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Data for most sensitive species for non-carcinogenic effects?

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hannaholmquist
hannaholmquist's picture
Data for most sensitive species for non-carcinogenic effects?

Hello!

In the USEtox 2 manual there is (as far as I can see) no guidance how to select or calculate one single ED50 value for input into the USEtox input data sheet in cases when data are available from several species. One example could be if I have oral  non-carcinogenic NOAEL values for rat and for mice for the same substance and recalcule those to chronic ED50s according to the manual instructions, I end up with two ED50 values. Should I use an average of the two or select the lowest one?

When consuling the background literature I find that Rosenbum (2008) states that "For cancer, te harmonic mean of al posive ED50 is retained for the most sensitiv species of animal cancr tests between mice and rats after applicaton of an allometric factor proportional to bodyweght to th power of 0.25". And in the manal for the oganic substances database it is stated that" "For cancer, the harmonic mean of all positive ED50 in the CPD is retined for the most sensitiv sprecies of animal cancer tests after application of a allometric interspecies conversion factor...". But that Huijbregts (2005) state that "If a substance in the CPDB has a carcinogenic ED50 for more than 1 species, the order of preference is monkey, then dog, rat, hamster and mouse".

All in all, I interpret this informaton as if there is no guidance on how to select/calculate ED50 for new CFs if more than one data point is available. For the CFs that have been published by the USEtox team, data for the most sensitive species have been used for the carcinogenic effects. But, how were the data treated for the non-cacinogenic effects?

Thank you in advance!

USEtox Team
USEtox Team's picture
Data selection for human toxicity effects

Please take as reference guidance document Rosenbaum et al. 2011, where it is stated that "In USEtox, for each exposure route, the lower (more potent) harmonic mean of TD50 in rats or mice is retained after application of an interspecies allometric factor". This means in cases where more than one species is available to extrapolate from, the lowest TD50 for cancer or the lowest ED50 for non-cancer effects should be used as most representative for humans.

This information will also be incorporated into the updated user manual as well as the soo-to-be-released full USEtox documentation.

hannaholmquist
hannaholmquist's picture
Non-cancer effects, several endpoints

Thank you for your answer!

 

For the cancer effect there is one endpoint (cancer) and taking the mean value per species seem reasonable. For the non-cancer effects however there could be several endpoints (type of effect, e.g. reproductive failure or liver damage); does the USEtox procedure still recommend taking the harmonic mean per species? Do the USEtox procedure specify relevant endpoints for non-cancer effects or should all adverse effects be included? Has it been specified what is considered an adverse effect?

USEtox Team
USEtox Team's picture
Non-cancer effects in USEtox

As stated in Rosenbaum et al. 2011, "For effects other than cancer, insufficient data were available for most substances to recalculate an ED50 with dose-response models" meaing for endpoints other than cancer, there are not enough data available for estimating respective effect factors across many chemicals. This is why it is recommended to include all non-cancer endpoints in the calculation of ED50 for non-cancer effects in USEtox, where the background statistics for the extrapolation factors and considered non-cancer endpoints are given in Huijbregts et al. 2005.