Toxicology-species extrapolation

Hengstler JG, Oesch F. Interspecies differences in xenobiotic metabolizing enzymes and their importance for inter species extrapolation of toxicity. In Ballantyne B, Marrs TC, Syversen T, eds. General and Applied Toxicology. Vol. 1. London Macmillan, 2000. 

Genomic Approaches for Cross-Species Extrapolation in Toxicology Benson and Di Giulio, editors 2007... 

Forbes V.E., Calow P., Sibly R.M. (2001) Are current species extrapolation models a good basis for ecological risk assessment Environmental Toxicology and Chemistry 20(2) 442-447. 

R. C. Hertzberg and M. Miller, A Statistical Model for Species Extrapolation Using Categorical Response Data, Toxicology and Industrial Health, 1, 43-57 (1985). 

Batten, P.L. and Hutson, D.H. (1995). Species differences and other factors affecting metaholism and extrapolation to man. In The Metabolism of Agrochemicals, Vol. 8 of Progress in Pesticide Biochemistry and Toxicology. D.H. Hutson and G.D. Paulson (Eds.). Chichester, UK John Wiley, 267-308. 

As mentioned previously, the assessment of hazard and risk to humans from exposure to chemical substances is generally based on the extrapolation from data obtained in smdies with experimental animals. In the absence of comparative data in humans, a basic assumption for toxicological risk assessment is that effects observed in laboratory animals are relevant for humans, i.e., would also be expressed in humans. In assessing the risk to humans, an assessment factor is applied to take account of uncertainties in the differences in sensitivity to the test substance between the species, i.e., to account for interspecies variability (Section 5.3). If data are available from more than one species or strain, the hazard and risk assessment is generally based on the most susceptible of these except where data strongly indicate that a particular species is more similar to man than the others with respect to toxicokinetics and/or toxicodynamics. Two main aspects of toxicity, toxicokinetics and toxicodynamics, account for the namre and extent of differences between species in their sensitivity to xenobiotics this is addressed in detail in Chapter 5. 

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. 

Wheeler, J.R., Leung, K.M.Y., Morrit, D., Sorokin, N., Rogers, H., Toy, R., Holt, M., Whitehouse, P. and Crane, M. (2002). Freshwater to saltwater toxicity extrapolation using species sensitivity distributions. Environmental Toxicology and Chemistry, 21, 2459-2467. 

An important outcome of the JECFA evaluation is the establishment of an ADI for a food additive. The ADI is based on the available toxicological data and the no adverse effect level in the relevant species. JECFA defines the ADI as an estimate of the amount of a food additive, expressed on a body weight basis, that can be ingested daily over a lifetime without appreciable health risk (8). JECFA utilizes animal data to determine the ADI based on the highest no-observed-adverse-effect level (NOAEL), and a safety factor is applied to the NOAEL to provide a margin of safety when extrapolating animal data to humans. JECFA typically uses safety factors of 50, 100, or 200 in the determination of an ADI. The NOAEL is divided by the safety factor to calculate the ADI. The food additive is considered safe for its intended use if the human exposure does not exceed the ADI on a chronic basis. This type of information may potentially be used to help assess the safety of a pharmaceutical excipient that is also used as a food additive, based on a comparison of the ADI to the estimated daily intake of the excipient. 

Whatever methods are employed to link assessment end points with measures of effect, it is important to apply the methods in a manner consistent with sound ecological and toxicological principles. For example, it is inappropriate to use structure-activity relationships to predict toxicity from chemical structure unless the chemical under consideration has a similar mode of toxic action to the reference chemicals. Similarly extrapolations from upland avian species to waterfowl may be more credible if factors such as differences in food preferences, physiology, and seasonal behavior (e.g., mating and migration habits) are considered. 

Drug metabolism and pharmacokinetic (DMPK) studies are used to show how the concentrations of the drug and its metabolites vary with the administered dose of the drug and the time from administration. They are normally carried out using suitable animal species and in humans in Phase I trials. The information obtained from animal studies is used to determine safe dose levels for use in the Phase I clinical trials in humans. However, the accuracy of the data obtained from animal tests is limited, since it is obtained by extrapolation. In addition, it is necessary to determine the dose that just saturates the absorption and elimination processes so that the toxicological and pharmacological events may be correctly interpreted. 

An approach to estimating thresholds of effect for multiple endpoints within a species has been proposed in which distributions of effect measures from different assay endpoints in a species can be used to extrapolate to a no-effect measure for all possible endpoints (Hanson and Solomon 2002). In practice, a distribution of effect measures is constructed and extrapolated to a low probability (Figure 1.5). This value is used as an estimate of the toxicological benchmark concentration (TBC), below which no effect... 

FIGURE 1.5 Illustration of the method for determining a toxicological benchmark concentration (TBC). Note A distribution of endpoints for a species is used to extrapolate to a TBC, below which the likelihood of unmeasured responses being observed is very small. 

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