LOAEL to NOAEL extrapolation

UFm accounts for the quality and relevance of the database, i.e., accounts for the uncertainties in the establishment of a NOAEL for the critical effect. The UFm includes elements such as (1) the quality of the database, e.g., data on specific toxic endpoints are lacking or inadequate, default value of 1-10 (2) route-to-route extrapolation, e.g., no studies using the appropriate exposure route are available, no default value (3) LOAEL-to-NOAEL extrapolation, e.g., a NOAEL cannot be established for the critical effect, default value of 10 (4) subchronic-to-chronic extrapolation, e.g., no chronic studies on which to establish the NOAEL are available, default value of 10 and (5) nature and severity of toxicity, e.g., the critical effect is toxicity to reproduction, carcinogenicity or sensitization, default value of up to 10. A default value for UFm has not been recommended however, a value from 1 to 100 is generally used. The value is evaluated case-by-case based on expert judgment. 

DOSE-RESPONSE CURVE (LOAEL-TO-NOAEL EXTRAPOLATION)... 

Assessment factors between 1 and 10 have been suggested or applied by various national and international bodies for the extrapolation from a LOAEL to a NOAEL. Some analyses have been performed in order to evaluate the magnitude of an appropriate assessment factor for the LOAEL-to-NOAEL extrapolation, based on evaluations of LOAEL/NOAEL ratios. This section gives an overview of such analyses and evaluations. Then, the key issues are summarized and our recommendations are presented. 

Kadry et al. (1995) evaluated the UF for LOAEL to NOAEL extrapolation by comparing subchronic (23) and chronic (23) LOAEL/NOAEL ratios for six chlorinated compounds. All of the ratios were 10 or less for subchronic exposure, 91.3% of the ratios were sixfold or less and for chronic exposure, 87% of the ratios were 5 of less. The authors concluded that automatic safety factors of 10-fold are not scientifically supportable and are overly conservative for the chlorinated compounds included in their analysis. 

The EU TGD (EC 2003) recognized that the NOAEL is not very accurate with respect to the degree to which it corresponds with the (unknown) true NAEL. In the case of a steep curve the derived NOAEL can be considered as more reliable (the greater the slope, the greater the reduction in response to reduced doses) in the case of a shallow curve, the uncertainty in the derived NOAEL may be higher and this has to be taken into account in the assessment. If a LOAEL has to be used in the assessment, then this value can only be considered reliable in the case of a very steep curve. According to KEMI (2003), extrapolation factors of between 3-5 are used for LOAEL-to-NOAEL extrapolation without any scientific basis in risk assessment reports of existing substances within the European Union. 

Dose-Response Curve (LOAEL-to-NOAEL Extrapolation) Summary AND Recommendations... 

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. 

Dourson et al. (1996) considered that when a NOAEL is not available, the choice of a UF for LOAEL-to-NOAEL extrapolation should generally depend on the severity of the effect seen at the LOAEL, see Section 5.7. 

US-EPA (1993) stated that in addition to the standard factors (for inter- and intraspecies differences, less than chronic duration studies, and LOAEL-to-NOAEL extrapolation), an extra factor should be included if the total toxicological database is incomplete, i.e., the so-called modifying factor (ME). It was stated that the magnitude of the MF depends upon a professional assessment of scientific uncertainties of the study and database not explicitly accounted for by the standard factors, e.g., the completeness of the overall database and the number of species tested. The default value for the MF is 1. 

Because the literature describes several limitations in the use of NOAELs (Gaylor 1983 Crump 1984 Kimmel and Gaylor 1988), the evaluative process considers other methods for expressing quantitative dose-response evaluations. In particular, the BMD approach originally proposed by Crump (1984) is used to model data in the observed range. That approach was recently endorsed for use in quantitative risk assessment for developmental toxicity and other noncancer health effects (Barnes et al. 1995). The BMD can be useful for interpreting dose-response relationships because it accounts for all the data and, unlike the determination of the NOAEL or LOAEL, is not limited to the doses used in the experiment. The BMD approach is especially helpful when a NOAEL is not available because it makes the use of a default uncertainty factor for LOAEL to NOAEL extrapolation unnecessary. 

UFi UFo UF3 UF4 UF5 MF 10 (sensitive subpopulations) 10 (animal to human extrapolation) 3 (extrapolation from subchronic to chronic exposures). 1 (LOAEL to NOAEL extrapolation) 3 (data base incomplete) 3 (modifying factor). ... 

LOAEL to NOAEL extrapolation altered plasma-AChE is not overtly toxic)... 

Agent HD (Sulfur Mustard). RfDe = 7 x 10 mg kg d. A LOiAEL was identified in a two-generation reproductive toxicity study conducted in rats. A total uncertainty factor of 3000 was applied to account for protection of sensitive subpopulations (10), animal-to-human extrapolation (10), LOAEL-to-NOAEL extrapolation (3), and extrapolation from a subchronic to chronic exposure (10). A LOAEL-to-NOAEL UF of 3, instead of the default value of 10, was used because the critical effect (stomach lesions) was considered to be mild in severity and may have been enhanced by the vehicle used (sesame oil in which sulfur mustard is fully soluble) and the route of administration (gavage), which is more likely to result in localized irritant effects. The key study did identify a toxic effect that is consistent with the vesicant properties of sulfur mustard. In none of the other available studies was there any indication of a different effect occurring at a lower exposure level. 

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