From 67eb582eea1842491af7214db9e315a78fe61904 Mon Sep 17 00:00:00 2001 From: pdp8 Date: Thu, 22 Sep 2022 12:59:50 +0200 Subject: epa-namm presentation --- presentations/epa-nam-2022/.gitignore | 6 + presentations/epa-nam-2022/Makefile | 7 + presentations/epa-nam-2022/fig2.png | Bin 0 -> 65145 bytes presentations/epa-nam-2022/fphar-09-00413-g003.jpg | Bin 0 -> 244695 bytes presentations/epa-nam-2022/fphar-09-00413-g004.jpg | Bin 0 -> 173990 bytes presentations/epa-nam-2022/fphar-09-00413-g005.jpg | Bin 0 -> 224086 bytes presentations/epa-nam-2022/index.html | 200 +++++++++++++++++++++ presentations/epa-nam-2022/index.md | 137 ++++++++++++++ presentations/epa-nam-2022/style.css | 2 + 9 files changed, 352 insertions(+) create mode 100644 presentations/epa-nam-2022/.gitignore create mode 100644 presentations/epa-nam-2022/Makefile create mode 100644 presentations/epa-nam-2022/fig2.png create mode 100644 presentations/epa-nam-2022/fphar-09-00413-g003.jpg create mode 100644 presentations/epa-nam-2022/fphar-09-00413-g004.jpg create mode 100644 presentations/epa-nam-2022/fphar-09-00413-g005.jpg create mode 100644 presentations/epa-nam-2022/index.html create mode 100644 presentations/epa-nam-2022/index.md create mode 100644 presentations/epa-nam-2022/style.css diff --git a/presentations/epa-nam-2022/.gitignore b/presentations/epa-nam-2022/.gitignore new file mode 100644 index 0000000..365427b --- /dev/null +++ b/presentations/epa-nam-2022/.gitignore @@ -0,0 +1,6 @@ +10.3389-fphar.2018.00413-citation.txt +20220922_00h45m07s_grim.png +dataset-variability.pdf +ehp.01109509.pdf +EPA NAM Conference_Draft Agenda_2022_v4.pdf +page5.pdf diff --git a/presentations/epa-nam-2022/Makefile b/presentations/epa-nam-2022/Makefile new file mode 100644 index 0000000..bc165d5 --- /dev/null +++ b/presentations/epa-nam-2022/Makefile @@ -0,0 +1,7 @@ +all: html #pptx + +pptx: index.md + pandoc index.md -o epa-nam-2022.pptx + +html: index.md + pandoc -s -t slidy --css style.css -o index.html index.md diff --git a/presentations/epa-nam-2022/fig2.png b/presentations/epa-nam-2022/fig2.png new file mode 100644 index 0000000..a7af33a Binary files /dev/null and b/presentations/epa-nam-2022/fig2.png differ diff --git a/presentations/epa-nam-2022/fphar-09-00413-g003.jpg b/presentations/epa-nam-2022/fphar-09-00413-g003.jpg new file mode 100644 index 0000000..fc2adc7 Binary files /dev/null and b/presentations/epa-nam-2022/fphar-09-00413-g003.jpg differ diff --git a/presentations/epa-nam-2022/fphar-09-00413-g004.jpg b/presentations/epa-nam-2022/fphar-09-00413-g004.jpg new file mode 100644 index 0000000..0b2975a Binary files /dev/null and b/presentations/epa-nam-2022/fphar-09-00413-g004.jpg differ diff --git a/presentations/epa-nam-2022/fphar-09-00413-g005.jpg b/presentations/epa-nam-2022/fphar-09-00413-g005.jpg new file mode 100644 index 0000000..25dfefd Binary files /dev/null and b/presentations/epa-nam-2022/fphar-09-00413-g005.jpg differ diff --git a/presentations/epa-nam-2022/index.html b/presentations/epa-nam-2022/index.html new file mode 100644 index 0000000..020ddcd --- /dev/null +++ b/presentations/epa-nam-2022/index.html @@ -0,0 +1,200 @@ + + + + + + + + + + Variability of chronic rodent bioassays + + + + + + +
+

Variability of chronic rodent bioassays

+

+Christoph Helma +

+

October 12, 2022

+
+
+

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

+ +
+
+

Carcinogenicity Classification

+ +
+
Rats
+
+62% concordant classifications +
+
Mice
+
+49% concordant classifications +
+
Multi species carcinogens
+
+58% concordant classifications +
+
Multi organ carcinogens:
+
+52% concordant classifications +
+
+ +
+
+

Carcinogenicity TD50’s

+

+
+
+

Carcinogenicity caveats

+ +
+
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

+
+ +

r^2: 0.52, RMSE: 0.59, p-value < 2.2e-16

+
+

As both databases contain duplicates medians were used for the +correlation plot and statistics

+
+
+

LOAEL Experiments vs Predictions

+

+
+
+

Conclusions

+ +


+
+https://in-silico.ch/presentations/epa-nam-2022/

+
+ + 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)\ + + +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)\ + + +# 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 + +![](fig2.png) + +# 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 + +![](fphar-09-00413-g003.jpg) + +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 + +![r\^2: 0.52, RMSE: 0.59, p-value \< 2.2e-16](fphar-09-00413-g004.jpg) + +As both databases contain duplicates medians were used for the +correlation plot and statistics + +# LOAEL Experiments vs Predictions + +![](fphar-09-00413-g005.jpg) + +# 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** + +\ +\ + diff --git a/presentations/epa-nam-2022/style.css b/presentations/epa-nam-2022/style.css new file mode 100644 index 0000000..477e084 --- /dev/null +++ b/presentations/epa-nam-2022/style.css @@ -0,0 +1,2 @@ +div.slide { padding: 2em;} + -- cgit v1.2.3