estimate of the tme NAEL, the quality of the estimate cannot be assessed. For the dose-response relationship and precision in the NOAEL, consideration should therefore be given to the uncertainties in the NOAEL as the surrogate for the NAEL. 

In conclusion, the uncertainty related to the confidence in the database should be taken into account by the use of an assessment factor. Since the quality, completeness, and/or consistency of different databases vary, the assessment factor will also vary and can only be assigned on the basis of expert judgment, preferably made transparent through the application of a set of criteria. In any case, the size of the factor should be considered in terms of other information in the database. The default value should be 1 in case of a high-confidence database, and a factor of 10 would be appropriate where major deficiencies in the data exist, e.g., a lack of chronic and reproductive toxicity studies when setting a tolerable intake. 

One of the crucial assumptions affecting how the assessment factors are implemented in the derivation of tolerable intakes is that they are independent of each other. This assumption has led to the conclusion that the overall assessment factor is obtained by multiplication of the individual assessment factors discussed in the previous Sections 5.3 through 5.9. This section gives an overview of the validity of this approach. Then, the key issues are summarized and our recommendations are presented. 

In conclusion, discussion and weighing of the individual assessment factors are essential in order to establish a rehable and justifiable overall assessment factor, and the possible overlap in the individual assessment factors should be recognized in the justification for the overall factor. If an unreasonable high total factor (in the order of 10,000) is established, then the resulting tolerable intake is considered to be too imprecise, and it should be realized that the database is too limited in order to derive a tolerable intake. 

The tolerable intake (TI) is calculated by dividing the NOAEL (or LOAEL) for the critical effect(s) by the derived overall assessment factor (AF) ... 

The precision of the tolerable intake depends therefore largely on the magnimde of the overall assessment factor. The precision is probably to one significant figure at best, and more usually to one order of magnitude for assessment factors of 1000 or more, the precision becomes even less. 

Implicit from the definition of the tolerable intake, i.e., an estimate of the intake of a substance over a lifetime that is considered to be without appreciable health risk, arises the question What are the health implications of exceeding the tolerable intake This issue has been discussed at an ELSI (International Life Science Instimte) Europe Workshop on the Significance of Excursions of Intake above the Acceptable Daily Intake (ADI) in 1999. The following questions were asked (Larsen and Richold 1999, Larsen 2006) ... 

The approach of deriving a tolerable intake for non-threshold effects has been described and discussed extensively in the scientific hteramre. It is beyond the scope of this book to review all... 

The approach of deriving a tolerable intake for threshold effects is addressed in Chapter 5. 

The development of health-based guidance values, which are derived from the tolerable intake, is addressed in Chapter 9. 

Valid epidemiological studies are preferable for the quantitative risk assessment of genotoxic carcinogens for the purpose of deriving a tolerable intake. If such data are available, for example in the working environment, they can be used quantitatively to convert work exposure to lifetime exposure, i.e., to convert intermittent exposure to continuous exposure (see Section 5.1 for adjustment of concentrations). However, as addressed in Chapter 3, valid human data are seldom available. 

The outcome of low-dose extrapolation is the resulting lifetime cancer risk associated with estimated exposure for a particular population. A wide range of models have been developed for low-dose extrapolation of animal data to calculate a tolerable intake for an acceptable risk, often set at one extra cancer per million exposed persons (see Section 6.2.4 for acceptable risk). 

An alternative approach to a quantitative assessment is to divide the highest dose at which there is no observed increase in tumor incidence in comparison with controls by a large composite UF, for example 5000 as suggested by Wed (1972). The magnimde of the factor could be a function of the weight of evidence, e.g., numbers of species in which the mmors have been observed or namre of the mmors (WHO/IPCS 1994). The adequacy of this approach, which is sometimes used when data on dose-response are limited, must be judged by criteria similar to those used in developing a tolerable intake for threshold effects this is addressed in detail in Chapter 5. 

Risk characterization is thus the step in the risk assessment process where the outcome of the exposure assessment (e.g., daily intake via food and drinking water, or via inhalation of airborne substances) and the hazard (effects) assessment (e.g., NOAEL and tolerable intake) are compared. If possible, an uncertainty analysis should be carried out, which produces an estimation of the risk. Several questions should be answered before comparison of hazard and exposure is made ... 

The most frequently used POD for threshold effects (Section 4.2) is the NOAEL (Section 4.2.4). This NOAEL is generally obtained from studies in experimental animals. If reliable human data are available to derive the NOAEL, this value is preferable to the NOAEL from experimental animals. Where a NOAEL cannot be derived, a LOAEL, if available, can be used. An alternative POD to the NOAEL/LOAEL is the benchmark dose (BMD) (Section 4.2.5). The tolerable intake can also, in some cases, form the basis as the POD. In this chapter, the POD will be denoted as a derived no-effect level (DNEL) in order to provide a general term for the various types of PODs that can form the basis for the risk characterization. 

This form of risk assessment is based on the concept of defining an exposure level, the derived standard, expressed usually on a temporal basis (e.g., daily, weekly), which is considered to offer sufficient reassurance of protection of human health, and then comparing this with an estimated level of exposure. If the estimated exposure is higher than the standard, then further regulatory intervention may be needed. Please see Section 5.12 for a discussion of the health implications of exceeding the tolerable intake. 

Expert judgment is required to weigh these individual parameters on a case-by-case basis. The approach used should be transparent and a justification should be provided by the risk assessor for the conclusion reached. It should be recognized that these parameters are parallel to those being considered in the evaluation of the assessment factors to be apphed in the estabhshment of a tolerable intake (Chapter 5). It should be noted that the first edition of the TGD (EC 1996) did not provide any quantitative guidance on the minimal size of the MOS. 

Total allocations of less than 100% of the tolerable intake are recommended to account for, e.g., those media for which exposure has not been characterized, and cross-route exposure. The proportion of the total intake, which is not allocated, should vary according to the adequacy of the exposure characterization from all media. 

---