Overall assessment factor

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. 

Calabrese and Gilbert (1993) reassessed the use of multiple UFs in the risk assessment process. Their intention was to establish that the UFs display a mixture of independence and interdependence based on their inherent properties and the nature of specific toxicological and epidemiological studies. The authors demonstrated the lack of independence of the interspecies and intraspecies UFs, as well as of the intraspecies and the less-than-Ufetime UFs, and proposed revised UF values based on the concept of the relationship of independent and interdependent UFs, see Section 5.2.1.2. 

Vermeire et al. (1999) stated that in the standard procedure for deriving acceptable limit values, various assessment factors are multiplied to obtain an overall assessment factor. However, multiplication of assessment factors implies a piling up of worst-case assumptions the probability of simultaneous occurrence of worst-case situations for the same chemical is smaller than the occurrence of a single worst-case situation. Therefore, the higher the number of extrapolation steps, the higher the level of conservatism. The piling up of worst-case assumptions can be avoided by using probability distributions (Section 5.11). 

Gaylor et al. (1999) have proposed a total default UF in the order of 10,000 for severe, irreversible adverse health effects when establishing human exposure guidelines based on a benchmark dose (BMDLjo) derived from animal data. For reversible biological effects, a smaller default UF in the order of 1000 may be employed. 

In the 2002 review (US-EPA 2002) of the RfD and RfC processes the US-EPA stated that the exact value of the UFs chosen should depend on the quality of the studies available, the extent of the 

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The risk assessment comprises an effect assessment (hazard identification and hazard characterization) and an exposure assessment. The principles for the effect assessment of the active substances are in principle similar to those for existing and new chemicals and are addressed in detail in Chapter 4. Based on the outcome of the effect assessment, an Acceptable Daily Intake (ADI) and an Acceptable Operator Exposure Level (AOEL) are derived, usually from the NOAEL by applying an overall assessment factor addressing differences between experimental effect assessment data (usually from animal studies) and the real human exposure situation, taking into account variability and uncertainty for further details the reader is referred to Chapter 5. As a part of the effect assessment, classification and labeling of the active substance according to the criteria laid down in Directive 67/548/EEC (EEC 1967) is also addressed (Section 2.4.1.8). 

The TGD has been revised and the second edition was published in 2003 (EC 2003). However, the human health risk characterization part was not included in this second edition. A final draft version of the human health risk characterization part was released in 2005 with a detailed guidance on, among others, the main issues to be included in derivation of the reference MOS (MOSref), which is analogous to an overall assessment factor. The individual factors contributing to the MOSref are described separately and guidance is given on how to combine these into the MOSref. The guidance provided in this draft version has been extensively used in relation to the risk assessment of prioritized substances carried out since the draft version was released however, this version is not publicly available. 

Principally, the overall assessment factor is established by multiplication of the separate factors. The authors note that in practice it is not possible to distinguish all above-mentioned factors, and some factors are not independent of each other. Therefore, straightforward multiplication may lead... 

Application of assessment factors derived from currently estimated distributions of assessment factors may lead to very wide distributions of the overall assessment factor. 

The EU TGD (EC 2003) pointed out that the nature and severity of the effect needs to be considered in the evaluation of the MOS (can be interpreted as an overall assessment factor). 

KEMI (2003) noted the high level of conservatism in the standard procedure to obtain an overall assessment factor by multiplication of the individual assessment factors. It was therefore recommended that distributions of the assessment factors should be used in the calculation of the overall assessment factor, if available (Section 5.11). However, it was recognized that such data are only available for the interspecies factor and the factor for duration of exposure. 

The overall assessment factor is the product of a number of assessment factors accounting for uncertainties related to various extrapolation steps (inter- and intraspecies, route-to-route, subchro-nic-to-chronic, LOAEL-to-NOAEL, namre and severity of effect, and database-deficiency). However, the higher the number of extrapolation steps, the higher the level of conservatism. Since the different assessment factors are not always independent of each other, straightforward multiplication may lead to unreasonably high factors, and discussion are and weighing of individual factors are essential to establish a reliable and justifiable overall assessment factor. Some aspects to consider in the final qualitative discussion are ... 

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. 

It has been suggested by, e.g.. Slob and Pieters (1998), Kalberlah and Schneider (1998), Vermeire et al. (1999), and KEMI (2003) to use probabihty distributions for the various types of assessment factors in order to achieve a more precise estimation of the degree of statistical certainty and to avoid the piling up of worst-case assumptions in the overall assessment factor. 

In this method, each assessment factor is considered uncertain and characterized as a random variable with a lognormal distribution with a GM and a GSD. Propagation of the uncertainty can then be evaluated using Monte Carlo simulation (a repeated random sampling from the distribution of values for each of the parameters in a calculation to derive a distribution of estimates in the population), yielding a distribution of the overall assessment factor. This method requires characterization of the distribution of each assessment factor and of possible correlations between them. As a first approach, it can be assumed that all factors are independent, which in fact is not correct. 

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. 

The toxicity exposure ratio approach, rather than a more rigid standard setting approach (Section 8.2.2), allows greater room for expert judgment because the size of an overall assessment factor is not fixed. Furthermore, this approach can be readily applied to substances for which limited data are available. The risk assessor can decide how wide the MOS should be in the light of the data available. 

Guidance values are developed from a standard such as, e.g., an Acceptable/Tolerable Daily Intake (ADI/TDI), and Reference Dose/Concentration (RfD/RfC). For threshold effects, the standard is derived by dividing the No-Observed-Adverse-Effect Level (NOAEL) or Lowest-Observed-Adverse-Effect Level (LOAEL), or alternatively a Benchmark Dose (BMD) for the critical effect (s) by an overall assessment factor, described in detail in Chapter 5. For non-threshold effects, the standard is derived by a quantitative assessment, described in detail in Chapter 6. 

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