epa-namm presentation

author: pdp8 <pdp8@pdp8.info> 2022-09-22 12:59:50 +0200
committer: pdp8 <pdp8@pdp8.info> 2022-09-22 12:59:50 +0200
commit: 67eb582eea1842491af7214db9e315a78fe61904 (patch)
tree: d1152b16a5d009563dfac7c36fbd97106e035edc
parent: 9fea0ee9b32a606ce37dcadb3a0c3855a1720d8c (diff)
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+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
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+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 
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+<?xml version="1.0" encoding="utf-8"?>
+<!DOCTYPE html PUBLIC "-//W3C//DTD XHTML 1.0 Strict//EN"
+ "http://www.w3.org/TR/xhtml1/DTD/xhtml1-strict.dtd">
+<html xmlns="http://www.w3.org/1999/xhtml">
+<head>
+  <meta http-equiv="Content-Type" content="text/html; charset=utf-8" />
+  <meta http-equiv="Content-Style-Type" content="text/css" />
+  <meta name="generator" content="pandoc" />
+  <meta name="author" content="Christoph Helma" />
+  <meta name="date" content="2022-10-12" />
+  <title>Variability of chronic rodent bioassays</title>
+  <style type="text/css">
+    code{white-space: pre-wrap;}
+    span.smallcaps{font-variant: small-caps;}
+    span.underline{text-decoration: underline;}
+    div.column{display: inline-block; vertical-align: top; width: 50%;}
+    div.hanging-indent{margin-left: 1.5em; text-indent: -1.5em;}
+    ul.task-list{list-style: none;}
+    .display.math{display: block; text-align: center; margin: 0.5rem auto;}
+  </style>
+  <link rel="stylesheet" type="text/css" media="screen, projection, print"
+    href="https://www.w3.org/Talks/Tools/Slidy2/styles/slidy.css" />
+  <link rel="stylesheet" type="text/css" media="screen, projection, print"
+   href="style.css" />
+  <script src="https://www.w3.org/Talks/Tools/Slidy2/scripts/slidy.js"
+    charset="utf-8" type="text/javascript"></script>
+</head>
+<body>
+<div class="slide titlepage">
+  <h1 class="title">Variability of chronic rodent bioassays</h1>
+  <p class="author">
+Christoph Helma
+  </p>
+  <p class="date">October 12, 2022</p>
+</div>
+<div id="content" class="slide section level1">
+<h1>Content</h1>
+<dl>
+<dt>Rodent Carcinogenicity</dt>
+<dd>
+<p>E Gottmann, S Kramer, B Pfahringer and C Helma<br />
+<em>Data quality in predictive toxicology: reproducibility of rodent
+carcinogenicity experiments</em><br />
+Environ Health Perspect 109:509–514 (2001)<br />
+<a href="https://doi.org/10.1289/ehp.01109509"
+class="uri">https://doi.org/10.1289/ehp.01109509</a></p>
+</dd>
+<dt>Lowest observed adverse effect level (LOAEL)</dt>
+<dd>
+<p>C Helma, D Vorgrimmler, D Gebele, M Gütlein, B Engeli, J Zarn, B
+Schilter and E Lo Piparo<br />
+<em>Modeling Chronic Toxicity: A Comparison of Experimental Variability
+With (Q)SAR/Read-Across Predictions</em><br />
+Front Pharmacol 9 (2018)<br />
+<a href="https://doi.org/10.3389/fphar.2018.00413"
+class="uri">https://doi.org/10.3389/fphar.2018.00413</a></p>
+</dd>
+</dl>
+</div>
+<div id="carcinogenicity-data" class="slide section level1">
+<h1>Carcinogenicity Data</h1>
+<ul>
+<li>Carcinogenic Potency Database(CPDB, Gold 1997)</li>
+<li>1,289 unique compounds</li>
+<li>2 Subsets
+<ul>
+<li>National Toxicology Program (NTP)</li>
+<li>General literature</li>
+</ul></li>
+<li>121 common compounds in both subsets</li>
+</ul>
+</div>
+<div id="carcinogenicity-classification" class="slide section level1">
+<h1>Carcinogenicity Classification</h1>
+<ul>
+<li><strong>57%</strong> concordant classifications (69/121 compounds,
+39 carcinogens, 30 non-carcinogens)</li>
+</ul>
+<dl>
+<dt>Rats</dt>
+<dd>
+62% concordant classifications
+</dd>
+<dt>Mice</dt>
+<dd>
+49% concordant classifications
+</dd>
+<dt>Multi species carcinogens</dt>
+<dd>
+58% concordant classifications
+</dd>
+<dt>Multi organ carcinogens:</dt>
+<dd>
+52% concordant classifications
+</dd>
+</dl>
+<ul>
+<li>poor reproducibility of sex, species and organ specific effects</li>
+</ul>
+</div>
+<div id="carcinogenicity-td50s" class="slide section level1">
+<h1>Carcinogenicity TD50’s</h1>
+<p><img src="fig2.png" /></p>
+</div>
+<div id="carcinogenicity-caveats" class="slide section level1">
+<h1>Carcinogenicity caveats</h1>
+<ul>
+<li>low sample size</li>
+<li>no standardized protocols for literature data</li>
+</ul>
+<dl>
+<dt>Gold et al. (1987)</dt>
+<dd>
+<ul>
+<li>38 compounds from the literature</li>
+<li>93% reproducibility for rats</li>
+<li>76% for mice</li>
+<li>34 studies were published by the same authors (!)</li>
+</ul>
+</dd>
+</dl>
+</div>
+<div id="loael-data" class="slide section level1">
+<h1>LOAEL Data</h1>
+<p>Chronic (&gt;180 days) lowest observed effect levels (LOAEL) for rats
+(Rattus norvegicus) after oral (gavage, diet, drinking water)
+administration</p>
+<dl>
+<dt>Nestlé Database</dt>
+<dd>
+<p>567 LOAEL values for 445 unique chemical structures from the
+literature (Mazzatorta et al., 2008)</p>
+</dd>
+<dt>Swiss Food Safety and Veterinary Office (FSVO) Database</dt>
+<dd>
+<p>493 rat LOAEL values for 381 unique chemical structures from
+pesticide evaluations (Zarn et al., 2011, 2013)</p>
+<ul>
+<li>European Food Safety Authority (EFSA) (EFSA, 2014)</li>
+<li>Joint FAO/WHO Meeting on Pesticide Residues (JMPR) (WHO, 2011)</li>
+<li>US EPA (US EPA, 2011)</li>
+</ul>
+</dd>
+<dt>Combined dataset</dt>
+<dd>
+<ul>
+<li>compounds that occur in both databases</li>
+<li>375 LOAEL values for 155 unique chemical structures</li>
+</ul>
+</dd>
+</dl>
+</div>
+<div id="loael-variability" class="slide section level1">
+<h1>LOAEL Variability</h1>
+<p><strong>Both</strong> datasets contain substances with multiple
+measurements</p>
+<p><img src="fphar-09-00413-g003.jpg" /></p>
+<p>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))</p>
+</div>
+<div id="loael-correlation" class="slide section level1">
+<h1>LOAEL Correlation</h1>
+<div class="figure">
+<img src="fphar-09-00413-g004.jpg" alt="" />
+<p class="caption">r^2: 0.52, RMSE: 0.59, p-value &lt; 2.2e-16</p>
+</div>
+<p>As both databases contain duplicates medians were used for the
+correlation plot and statistics</p>
+</div>
+<div id="loael-experiments-vs-predictions" class="slide section level1">
+<h1>LOAEL Experiments vs Predictions</h1>
+<p><img src="fphar-09-00413-g005.jpg" /></p>
+</div>
+<div id="conclusions" class="slide section level1">
+<h1>Conclusions</h1>
+<ul>
+<li><p>Carcinogenicity classifications seem to be poorly reproducible
+(57% concordant classifications for repeated experiments)</p></li>
+<li><p>Experimental LOAEL values have a variablity of approximately 1.5
+log units (orders of magnitude)</p></li>
+<li><p>Variability in chronic <em>in vivo</em> bioassays might be caused
+by</p>
+<ul>
+<li>biological complexity</li>
+<li>long term experimental conditions</li>
+<li>evaluation complexity</li>
+<li>statistical limitations (low number of animals/treatment)</li>
+</ul></li>
+<li><p>Good <em>in-silico</em> models have the same accuracy as
+biological experiments (<em>in-vivo</em> and <em>in-vitro</em>) for
+<strong>compounds in their applicability domain</strong></p></li>
+</ul>
+<p><br />
+<br />
+<a href="https://in-silico.ch/presentations/epa-nam-2022/"
+class="uri">https://in-silico.ch/presentations/epa-nam-2022/</a></p>
+</div>
+</body>
+</html>
diff --git a/presentations/epa-nam-2022/index.md b/presentations/epa-nam-2022/index.md
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+---
+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
+
+![](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**
+
+\
+\
+<https://in-silico.ch/presentations/epa-nam-2022/>
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author	pdp8 <pdp8@pdp8.info>	2022-09-22 12:59:50 +0200
committer	pdp8 <pdp8@pdp8.info>	2022-09-22 12:59:50 +0200
commit	67eb582eea1842491af7214db9e315a78fe61904 (patch)
tree	d1152b16a5d009563dfac7c36fbd97106e035edc
parent	9fea0ee9b32a606ce37dcadb3a0c3855a1720d8c (diff)