Intraspecies extrapolation

Intraspecies extrapolation (human-to-human) a default value of 3 for the general population a default value of 2 for workers... 

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. 

In a report on a research project quantification of extrapolation factors (Kalberlah and Schneider 1998), it is noted that extrapolation factors are intended to replace lack of knowledge by a plausible assumption, and that instimtions with responsibihty for establishing the mles must decide which level of statistical certainty, e.g., applicable for 50% or for 90% of a representative selection of substances, is desired for the selection of a standard value. It is furthermore noted that extrapolation factors are required for (1) time extrapolation, e.g., from a subchronic to a chronic duration of exposure (2) extrapolation from the LOAEL to the NAEL (3) interspecies extrapolation, i.e., from experimental animals to humans and (4) intraspecies extrapolation, i.e., from groups of persons with average sensitivity to groups of persons characterized by special sensitivity. In addition to these extrapolations, route-to-route extrapolation, e.g., oral-to-inhalation or dermal-to-oral must also be discussed. 

Intraspecies Extrapolation (Human-to-Human) Summary and Recommendations... 

Most extrapolations from animal experimental data in the risk assessments require the utilization of uncertainty factors. This is because we are not certain how to extrapolate across species, with species for the most sensitive population, and across duration. To account for variations in the general population and to protect sensitive subpopulations, an uncertainty factor of 10 is used by EPA and ATSDR. The value of 10 is derived from a threefold factor for differences in toxicokinetics and for threefold factor for toxicodynamics. To extrapolate from animals to humans and account for interspecies variability between humans and other mammals, an uncertainty factor of 10 is used by EPA and ATSDR, and as with intraspecies extrapolations, this 10-fold factor is assumed to be associated with in toxicodynamics and toxicokinetics. An uncertainty... 

Renwick examined in detail the relative magnitude of toxicokinetic and toxicodynamic variations between and within species. Results suggested that toxicokinetic differences were generally greater than toxicodynamic differences. Thus, he proposed that the 10-fold overall UF be subdivided into factors of 4 for kinetics and 2.5 for dynamics. The International Programme on Chemical Safety (IPCS) has adopted the principles set forth by Renwick, but has suggested that while the UF for interspecies extrapolation be subdivided unequally into four-fold (toxicokinetics) and 2.5-fold (toxicodynamics), the UF for intraspecies extrapolation should be split evenly (3.16-fold for both kinetics and dynamics) (see Figure 1). 

Although several data sets could be used to derive AEGL-3 values, the 1-h exposure data from the mouse study by Peterson and Bhattacharyya (1985) provided the most sound basis and were selected to derive AEGL-3 values. Due to the steep concentration-response curve for arsine, the 15-ppm exposure (where there was no lethality) was considered an estimate of the lethality threshold. An uncertainty factor of 30-fold was applied to account for interspecies extrapolation (10-fold) and intraspecies variability (3-fold) (see Section 6.3). 

An assessment factor of 240 is applied to take into consideration extrapolation from LOAEL to NOAEL (a factor of 6), extrapolation from subchronic to chronic study (a factor of 2), and inter- and intraspecies variation (a factor of 4 and 5, respectively). 

The approach proposed by Renwick (1991, 1993) is also based on the 100-fold factor. It attempts to give a scientihc basis to the default values of 10 for the interspecies and 10 for the intraspecies (interindividual human) differences. Renwick also proposed a division of each of these UEs into sub-factors to allow for separate evaluations of differences in toxicokinetics and toxicodynamics. The advantage of such a subdivision is that components of these UEs can be addressed where data are available for example, if available data show similar toxicokinetics of a given chemical in experimental animals and humans, then only an interspecies extrapolation factor would be needed to account for differences in toxicodynamics. Renwick examined the relative magnitude of toxicoki-netic and toxicodynamic variations between and within species in detail. He found that toxicokinetic differences were generally greater than toxicodynamic differences resulting in the proposal that the 10-fold factors (for inter- and intraspecies variation) should, by default, be subdivided into factors of 4 for toxicokinetics and 2.5 for toxicodynamics. It should be noted that the proposed default values were derived from limited data. 

Vermeire et al. (1999) have noted that scaling on the basis of surface area or caloric demand can be considered more appropriate compared to extrapolation based on body weight however, they also noted that experimental work did not answer the question regarding which of these two methods is the most correct. Based on theoretical grounds, and supported by their own analyses, Vermeire et al. (1999) concluded that scaling on the basis of caloric demand to adjust oral NOAELs for metabolic size can be considered more appropriate compared with extrapolation based on body weight. It was also noted that an allometric exponent of 0.67, i.e., the body surface area approach, seems to better describe intraspecies relations. 

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. 

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 ... 

Uncertainty in extrapolating toxicity from laboratory species to focal species uncertainty in estimating intraspecies variation... 

The inhalation RfC for naphthalene was 0.003 mg/m3, and this RfC was derived from a chronic (2-year) NTP inhalation study in mice using exposures of 0, 10, or 30 ppm (NTP, 1992). Groups of mice were exposed for 5 days a week and 6 hours a day. This study identified a LOAEL of 10 ppm. A dose-related incidence of chronic inflammation of the epithelium of the nasal passages and lungs was observed. This LOAEL concentration was normalized by adjusting for the 6-hour-per-day and 5-day-per-week exposure pattern. A LOAEL of 9.3 mg/m3 was obtained was derived by converting 10 ppm first to mg/m3 and then duration-adjusted levels for 6 h/day and 5 days/week for 103 weeks. An UP of 3000 was used, where 10 was for the interspecies (mice to humans) extrapolations, 10 for intraspecies variation in humans, 10 for using a LOAEL instead of a NOAEL, and 3 for database deficiencies. 

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