Tolerance to multiple doses of the pulmonary toxicant, naphthalene

O'Brien, K.A.F.; Suverkropp, Claus; Kanekal, Sarathchandra; Plopper, Charles G.; Buckpitt, Alan R.

doi:10.1016/0041-008x(89)90156-7

Cited by 54 publications

(25 citation statements)

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“…CYP1A2 and 2D6*1 were identified as the most active isoforms for producing 1,4-naphthoquinone, and CYP3A4 and CYP2A6 the most active at metabolizing dihydrodiol, though at rates less than those at which 1-naphthol was observed to be metabolized (Cho et al, 2006). Necrosis of bronchial epithelial (Clara) cells in mice (O'Brien et al, 1985(O'Brien et al, , 1989Tong et al, 1981) and necrosis of olfactory epithelial cells in mice, rats and hamsters following intraperitoneal injection of naphthalene strongly indicate that metabolic activation in target tissues plays a dominant, and possibly exclusive, role in site-specific naphthalene cytotoxicity. There is no evidence that unmetabolized naphthalene is cytotoxic, or that unmetabolized naphthalene is genotoxic at non-cytotoxic concentrations.…”

Section: Naphthalene Cytotoxicity Requires Metabolic Activation; Unmementioning

confidence: 99%

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

Bogen

Benson

Yost

et al. 2008

Regulatory Toxicology and Pharmacology

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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 (NS 3 ), 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 © 2007 Elsevier Inc. All rights reserved. * Corresponding author. Fax: +1 510 286 5099. ktbogen@exponent.com (K.T. Bogen). Conflict of interest disclosureThe authors declare that they have no conflicts of interest. Each received an honorarium from Regulatory Checkbook, PO Box 319, Mt. Vernon, VA 22121, for service as set forward in Belzer et al. (2008). NIH Public Access Author ManuscriptRegul Toxicol Pharmacol. Author manuscript; available in PMC 2014 May 22. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 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, cytotox...

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Section: Naphthalene Cytotoxicity Requires Metabolic Activation; Unmementioning

confidence: 99%

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

Bogen

Benson

Yost

et al. 2008

Regulatory Toxicology and Pharmacology

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“…This is poorly understood. Previous publications have reported that, after seven daily exposures to NA by inhalation and intraperitoneal injection, adult males develop airway epithelial tolerance described as diminished cytotoxicity with subsequent dosing and an epithelium resembling that of control animals (10,25). The development of tolerance in these studies was characterized by a decreased number of Clara cells, decreased enzymes involved in NA bioactivation (P-450 isozymes and P-450 reductase), and upregulation of the detoxifying tripeptide GSH concomitant with increased GSH-synthesizing enzyme glutamate-cysteine ligase (GCL) (6,24).…”

mentioning

confidence: 99%

“…Tolerance is characterized by resistance to injury from a high dose conferred by repeated exposures at a moderate dose. Tolerance in the lung has been described for male animals exposed to the P-450 activated polycyclic aromatic hydrocarbon (PAH) naphthalene (NA), which is also a prominent constituent of mainstream tobacco smoke and the most abundant PAH in sidestream smoke (10,27). Humans are exposed to NA at sufficient levels that it is detectable in adipose tissue, breast milk, and placental tissue (12,16,17).…”

mentioning

confidence: 99%

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Sex differences in the development of airway epithelial tolerance to naphthalene

Sutherland¹,

Edwards²,

Combs³

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Necrosis of bronchial epithelial (Clara) cells in mice (Tong et al, 1981;Buckpitt and Warren, 1983;O'Brien et al, 1985O'Brien et al, , 1989 and necrosis of olfactory epithelial cells in mice, rats and hamsters following intraperitoneal injection of naphthalene strongly indicate that metabolic activation in target tissues plays a dominant, and possibly exclusive, role in site-specific naphthalene cytotoxicity. There is no evidence that unmetabolized naphthalene is cytotoxic.…”

Section: Naphthalene Metabolite Cytotoxicitymentioning

confidence: 99%

Mode-of-Action Uncertainty for Dual-Mode Carcinogens:Lower Bounds for Naphthalene-Induced Nasal Tumors in Rats Implied byPBPK and 2-Stage Stochastic Cancer Risk Models

Bogen¹

2007

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As reflected in the 2005 USEPA Guidelines for Cancer Risk Assessment, some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate "linear" (genotoxic) vs. "nonlinear" (nongenotoxic) approaches to low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient to parameterize a biologically based model that reliably extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach-similar to that used in reference dose procedures for classic toxicity endpoints-can address MOA uncertainty in a way that avoids explicit modeling of low-dose risk as a function of administered or internal dose. Even when a "nonlinear" toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was illustrated for the rodent carcinogen naphthalene. Bioassay data, supplemental toxicokinetic data, and related physiologically based pharmacokinetic and 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rattumor-type specific DMOA-related uncertainty were obtained using a 2-stage model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2-and 1,4-naphthoquinone. Resulting bounds each provided the basis for a corresponding "uncertainty" factor <1 appropriate to apply to estimates of naphthalene risk obtained by linear extrapolation under a default genotoxic MOA assumption.This procedure is proposed as scientifically credible method to address MOA uncertainty for DMOA carcinogens.3

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Tolerance to multiple doses of the pulmonary toxicant, naphthalene

Cited by 54 publications

References 20 publications

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

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

Sex differences in the development of airway epithelial tolerance to naphthalene

Mode-of-Action Uncertainty for Dual-Mode Carcinogens:Lower Bounds for Naphthalene-Induced Nasal Tumors in Rats Implied byPBPK and 2-Stage Stochastic Cancer Risk Models

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