Animal-human extrapolation

In 1981 a new list with 86 additional substances became available (ref. 8). The computer search of the RTECS was reasonably straightforward at that time. The key word "teratogen" was used and the RTECS data base searched for the names of compounds under this classification. The size of the printed file was reasonable (500-600 entries). A copy of the file could be posted in the laboratory, with a short explanation that the list of teratogens should be viewed with caution due to the fact that data from the RTECS are unevaluated and that uncertainties exist about animal-human extrapolations. Any librarian having access to NLM-MEDLARS (National Library of Medicine-... 

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

An attempt to estimate human daily impact of N nitroso compounds is shown in Table I. The apparent intake from food of preformed nitrosamines is comparatively low, at least in these surveys of a Western diet in England (3). The Intake directly to the respiratory tract from smoking could be somewhat larger. However, if the blood levels reported are confirmed as correct, then inputs of up to 700 meg per day of at least N nitrosodimethylamine (NDMA) may be calculated, based on pharmacokinetic considerations of data obtained in animals and extrapolated to man. It should be emphasized that no information is available at present on nitrosamide intake or in vivo formation, largely because of analytical limitations. 

For most chemicals, actual human toxicity data are not available or critical information on exposure is lacking, so toxicity data from studies conducted in laboratory animals are extrapolated to estimate the potential toxicity in humans. Such extrapolation requires experienced scientific judgment. The toxicity data from animal species most representative of humans in terms of pharmacodynamic and pharmacokinetic properties are used for determining AEGLs. If data are not available on the species that best represents humans, the data from the most sensitive animal species are used to set AEGLs. Uncertainty factors are commonly used when animal data are used to estimate minimal risk levels for humans. The magnitude of uncertainty factors depends on the quality of the animal data used to determine the no-observed-adverse-effect level (NOAEL) and the mode of action of the substance in question. When available, pharmocokinetic data on tissue doses are considered for interspecies extrapolation. 

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. 

Used to derive acute inhalation Minimal Risk Level (MRL) of 0.05 ppm (50 ppb) animal dose extrapolated to human dose according to method of EPA (1989d) values of blood/air partition coefficients assumed to be equal for animals and humans dose adjusted for 1 ess-than-continuous exposure (8 hours/24 hours), and divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans, and 10 for human variability). 

If the NOAEL is derived from an animal study, a UE of 10 is used typically to extrapolate to the average human. This UE has some limited empirical basis. The available data suggest that most animal-human differences in response are less than a factor of 10, but the evidence supporting this conclusion is not strong. 

Second, there is a procedure for scaling doses between animals and humans, to take account of differences in body size and rates of various physiological processes. Interestingly, as the EPA and other regulators practice risk assessment, animal-to-human extrapolation for carcinogens is based on the use of such scaling factors, rather than... 

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