Assessment factors approach

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). 

As described in detail in this book, the use of assessment factors is an established practice in chemical risk assessment to account for uncertainties inherent in the hazard (effects) assessment and consequently, inherent in the risk assessment. The use of assessment factors to address this uncertainty is part of the conventional approach that has developed over the years. According to the current risk assessment paradigm, the usual approach is simply to multiply these individual assessment factors in order to establish an overall composite numerical assessment factor (Section 5.10). An alternative to the traditional assessment factor approach is to combine estimates of the ranges that these factors may encompass through a probabilistic assessment this is essentially a variation of the standard paradigm. 

Safe, S. (1998) Hazard and Risk Assessment of Chemical Mixtures Using the Toxic Equivalency Factor Approach. Environmental Health Perspectives, 106(Suppl. 4), 1051-1058. 

For threshold effects, traditionally, a level of exposure below which it is believed that there are no adverse effects estimated, based on an approximation of the threshold termed the No-Observed-(Adverse)-Effect Level (NO(A)EL) and assessment factors this is addressed in detail in Chapter 5. This estimated level of exposure will in this book be termed tolerable exposure level. Examples, where this approach is used, include establishment of the Acceptable/Tolerable... 

Use of assessment factors seems rather controversial in this approach. 

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. 

Gronlund (1992) has investigated methods used for quantitative risk assessment of non-genotoxic substances, with special regard to the selection of assessment factors. Gronlund found that humans, in most cases, seem to be more sensitive to the toxic effects of chemicals than experimental animals, and that the traditional 10-fold factor for interspecies differences apparently is too small in order to cover the real variation. It was also noted that a general interspecies factor to cover all types of chemicals and all types of experimental animals cannot be expected. It was concluded that a 10-fold factor for interspecies variability probably protects a majority, but not all of the population, provided that the dose correction for differences in body size between experimental animals and humans is performed by the body surface area approach (Section 5.3.2.2). If the dose correction is based on the body weight approach (Section 5.3.2.1), the 10-fold factor was considered to be too small in most cases. 

ECETOC (2003) recommended that in the absence of any substance- or species-specific mechanism or PBPK modeling (Section 4.3.6), allometric seating based on metabolic rate (W° ) (caloric requirement approach. Section 5.3.2.3) is considered to provide an appropriate default for an assessment factor for interspecies differences with respect to systemic effects. Allometric scaling was stated as being a tool for estimating interspecies differences of internal exposure or body burden and to provide indirectly information on differences in sensitivity between species. Typical scaling factors for interspecies adjustment were noted as 7 for mouse, 4 for rat, and 2 for dog however. 

In conclusion, if no substance-specific data are available, it is recommended as a default to correct for differences in metabolic size (differences in body size between humans and experimental animals) by using allometric scaling based on the caloric requirement approach (see Table 5.4). The assessment factor accounting for remaining interspecies differences should preferentially be described probabilistically as suggested by Vermeire et al. (1999, 2001) and KEMI (2003), or a deterministic default factor of 2.5 could be used for extrapolation of data from rat studies to the human situation. 

In conclusion, the assessment factor for interindividual variability should preferentially be described probabilistically. However, at present there is no database-derived distribution of the interindividual factor and thus a deterministic default factor of 10, split evenly into a sub-factor of 3.16 for both toxicokinetics and toxicodynamics, respectively, is recommended in order to account for the interindividual variability in the human population. Alternatively, the pathway-related UF approach suggested by Renwick and Lazams (1998) and further developed as reviewed by Dome et al. (2005) could be applied in case the pathway(s) of the metabolism of the chemical in humans... 

KEMl (2003) suggested that, if necessary, extrapolation can be performed from subchronic to chronic exposure and that such an extrapolation should be based on the distribution of NOAEL ratios reported by Vermeire et al. (2001). If the 95th percentile is chosen, i.e., covering 95% of the substances compared, the corresponding assessment factor is 16. Extrapolation from subacute to chronic exposure should preferably not be performed, but if it is necessary a similar approach is suggested for this extrapolation, an assessment factor of 39 corresponds to the 95th percentile based on the lognormal distribution of NOAEL ratios from subacute and chronic exposure studies in Vermeire et al. (2001). 

ECETOC (2003) recommended that if an appropriate NOAEL is available, then no extrapolation and hence, no assessment factor is necessary. Where it is considered more appropriate to use the LOAEL, a default assessment factor of 3 was recommended however, the factor may need to be adjusted depending on the effects observed at the LOAEL and the slope of the dose-response curve. The BMD could be an alternative approach for defining or confirming a NOAEL depending on the data quality and dose spacing. 

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. 

The probabilistic approach allows for a closer link with specific knowledge or lack of knowledge in specific assessments. For example, one may be more confident in the magnimde of the possible interspecies difference in one case than another. This may be expressed in the width of the relevant distribution for the assessment factor. However, in many cases, even the range of uncertainty is uncertain, and for those situations default distributions are called for. 

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. 

Slob and Pieters (1998) have proposed a probabilistic approach for deriving acceptable human intake limits and human health risks from toxicological studies in which it is acknowledged that both the effect parameter (e.g., NOAEL, BMD) and the assessment factors are uncertain and can best be described by lognormal distributions. 

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. 

In both approaches, allowance is often made for these uncertainties by the application of numerical factors (assessment factors, extrapolation factors, uncertainty factors). 

In the case of the standard setting approach, assessment factors are directly applied to the hazard assessment output (i.e., the NOAEL/LOAEL or BMD) in order to derive a standard (Chapter 5). 

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. 

To assess whether a reaction is influenced by intraparticle diffusion effects, Weisz and Prater [11] developed a criterion for isothermal reactions based upon the observation that the effectiveness factor approaches unity when the generalised Thiele modulus is of the order of unity. It has been shown that the effectiveness factor for all catalyst geometries and reaction orders (except zero order) tends to unity when... 

Factor Approach for Risk Assessment of Dioxins and Related Compounds. Journal of Animal Science 76 134-41. 

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