Animal models alternatives

Andersen ME, Kirshnan K. 1994. Relating in vitro to in vivo exposures with physiologically based tissue dosimetry and tissue response models. In Salem H,ed. Animal test alternatives Refinement, reduction, replacement. New York, NY Marcel Dekker, Inc., 9-25. 

Hastings, K.L., Assessment of immunosuppressant drug carcinogenicity standard and alternative animal models, Hum. Exptl. Toxicol., 19, 261, 2000. 

Zelikoff, J.T. et al., Immunotoxicology of low level cadmium exposure in fish An alternative animal model for immunotoxicological studies, J. Toxicol. Environ. Health, 45, 235, 1995. 

Ethical issues as well as difficulty in obtaining enough human nasal tissue specimens have called for the need to use alternative in vitro and in vivo methods. Various in vivo animal models and in vitro excised tissue models have been described in the literature for nasal drug transport studies. However, due to the difficulty in both controlling the experimental conditions in in vivo animal models and obtaining intact excised tissue samples, in vitro cell culture models are also being actively developed. 

During the last 10 years it has been attempted to develop in vitro methods as alternative methods in the study of effects where animal models have previously been necessary. Such effects include skin and eye irritation and specific organ damage. Validation programs have been launched, and some of the above-mentioned methods have been sufficiently validated for use in regulatory risk assessment of chemical substances and may now for certain purposes be used as stand-alone evidence. Results from nonvahdated methods can in some cases be used as supportive evidence to human and animal data. 

A number of limitations related to PK/PD modeling are also a reality in situations where predictability of the animal model to man is questionable, where the time course of the pharmacodynamic effect cannot be assessed for drug candidates and when, for example, no accessible/ valid pharmacodynamic endpoint for PK/PD is available. The relevance of the animal model for human could be addressed to some extent at least by measuring relative potency in animal versus man in vitro. In situations where no relevant PD endpoint is available (e.g., for CNS efficacy models), effects at target level (i.e., enzyme inhibition, receptor occupancy) might represent a valuable alternative. In this context however the level and duration of target effect required for clinical efficacy requires careful considerations. 

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