Extrapolation animal to human

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... 

A UF of 10 is used when extrapolating from animals to humans. This factor is intended to account for the intcrspccies variability between humans and other mammals. 

Animal-to-Human Extrapolations ENDOCRINE DISRUPTION CHILDREN S SUSCEPTIBILITY BIOMARKERS OF EXPOSURE AND EFFECT... 

An intermediate-duration oral MRL of 0.0007 mg/kg/day was derived for methyl parathion based on the observation of electrophysiological effects in the central and peripheral nervous systems of male rats exposed to methyl parathion through gavage administration of 0.22 mg/kg/day to the dams on days 5-15 of gestation and days 2-28 of lactation, followed by direct administration of the same dose to the male pups for 8 weeks. More marked effects occurred at the two higher doses, 0.44 and 0.88 mg/kg/day. The effects were dose-related, and were statistically significant at all three dose levels. The MRL was derived by dividing the LOAEL from this study (0.22 mg/kg/day) by an uncertainty factor of 300 (3 for a minimal LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). 

Used to derive an intermediate oral MRL of0.0007 mg/kg/day dose divided by an uncertainty factor of300 (10 for extrapolation from animals to humans, 10 for human variability, and 3 for a minimal LOAEL). 

The chronic-duration oral MRL was derived based on the observation of increased serum levels of alkaline phosphatase (an indicator of hepatotoxicity) in dogs consuming 0.6 mg/kg/day for 1 year (Hoechst 1989c). The choice of this end point is supported by the observation of hydropic hepatic cells in rats that consumed 5 mg/kg/day for 2 years (EMC 1959b). The chronic-duration MRL of 0.002 mg/kg/day was derived by dividing the NOAEL for elevated serum alkaline phosphatase (0.18 mg/kg/day) by an uncertainty factor of 100 (10 for extrapolating from animals to humans, and 10 for human variability). 

Used to derived an intermediate-duration inhalation Minimal Risk Level (MRL) of 0.1 ppm for trichloroethylene 50 ppm adjusted tor duration (5/7 days x 8 hr/d) and species-specific ratio of daiiy inhalation volume (m /day)/body weight(kg) ratio for rat (0.23/2.17) to human (20/70) to 44.2 ppm, divided by an uncertainty factor of 300 (10 for using a LOAEL, 3 tor extrapolation from animals to humans, and 10 tor human variability) = 0.147 ppm, rounded to 0.1 ppm. 

NOAEL (no-observed-adverse-effect level) is defined as the highest dose at which no adverse effects are observed in the most susceptible animal species. The NOAEL is used as a basis for setting human safety standards for acceptable daily intakes (ADIs), taking into account uncertainty factors for extrapolation from animals to humans and inter-individual variabilities of humans. The adequacy of any margin of safety or margin of exposure must consider the nature and quality of the available hazard identification and dose-response data and the reliability and relevance of the exposure estimations. In some cases, no adverse endpoint can be identified such as for many naturally occurring compounds that are widespread in foods. In that case, an ADI Not Specified is assigned. ... 

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