15 In Silico Prediction of the Point of Departure (POD) …
311
on how to perform this type of study. Usually, multiple approaches will arrive at
PODs within ±1 of the apical-endpoint-based PODs on the log 10 scale, which lends
confidence for using transcriptomic data.
A more ambitious and more difficult task is to utilize in vitro assay endpoints
to infer in vivo PODs. As shown in [34], the ToxCast data already provide valuable
information that can be used to build predictive models for this purpose. However, due
to the incompleteness in coverage of important toxicity pathways, some chemicals
have to be treated as outliers. Fortunately, more complete data sets may soon be
available. The Tox21 program is working to screen a large collection of chemicals
with a set of toxicologically relevant “sentinel” genes. The S1500+ sentinel gene
list has been created [38], containing 1500 genes designed to comprehensively cover
toxicologically relevant pathways by taking advantage of the co-expression patterns
between genes. Upon sufficient accumulation of data along these lines, there will
be opportunity to develop more powerful models to infer in vivo PODs with highthroughput assays.
Acknowledgements The author would like to thank the editor and an anonymous reviewer for
valuable suggestions. The opinions expressed in this paper are those of the author and do not
necessarily reflect the views of the US Food and Drug Administration.
References
1. NRC (National Research Council) (2007) Toxicity testing in the 21st century: a vision and a
strategy. The National Academies Press, Washington, DC
2. NRC (National Research Council) (2017) Using 21st century science to improve risk-related
evaluations. The National Academies Press, Washington, DC
3. Locke PA, Westphal M, Tischler J, Hessler K, Frasch P, Myers B, Krewski D (2017) Implementing toxicity testing in the 21st century: challenges and opportunities. Int J Risk Assess
Manage 20(1–3):198–225
4. Rudén C, Hansson SO (2010) Registration, evaluation, and authorization of chemicals
(REACH) is but the first step. How far will it take us? Six further steps to improve the European
chemicals legislation. Environ Health Perspect 118(1):6–10
5. Igarashi Y, Nakatsu N, Yamashita T, Ono A, Ohno Y, Urushidani T, Yamada H (2015) Open
TG-GATEs: a large-scale toxicogenomics database. Nucleic Acids Res 43(D1):D921–D927
6. Collins FS, Gray GM, Bucher JR (2008) Transforming environmental health protection. Science
319(5865):906–907
7. Tice RR, Austin CP, Kavlock RJ, Bucher JR (2013) Improving the human hazard characterization of chemicals: a Tox21 update. Environ Health Perspect 121(7):756–765
8. Judson R, Houck K, Martin M, Knudsen T, Thomas R, Sipes N, Shah I, Wambaugh J,
Crofton K (2014) In vitro and modeling approaches to risk assessment from the U.S. environmental protection agency ToxCast program. Basic Clin Pharmacol Toxicol 115(1):69–76
9. Richard A, Judson R, Houck K, Grulke C, Volarath P, Thillainadarajah I et al (2016) The
ToxCast chemical landscape—paving the road to 21st century toxicology. Chem Res Toxicol
29(8):1225–1251
10. Silva M, Pham N, Lewis C, Iyer S, Kwok E, Solomon G, Zeise L (2015) A comparison
of ToxCast test results with in vivo and other in vitro endpoints for neuro, endocrine, and
developmental toxicities: a case study using endosulfan and methidathion. Birth Defects Res
B Dev Reprod Toxicol 104(2):71–89
311
on how to perform this type of study. Usually, multiple approaches will arrive at
PODs within ±1 of the apical-endpoint-based PODs on the log 10 scale, which lends
confidence for using transcriptomic data.
A more ambitious and more difficult task is to utilize in vitro assay endpoints
to infer in vivo PODs. As shown in [34], the ToxCast data already provide valuable
information that can be used to build predictive models for this purpose. However, due
to the incompleteness in coverage of important toxicity pathways, some chemicals
have to be treated as outliers. Fortunately, more complete data sets may soon be
available. The Tox21 program is working to screen a large collection of chemicals
with a set of toxicologically relevant “sentinel” genes. The S1500+ sentinel gene
list has been created [38], containing 1500 genes designed to comprehensively cover
toxicologically relevant pathways by taking advantage of the co-expression patterns
between genes. Upon sufficient accumulation of data along these lines, there will
be opportunity to develop more powerful models to infer in vivo PODs with highthroughput assays.
Acknowledgements The author would like to thank the editor and an anonymous reviewer for
valuable suggestions. The opinions expressed in this paper are those of the author and do not
necessarily reflect the views of the US Food and Drug Administration.
References
1. NRC (National Research Council) (2007) Toxicity testing in the 21st century: a vision and a
strategy. The National Academies Press, Washington, DC
2. NRC (National Research Council) (2017) Using 21st century science to improve risk-related
evaluations. The National Academies Press, Washington, DC
3. Locke PA, Westphal M, Tischler J, Hessler K, Frasch P, Myers B, Krewski D (2017) Implementing toxicity testing in the 21st century: challenges and opportunities. Int J Risk Assess
Manage 20(1–3):198–225
4. Rudén C, Hansson SO (2010) Registration, evaluation, and authorization of chemicals
(REACH) is but the first step. How far will it take us? Six further steps to improve the European
chemicals legislation. Environ Health Perspect 118(1):6–10
5. Igarashi Y, Nakatsu N, Yamashita T, Ono A, Ohno Y, Urushidani T, Yamada H (2015) Open
TG-GATEs: a large-scale toxicogenomics database. Nucleic Acids Res 43(D1):D921–D927
6. Collins FS, Gray GM, Bucher JR (2008) Transforming environmental health protection. Science
319(5865):906–907
7. Tice RR, Austin CP, Kavlock RJ, Bucher JR (2013) Improving the human hazard characterization of chemicals: a Tox21 update. Environ Health Perspect 121(7):756–765
8. Judson R, Houck K, Martin M, Knudsen T, Thomas R, Sipes N, Shah I, Wambaugh J,
Crofton K (2014) In vitro and modeling approaches to risk assessment from the U.S. environmental protection agency ToxCast program. Basic Clin Pharmacol Toxicol 115(1):69–76
9. Richard A, Judson R, Houck K, Grulke C, Volarath P, Thillainadarajah I et al (2016) The
ToxCast chemical landscape—paving the road to 21st century toxicology. Chem Res Toxicol
29(8):1225–1251
10. Silva M, Pham N, Lewis C, Iyer S, Kwok E, Solomon G, Zeise L (2015) A comparison
of ToxCast test results with in vivo and other in vitro endpoints for neuro, endocrine, and
developmental toxicities: a case study using endosulfan and methidathion. Birth Defects Res
B Dev Reprod Toxicol 104(2):71–89