Proposal for a tiered approach to developmental toxicity testing for veterinary pharmaceutical products for food-producing animals

The ChemScreen project to design a pragmatic alternative approach to predict reproductive toxicity of chemicals

“…We found that even with a relatively small number of tests, either apical tests combined with mechanistic tests or an relatively small number of mechanistic tests predictivities ranging from 74 to 94% can be reached [20,25], which is comparable to that obtained with much larger ToxCast screening panels [21], the ReProTect battery [7], or the zebrafish ELS tests [49], a human embryonic stem cell test [50]. This is remarkable, since the concordance between different test species, like rabbit and rat has been estimated to be not more than 60% [6]. It seems that these validation results may be biased to some extent, e.g.…”

“…In addition, a single test only gives part of the puzzle and only batteries such as the ChemScreen battery can be effective in replacing animal studies. The validation of such a battery is a challenge, in particular in the absence of gold standard, caused by relatively poor predictivity of animal data for humans [6]. An interesting approach in this light was to cluster apical reproductive toxic effects of chemicals when comparing this with data of molecular screening assays, resulting in a strong correlation of relevant CALUX assays with those clustered apical effects [20,41].…”

“…Even then, it has been shown that large species differences exist and interspecies extrapolation of developmental toxicity typically usually is not much higher than 60% between single species when using apical endpoints in animals [6]. Nevertheless, results from the Framework program (FP)6 program ReProTect very clearly showed that an in vitro test battery covering only part of the reproductive cycle processes can provide very promising results with respect to reproductive toxicity testing [7].…”

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

“…There is no reason to assume that any species predicts humans better than, e.g., mice predict rat developmental toxicity of a given chemical. Hurtt et al (2003) have demonstrated by analyzing 91 veterinary drugs that no single species especially at normal exposures and therapeutic dose levels. Notable examples include glucocorticoids, benzodiazepines, caffeine, carbon dioxide, dopamine, indomethacin, and aspirin (Bailey et al, 2005;Hartung, 2009c).…”

A critique of the EC’s expert (draft) reports on the status of alternatives for cosmetics testing to meet the 2013 deadline

“…this is a concern because there is evidence that the predictive power of the prenatal developmental toxicity test is rather poor. For example, Hurtt et al (2003) found that the positive predictivity of one species to teratogenic effects in rat, mouse, or rabbit was around 60% for 105 veterinary pharmaceuticals. Bailey et al (2005) found that the rat was positively predictive of 35 known human teratogens in 61% of cases and the rabbit in 41%.…”