Extrapolation, interspecies

Stages in hazard characterization according to the European Commission s Scientific Steering Committee are (1) establishment of the dose-response relationship for each critical effect (2) identification of the most sensitive species and strain (3) characterization of the mode of action and mechanisms of critical effects (including the possible roles of active metabolites) (4) high to low dose (exposure) extrapolation and interspecies extrapolation and (5) evaluation of factors that can influence severity and duration of adverse health effects. 

EPA has derived both an oral reference dose (RfD) and an inhalation reference concentration (RfC) for chronic exposure to hydrogen sulfide. The RfD of 0.003 mg/kg/day is based on the NOAEL of 3.1 mg/kg/day for gastrointestinal disturbance in pigs in a study by Wetterau et al. (1964) (IRIS 1998). The NOAEL value of 3.1 mg/kg/day was divided by an uncertainty factor of 1,000 to account for interspecies extrapolation (10), sensitive individuals (10), and subchronic exposure (10) (IRIS 1998). 

A hallmark of PB-PK models is the ability to scale up animal-based models to humans, thus allowing tissue drug concentrations to be predicted in the absence of data that are difficult or impossible to collect. Initial efforts to apply interspecies extrapolations to anticancer drugs have been greatly extended to chemical risk assessment based on PB-PK models [14]. Empirical allometric equations based on animal body weight have been the mainstay to scale organ weights and... 

KH Watanabe, FY Bois. Interspecies extrapolations of physiological pharmacokinetic parameter distributions. Risk Anal 16 741-754, 1996. 

In order to extrapolate laboratory animal results to humans, an interspecies dose conversion must be performed. Animals such as rodents have different physical dimensions, rates of intake (ingestion or inhalation), and lifespans from humans, and therefore are expected to respond differently to a specified dose level of any chemical. Estimation of equivalent human doses is usually performed by scaling laboratory doses according to observable species differences. Unfortunately, detailed quantitative data on the comparative pharmacokinetics of animals and humans are nonexistent, so that scaling methods remain approximate. In carcinogenic risk extrapolation, it is commonly assumed that the rate of response for mammals is proportional to internal surface area... 

Human studies including case reports, epidemiological studies, and, in some cases, direct human studies (with volunteers). The advantages of these studies are that toxic effects are evaluated in humans and no interspecies extrapolation is... 

Animal toxicological and in vitro studies. In animal or in vitro studies the system is more controlled than in human studies, the external influences are minimized (more in in vitro than in animal tests). However, in both cases, an extrapolation is required interspecies in the case of animal studies and at least from system to organism extrapolation in the case of in vitro test. 

In the case of noncarcinogenic substances, there exists a threshold this is an exposure with a dose below which there would not be adverse effect on the population that is exposed. This is the reference dose (RfD), and it is defined as the daily exposure of a human population without appreciable effects during a lifetime. The RfD value is calculated by dividing the no observed effect level (NOEL) by uncertainty factors. When NOEL is unknown, the lowest observed effect level (LOEL) is used. NOEL and LOEL are usually obtained in animal studies. The main uncertainty factor, usually tenfold, used to calculate the RfD are the following the variations in interspecies (from animal test to human), presence of sensitive individuals (child and old people), extrapolation from subchronic to chronic, and the use of LOEL instead of NOEL. Noncancer risk is assessed through the comparison of the dose exposed calculated in the exposure assessment and the RfD. The quotient between both, called in some studies as hazard quotient, is commonly calculated (Eq. 2). According to this equation, population with quotient >1 will be at risk to develop some specific effect related to the contaminant of concern. 

Lin, J.H., Applications and limitations of interspecies scaling and in vitro extrapolation in pharmacokinetics, Drug Metab. Dispos. 26(12), 1202-1212, 1998. 

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. 

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). 

Interspecies 3—The toxic response to dimethylhydrazine (LC50 values) was similar across species. The 4-h LC50 values for mouse, rat, and hamster differ by a factor of approximately 2 and were consistent with the dog data when extrapolated from 1 h using n=l. The more sensitive species, the dog, was used to derive the AEGL-2 values. 

EPA has derived a chronic oral RfD of 0.001 mg/kg/day for hexachloroethane (IRIS 1995). This value is based on a NOAEL of 1 mg/kg/day for atrophy and degeneration of the renal tubules in rats exposed for 16 weeks (Gorzinski et al. 1985). The NOAEL was divided by an uncertainty factor of 1,000 to account for interspecies extrapolation, human variability, and the use of a subchronic study. EPA places medium confidence in this RfD (IRIS 1995). 

The 30-min and 1-, 4-, and 8-h AEGL-3 values were based on the highest concentration causing no mortality in the rat after a 30-min exposure (15 ppm) (Zwart et al. 1990). A UF of 3 was applied for interspecies extrapolation because little species variability is observed for lethal and nonlethal end points after exposure to phosgene. A UF of 3 was applied to account for sensitive human subpopulations due to the steep concentration-response curve and... 

It should be noted that, for establishment of a 1-h Emergency Exposure Guidance Level (EEGL) for another halocarbon, the NRC (NRC 1996 Bakshi et al. 1998) recommended application of a single interspecies UF of 10 to the cardiac sensitization test with the dog. Because blood concentrations of several halocarbons rapidly reached equilibrium, the NRC also extrapolated this 10-min test to the longer time period of 1 h. Controlled human data were not available for many of the materials considered by the NRC, whereas human data are available for HCFC-141b. 

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