Naphthalene metabolism in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action

Kenneth T. Bogen, Janet M. Benson, Garold S. Yost, John B. Morris, Alan R. Dahl, Harvey J. Clewell, Kannan Krishnan, Curtis John Omiecinski

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Abstract

This report provides a summary of deliberations conducted under the charge for members of Module C Panel participating in the Naphthalene State-of-the-Science Symposium (NS3), Monterey, CA, October 9-12, 2006. The panel was charged with reviewing the current state of knowledge and uncertainty about naphthalene metabolism in relation to anatomy, physiology and cytotoxicity in tissues observed to have elevated tumor incidence in these rodent bioassays. Major conclusions reached concerning scientific claims of high confidence were that: (1) rat nasal tumor occurrence was greatly enhanced, if not enabled, by adjacent, histologically related focal cellular proliferation; (2) elevated incidence of mouse lung tumors occurred at a concentration (30 ppm) cytotoxic to the same lung region at which tumors occurred, but not at a lower and less cytotoxic concentration (tumorigenesis NOAEL = 10 ppm); (3) naphthalene cytotoxicity requires metabolic activation (unmetabolized naphthalene is not a proximate cause of observed toxicity or tumors); (4) there are clear regional and species differences in naphthalene bioactivation; and (5) target tissue anatomy and physiology is sufficiently well understood for rodents, non-human primates and humans to parameterize species-specific physiologically based pharmacokinetic (PBPK) models for nasal and lung effects. Critical areas of uncertainty requiring resolution to enable improved human cancer risk assessment were considered to be that: (1) cytotoxic naphthalene metabolites, their modes of cytotoxic action, and detailed low-dose dose-response need to be clarified, including in primate and human tissues, and neonatal tissues; (2) mouse, rat, and monkey inhalation studies are needed to better define in vivo naphthalene uptake and metabolism in the upper respiratory tract; (3) in vivo validation studies are needed for a PBPK model for monkeys exposed to naphthalene by inhalation, coupled to cytotoxicity studies referred to above; and (4) in vivo studies are needed to validate a human PBPK model for naphthalene. To address these uncertainties, the Panel proposed specific research studies that should be feasible to complete relatively promptly. Concerning residual uncertainty far less easy to resolve, the Panel concluded that environmental, non-cytotoxic exposure levels of naphthalene do not induce tumors at rates that can be predicted meaningfully by simple linear extrapolation from those observed in rodents chronically exposed to far greater, cytotoxic naphthalene concentrations.

Original languageEnglish (US)
Pages (from-to)27-36
Number of pages10
JournalRegulatory Toxicology and Pharmacology
Volume51
Issue number2 SUPLL
DOIs
StatePublished - Jan 1 2008

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Physiology
Cytotoxicity
Metabolism
Anatomy
Tissue
Tumors
Uncertainty
Pharmacokinetics
Neoplasms
Rodentia
Nose
Lung
Inhalation
Primates
Haplorhini
Rats
naphthalene
No-Observed-Adverse-Effect Level
Bioassay
Validation Studies

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Bogen, K. T., Benson, J. M., Yost, G. S., Morris, J. B., Dahl, A. R., Clewell, H. J., ... Omiecinski, C. J. (2008). Naphthalene metabolism in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action. Regulatory Toxicology and Pharmacology, 51(2 SUPLL), 27-36. https://doi.org/10.1016/j.yrtph.2007.10.018
Bogen, Kenneth T. ; Benson, Janet M. ; Yost, Garold S. ; Morris, John B. ; Dahl, Alan R. ; Clewell, Harvey J. ; Krishnan, Kannan ; Omiecinski, Curtis John. / Naphthalene metabolism in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action. In: Regulatory Toxicology and Pharmacology. 2008 ; Vol. 51, No. 2 SUPLL. pp. 27-36.
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Bogen, KT, Benson, JM, Yost, GS, Morris, JB, Dahl, AR, Clewell, HJ, Krishnan, K & Omiecinski, CJ 2008, 'Naphthalene metabolism in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action', Regulatory Toxicology and Pharmacology, vol. 51, no. 2 SUPLL, pp. 27-36. https://doi.org/10.1016/j.yrtph.2007.10.018

Naphthalene metabolism in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action. / Bogen, Kenneth T.; Benson, Janet M.; Yost, Garold S.; Morris, John B.; Dahl, Alan R.; Clewell, Harvey J.; Krishnan, Kannan; Omiecinski, Curtis John.

In: Regulatory Toxicology and Pharmacology, Vol. 51, No. 2 SUPLL, 01.01.2008, p. 27-36.

Research output: Contribution to journalArticle

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T1 - Naphthalene metabolism in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action

AU - Bogen, Kenneth T.

AU - Benson, Janet M.

AU - Yost, Garold S.

AU - Morris, John B.

AU - Dahl, Alan R.

AU - Clewell, Harvey J.

AU - Krishnan, Kannan

AU - Omiecinski, Curtis John

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N2 - This report provides a summary of deliberations conducted under the charge for members of Module C Panel participating in the Naphthalene State-of-the-Science Symposium (NS3), Monterey, CA, October 9-12, 2006. The panel was charged with reviewing the current state of knowledge and uncertainty about naphthalene metabolism in relation to anatomy, physiology and cytotoxicity in tissues observed to have elevated tumor incidence in these rodent bioassays. Major conclusions reached concerning scientific claims of high confidence were that: (1) rat nasal tumor occurrence was greatly enhanced, if not enabled, by adjacent, histologically related focal cellular proliferation; (2) elevated incidence of mouse lung tumors occurred at a concentration (30 ppm) cytotoxic to the same lung region at which tumors occurred, but not at a lower and less cytotoxic concentration (tumorigenesis NOAEL = 10 ppm); (3) naphthalene cytotoxicity requires metabolic activation (unmetabolized naphthalene is not a proximate cause of observed toxicity or tumors); (4) there are clear regional and species differences in naphthalene bioactivation; and (5) target tissue anatomy and physiology is sufficiently well understood for rodents, non-human primates and humans to parameterize species-specific physiologically based pharmacokinetic (PBPK) models for nasal and lung effects. Critical areas of uncertainty requiring resolution to enable improved human cancer risk assessment were considered to be that: (1) cytotoxic naphthalene metabolites, their modes of cytotoxic action, and detailed low-dose dose-response need to be clarified, including in primate and human tissues, and neonatal tissues; (2) mouse, rat, and monkey inhalation studies are needed to better define in vivo naphthalene uptake and metabolism in the upper respiratory tract; (3) in vivo validation studies are needed for a PBPK model for monkeys exposed to naphthalene by inhalation, coupled to cytotoxicity studies referred to above; and (4) in vivo studies are needed to validate a human PBPK model for naphthalene. To address these uncertainties, the Panel proposed specific research studies that should be feasible to complete relatively promptly. Concerning residual uncertainty far less easy to resolve, the Panel concluded that environmental, non-cytotoxic exposure levels of naphthalene do not induce tumors at rates that can be predicted meaningfully by simple linear extrapolation from those observed in rodents chronically exposed to far greater, cytotoxic naphthalene concentrations.

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