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Naphthalene Research: The Relevance of Tumors in Rodents to Human Risk Assessment LeHuray, AP1, Bird, MG2, Hammon, TL3, Juba, MH4, Lewis, RJ2, Reitman, F5, Sun, T-J6, White, RD7, Wise, K7 1 Naphthalene Council; 2 ExxonMobil Biomedical Sciences, Inc.; 3 ConocoPhillips; 4 Koppers, Inc.; 5 Shell; 6 Chevron; 7 American Petroleum Institute Introduction NRC Research Program Overview In 2007, industry associations and individual companies formed the Naphthalene Research Committee (NRC) to co-sponsor multi-year research that strives to improve naphthalene risk assessments. The NRC’s objective is to reduce the use of default assumptions in assessing cancer risks potentially posed by exposure to naphthalene. To further its objective, the NRC funds basic research that is published in the peer-reviewed scientific literature. What is Naphthalene? The NRC research program will focus on studies designed to define the mode of action of carcinogenicity in rodents exposed to naphthalene, and the relevance of the rodent mode of action to humans. Specifically, the research program is testing the following hypotheses: • Naphthalene is metabolized by specific cytochrome P450 enzymes, • At high concentration of naphthalene above a threshold the resulting metabolism leads to genotoxic as well as cytotoxic effects in the mouse lung and rat nasal tissues, and • The chronic inflammation, regenerative hyperplasia, potential genotoxicity, and carcinogenicity are related to site- and speciesspecific metabolism at high concentrations. Parts per Trillion (ppt) Based on EPA’s previous estimate of carcinogenic risk from inhalation exposure (rat nasal tumors), ambient air concentrations of naphthalene would need to be less than 2 ppt 41 ppt 14 ppt 2 ppt Naphthalene Butadiene Benzene 2004 Draft IRIS (withdrawn/ deferred) 2002 IRIS 1998 IRIS In 2006, the independently organized Naphthalene State-of-theScience Symposium (NS3) was conducted. This symposium was funded by EPA, NRC members, and others. The expert panels convened by NS3 recently published their findings and research recommendations in six peer-reviewed papers. A consistent observation among the scientists who participated in NS3 is that physiologic and metabolic differences between rodents and primates exposed to naphthalene introduce significant uncertainty into the applicability of studies conducted in rats and mice to human risk assessment. TEMPLATE DESIGN © 2008 www.PosterPresentations.com Acute (single 6-hour) and 5 day exposure studies conducted in Fischer and SD rats examined whether the NTP chronic studies were conducted at concentrations that exceed the maximally tolerated dose (MTD) for naphthalene. The NRC research program will continue to focus on studies to define the mode of action of carcinogenicity in rodents exposed to naphthalene, and the relevance of the rodent mode of action to humans. These studies showed that the high concentrations used by NTP in the two-year studies would have resulted in severe damage to the olfactory epithelium - a target tissue for subsequent tumor formation, indicative of an MTD exceedance. Results of the short-term studies established no-effect concentrations for naphthalene in the range of 100 ppb to 1 ppm (Gross et al., 2007; Dodd et al., 2008; Dodd et.al., 2009). Results from other NRC-funded respiratory uptake studies of naphthalene in rats, demonstrate that use of the Category 1 gas model is an inappropriate default assumption in assessing naphthalene risk (Simmons et al., 2008; Morris and Buckpitt, submitted to Tox. Sci.). Ongoing research projects include: Follow on work to the 90 day inhalation study will include a focus on how exposure to naphthalene could be expressed in specific genes. Methods are being developed for the potential study of naphthalene biomarkers in humans. Assessment of future research needs to evaluate human relevance The NRC prefers that all study results be published in the peerreviewed literature. Why are we doing this Research? Air Concentrations at the One in a Million Risk Level Ongoing NRC funded Research Respiratory uptake data and histological lesion mapping of the rat nose after naphthalene exposure are being used to develop a PBPK model incorporating naphthalene-specific data (Campbell et al., 2008; Mannix et al., 2008). Naphthalene is a naturally occurring component of fossil fuels. Naphthalene is also a byproduct of incomplete combustion of organic materials. The National Toxicology Program (NTP) conducted 2-year naphthalene inhalation cancer studies in mice (1992) and in rats (2000) and found evidence, at the high concentrations used in the studies, of lung cancer in mice and nasal cancer in rats. In 2004, EPA’s Integrated Risk Information System (IRIS) released a draft risk assessment, largely based on default assumptions, that proposed naphthalene as “likely to be carcinogenic in humans” with a cancer potency 10x to 40x greater than benzene. What has the NRC Found? ~80% of metabolism What sort of studies have been funded by the NRC? Acute inhalation exposure studies (1 and 5 day) in Fischer & SD rats Subchronic 90 day inhalation exposure study in SD rats Blood and urine studies Genomics – microarray analysis p53 gene expression study Biomarker/metabolism/protein adduct studies Upper respiratory tract uptake studies in rats & mice Preliminary metabolism & biomarker studies (urinalysis; identification of metabolites using radiolabeled naphthalene; protein adduct method development) Preliminary physiologically based pharmacokinetic (PBPK) modeling Preliminary cross-species CYP metabolism studies & modeling References ~20% of metabolism Reference List is available upon request Implications on Human Risk Assessment Several completed and ongoing NRC-funded studies could significantly contribute to the draft IRIS assessment. vNTP studies conducted above the MTD Current Sponsors NRC funding organizations are: Asphalt Institute, American Petroleum Institute, Flint Hills Resources, Naphthalene Council, Utilities Solid Waste Activities Group. Contact information vCategory 1 gas model is an inappropriate default assumption in assessing naphthalene risk vPlanning to apply the human relevance framework (Meek et al., 2005) to naphthalene. vNRC has funded publication of a hypothesis-based weight of evidence analysis to evaluate assumptions, alternative hypotheses, and guide development of data needed for a robust mode of action hypothesis (Bailey and Rhomberg, 2009). Anne LeHuray Russ White Naphthalene Council 2308 Mt Vernon Ave, Suite 134 Alexandria, VA 22301 [email protected] American Petroleum Institute 1220 L Street NW Washington DC, 20005 [email protected]