102
P. Gong et al.
In 2007, the US National Research Council (NRC) published a landmark report entitled “Toxicity Testing in the twenty-first Century: A Vision and a Strategy”, which
envisioned a paradigm shift from in vivo animal-based studies to target-specific,
mechanism-based toxicity pathway perturbations using in vitro and computational
modeling approaches [13]. Implementation of this new vision is believed to be able
to transform toxicology from a largely observational science to a more predictive one
[14]. Since then, the toxicology community has made significant progress developing
in vitro assays and computational tools that help achieve the predictive toxicology
goal outlined in the seminal NRC report [8]. Regulatory bodies are also increasingly turning to alternative toxicity testing methods, among which at least 63 have
been approved or endorsed by US federal regulatory agencies and international test
guideline organizations, such as the Organization for Economic Cooperation and
Development (OECD) [15–17].
6.1.1 Highlights of Recent Progress in the Development
of Alternative Testing Methods
Over the past decade, a number of efforts have been initiated toward developing
innovative in vitro and in silico tools and methodology for toxicity testing. The
most prominent ones include use of induced pluripotent stem cell (iPSC)-derived
human cells, development of defined heterotypic cell and three-dimensional (3D)
cell/tissue models, engineered human “organ-on-a-chip” microscale physiological
systems, mathematical modeling of cellular processes and morphogenesis, adverse
outcome pathways (AOPs), a molecular initiating event (MIE) atlas for toxicities, and
next-generation quantitative structure–activity relationship (QSAR) models [8, 12,
18]. These efforts have been mostly carried out within large-scale research programs,
such as toxicology in the twenty-first Century (Tox21) [19], Toxicity Forecaster (ToxCast) [20], Safety Evaluation Ultimately Replacing Animal Testing (SEURAT)-1
[21], Risk Assessment in the twenty-first Century (Risk21) [22], human-on-a-chip
[23], the Human Toxome Project [24], carcinoGENOMICS [22], the US Endocrine
Disruptor Screening Program (EDSP) [8], and virtual tissues [25] (e.g., virtual brain
[26], embryo, liver and thyroid models; see also www.epa.gov/chemical-research/
virtual-tissue-models-predicting-how-chemicals-impact-development). Looking at
Tox21 as an example, high-throughput in vitro screening assays have been developed using a highly automated robotics platform to quickly and efficiently assess
whether certain chemical compounds have the potential to disrupt processes in the
human body and possibly lead to negative health effects [19]. All these efforts also
share a common strategic goal—turn the knowledge of toxicological modes of action
(MoAs) and perturbed toxicity pathways or AOPs into in vitro and in silico models
that quantitatively predict points of departure or other end points (e.g., ED 50 and
AC 50 ) for chemical toxicity/risk/safety assessment [8, 19–24].
P. Gong et al.
In 2007, the US National Research Council (NRC) published a landmark report entitled “Toxicity Testing in the twenty-first Century: A Vision and a Strategy”, which
envisioned a paradigm shift from in vivo animal-based studies to target-specific,
mechanism-based toxicity pathway perturbations using in vitro and computational
modeling approaches [13]. Implementation of this new vision is believed to be able
to transform toxicology from a largely observational science to a more predictive one
[14]. Since then, the toxicology community has made significant progress developing
in vitro assays and computational tools that help achieve the predictive toxicology
goal outlined in the seminal NRC report [8]. Regulatory bodies are also increasingly turning to alternative toxicity testing methods, among which at least 63 have
been approved or endorsed by US federal regulatory agencies and international test
guideline organizations, such as the Organization for Economic Cooperation and
Development (OECD) [15–17].
6.1.1 Highlights of Recent Progress in the Development
of Alternative Testing Methods
Over the past decade, a number of efforts have been initiated toward developing
innovative in vitro and in silico tools and methodology for toxicity testing. The
most prominent ones include use of induced pluripotent stem cell (iPSC)-derived
human cells, development of defined heterotypic cell and three-dimensional (3D)
cell/tissue models, engineered human “organ-on-a-chip” microscale physiological
systems, mathematical modeling of cellular processes and morphogenesis, adverse
outcome pathways (AOPs), a molecular initiating event (MIE) atlas for toxicities, and
next-generation quantitative structure–activity relationship (QSAR) models [8, 12,
18]. These efforts have been mostly carried out within large-scale research programs,
such as toxicology in the twenty-first Century (Tox21) [19], Toxicity Forecaster (ToxCast) [20], Safety Evaluation Ultimately Replacing Animal Testing (SEURAT)-1
[21], Risk Assessment in the twenty-first Century (Risk21) [22], human-on-a-chip
[23], the Human Toxome Project [24], carcinoGENOMICS [22], the US Endocrine
Disruptor Screening Program (EDSP) [8], and virtual tissues [25] (e.g., virtual brain
[26], embryo, liver and thyroid models; see also www.epa.gov/chemical-research/
virtual-tissue-models-predicting-how-chemicals-impact-development). Looking at
Tox21 as an example, high-throughput in vitro screening assays have been developed using a highly automated robotics platform to quickly and efficiently assess
whether certain chemical compounds have the potential to disrupt processes in the
human body and possibly lead to negative health effects [19]. All these efforts also
share a common strategic goal—turn the knowledge of toxicological modes of action
(MoAs) and perturbed toxicity pathways or AOPs into in vitro and in silico models
that quantitatively predict points of departure or other end points (e.g., ED 50 and
AC 50 ) for chemical toxicity/risk/safety assessment [8, 19–24].