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<title>Variability of chronic rodent bioassays</title>
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<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>
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