Interspecies Extrapolation Animal-to-Human

Data from studies in experimental animals are the typical starting points for hazard and risk assessments of chemical substances and thus differences in sensitivity between experimental animals and humans need to be addressed, with the default assumption that humans are more sensitive than experimental animals. The rationale for extrapolation of toxicity data across species is founded in the commonality of anatomic characteristics and the universality of physiological functions and biochemical reactions, despite the great diversity of sizes, shapes, and forms of mammalian species. 

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). 

Toxicological Risk Assessments of Chemicals A Practical Guide 

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First, the procedure now used by the EPA for inhalation data differs from what we have described above, in that the ten-fold factor for interspecies extrapolation (animal-to-human) is dropped in favor of a specific model that describes the well-known physiological differences between animals and humans that affect the relative rates of movement of a given administered dose of a chemical in the respiratory tracts of animals and humans. These physiological models provide fairly accurate predictions of the relative doses of chemicals delivered into the respiratory regions of animals and humans who have received identical administered (inhaled) doses. The estimate of delivered dose offers a well-accepted scientific approach to at least part of the problem of interspecies differences. Details of the delivered dose calculations are beyond the scope of this book (see references in Sources and recommended reading). 

Interspecies extrapolation (animal-to-human) a default value of 4 for oral exposure (for the rat with a body weight of 250 g and based on caloric demands) a default value of 1 for inhalation... 

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. 

Interspecies Extrapolation (Animal-to-Human) Summary and Recommendations... 

The selection and justification of uncertainty factors are critical in using this approach. The National Academy of Science has provided guidelines for using uncertainty factors (13). "Safety factor" or "uncertainty factor" is defined as a number that reflects the degree or amount of uncertainty that must be considered when ADIs are estimated from variable toxicity data bases. It includes extrapolation based on intraspecies (human population) as well as interspecies (from animal to human) variability. When the quality and quantity of experimental data are satisfactory, a low uncertainty factor is used when data are judged to be inadequate or equivocal, a larger uncertainty factor is needed. In those cases where the data do not completely fulfill the conditions for one category, or... 

Intermediate-duration oral studies in humans for mirex are lacking. A review of the animal oral intermediate toxicity data for mirex indicates that the available studies are not adequate to derive intermediate oral MRL for mirex. The most suitable study provides a LOAEL of 0.25 mg/kg/day for endocrine effects-dilation of rough endoplasmic reticulum cisternae of the thyroid of weanling Sprague-Dawley rats (Singh et al. 1985). Adjusting the LOAEL of 0.25 mg/kg/day determined from this study with a total uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for animal to human extrapolation, and 10 for interspecies variability) yields an intermediate oral MRL of 0.0003 mg/kg/day, which is lower than the chronic-duration oral MRL of 0.0008 mg/kg/day derived from an NTP (1990) study in rats (see chronic-duration MRL). Therefore, no oral intermediateduration MRL was developed for mirex. 

For interspecies (animal-to-human) extrapolation, allometric scahng on the basis of caloric demands (the 0.75th power of body weight) is considered preferable above scahng on body weight. 

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. 

In their analyses, statistics on the relevant extrapolation factor from animals to humans, as reported in the literature, were considered synoptically, and distinctions were made between (1) publications which focused on allometrically justifiable differences (2) publications which examined the toxicodynamic or toxicokinetic variability and (3) pubhcations which considered the total (gross) interspecies factor. In addition, consideration of PBPK models was discussed as a possible alternative. 

The WHO/IPCS (1994,1996, 1999) has adopted the approach set forth by Renwick (1993), i.e., the UF for interspecies (animal-to-human) extrapolation should be split into default values of 4 for toxicokinetics and 2.5 for toxicodynamics, see Section 5.2.I.3. In situations where appropriate toxicokinetic and/or toxicodynamic data are available for a particular compound, the relevant UF should be replaced by the data-derived factor. If a data-derived factor is introduced, then the commonly used 10-fold factor would be replaced by the product of that data-derived factor and the remaining default factor. It is also noted that for some classes of compounds, a data-derived factor for one member of the class may be applicable to aU members thereby producing a group-based data-derived factor. 

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