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\begin{document}

\title{Quantitative in vitro to in vivo Extrapolation (IVIVE) of Genotoxicity
Data Provides Protective Estimates of in vivo Dose}



\author[1]{Marc Beal}%
\author[2]{Marc Audebert}%
\author[3]{Tara Barton-Maclaren}%
\author[3]{Hannah Battaion}%
\author[4]{Jeffrey Bemis}%
\author[5]{Xuefei Cao}%
\author[6]{Connie Chen}%
\author[4]{Stephen Dertinger}%
\author[7]{Roland Froetschl}%
\author[8]{Xiaoqing Guo}%
\author[9]{George Johnson}%
\author[10]{Giel Hendriks}%
\author[11]{Laure Khoury}%
\author[1]{Alexandra Long}%
\author[12]{Stefan Pfuhler}%
\author[13]{Raja Settivari}%
\author[3]{Shamika Wickramasuriya}%
\author[1]{Paul White}%
\affil[1]{Health Canada}%
\affil[2]{INRAE}%
\affil[3]{Health Canada Healthy Environments and Consumer Safety Branch}%
\affil[4]{Litron Laboratories}%
\affil[5]{USFDA-NCTR}%
\affil[6]{Health and Environmental Sciences Institute}%
\affil[7]{BfArM Bundesinsitut für Arzneimittel und Medizinprodukte (Federal Institute for Drug and Medical Devices)}%
\affil[8]{NCTR/FDA}%
\affil[9]{Swansea University}%
\affil[10]{Toxys}%
\affil[11]{Preditox}%
\affil[12]{Procter \& Gamble, Cosmital SA}%
\affil[13]{Corteva Agriscience}%


\vspace{-1em}



  
  \date{May 23, 2024}


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\begin{abstract}
Genotoxicity assessment is a critical component in the development and
evaluation of chemicals. Traditional genotoxicity assays (i.e.,
mutagenicity, clastogenicity, aneugenicity) have been limited to
dichotomous hazard classification, while other toxicity endpoints are
assessed through quantitative determination of points-of-departure
(PODs) for setting exposure limits. The more recent higher-throughput in
vitro genotoxicity assays, many of which also provide mechanistic
information, offer a powerful approach for determining high-precision
PODs for potency ranking and risk assessment. In order to obtain
relevant human dose context from the in vitro assays, in vitro to in
vivo extrapolation (IVIVE) models are required to determine what dose
would elicit a concentration in the body demonstrated to be genotoxic
using in vitro assays. Previous work has demonstrated that application
of IVIVE models to in vitro bioactivity data can provide PODs that are
protective of human health, but there has been no evaluation of how
these models perform with in vitro genotoxicity data. Thus, the Genetic
Toxicology Technical Committee, under the Health and Environmental
Sciences Institute, conducted a case study on 31 reference chemicals to
evaluate the performance of IVIVE application to genotoxicity data. The
results demonstrate that for most chemicals (20/31), the PODs derived
from in vitro data and IVIVE are highly health protective relative to in
vivo PODs from animal studies. PODs were also protective by individual
assay type: mutations (8/13 chemicals), micronuclei (9/12) and
aneugenicity markers (4/4). It is envisioned that this novel testing
strategy could enhance prioritization, rapid screening, and risk
assessment of genotoxic chemicals.%
\end{abstract}%



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