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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 @@ +<?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 (>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 < 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> |