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Title: Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

Abstract

A relatively simple, quantitative approach is proposed to address a specific, important gap in the appr approach recommended by the USEPA Guidelines for Cancer Risk Assessment to oach address uncertainty in carcinogenic mode of action of certain chemicals when risk is extrapolated from bioassay data. These Guidelines recognize that 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 low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient t to parameterize a biologically based model that reliably o 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 modelingmore » of low low-dose risk as a function of administere administered or internal dose. Even when a 'nonlinear' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was i illustrated llustrated for a likely DMOA rodent carcinogen naphthalene, specifically to the issue of risk extrapolation from bioassay data on naphthalene naphthalene-induced nasal tumors in rats. Bioassay data, supplemental toxicokinetic data, and related physiologically based p pharmacokinetic and 2 harmacokinetic 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rat rat-tumor tumor-type specific DMOA DMOA-related uncertainty were obtained using a 2-stage model adapted to reflec reflect the empirical link between genotoxic and cytotoxic effects of t the most potent identified genotoxic naphthalene metabolites, 1,2 1,2- and 1,4 1,4-naphthoquinone. Bound Bound-specific 'adjustment' factors were then used to reduce naphthalene risk estimated by linear ex extrapolation (under the default genotoxic MOA assumption), to account for the DMOA trapolation exhibited by this compound.« less

Authors:
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
919619
Report Number(s):
UCRL-TR-227766-REV-1
TRN: US200825%%357
DOE Contract Number:
W-7405-ENG-48
Resource Type:
Technical Report
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; 54 ENVIRONMENTAL SCIENCES; BIOASSAY; CARCINOGENESIS; CARCINOGENS; CELL KILLING; EXTRAPOLATION; METABOLITES; MUTATIONS; NAPHTHALENE; NEOPLASMS; RECOMMENDATIONS; RISK ASSESSMENT; RODENTS; SIMULATION; TARGETS; TOXICITY

Citation Formats

Bogen, K T. Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models. United States: N. p., 2007. Web. doi:10.2172/919619.
Bogen, K T. Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models. United States. doi:10.2172/919619.
Bogen, K T. Fri . "Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models". United States. doi:10.2172/919619. https://www.osti.gov/servlets/purl/919619.
@article{osti_919619,
title = {Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models},
author = {Bogen, K T},
abstractNote = {A relatively simple, quantitative approach is proposed to address a specific, important gap in the appr approach recommended by the USEPA Guidelines for Cancer Risk Assessment to oach address uncertainty in carcinogenic mode of action of certain chemicals when risk is extrapolated from bioassay data. These Guidelines recognize that 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 low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient t to parameterize a biologically based model that reliably o 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 low-dose risk as a function of administere administered or internal dose. Even when a 'nonlinear' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was i illustrated llustrated for a likely DMOA rodent carcinogen naphthalene, specifically to the issue of risk extrapolation from bioassay data on naphthalene naphthalene-induced nasal tumors in rats. Bioassay data, supplemental toxicokinetic data, and related physiologically based p pharmacokinetic and 2 harmacokinetic 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rat rat-tumor tumor-type specific DMOA DMOA-related uncertainty were obtained using a 2-stage model adapted to reflec reflect the empirical link between genotoxic and cytotoxic effects of t the most potent identified genotoxic naphthalene metabolites, 1,2 1,2- and 1,4 1,4-naphthoquinone. Bound Bound-specific 'adjustment' factors were then used to reduce naphthalene risk estimated by linear ex extrapolation (under the default genotoxic MOA assumption), to account for the DMOA trapolation exhibited by this compound.},
doi = {10.2172/919619},
journal = {},
number = ,
volume = ,
place = {United States},
year = {Fri May 11 00:00:00 EDT 2007},
month = {Fri May 11 00:00:00 EDT 2007}
}

Technical Report:

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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 lowmore » 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 rat-tumor-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.« less
  • We have developed a comprehensive, Bayesian, PBPK model-based analysis of the population toxicokinetics of trichloroethylene (TCE) and its metabolites in mice, rats, and humans, considering a wider range of physiological, chemical, in vitro, and in vivo data than any previously published analysis of TCE. The toxicokinetics of the 'population average,' its population variability, and their uncertainties are characterized in an approach that strives to be maximally transparent and objective. Estimates of experimental variability and uncertainty were also included in this analysis. The experimental database was expanded to include virtually all available in vivo toxicokinetic data, which permitted, in rats andmore » humans, the specification of separate datasets for model calibration and evaluation. The total combination of these approaches and PBPK analysis provides substantial support for the model predictions. In addition, we feel confident that the approach employed also yields an accurate characterization of the uncertainty in metabolic pathways for which available data were sparse or relatively indirect, such as GSH conjugation and respiratory tract metabolism. Key conclusions from the model predictions include the following: (1) as expected, TCE is substantially metabolized, primarily by oxidation at doses below saturation; (2) GSH conjugation and subsequent bioactivation in humans appear to be 10- to 100-fold greater than previously estimated; and (3) mice had the greatest rate of respiratory tract oxidative metabolism as compared to rats and humans. In a situation such as TCE in which there is large database of studies coupled with complex toxicokinetics, the Bayesian approach provides a systematic method of simultaneously estimating model parameters and characterizing their uncertainty and variability. However, care needs to be taken in its implementation to ensure biological consistency, transparency, and objectivity.« less
  • The U.S. Environmental Protection Agency has carried out risk assessments on a variety of chemicals that have been shown to induce nasal tumors in animals and/or humans. Human cancer-potency estimates, however, were not always based on the induction of nasal tumors. For those that were, studies employing the inhalation route of exposure were used, with one exception. Extrapolation from the inhalation to the oral route has not been attempted for nasal carcinogens. A variety of uncertainties in assessing potency of nasal carcinogens is being addressed.
  • A request was made by the Mine Safety and Health Administration to assess quantitatively the risk of lung cancer among those occupationally exposed to diesel exhaust. The Armitage-Doll multistage model was adapted to fit both the cases of all tumors and malignant neoplasms alone. A number of assumptions were made to extend the risk estimates derived from the models of tumor response in rats to the risks for humans. These assumptions fell into three categories: those concerning the development of biologically equivalent doses for rats and humans, those relating external exposure to internal dose, and those concerning the scaling ofmore » age between rats and humans to account for the temporal aspects of exposure. Uncertainties in the study included the effects of exposure on lung clearance mechanisms, the deposition rates in humans, and the relevance of the exposure index limit. Based on the findings of the study the excess risk to miners of lung cancer at the upper range of the diesel particulate exposure reported, 1.5mg/cu m, was approximately 1.5 to 3 in 100. According to the authors, the results are consistent with previous recommendations by NIOSH that diesel exhaust should be regarded as a potential human carcinogen, and that efforts should be made to reduce exposures to the lowest feasible concentration.« less