Download Naphthalene Research: The Relevance of Tumors

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(withdrawn/ deferred)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]