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The 10 mM Debate

The 10 mM Debate. Prof. David Kirkland Kirkland Consulting. Why are we debating this issue?. For many, the frequency of misleading positive results in vitro is unacceptable

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The 10 mM Debate

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  1. The 10 mM Debate Prof. David Kirkland Kirkland Consulting

  2. Why are we debating this issue? • For many, the frequency of misleading positive results in vitro is unacceptable • Where follow-up testing in vivo is not permitted (e.g. cosmetics ingredients in EU) new products may be abandoned and businesses suffer • For other chemicals in vivo follow-up may be triggered by in vitro +ve when not otherwise required • Low tonnage industrial chemicals • Food flavours and additives • In such cases, unnecessary animal use occurs

  3. Why this debate? • ECVAM workshop (Kirkland et al, 2007) identified several “design” issues of mammalian cell tests thought to contribute to high level of misleading positives – including top conc.; extent & measures of cytotoxicity • Others will be discussed in Stefan Pfuhler’s group • Proposed revisions to ICH S2 guideline for pharmaceuticals suggested lowering top conc. for non-toxic drugs to 1 mM (Lutz Müller will present) • So are there data to suggest a reduction in the top conc. for non-pharmaceutical chemicals can also be considered?

  4. Review of published data • ECVAM commissioned Jim and Liz Parry to review published literature • At what concs. do carcinogens that are –ve in Ames test give detectable +ve responses in mammalian cells? • Raffaella Corvi will discuss this review • I will discuss some of the “key” chemicals from this review • From the 19 chemicals identified (Kirkland et al, 2008) as giving misleading +ve results in mammalian cells, 12 are only +ve above 1 mM, and 11 are only +ve above 2 mM • These would be avoided if lower top conc.

  5. 7/19 Misleading positives at <1 mM +ve MLA = >GEF; +ve CA = >5% cells with abs

  6. 12/19 Misleading positives at >1 mM

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