Toxicity testing in the 21st century: Defining new risk assessment approaches based on perturbation of intracellular toxicity pathways

Sudin Bhattacharya, Qiang Zhang, Paul L. Carmichael, Kim Boekelheide, Melvin E. Andersen

Research output: Research - peer-reviewArticle

  • 102 Citations

Abstract

The approaches to quantitatively assessing the health risks of chemical exposure have not changed appreciably in the past 50 to 80 years, the focus remaining on high-dose studies that measure adverse outcomes in homogeneous animal populations. This expensive, low-throughput approach relies on conservative extrapolations to relate animal studies to much lower-dose human exposures and is of questionable relevance to predicting risks to humans at their typical low exposures. It makes little use of a mechanistic understanding of the mode of action by which chemicals perturb biological processes in human cells and tissues. An alternative vision, proposed by the U.S. National Research Council (NRC) report Toxicity Testing in the 21st Century: A Vision and a Strategy, called for moving away from traditional high-dose animal studies to an approach based on perturbation of cellular responses using well-designed in vitro assays. Central to this vision are (a) "toxicity pathways" (the innate cellular pathways that may be perturbed by chemicals) and (b) the determination of chemical concentration ranges where those perturbations are likely to be excessive, thereby leading to adverse health effects if present for a prolonged duration in an intact organism. In this paper we briefly review the original NRC report and responses to that report over the past 3 years, and discuss how the change in testing might be achieved in the U.S. and in the European Union (EU). EU initiatives in developing alternatives to animal testing of cosmetic ingredients have run very much in parallel with the NRC report. Moving from current practice to the NRC vision would require using prototype toxicity pathways to develop case studies showing the new vision in action. In this vein, we also discuss how the proposed strategy for toxicity testing might be applied to the toxicity pathways associated with DNA damage and repair.

LanguageEnglish (US)
Article numbere20887
JournalPLoS One
Volume6
Issue number6
DOIs
StatePublished - 2011
Externally publishedYes

Profile

risk assessment process
toxicity testing
toxicity
Risk assessment
Toxicity
Testing
Animals
European Union
Health
dosage
animals
Animal Testing Alternatives
Pharmacologic Actions
Biological Phenomena
Cosmetics
DNA Repair
DNA Damage
Veins
Outcome Assessment (Health Care)
Population

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Toxicity testing in the 21st century : Defining new risk assessment approaches based on perturbation of intracellular toxicity pathways. / Bhattacharya, Sudin; Zhang, Qiang; Carmichael, Paul L.; Boekelheide, Kim; Andersen, Melvin E.

In: PLoS One, Vol. 6, No. 6, e20887, 2011.

Research output: Research - peer-reviewArticle

Bhattacharya, Sudin ; Zhang, Qiang ; Carmichael, Paul L. ; Boekelheide, Kim ; Andersen, Melvin E./ Toxicity testing in the 21st century : Defining new risk assessment approaches based on perturbation of intracellular toxicity pathways. In: PLoS One. 2011 ; Vol. 6, No. 6.
@article{f5c1175f23984c088d9a6a8a95f1b765,
title = "Toxicity testing in the 21st century: Defining new risk assessment approaches based on perturbation of intracellular toxicity pathways",
abstract = "The approaches to quantitatively assessing the health risks of chemical exposure have not changed appreciably in the past 50 to 80 years, the focus remaining on high-dose studies that measure adverse outcomes in homogeneous animal populations. This expensive, low-throughput approach relies on conservative extrapolations to relate animal studies to much lower-dose human exposures and is of questionable relevance to predicting risks to humans at their typical low exposures. It makes little use of a mechanistic understanding of the mode of action by which chemicals perturb biological processes in human cells and tissues. An alternative vision, proposed by the U.S. National Research Council (NRC) report Toxicity Testing in the 21st Century: A Vision and a Strategy, called for moving away from traditional high-dose animal studies to an approach based on perturbation of cellular responses using well-designed in vitro assays. Central to this vision are (a) {"}toxicity pathways{"} (the innate cellular pathways that may be perturbed by chemicals) and (b) the determination of chemical concentration ranges where those perturbations are likely to be excessive, thereby leading to adverse health effects if present for a prolonged duration in an intact organism. In this paper we briefly review the original NRC report and responses to that report over the past 3 years, and discuss how the change in testing might be achieved in the U.S. and in the European Union (EU). EU initiatives in developing alternatives to animal testing of cosmetic ingredients have run very much in parallel with the NRC report. Moving from current practice to the NRC vision would require using prototype toxicity pathways to develop case studies showing the new vision in action. In this vein, we also discuss how the proposed strategy for toxicity testing might be applied to the toxicity pathways associated with DNA damage and repair.",
author = "Sudin Bhattacharya and Qiang Zhang and Carmichael, {Paul L.} and Kim Boekelheide and Andersen, {Melvin E.}",
year = "2011",
doi = "10.1371/journal.pone.0020887",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "6",

}

TY - JOUR

T1 - Toxicity testing in the 21st century

T2 - PLoS One

AU - Bhattacharya,Sudin

AU - Zhang,Qiang

AU - Carmichael,Paul L.

AU - Boekelheide,Kim

AU - Andersen,Melvin E.

PY - 2011

Y1 - 2011

N2 - The approaches to quantitatively assessing the health risks of chemical exposure have not changed appreciably in the past 50 to 80 years, the focus remaining on high-dose studies that measure adverse outcomes in homogeneous animal populations. This expensive, low-throughput approach relies on conservative extrapolations to relate animal studies to much lower-dose human exposures and is of questionable relevance to predicting risks to humans at their typical low exposures. It makes little use of a mechanistic understanding of the mode of action by which chemicals perturb biological processes in human cells and tissues. An alternative vision, proposed by the U.S. National Research Council (NRC) report Toxicity Testing in the 21st Century: A Vision and a Strategy, called for moving away from traditional high-dose animal studies to an approach based on perturbation of cellular responses using well-designed in vitro assays. Central to this vision are (a) "toxicity pathways" (the innate cellular pathways that may be perturbed by chemicals) and (b) the determination of chemical concentration ranges where those perturbations are likely to be excessive, thereby leading to adverse health effects if present for a prolonged duration in an intact organism. In this paper we briefly review the original NRC report and responses to that report over the past 3 years, and discuss how the change in testing might be achieved in the U.S. and in the European Union (EU). EU initiatives in developing alternatives to animal testing of cosmetic ingredients have run very much in parallel with the NRC report. Moving from current practice to the NRC vision would require using prototype toxicity pathways to develop case studies showing the new vision in action. In this vein, we also discuss how the proposed strategy for toxicity testing might be applied to the toxicity pathways associated with DNA damage and repair.

AB - The approaches to quantitatively assessing the health risks of chemical exposure have not changed appreciably in the past 50 to 80 years, the focus remaining on high-dose studies that measure adverse outcomes in homogeneous animal populations. This expensive, low-throughput approach relies on conservative extrapolations to relate animal studies to much lower-dose human exposures and is of questionable relevance to predicting risks to humans at their typical low exposures. It makes little use of a mechanistic understanding of the mode of action by which chemicals perturb biological processes in human cells and tissues. An alternative vision, proposed by the U.S. National Research Council (NRC) report Toxicity Testing in the 21st Century: A Vision and a Strategy, called for moving away from traditional high-dose animal studies to an approach based on perturbation of cellular responses using well-designed in vitro assays. Central to this vision are (a) "toxicity pathways" (the innate cellular pathways that may be perturbed by chemicals) and (b) the determination of chemical concentration ranges where those perturbations are likely to be excessive, thereby leading to adverse health effects if present for a prolonged duration in an intact organism. In this paper we briefly review the original NRC report and responses to that report over the past 3 years, and discuss how the change in testing might be achieved in the U.S. and in the European Union (EU). EU initiatives in developing alternatives to animal testing of cosmetic ingredients have run very much in parallel with the NRC report. Moving from current practice to the NRC vision would require using prototype toxicity pathways to develop case studies showing the new vision in action. In this vein, we also discuss how the proposed strategy for toxicity testing might be applied to the toxicity pathways associated with DNA damage and repair.

UR - http://www.scopus.com/inward/record.url?scp=79959310697&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79959310697&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0020887

DO - 10.1371/journal.pone.0020887

M3 - Article

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 6

M1 - e20887

ER -