Society For Risk Analysis Annual Meeting 2013

Session Schedule & Abstracts

* Disclaimer: All presentations represent the views of the authors, and not the organizations that support their research. Please apply the standard disclaimer that any opinions, findings, and conclusions or recommendations in abstracts, posters, and presentations at the meeting are those of the authors and do not necessarily reflect the views of any other organization or agency. Meeting attendees and authors should be aware that this disclaimer is intended to apply to all abstracts contained in this document. Authors who wish to emphasize this disclaimer should do so in their presentation or poster. In an effort to make the abstracts as concise as possible and easy for meeting participants to read, the abstracts have been formatted such that they exclude references to papers, affiliations, and/or funding sources. Authors who wish to provide attendees with this information should do so in their presentation or poster.

Common abbreviations

Symposium: The Naphthalene Research Program: From Problem Formulation to Risk Assessment

Room: Peale A&B   3:30 PM - 6:30 PM

Chair(s): Anne LeHuray

W4-G.1  15:30  Naphthalene Rodent Inhalation Bioassays and Assessment of Risk to Exposed Humans: Problem Formulation. Reitman* F*, Sun T-J, Beatty P, LeHuray AP, Hammon TL, Juba MH, Palermo C, Lewis RJ, White RD; 1 Shell; 2 Chevron; 3 American Petroleum Institute; 4 Naphthalene Council; 5 ConocoPhillips; 6 Koppers, Inc.; 7, 8 ExxonMobil Biomedical Sciences, Inc. 9 American Petroleum Institute

Abstract: The National Toxicology Program (NTP) conducted 2-year naphthalene inhalation cancer bioassays in B6C3F1 mice (1992) and in F-344 rats (2000) and observed cancers in the mouse lung and the rat nose. Naphthalene exposure was not previously thought to pose a cancer risk, however, based on these two NTP studies EPA’s Integrated Risk Information System (IRIS) released a draft cancer risk assessment in 2004 which proposed naphthalene as “likely to be carcinogenic in humans”, with a calculated cancer potency 10 to 40-fold greater than benzene. However, the available human and mechanistic toxicity data did not support the association between naphthalene exposure and cancer, particularly nasal cancer. A 2006 Naphthalene State- of- Science Symposium (NS3), independently organized and funded by EPA, Naphthalene Research Committee (NRC) members and others, provided a rigorous review of the state -of-science for cancer risk assessment. The NS3 raised concerns in extrapolating these rodent bioassay results to human cancer risks including: (1) the NTP bioassays were conducted at high vapor concentrations above the Maximum Tolerated Dose, complicating low-dose extrapolation, (2) naphthalene likely does not represent a classical genotoxic carcinogen, (3) cytotoxicity and cellular proliferation appears to have played a role in the carcinogenic responses, (4) tumor formation rates at environmental, noncytotoxic exposure levels cannot be meaningfully predicted by simple linear extrapolation from the tumor rates observed in the rodent bioassays, and (5) there are important differences in naphthalene metabolism and toxicity between rodents and humans. Based on the study recommendations from NS3, industry associations and individual companies formed the NRC to co-sponsor research that strives to improve naphthalene risk assessments. The NRC’s objective has been to collect data to properly evaluate the carcinogenic potential of naphthalene.

W4-G.2  15:50  Hypothesis-based weight-of-evidence and dose-response evaluation for naphthalene carcinogenicity. Rhomberg LR*, Bailey LA, Nascarella MA; Gradient

Abstract: Human health risk assessment consists of bringing to bear a large body of in vitro, animal, and epidemiologic studies on the question of whether environmental exposures to a substance are a potential risk to humans. The body of scientific information, however, is typically less than definitive and often contains apparent contradictions. We applied our Hypothesis-Based Weight-of-Evidence (HBWoE) method to systematically and comparatively evaluate the large body of data and hypothesized modes of action for inhaled naphthalene carcinogenesis, expressing the relative degrees of credence that should be placed in alternative possible interpretations of the data, considering consistencies, inconsistencies, and contradictions within the data set. Guided by the outcome of our WoE evaluation, we conducted a dose-response evaluation of naphthalene exposure and neoplastic and non-neoplastic lesions, with the ultimate goal of deriving naphthalene toxicity values applicable to human health risk assessment. Our approach was to consider the applicability of the rat nasal tumors to serve as a basis for estimation of potential human respiratory-tract cancer risk. We did this by considering the mode of action (MoA) underlying the animal tumors seen in bioassays, including the metabolic activation and detoxification of inhaled naphthalene as they depend on air concentration, as well as the nature, tissue locations, and dependence on tissue-dose of key precursor responses. Species differences in tissue dosimetry were used to evaluate whether parallel tissues in humans, or other tissues in the respiratory tract, could be subject to tissue doses that could prompt the key events of the apparent MoA. The points of departure derived from rodent dose-response evaluations were extrapolated to human equivalent concentrations through application of a rat/human PBPK model that describes cross-species dosimetry of the upper respiratory tract, lung, and liver.

W4-G.3  16:10  Assessing the Human Health Risks from Exposure to Naphthalene. Flowers L*, Keshava C, Chiu W; National Center for Environmental Assessment, Office of Research and Development, USEPA

Abstract: EPA’s Integrated Risk Information System (IRIS) Program develops human health assessments that provide health effects information on environmental chemicals to which the public may be exposed and is currently developing an updated health assessment for naphthalene. Naphthalene is ubiquitous in the environment from the combustion of wood and fossil fuels, and can also be released into air, soil and water from its production and use as an intermediate in chemical synthesis. IRIS assessments contain information to support the first two steps (hazard identification and dose-response analysis) of the risk assessment paradigm and develop quantitative toxicity values for cancer and noncancer health effects. IRIS assessments are not regulations, but they provide a critical part of the scientific foundation for decisions to protect public health across EPA’s programs and regions under an array of environmental laws. For naphthalene, perhaps the most scientifically debated topic has focused on the mode of action of carcinogenicity following inhalation exposure in animals, particularly with respect to the human relevance of the observed tumors and the shape of the dose-response curve at low dose. The development of the naphthalene IRIS assessment will be discussed, including how 1) recent enhancements to the IRIS process will impact the assessment, 2) information from recent scientifically relevant workshops will be utilized, and 3) recent recommendations from the National Research Council on IRIS assessment development will be incorporated. The views expressed are those of the authors and do not necessarily reflect the views or policies of the U.S. EPA.

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