6 Mode-of-Action-Guided, Molecular …
101
MMDB
Molecular Modeling DataBase
MoA
Mode of Action
NCBI
National Center for Biotechnology Information
NRC
National Research Council
OECD
Organization for Economic Cooperation and Development
PBPK
Physiologically based pharmacokinetic
PDB
Protein Data Bank
QSAR
Quantitative structure–activity relationship
RC
Reference chemical
REACH
Registration, Evaluation, Authorization, and Restriction of Chemicals
Risk21
Risk Assessment in the twenty-first century
SEURAT
Safety Evaluation Ultimately Replacing Animal Testing
SPLIF
Structural protein–ligand interaction fingerprints
T3DB
Toxin and Toxin Target Database
Tox21
Toxicology in the twenty-first century
ToxCast
Toxicity Forecaster
TsTKb
Target-specific toxicity knowledgebase
USDA
US Department of Agriculture
6.1 Introduction
All chemical substances are required to be tested for their toxicological and environmental properties before being approved for use by regulatory authorities, such as
the US Environmental Protection Agency (EPA), the US Food and Drug Administration (FDA) and the US Department of Agriculture (USDA). Three strategies are
commonly adopted for toxicity testing: in vivo, in vitro, and in silico [1–4]. Driven
by public concerns about animal welfare in research and testing, the European Union
(EU) and most individual countries now have laws, policies, and regulations that aim
to refine, reduce, and replace animal use (commonly referred to as the “3Rs”) [5]. For
instance, the US Animal Welfare Act requires consideration of alternatives whenever
procedures involve more than slight or momentary pain or distress for warm-blooded
animals in research and testing [6, 7]. The US FDA endorses the effort “to reduce
animal testing [and] to work toward replacement of animal testing” as a basis for regulatory action [8]. In Europe, Directive 2010/63/EU [9] legislates an end to “the use
of animals in toxicology and biomedical research as soon as scientifically feasible to
do so.” The EC 1907/2006 Registration, Evaluation, Authorization and Restriction of
Chemicals (REACH) regulation [10] restricts animal testing only “as a last resort to
satisfy registration information requirements”, and Regulation 1223/2009/EU [11]
introduces a comprehensive ban on marketing within the EU of any cosmetic product
(or ingredient thereof) that has been tested on animals since March 2013 [8, 12].
Another incentive for modernizing chemical toxicity testing is the combination of
the large number of chemicals found in the environment with no or little toxicity data
and the prohibitively high costs associated with traditional toxicity testing methods.
101
MMDB
Molecular Modeling DataBase
MoA
Mode of Action
NCBI
National Center for Biotechnology Information
NRC
National Research Council
OECD
Organization for Economic Cooperation and Development
PBPK
Physiologically based pharmacokinetic
PDB
Protein Data Bank
QSAR
Quantitative structure–activity relationship
RC
Reference chemical
REACH
Registration, Evaluation, Authorization, and Restriction of Chemicals
Risk21
Risk Assessment in the twenty-first century
SEURAT
Safety Evaluation Ultimately Replacing Animal Testing
SPLIF
Structural protein–ligand interaction fingerprints
T3DB
Toxin and Toxin Target Database
Tox21
Toxicology in the twenty-first century
ToxCast
Toxicity Forecaster
TsTKb
Target-specific toxicity knowledgebase
USDA
US Department of Agriculture
6.1 Introduction
All chemical substances are required to be tested for their toxicological and environmental properties before being approved for use by regulatory authorities, such as
the US Environmental Protection Agency (EPA), the US Food and Drug Administration (FDA) and the US Department of Agriculture (USDA). Three strategies are
commonly adopted for toxicity testing: in vivo, in vitro, and in silico [1–4]. Driven
by public concerns about animal welfare in research and testing, the European Union
(EU) and most individual countries now have laws, policies, and regulations that aim
to refine, reduce, and replace animal use (commonly referred to as the “3Rs”) [5]. For
instance, the US Animal Welfare Act requires consideration of alternatives whenever
procedures involve more than slight or momentary pain or distress for warm-blooded
animals in research and testing [6, 7]. The US FDA endorses the effort “to reduce
animal testing [and] to work toward replacement of animal testing” as a basis for regulatory action [8]. In Europe, Directive 2010/63/EU [9] legislates an end to “the use
of animals in toxicology and biomedical research as soon as scientifically feasible to
do so.” The EC 1907/2006 Registration, Evaluation, Authorization and Restriction of
Chemicals (REACH) regulation [10] restricts animal testing only “as a last resort to
satisfy registration information requirements”, and Regulation 1223/2009/EU [11]
introduces a comprehensive ban on marketing within the EU of any cosmetic product
(or ingredient thereof) that has been tested on animals since March 2013 [8, 12].
Another incentive for modernizing chemical toxicity testing is the combination of
the large number of chemicals found in the environment with no or little toxicity data
and the prohibitively high costs associated with traditional toxicity testing methods.