Rights statement: This dissertation contains several peer-reviewed manuscripts that were published by Oxford University Publishing's "Carcinogenesis" and in Elsevier's "Seminars in Cancer Biology" in Open Access format
Final published version, 15.5 MB, PDF document
Available under license: CC BY: Creative Commons Attribution 4.0 International License
Research output: Thesis › Doctoral Thesis
Research output: Thesis › Doctoral Thesis
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TY - BOOK
T1 - Towards an integrated understanding of low-dose chemical exposures in the development of human cancer
AU - Lowe, Leroy
PY - 2015/12
Y1 - 2015/12
N2 - Both genetic and environmental factors can play a role in an individual’s cancer susceptibility, and lifestyle-related factors have been a primary focus of our prevention efforts for several decades. However, advances in our understanding of cancer causation have resulted in additional concerns being raised about exposures to chronic, low-level exposures to combinations of chemicals. In this project, a large multinational task force comprised of twelve teams was organized to review 11 hallmark phenotypes of cancer and identify priority target sites for disruption in each area. Prototypical chemical disruptors for all targets were then identified, and dose-response information was gathered. Evidence of low-dose effects for each chemical was noted and cross-hallmark effects for all targets and chemicals were documented. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of adose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). This analysis reveals that every day exposures to individual (non-carcinogenic) chemicals that act on a range of mechanisms, pathways, and systems could conspire to instigate environmental carcinogenesis. Additional research on carcinogenesis is needed and the carcinogenic potential of low-dose exposures to mixtures of chemical that act selectively to enable these hallmark phenotypes also needs to be explored. Current models of risk assessment will also need to be revisited as they are not at aligned with our current understanding of cancer biology.
AB - Both genetic and environmental factors can play a role in an individual’s cancer susceptibility, and lifestyle-related factors have been a primary focus of our prevention efforts for several decades. However, advances in our understanding of cancer causation have resulted in additional concerns being raised about exposures to chronic, low-level exposures to combinations of chemicals. In this project, a large multinational task force comprised of twelve teams was organized to review 11 hallmark phenotypes of cancer and identify priority target sites for disruption in each area. Prototypical chemical disruptors for all targets were then identified, and dose-response information was gathered. Evidence of low-dose effects for each chemical was noted and cross-hallmark effects for all targets and chemicals were documented. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of adose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). This analysis reveals that every day exposures to individual (non-carcinogenic) chemicals that act on a range of mechanisms, pathways, and systems could conspire to instigate environmental carcinogenesis. Additional research on carcinogenesis is needed and the carcinogenic potential of low-dose exposures to mixtures of chemical that act selectively to enable these hallmark phenotypes also needs to be explored. Current models of risk assessment will also need to be revisited as they are not at aligned with our current understanding of cancer biology.
M3 - Doctoral Thesis
ER -