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
. 2022 May 3;56(9):5620-5631.
doi: 10.1021/acs.est.1c07143. Epub 2022 Apr 21.

Impact of High-Throughput Model Parameterization and Data Uncertainty on Thyroid-Based Toxicological Estimates for Pesticide Chemicals

Jeffrey M Carlson  1 , Patricia A Janulewicz  1 , Nicole C Kleinstreuer  2 , Wendy Heiger-Bernays  1
Affiliations

Impact of High-Throughput Model Parameterization and Data Uncertainty on Thyroid-Based Toxicological Estimates for Pesticide Chemicals

Jeffrey M Carlson et al. Environ Sci Technol. .

Abstract

Chemical-induced alteration of maternal thyroid hormone levels may increase the risk of adverse neurodevelopmental outcomes in offspring. US federal risk assessments rely almost exclusively on apical endpoints in animal models for deriving points of departure (PODs). New approach methodologies (NAMs) such as high-throughput screening (HTS) and mechanistically informative in vitro human cell-based systems, combined with in vitro to in vivo extrapolation (IVIVE), supplement in vivo studies and provide an alternative approach to calculate/determine PODs. We examine how parameterization of IVIVE models impacts the comparison between IVIVE-derived equivalent administered doses (EADs) from thyroid-relevant in vitro assays and the POD values that serve as the basis for risk assessments. Pesticide chemicals with thyroid-based in vitro bioactivity data from the US Tox21 HTS program were included (n = 45). Depending on the model structure used for IVIVE analysis, up to 35 chemicals produced EAD values lower than the POD. A total of 10 chemicals produced EAD values higher than the POD regardless of the model structure. The relationship between IVIVE-derived EAD values and the in vivo-derived POD values is highly dependent on model parameterization. Here, we derive a range of potentially thyroid-relevant doses that incorporate uncertainty in modeling choices and in vitro assay data.

Keywords: EDSP; NAMs; hazard assessment; in vivo to in vitro extrapolation; pesticides; point of departure; thyroid.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
AOP network for thyroid-based in vitro assays on neurodevelopment.
Figure 2
Figure 2
Comparison of models’ compartments and blood flows.
Figure 3
Figure 3
Comparing model-specific EAD estimates for insecticides.
Figure 4
Figure 4
Comparing model-specific EAD estimates for fungicides.
Figure 5
Figure 5
Comparing model-specific EAD estimates for acaricides, herbicides, and other pesticides.
Figure 6
Figure 6
Comparing dosing schedule on EAD estimates for pesticides.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Makri A.; Goveia M.; Balbus J.; Parkin R. Children’s Susceptibility to Chemicals: A Review By Developmental Stage. J. Toxicol. Environ. Health, Part B 2004, 7, 417–435. 10.1080/10937400490512465. - DOI - PubMed
    1. Landrigan P. J.; Goldman L. R. Children’s Vulnerability To Toxic Chemicals: A Challenge And Opportunity To Strengthen Health And Environmental Policy. Health Affairs 2011, 30, 842–850. 10.1377/hlthaff.2011.0151. - DOI - PubMed
    1. Landrigan P. J.; Etzel R. A.. Textbook of Children’s Environmental Health; OUP, 2013.
    1. Bruckner J. V. Differences in Sensitivity of Children and Adults to Chemical Toxicity: The NAS Panel Report. Regul. Toxicol. Pharmacol. 2000, 31, 280–285. 10.1006/rtph.2000.1393. - DOI - PubMed
    1. National Research Council . Pesticides in the Diets of Infants and Children; The National Academies Press, 1993, https://doi.org/10.17226/2126. - PubMed

Publication types