Default assessment factors

Default Assessment Factors Used or Suggested for the Establishment of a Regulatory Standard or Health-Based Guidance Value for Threshold Effects... 

Worst-case character of the traditional default assessment factors is considered doubtful as the 95th percentile for the proposed distributions for the interspecies (anrmal-to-human) factor and the subchronic-to-chronic duration factor are considerably higher than 10. In addition, the limited data on intraspecies (human-to-human) variation is also considered to indicate that a default factor of 10 may not be sufficient. 

A more recent Dutch report (Vermeire et al. 2001) provides a practical guide for the application of probabilistic distributions of default assessment factors in human health risk assessments, and it is stated that the proposed distributions will be applied in risk assessments of new and existing substances and biocides prepared at RIVM (the National Institute of Public Health and the Environment) and TNO. The report concentrated on the quantification of default distributions of the assessment factors related to interspecies extrapolation (animal-to-human), intraspecies extrapolation (human-to-human), and exposure duration extrapolation. 

One of the main conclusions drawn from the evaluation of the available data on default assessment factors was that the conventionally used factor of 100 (10 for animal-to-human and 10 for human-to-human variations) is probably an underestimate. It is stated that it is likely that the animal-to-human extrapolation is greatly underestimated, and in the case of human-to-human variability, an assessment factor of 10-16 is considered as a minimum. 

The use of default assessment factors is recommended in risk assessments, when justifiable, although the scientific background for such factors in general was considered unsatisfactory. The default assessment factors suggested are summarized in Table 5.2. It is recommended to use assessment factors derived from probabilistic distributions in favor of deterministic assessment factors, see Table 5.2. 

A WHO/IPCS (2005) Harmonization Project Document has proposed using chemical-specific toxicological data instead of default assessment factors, when possible. The concept of Chemical-Specific Adjustment Factors (CS AFs) has been introduced to provide a method for the incorporation of quantitative data on interspecies differences or human variability in either toxicokinetics or toxicodynamics into the risk assessment procedure, by modifying the relevant default UF of 10. Incorporation of toxicokinetic or toxicodynamic data becomes possible if each factor of 10 is divided into appropriately weighted sub-factors as suggested by Renwick (1991, 1993) and adopted by WHO/IPCS (1994), see Section 5.2.1.3. 

This section gives a short introduction regarding the biological variation between mammalian species (Section 5.3.1) as a basis for the subsequent section on aUometric scaling (Section 5.3.2). Then a number of analyses performed regarding the validity of the default assessment factor of 10 are reviewed (Sections 5.3.3 and 5.3.4). Finally, the key issues are summarized and our recommendations are presented (Section 5.3.5). 

For local effects, a default assessment factor of 1 for interspecies extrapolation for water-soluble gases and vapors was considered to be sufficiently conservative, as well as for aerosols since the respiratory rate of rodents leads to a greater respiratory tract burden as compared to humans. 

If route-to-route extrapolation implies a lower rate of dosing, this can be considered to provide a built-in safety margin and in such cases no assessment factor is needed, i.e., an assessment factor of 1 is appropriate. It is not appropriate to define a default assessment factor (ECETOC 2003). 

For systemic effects, ECETOC (2003) recommended a default assessment factor of 6 for extrapolation from subacute (28 days) to chronic exposure, and a factor of 2 from subchronic (90 days) to chronic exposure. For local effects, no additional assessment factor is needed for duration of exposure extrapolation for substances with a local effect below the threshold of cytotoxicity. 

WHO/IPCS (1994, 1996, 1999) did not consider an extrapolation factor for duration of exposure specifically, but the uncertainty related to this element is included in a broader defined additional factor addressing the adequacy of the overall database (Section 5.9). The US-EPA (1993) has adopted the 10-fold factor to account for the uncertainty involved in extrapolating from less than chronic NOAELs to chronic NOAELs. This default value has later on been reconfirmed (US-EPA 2002) when only a subchronic duration smdy is available to develop a chronic reference value no chronic reference value is derived if neither a subchronic nor a chronic smdy is available. For systemic effects, ECETOC (2001) recommended a default assessment factor of 6 for extrapolation from subacute (28 days) to chronic exposure, and a factor of 2 from subchronic (90 days) to chronic exposure. For local effects, no additional assessment factor is needed for duration of exposure extrapolation for substances with a local effect below the threshold of cytotoxicity. KEMl (2003) suggested that extrapolation from subchronic to chronic exposure should be based on the distribution of NOAEL ratios reported by Vermeire et al. (2001) with an assessment factor of 16 covering 95% of the substances compared and for extrapolation from subacute to chronic exposure, with an assessment factor of 39 covering 95% of the substances. 

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. 

A default assessment factor of 10 has been used traditionally for the extrapolation from a LOAEL to a NOAEL. Some analyses have been performed in order to evaluate the size of an appropriate assessment factor for the LOAEL-to-NOAEL extrapolation, based on evaluations of LOAEL/NOAEL ratios. A number of evaluations have been based on data from Weil and McCollister (1963) and adapted by Dourson and Stara (1983). Some evaluations found that this analysis supports that a factor of 10 or lower is adequate while others found the factor of 10 to be overly conservative as the LOAEL rarely exceeded the NOAEL by more than about 5-6 fold and was typically closer to a value of 3. The analysis on LOAEL/NOAEL ratios performed on LOAEL/NOAEL ratios showed 95th percentiles of 9, 16, and 11 for subacute, subchronic, and chronic exposure durations, respectively, supporting the 10-fold factor to account for about 95% of the chemicals evaluated. 

TNO has stated that the size, quality, completeness, and consistency of the database should be considered (Hakkert et al. 1996). Major aspects for the evaluation of the quality of the data supporting the NOAEL are (1) deviations from official guidelines, which are not properly substantiated, (2) number of animals used, (3) number of dose levels tested, and (4) adequacy of hematological, biochemical, and pathological examinations. Indications for doubts on the confidence in the database are (1) the absence of certain types of smdies, (2) conflicting results between studies, and (3) doubts on the reliability of the route-to-route extrapolation. However, consistency of results from different studies, consistency of animal and human data, and rehable mechanistic data are indicative for a high-confidence database. The default assessment factor for confidence of the database is 1. 

The analysis need not be confined to the estimation of a standard that uses conventional methods of extrapolation (e.g., default assessment factors). It might usefully be accompanied by an analysis of the consequences of exceeding a particular standard. If a standard is proposed that sits within the range of available toxicological or ecotoxicological data or close to the lower limit of experimental data, then we should try to predict what impact an exceedance will have (e.g., excess cancer risk, proportion of species affected, or number of individuals affected). 

---