Exposure considerations in human safety assessment: Report from an EPAA Partners' Forum.

Understanding and estimating the exposure to a substance is one of the fundamental requirements for safe manufacture and use. Many approaches are taken to determine exposure to substances, mainly driven by potential use and regulatory need. There are many opportunities to improve and optimise the use of exposure information for chemical safety. The European Partnership for Alternative Approaches to Animal Testing (EPAA) therefore convened a Partners' Forum (PF) to explore exposure considerations in human safety assessment of industrial products to agree key conclusions for the regulatory acceptance of exposure assessment approaches and priority areas for further research investment. The PF recognised the widescale use of exposure information across industrial sectors with the possibilities of creating synergies between different sectors. Further, the PF acknowledged that the EPAA could make a significant contribution to promote the use of exposure data in human safety assessment, with an aim to address specific regulatory needs. To achieve this, research needs, as well as synergies and areas for potential collaboration across sectors, were identified.

The mouse carcinogenicity study is no longer a scientifically justifiable core data requirement for the safety assessment of pesticides.

Regulatory tests investigating pesticide carcinogenicity potential routinely comprise a battery of in vitro and in vivo genotoxicity studies and two cancer bioassays, one in rats and one in mice. The genotoxicity testing strategy essentially ensures that genotoxic compounds are eliminated, and any carcinogens identified in subsequent lifetime studies are probably nongenotoxic in character. Assessment of 202 pesticide evaluations from the European Union review programme under Directive 91/414/EEC indicated that the mouse carcinogenicity study contributed little or nothing to either derivation of an acceptable daily intake (ADI) for assessment of chronic risk to humans, or hazard classification for labelling purposes. From a pesticide approval perspective, the mouse study did not influence a single outcome. From a risk assessment perspective, the ADI for just one pesticide was based on tumours in mice and this would have barely changed if the mouse data had not been available. In total, only 10 (5%) pesticide ADIs were based solely on the mouse carcinogenicity study and even in these few cases, a similar value would have been identified from other studies if the mouse study had not been available. For pesticides with treatment-related tumours only in mice, just three, or 1.5%, were classified as carcinogens and all were in the lowest category, Category 3 (R40). For pesticides with treatment-related tumours in mice and rats, the mouse data were probably the main, if not the only, cause for another three cases of R40 classification. Absence of the mouse studies would not have influenced assignment of the higher, Category 2 (R45), cancer classification for any substance with treatment-related tumours in both species as all decisions for these substances were limited to Category 3 or 'unclassified' outcomes. Over 100,000 mice were used to test these pesticides. This review shows that the mouse carcinogenicity studies did not provide significant information over and above that provided by the rat studies, and underpins the opportunity, from both a scientific and an animal welfare perspective, to remove the mouse carcinogenicity study from regulatory data requirements for the testing of pesticides.