The Utility of Two Rodent Species in Carcinogenic Risk Assessment of Pharmaceuticals in Europe

A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing

“…the discussion surrounding tox-21c has accelerated this process, as many have started to develop and commercialize these technologies, which lend themselves to the vision's implementation (van Vliet, 2011). this parallels developments in all life sciences implementing and exploiting the new technologies.…”

“…The two-species paradigm also has been challenged (Alden et al, 1996) by studies showing that rats are more sensitive, and regulatory action is rarely taken on the basis of bioassay results in mice (Van Oosterhout et al, 1997; Although it is in many respects a well-standardized protocol, it has been criticized as having poorly defined endpoints and a high level of uncontrolled variation. Suggestions for aspects of the test that could be optimized include proper randomization, blinding, better necroscopy work, and adequate statistics (Freedman and Zeisel, 1988).…”

“…Among these, the ones not identified in acute studies need to be identified. Many such examples are known from the pesticides field (Spielmann and Gerbracht, 2001;van Ravenzwaay, 2010). A first selection would involve those that result in human toxicity, or for which the animal toxicity is seen in the range of human exposure.…”

Power, expertise and the limits of representative democracy: genetics as scientific progress or political legitimation in carcinogenic risk assessment of pharmaceuticals?

“…The ICH experts interpreted this (40) as a low percentage 4 and consequently, considered it to be further evidence that mouse studies were of little regulatory significance (Van Oosterhout et al 1997). Regarding the 14 trans-species rodent carcinogens in the database, it was found that regulatory judgements were usually based on considerations other than the fact that tumour sites in mice corresponded to those in rats, such as: mechanism of cancer induction assumed to be rodentspecific; over-sensitivity of rodents to liver tumours; sufficient safety margin because tumours generated only in high doses in the rodents (Van Oosterhout et al 1997, p. 15).…”

A Tiered Approach to Systemic Toxicity Testing for Agricultural Chemical Safety Assessment

“…The Task Force supports the view that the conventional mouse bioassay does not add significant additional information for carcinogenicity evaluation over and above the use of the 24-month carcinogenicity assay in the male and female rat (Battershill and Fielder, 1998;Cohen, 2004;Monro, 1993;Usui et al, 1996;Van Oosterhout et al, 1997). The Task Force agrees that the 24-month rat carcinogenicity assay is adequate to detect carcinogens, including those which only cause carcinogenicity following prolonged perturbation of physiological mechanisms.…”