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diff --git a/presentations/epa-nam-2022/index.md b/presentations/epa-nam-2022/index.md new file mode 100644 index 0000000..9267915 --- /dev/null +++ b/presentations/epa-nam-2022/index.md @@ -0,0 +1,137 @@ +--- +author: Christoph Helma +date: October 12, 2022 +title: Variability of chronic rodent bioassays +--- + +# Content + +Rodent Carcinogenicity + +: E Gottmann, S Kramer, B Pfahringer and C Helma\ + *Data quality in predictive toxicology: reproducibility of rodent + carcinogenicity experiments*\ + Environ Health Perspect 109:509--514 (2001)\ + <https://doi.org/10.1289/ehp.01109509> + +Lowest observed adverse effect level (LOAEL) + +: C Helma, D Vorgrimmler, D Gebele, M Gütlein, B Engeli, J Zarn, + B Schilter and E Lo Piparo\ + *Modeling Chronic Toxicity: A Comparison of Experimental Variability + With (Q)SAR/Read-Across Predictions*\ + Front Pharmacol 9 (2018)\ + <https://doi.org/10.3389/fphar.2018.00413> + +# Carcinogenicity Data + +- Carcinogenic Potency Database(CPDB, Gold 1997) +- 1,289 unique compounds +- 2 Subsets + - National Toxicology Program (NTP) + - General literature +- 121 common compounds in both subsets + +# Carcinogenicity Classification + +- **57%** concordant classifications (69/121 compounds, 39 + carcinogens, 30 non-carcinogens) + +Rats +: 62% concordant classifications + +Mice +: 49% concordant classifications + +Multi species carcinogens +: 58% concordant classifications + +Multi organ carcinogens: +: 52% concordant classifications + +- poor reproducibility of sex, species and organ specific effects + +# Carcinogenicity TD50's + + + +# Carcinogenicity caveats + +- low sample size +- no standardized protocols for literature data + +Gold et al. (1987) + +: - 38 compounds from the literature + - 93% reproducibility for rats + - 76% for mice + - 34 studies were published by the same authors (!) + +# LOAEL Data + +Chronic (\>180 days) lowest observed effect levels (LOAEL) for rats +(Rattus norvegicus) after oral (gavage, diet, drinking water) +administration + +Nestlé Database + +: 567 LOAEL values for 445 unique chemical structures from the + literature (Mazzatorta et al., 2008) + +Swiss Food Safety and Veterinary Office (FSVO) Database + +: 493 rat LOAEL values for 381 unique chemical structures from + pesticide evaluations (Zarn et al., 2011, 2013) + + - European Food Safety Authority (EFSA) (EFSA, 2014) + - Joint FAO/WHO Meeting on Pesticide Residues (JMPR) (WHO, 2011) + - US EPA (US EPA, 2011) + +Combined dataset + +: - compounds that occur in both databases + - 375 LOAEL values for 155 unique chemical structures + +# LOAEL Variability + +**Both** datasets contain substances with multiple measurements + + + +All datasets have almost the same experimental variability (standard +deviations: 0.56 mg/kg_bw/day (Nestlé), 0.57 mg/kg_bw/day (FSVO), 0.56 +mg/kg_bw/day (combined)) + +# LOAEL Correlation + + + +As both databases contain duplicates medians were used for the +correlation plot and statistics + +# LOAEL Experiments vs Predictions + + + +# Conclusions + +- Carcinogenicity classifications seem to be poorly reproducible (57% + concordant classifications for repeated experiments) + +- Experimental LOAEL values have a variablity of approximately 1.5 log + units (orders of magnitude) + +- Variability in chronic *in vivo* bioassays might be caused by + + - biological complexity + - long term experimental conditions + - evaluation complexity + - statistical limitations (low number of animals/treatment) + +- Good *in-silico* models have the same accuracy as biological + experiments (*in-vivo* and *in-vitro*) for **compounds in their + applicability domain** + +\ +\ +<https://in-silico.ch/presentations/epa-nam-2022/> |