Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Feb 29;5(3):773-787.
doi: 10.1039/c5tx00493d. eCollection 2016 May 1.

In silico prediction of the developmental toxicity of diverse organic chemicals in rodents for regulatory purposes

Nikita Basant  1 , Shikha Gupta  2 , Kunwar P Singh  2
Affiliations

In silico prediction of the developmental toxicity of diverse organic chemicals in rodents for regulatory purposes

Nikita Basant et al. Toxicol Res (Camb). .

Abstract

The experimental determination of the developmental toxicity potential (LEL) of chemicals is not only tedious, time and resource intensive, but it also involves unethical tests on animals. In this study, we have established quantitative structure activity relationship (QSAR) models for predicting the developmental toxicity potential of chemicals in rodents following the OECD guidelines. Accordingly, decision tree forest (DTF) and decision tree boost (DTB) based local (L-QSAR), global (G-QSAR) and interspecies quantitative structure activity-activity relationship (ISC QSAAR) models were developed for estimating the LEL (lowest effective level) dose of chemicals for developmental toxicity in rats and rabbits. The structural features of chemicals responsible for developmental toxicity in rodents were extracted and used in QSAR/QSAAR analysis. The external predictive power of the developed models was evaluated through the internal and external validation procedures. In test data, the L-QSAR models (DTF, DTB) yielded R2 values of >0.846 (rat) and >0.906 (rabbit), whereas in G-QSAR, the correlation value was >0.870 between the measured and predicted endpoint values. In ISC QSAAR models, the R2 values in test data were 0.830 (DTF) and 0.927 (DTB), respectively. Values of various statistical validation coefficients derived from the test data (except rm2 in DTF based rat L-QSAR and ISC QSAAR models) were above their respective threshold limits, thus putting a high confidence in this analysis. The prediction quality of the developed QSAR/QSAAR models was also assessed using the mean absolute error (MAE) criteria and found good. The applicability domains of the constructed models were defined using the descriptor range, leverage, and standardization approaches. The results suggest that the developed QSAR/QSAAR models can reliably predict the developmental toxicity potential of structurally diverse chemicals in rodents, generating useful toxicity data for risk assessment in humans.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1. A flow diagram showing QSAR modeling and OECD guidelines for predicting the developmental toxicity potential of chemicals.
Fig. 2
Fig. 2. Plot showing the distribution of the PCA scores of the descriptors in training and test compounds in (a) L-QSAR, (b) G-QSAR, and (c) ISC QSAAR analyses.
Fig. 3
Fig. 3. Conceptual diagram of the architecture of (a) DTF and (b) DTB models.
Fig. 4
Fig. 4. Plot showing the contributions of input descriptors in L-QSAR models (a) Rat L-QSAR and (b) Rabbit L-QSAR.
Fig. 5
Fig. 5. Plot showing the contributions of input descriptors in G-QSAR models.
Fig. 6
Fig. 6. 3-D plots of selected descriptors showing interaction trends between (a) GGI3 and minHBa, (b) ETA_Eta and nAtomP, and (c) TopoPSA and minHBa in the G-QSAR model.
Fig. 7
Fig. 7. Plot showing the distribution of measured and model predicted LEL values of chemicals (a) DTF G-QSAR and (b) DTB G-QSAR models.
Fig. 8
Fig. 8. Williams plot for the (a) rat L-QSAR, (b) rabbit L-QSAR, (c) G-QSAR, and (d) ISC QSAAR models.
See this image and copyright information in PMC

References

    1. Knudsen T. B., Martin M. T., Kavlock R. J., Judson R. S., Dix D. J., Singh A. V. Reprod. Toxicol. 2009;28:209–219. - PubMed

    1. Regulation of (EC) No. 1907/2006 of the European Parliament and of the Council, December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No. 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC, Off. J. Eur. Union, L396 (2007), pp. 1–849

    1. US Environmental Protection Agency, Laws & Regulations, http://www2.epa.gov/laws-regulations. - PubMed
    1. National Toxicology Programme, Prenatal Developmental Toxicity Study, available at: https://ntp.niehs.nih.gov/testing/types/dev/.
    1. U.S. Environmental Protection Agency, Health effects test guidelines OPPTS 870.3700 prenatal developmental toxicity study, Office of Prevention, Pesticides and Toxic Substances, Washington, DC, EPA Publication 712-C-98–207, 1998.

LinkOut - more resources