vvEPA
EPA/635/R-14/199
Scoping and Problem Formulation Materials
www. ep a. go v/ir is
Scoping and Problem Formulation for the Identification of Potential
Health Hazards for the Integrated Risk Information System (IRIS)
Toxicological Review of Naphthalene
[CASRN 91-20-3]
July 2014
NOTICE
Disclaimer: This document is comprised of scoping and problem formulation materials. This
information is distributed solely for the purpose of pre-dissemination review under applicable
information quality guidelines. It has not been formally disseminated by EPA. It does not represent
and should not be construed to represent any Agency determination or policy. It is being circulated
for review of its technical accuracy and completeness. Mention of trade names or commercial
products does not constitute endorsement or recommendation for use.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
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Scoping and Problem Formulation Materials for Naphthalene
CONTENTS
PREFACE iii
1. BACKGROUND 1
1.1. Production and Use 1
1.2. Environmental Fate 2
1.3. Human Exposure Pathways 2
2. SCOPE OF THIS ASSESSMENT 4
3. PROBLEM FORMULATION 5
3.1. Preliminary Literature Survey 5
3.2. Health Outcomes Identified by the Preliminary Literature Survey 6
3.3. Hazard Questions for Systematic Review 8
3.4. Key Issues 15
REFERENCES 19
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Scoping and Problem Formulation Materials for Naphthalene
1
2 PREFACE
3 The National Research Council's Review of EPA's Integrated Risk Information System (IRIS)
4 Process (NRC, 2014) discussed scoping and problem formulation as they apply specifically to IRIS
5 assessments. IRIS assessments evaluate the available scientific literature to identify potential
6 human health hazards of a chemical and to characterize dose-response relationships for each
7 hazard. Accordingly, the NRC discussed scoping and problem formulation for IRIS assessments as
8 being restricted to scientific questions that pertain only to hazard identification and dose-response
9 assessment Exposure assessment and risk characterization (the other components of a risk
10 assessment) are outside the scope of IRIS assessments, as are the legal, political, social, economic,
11 and technical aspects of risk management.
12 During scoping, the IRIS program seeks input from EPA's program and regional offices to
13 identify the information and level of detail needed to inform their decisions. This includes the
14 exposure pathways and specific exposed groups that the assessment will consider. The NRC's
15 Review of EPA's IRIS Process characterized this practice as consistent with the risk-assessment
16 guidance in Science and Decisions (NRC, 2009).
17 During problem formulation, the IRIS program seeks input from the scientific community
18 and the general public as it frames the specific scientific questions for the systematic reviews that it
19 will conduct in the assessment. The NRC's Review of EPA's IRIS Process identified the major
20 challenge of problem formulation as determining which adverse outcomes the assessment should
21 evaluate. The NRC suggested a three-step process for conducting problem formulation for IRIS
22 assessments: (1) a literature survey to identify the possible health outcomes associated with the
23 chemical, (2) construction of a table to guide the formulation of specific questions that will be the
24 subject of specific systematic reviews, and (3) examination of this table to determine which health
25 outcomes warrant a systematic review and to define the systematic-review questions. As an
26 example, the NRC provided the question, "Does exposure to chemical X result in neurotoxic effects?"
27 In addition to identifying health outcomes for systematic review, the problem formulation section
28 discusses key issues that the assessment will address.
29 This document begins with a brief background information on naphthalene, which will be
30 the subject of an IRIS assessment Next the three steps that the NRC suggested are presented along
31 with the systematic-review questions and key issues.
32 Early public involvement should increase the quality and transparency of IRIS assessments.
33 Accordingly, the IRIS program is releasing this document in anticipation of a public science meeting
34 focused on identifying the scientific information available for this assessment The IRIS program
35 encourages the scientific community and the general public to participate in this meeting.
in
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Scoping and Problem Formulation Materials for Naphthalene
l.BACKGROUND
2 1.1. Production and Use
3 Naphthalene is a polycyclic aromatic hydrocarbon chemical that is a white crystalline solid
4 at room temperature with an aromatic odor. It is insoluble in water but soluble in many organic
5 solvents. It is stable in closed containers under normal temperatures and pressures (NTP, 2011).
Naphthalene
8
9 CAS Number: 91-20-3
10
11 The largest source of naphthalene is fossil fuels, such as petroleum and coal (ATSDR, 2005).
12 Naphthalene also occurs at high levels (~10%) in coal tar, which is a byproduct in the production of
13 steel (HSDB, 2005).
14 Naphthalene is considered a High Production Volume chemical in the United States, though
15 domestic production of naphthalene has decreased significantly from a peak of 900 million pounds
16 in 1968 to 215 million pounds reported in 2004 (ATSDR, 2005) and 160 million pounds reported in
17 2012 (U.S. EPA, 2013a).
18 More than 60% of naphthalene in the U.S. is used in the production of phthalic anhydride,
19 which is an intermediate in the production of phthalate plasticizers, resins, phthaleins, dyes,
20 pharmaceuticals, insect repellents, and other materials (ATSDR, 2005). Naphthalene is also present
21 in certain jet fuels, just as JP-8 (ATSDR, 2013). The major consumer products made from
2 2 naphthalene are moth repellents, in the form of mothballs or crystals, and toilet deodorant blocks
23 (ATSDR, 2005). However, the use of naphthalene as a moth repellentand insecticide is decreasing
24 and it is being replaced by other compounds (HSDB, 2005). Other uses in consumer products
25 include: aerosol paint concentrates and other paint-related products, agricultural chemicals,
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Scoping and Problem Formulation Materials for Naphthalene
1 herbicides, caulking compounds and sealants, automotive chemicals, repellants and attractants,
2 synthetic resin and rubber adhesives, wall coverings, and wood office work surfaces (HSDB, 2005).
3 According to the U.S. EPA's Toxics Release Inventory (TRI) Program, the environmental
4 release of naphthalene in the US from facilities required to report in 2012 was approximately 1.5
5 million pounds into the atmosphere from fugitive emissions and point sources; 2.2 million pounds
6 to land from landfills, land treatment, underground injection and other land disposal sources; and
7 6,539 pounds to surface waters (U.S. EPA, 2013b).
8 1.2. Environmental Fate
9 Volatilization from soil is an important dissipation process for naphthalene. Based on its
10 affinity to soil organic matter (soil organic partitioning ratios of approximately 1000), the mobility
11 of naphthalene in soil is expected to be moderate to low (HSDB, 2005). The half-life of naphthalene
12 in soil is estimated to be on the order of days to weeks (HSDB, 2005). In soils previously exposed to
13 naphthalene or other PAHs, microbial degradation rates can be increased (HSDB, 2005).
14 In water, naphthalene tends to reversibly adsorb to suspended solids and sediment
15 Dissolved naphthalene can volatilize from surface water and photolysis may also occur in clear,
16 sunlit surface waters with a half-life of about 3 days. Bioconcentration factors in aquatic organisms
17 range from 23 to 168. The biodegradation half-life in water is estimated to range from a day to
18 more than a month. No abiotic hydrolysis of naphthalene is expected to occur in natural water
19 (HSDB, 2005).
20 In the atmosphere, naphthalene exists primarily as a gas and is degraded via reaction with
21 photochemically-produced hydroxyl radicals with a half-life of about 18-60 hours (HSDB, 2005).
22 1.3. Human Exposure Pathways
23 The general public can be exposed to naphthalene by inhalation, ingestion and dermal
24 routes, but inhalation is generally considered to be the largest contributor to exposure (HSDB,
25 2005). Naphthalene has been measured in indoor and outdoor air. The highest indoor air
26 concentrations generally occur in the homes of cigarette smokers, and the highest outdoor air
27 concentrations have been found in the vicinity of certain industrial sources and hazardous waste
28 sites (ATSDR, 2005).
29 Naphthalene has been detected infrequently in surface water and ground water (ATSDR,
30 2005; HSDB, 2005; U.S. EPA, 2003). Water concentrations are generally higher in urban areas and
31 in the immediate vicinity of point sources of release, such as production factories and chemical
32 waste sites (ATSDR, 2005). Detections in public drinking water systems are uncommon (U.S. EPA,
33 2003).
34
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Scoping and Problem Formulation Materials for Naphthalene
1 Dermal exposure to naphthalene may occur from handling naphthalene-containing
2 products or wearing clothing stored in naphthalene-containing moth repellents (ATSDR, 2005).
3 Children can be exposed to naphthalene via soil ingestion, food ingestion, and accidental
4 ingestion of household products containing naphthalene such as mothballs or deodorant blocks
5 (ATSDR, 2005). Naphthalene has been detected in food as a contaminant (ATSDR, 2005) or as a
6 result of food preparation (e.g., grilling and smoking) (HSDB, 2005).
7 Occupational exposure to naphthalene may occur through inhalation and dermal contact at
8 workplaces where naphthalene is produced or used. The industries with the highest respiratory
9 exposure to naphthalene are creosote impregnation, coal-tar processing, wood preserving, leather
10 tanning, and asphalt production (IARC, 2002). Naphthalene levels in breath is used as a measure of
11 occupational exposure to certain jet fuels (ATSDR, 2013).
12 Human exposure to naphthalene has been confirmed by detection of this compound in
13 human tissues. Six of eight samples of mother's milk from four U.S. urban areas were found to
14 contain naphthalene at detectable levels and 40% of human adipose tissue samples in a National
15 Human Adipose Tissue Survey contained detectable levels of naphthalene (HSDB, 2005).
16
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Scoping and Problem Formulation Materials for Naphthalene
2.SCOPE OF THIS ASSESSMENT
3 EPA's previous IRIS assessment of naphthalene (U.S. EPA, 1998) included a reference
4 concentration (RfC) for noncancer effects based on nasal effects and a reference dose (RfD) for
5 noncancer effects based on decreased body weight in male rats, and classified naphthalene as
6 Group C, a possible human carcinogen, based on inadequate data of carcinogenicity in humans
7 exposed to naphthalene via the oral and inhalation routes. Since that time, a number of
8 experimental animal and epidemiological studies have been published and the National Toxicology
9 Program's Report on Carcinogens (NTP, 2011) listed naphthalene as, "reasonably anticipated to be
10 a human carcinogen". Ethylbenzene and naphthalene oral bioassays with mice have both resulted
11 in lung tumors and raised similar questions of their relevance to human health. An EPA peer
12 consultation workshop on research needs related to mode of action for naphthalene-induced
13 carcinogenicity was conducted in April 2005 to identify data gaps. Additionally, an EPA workshop
14 on mouse lung tumors associated with exposure to several compounds, including ethylbenzene and
15 naphthalene, was conducted in January 2014. The IRIS program is evaluating these two chemicals
16 simultaneously due to their having some similar toxicological issues.
17 Naphthalene has been identified by EPA offices as a chemical for which an updated IRIS
18 assessment would be useful, particularly focusing on oral and inhalation routes of exposure.
19 Naphthalene is listed under several environmental acts that are implemented by EPA, including the
20 Clean Water Act (CWA), Clean Air Act (CAA), Federal Fungicide Insecticide and Rodenticide Act
21 (FIFRA), Emergency Planning and Community Right-to-Know Act (EPCRA), Comprehensive
22 Environmental Response, Compensation, and Liability Act (CERCLA), and the Resource
23 Conservation and Recovery Act (RCRA). The chemical is also listed as a Hazardous Air Pollutant by
24 EPA and is a contaminant found at more than 400 National Priority List (Superfund) sites (U.S. EPA,
25 2014). Naphthalene is used as an inert ingredient and a fragrance in non-food use pesticide
26 products regulated by EPA (U.S. EPA, 2012).
27 A new IRIS assessment will evaluate all potential human health hazards associated with
2 8 naphthalene exposure through oral and inhalation routes of exposure. An assessment for the
29 dermal route of exposure is not planned at this point because oral and inhalation exposure are
30 generally considered the major routes of exposure and evaluating risk from dermal exposure was
31 not identified as a priority need. Furthermore, although some occupational studies involving
32 primarily inhalation exposures may have also included some dermal exposure, no dermal-only
33 exposure studies in humans or experimental animals were identified.
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Scoping and Problem Formulation Materials for Naphthalene
3.PROBLEM FORMULATION
2 3.1. Preliminary Literature Survey
3 A preliminary literature survey was performed to identify health outcomes whose possible
4 association with naphthalene has been investigated. This survey consisted of a search for health
5 assessment information produced by other federal, state, and international health agencies, and an
6 additional broad search of PubMed to locate more recent studies. The review of health assessment
7 information results was used to narrow the list of potential health endpoints for consideration in
8 the IRIS assessment and was supplemented by the PubMed search covering dates after the health
9 assessments' publication. The PubMed search was not intended to be a comprehensive search of
10 the available literature, but was intended to identify naphthalene health outcomes that had not
11 been previously evaluated [i.e., they were not a part of previous study designs) or were not
12 observed in previous studies evaluated in prior health assessments. In addition, the preliminary
13 literature survey was used to identify key scientific issues, including potential mode of action
14 hypotheses that warrant evaluation in the assessment
15 The following assessments, in addition to EPA's 1998 IRIS assessment
16 [http://www.epa.gov/iris/subst/0436.htm: http://www.epa.gov/iris/toxreviews/0436tr.pdf). are
17 available from several federal, state, and international health agencies (in reverse chronological
18 order):
19 1. New Jersey Department of Environmental Protection (NJDEP), 2013, Site Remediation
20 Program - Vapor intrusion - Naphthalene,
21 http://www.nj.gov/dep/srp/guidance/vaporintrusion/
22 2. National Toxicology Program (NTP), 2011, NTP 12th Report on Carcinogens: Naphthalene,
23 http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/naphthalene.pdf
24 3. Centers for Disease Control and Prevention (CDC), National Institute for Occupational Safety
25 and Health (NIOSH), 2010, Pocket Guide to Chemical Hazards - Naphthalene,
26 http://www.cdc.gov/niosh/npg/npgd0439.html
27 4. U.S. EPA, 2008, Office of Prevention, Pesticides and Toxic Substances. Reregistration
28 Eligibility Decision for Naphthalene, EPA 738-R-07-010
29 http://www.epa.gov/pesticides/reregistration/REDs/naphthalene-red.pdf
30 5. Government of Canada, Environment Canada, Screening Assessment for the Challenge -
31 Naphthalene. 2008. http://www.ee.gc.ca/ese-ees/default.asp?lang=En&n=F212515C-1
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Scoping and Problem Formulation Materials for Naphthalene
1 6. U.K. Health Protection Agency, Naphthalene Toxicological review, 2007,
2 http://www.hpa.org.uk/webc/hpawebfile/hpaweb c/1203084377981
3 7. Agency for Toxic Substances and Disease Registry (ATSDR), 2005, Toxicological profile for
4 naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene,
5 http://www.atsdr.cdc.gov/toxprofiles/tp67.pdf
6 8. California EPA (CalEPA), Office of Environmental Health Hazard Assessment, 2004, Air
7 Toxic hot spots: Adoption of a unit risk value for naphthalene,
8 http://www.oehha.org/air/hot spots/naphth.html,
9 http://www.oehha.org/air/hot spots/pdf/naphth080304.pdf.
10 http://oehha.ca.gov/air/chronic rels/pdf/91203.pdf
11 9. U.S. EPA, 2003, Office of Water, Health Effects Support document for Naphthalene,
12 http://water.epa.gov/action/advisories/drinking/upload/2003 03 05 support ccl naphth
13 alene healtheffects.pdf
14 10. European Chemicals Agency, 2003, European Union Risk Assessment Report - naphthalene,
15 http://echa.europa.eu/documents/10162/4c955673-9744-4dlc-a812-2bf97863906a.
16 EINECS no 202-049-5
17 11. International Agency for Research on Cancer (IARC), 2002, IARC Monograph on the
18 Evaluation of Carcinogenic Risks to Humans: Some traditional herbal medicines, some
19 mycotoxins, naphthalene and styrene, Vol 82, Lyon, France,
20 http://monographs.iarc.fr/ENG/Monographs/vol82/mono82.pdf
21 12. International Programme on Chemical Safety (IPCS), 2001, Concise International Chemical
22 Assessment Document 34, Chlorinated Naphthalenes,
23 http://www.who.int/ipcs/publications/cicad/en/cicad34.pdf
24 3.2. Health Outcomes Identified by the Preliminary Literature Survey
25 The preliminary literature survey identified human, animal, and in vitro studies related to
26 multiple health outcomes, mechanism of action, mode of action hypotheses, pharmacokinetics, and
27 susceptible lifestages or subpopulations. Each row in Table 1 summarizes whether data are
28 available on a particular health outcome or other toxicologically-relevant information, with each
29 column indicating the types of studies that are available with respect to test system (human,
30 animal, or in vitro] and exposure route (oral or inhalation, for in vivo studies). In addition, the table
31 indicates whether animal studies of subchronic or chronic design are available, and whether the
32 human studies are in an occupational, community, or clinical exposure setting. Studies that do not
33 fall into any of these categories are indicated by checkmarks without an associated descriptor.
34
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Scoping and Problem Formulation Materials for Naphthalene
Table 1. Naphthalene Studies
Human Studies
Oral
Inhalation
Animal Studies
Oral
Inhalation
In Vitro
Studies
Health Outcomes
Body Weight
Cancer
Cardiovascular
Dermatological
Developmental
Gastrointestinal
Hematological
Immunological
Hepatic
Renal
Musculoskeletal
Neurological
Ocular
Reproductive
Respiratory
•/
(Community)
^
(Community)
•/
(Community)
^
(Community)
^
(Community)
,/
(Community)
•/
(Community)
•/
(Community)
•/
(Community)
^
(Community)
•/
(Occupational)
•/
(Occupational)1
•/
(Community &
Occupational)
•/
(Community &
Occupational)
•/
(Community &
Occupational)
,/
(Community)
•/
(Community &
Occupational)
,/
(Occupational)
•/
(Occupational)
•/
(Subchronic)
^
(Chronic)
•/
(Subchronic)
^
^
(Subchronic)
^
(Subchronic)
^
(Subchronic)
^
(Subchronic)
•/
(Subchronic)
•/
(Subchronic)
•/
(Subchronic, Chronic)
^
(Subchronic)
•/
(Subchronic)
Other Data and Analyses
ADME2
Toxicokinetic
models
Mode of action
hypotheses
Susceptibility data3
Genotoxicity
,/
^
,/
•/
^
^
^
•/
•/
(Subchronic, Chronic)
•/
(Chronic)
•/
(Chronic)
•/
(Chronic)
•/
(Chronic)
•/
(Chronic)
,/
(Chronic)
•/
(Chronic)
^
(Chronic)
•/
(Subchronic, Chronic)
•/
•/
•/
•/
•/
•/
1 Dermatological effects were observed in some occupational studies with possible dermal exposure.
2 Absorption, distribution, metabolism and excretion (ADME) data also collected from animal dermal studies.
3 Individuals with glucose-6-phosphate dehydrogenase deficiency may be more susceptible to hematological,
reproductive/developmental, and neurological effects. Hematological effects were also observed in dermal
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Scoping and Problem Formulation Materials for Naphthalene
exposure studies in G6PD deficient infants.
S Checkmark without an associated descriptor indicate information from other types of studies.
i 3.3. Hazard Questions for Systematic Review
2 The health agency reviews listed in Section 3.1 were used to "prescreen" end points
3 considered most relevant for assessment and the effects noted in these reviews are summarized
4 below. Based on the availability of health endpoint information indicated in Table 1, systematic
5 reviews of the available literature are proposed for multiple endpoints, including: cancer,
6 cardiovascular, dermatological, gastrointestinal, hematological, immunological, hepatic, renal,
7 neurological, ocular, respiratory, and reproductive and developmental effects. The summaries
8 reflect characterizations provided by the other assessments and may differ from the final IRIS
9 assessment's conclusions. The end points identified form the basis for developing the systematic
10 review questions for a revised IRIS assessment The systematic reviews would include analysis of
11 available human, experimental animal, and in vitro studies. Systematic review questions were only
12 developed where effects were noted.
13
14 Body weight effects
15 EPA's 1998 IRIS assessment derived a reference dose (RfD) for noncancer effects based on
16 decreased mean terminal body weight in male rats in a subchronic oral rat study (BCL, 1980).
17 Systematic review question: Integrating the human, animal, and mechanistic evidence,
18 what is the potential for naphthalene exposure to result in body weight effects in humans?
19
20 Cancer
21 EPA's 1998 IRIS assessment classified naphthalene as Group C, a possible human
2 2 carcinogen, based on inadequate data of carcinogenicity in humans exposed to naphthalene via the
23 oral and inhalation routes. Neither an inhalation unit risk nor an oral slope factor was derived
24 because of a lack of information regarding the carcinogenic potential of naphthalene in humans.
25 More recent reviews by federal (ATSDR, 2005) or international health agencies (IARC, 2002) have
26 noted that experiments in rodents conducted by NTP (1992, 2000) reported increased incidences
27 of cancers after inhalation exposure, and evaluated the carcinogenicity of naphthalene based on
28 NTP (2000) and other studies. The International Agency for Research on Cancer (2002) has
29 classified naphthalene as a 2B carcinogen (possibly carcinogenic to humans) based on inhalation
30 data in animals (IARC, 2002). The National Toxicology Program's 12th Report on Carcinogens
31 (2011) classified naphthalene as 'reasonably anticipated to be a human carcinogen' based on
32 sufficient evidence from studies in experimental animals. CalEPA has derived an inhalation unit
33 risk based on data for incidence of nasal respiratory epithelial adenoma and nasal olfactory
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Scoping and Problem Formulation Materials for Naphthalene
1 epithelial neuroblastoma in male rats (CalEPA, 2004). Additionally, some health agency reviews
2 have discussed mechanistic studies investigating the role of mutagenicity and/or genotoxicity in
3 inducing these cancers, as well as other mode of action hypotheses, including cytotoxicity and
4 regenerative hyperplasia (IARC, 2002; ATSDR, 2005). The IRIS Program follows the Supplemental
5 Cancer Guidelines that recommend an analysis of the available data for all carcinogenic chemicals
6 to determine whether a mutagenic mode of action may be operational. This recommendation stems
7 from a determination by the Agency that there is increased susceptibility for cancer when
8 exposures occur early in life. If it is determined that naphthalene has human carcinogenic potential
9 by the oral or inhalation routes of exposure, then a specific determination regarding the mode of
10 action as per the Supplemental Cancer Guidelines will be made. Further mode of action information
11 and key issues are discussed in section 3.4 below.
12 Systematic review questions: Integrating the human, animal, and mechanistic evidence,
13 what is the potential for naphthalene exposure to result in carcinogenesis in humans?
14 Is naphthalene exposure associated with genotoxic and/or mutagenic effects related to its
15 potential carcinogenicity? And if so, under what conditions?
16
17 Cardiovascular effects
18 NTP (2000) conducted a comprehensive chronic inhalation bioassay in mice and rats that
19 included evaluation of cardiovascular effects. However, neither NTP (2000) nor any of the available
20 reviews by government health agencies and international health organizations noted consistent,
21 treatment-related cardiovascular health effects from naphthalene exposure. This endpoint will not
22 be evaluated further unless evidence of cardiovascular effects are identified in the comprehensive
23 literature search.
24
25 Dermatological effects
26 IPCS (2001) reviewed cases of severe skin reactions following occupational exposure to
2 7 naphthalene. However, reviews by other government health agencies and international health
2 8 organizations did not note dermal health effects following oral or inhalation exposure to
29 naphthalene.
30 Systematic review question: Integrating the human, animal, and mechanistic evidence,
31 what is the potential for naphthalene exposure to result in dermatological effects in humans?
32
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Scoping and Problem Formulation Materials for Naphthalene
1 Gastrointestinal effects
2 Gastrointestinal effects in humans and animals were reviewed by IPCS (2001), ATSDR
3 (2005), U.S. EPA (2008), and UK HPA (2007). Nausea, vomiting, abdominal pain, and diarrhea have
4 been commonly documented in humans following inhalation or ingestion of naphthalene (ATSDR,
5 2005; U.S. EPA, 2008; IPCS, 2001). ATSDR (2005) summarized data indicating the formation of
6 stomach lesions and discoloration of the intestines in rats following oral administration of
7 naphthalene. U.S. EPA (2008) also noted diarrhea reported in orally exposed rabbits and rats.
8 Systematic review question: Integrating the human, animal, and mechanistic evidence,
9 what is the potential for naphthalene exposure to result in gastrointestinal effects in humans?
10
11 Hematological effects
12 ATSDR (2005), CalEPA (2004), EGA (2003), UK HPA (2007), and U.S. EPA (2008) have
13 summarized hematological effects observed in animal studies and humans. ATSDR (2005), UK HPA
14 (2007), and U.S. EPA (2003) have reviewed hematological effects observed in animals. Although
15 rats and mice do not appear to exhibit hemolytic effects, dogs orally exposed to naphthalene
16 appeared to develop both hemolytic anemia and reticulocytosis (ATSDR, 2005; UK HPA, 2007; U.S.
17 EPA, 2003).
18 Multiple reviews noted that human exposure to naphthalene by oral and inhalation is
19 associated with intravascular haemolysis, which can cause anemia, leukocytosis, hematuria, and
20 hemolytic anemia (IPCS, 2001; ATSDR, 2005; UK HPA, 2007; U.S. EPA, 2008). Hemolytic anemia,
21 being the most common hematological effect seen in individuals exposed to naphthalene, is
22 characterized by lowered hemoglobin, hematocrit, and erythrocyte values, elevated reticulocyte
23 counts, reticulocytosis, Heinz bodies, elevated serum bilirubin, and fragmentation of erythrocytes
24 (ATSDR, 2005). In severe cases, kernicterus was found to accompany hemolytic anemia (EGA,
25 2003). Observations of aplastic anemia in humans following ingestion or inhalation of naphthalene
26 have also been noted (IPCS, 2001; ATSDR, 2005; UK HPA, 2007; U.S. EPA, 2000). More severe
27 reactions, including the observation of Heinz body formation, hemoglobinuria and mild
28 methemoglobinemia, have also been noted (ECA 2003). ATSDR (2005) noted reports of hemolytic
29 anemia associated with dermal exposure to naphthalene. CalEPA (2004) noted that hematological
30 effects following naphthalene exposure are frequently seen in neonates and infants, who appear to
31 be more susceptible to hematological crises than adults due to their lower capacity for
32 methemoglobin reduction. ATSDR (2005), ECA (2003), and UK HPA (2007) have also reviewed
33 data identifying glucose-6-phosphate dehydrogenase deficiency as an additional factor that
34 increases a subject's sensitivity to chemically-induced hemolysis.
10
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Scoping and Problem Formulation Materials for Naphthalene
1 Systematic review question: Integrating the human, animal, and mechanistic evidence,
2 what is the potential for naphthalene exposure to result in hematological effects in humans?
3
4 Immunological effects
5 Immunologic effects in humans and animals were reviewed by U.S. EPA (1998, 2003) and
6 EGA (2003). U.S. EPA (2003) noted a report documenting an enlarged spleen in one human subject
7 following ingestion of naphthalene; however, it was suggested that this effect was associated with
8 chemically-induced hemolysis. Reviews of immunological effects in rodent species orally exposed
9 to naphthalene reported thymic lymphoid depletion and decreases in spleen weight (EGA, 2003;
10 U.S. EPA, 1998, 2003).
11 Systematic review question: Integrating the human, animal, and mechanistic evidence,
12 what is the potential for naphthalene exposure to result in immunological effects in humans?
13
14 Hepatic effects
15 ATSDR (2005) and EGA (2003) have summarized case studies of humans who experienced
16 jaundice following exposure to naphthalene, although it was noted that this may be attributed to
17 hemolytic anemia. Additionally, elevated levels of hepatic enzymes and liver enlargement were
18 observed following oral exposure to naphthalene as reviewed by ATSDR (2005). Liver disease was
19 seen in human subjects occupationally exposed to vapor-form naphthalene (IPCS, 2001), ATSDR
20 (2005), U.S. EPA (1998), IPCS (2001) and EGA (2003) reviewed studies that observed hepatic
21 effects, including evidence of liver damage and decreases in liver weight, in rodent species.
22 Systematic review question: Integrating the human, animal, and mechanistic evidence,
23 what is the potential for naphthalene exposure to result in hepatic effects in humans?
24
25
26 Renal effects
27 Renal effects in humans and animals were reviewed by EGA (2003), ATSDR (2005), U.S. EPA
28 (1998), and BCL (1980). EGA (2003) and ATSDR (2005) summarized reports of renal disease and
29 kidney damage in humans after oral and inhalation exposure to naphthalene. Increases in kidney
30 weightwere documented following ingestion of naphthalene in rodentspecies (IPCS, 2001), as was
31 kidney damage (BCL, 1980; U.S. EPA, 1998). No renal effects were seen in mice following a two
32 year inhalation study (ATSDR, 2005).
11
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Scoping and Problem Formulation Materials for Naphthalene
1 Systematic review question: Integrating the human, animal, and mechanistic evidence,
2 what is the potential for naphthalene exposure to result in renal effects in humans?
3
4 Musculoskeletal effects
5 ATSDR (2005) reviewed the comprehensive chronic inhalation bioassays conducted by NTP
6 (1992, 2000) in mice and rats that included evaluation of musculoskeletal effects. However, neither
7 NTP (1992, 2000) nor any of the available reviews by government health agencies and
8 international health organizations noted compound-related musculoskeletal health effects from
9 naphthalene exposure. This endpoint will not be evaluated further unless evidence of
10 musculoskeletal effects are identified in the comprehensive literature search.
11
12 Neurological effects
13 Neurological effects in humans and animals were noted in reviews by IPCS (2001), ATSDR
14 (2005), and EGA (2003). Studies following inhalation exposure to naphthalene in humans
15 document fatigue, headache, malaise, confusion, and listlessness (IPCS, 2001; ATSDR, 2005). In
16 addition to those effects, altered sensorium, lethargy, vertigo, muscle twitching, convulsions,
17 decreased responses to painful stimuli, and coma were reported after ingestion of naphthalene
18 (ATSDR, 2005; IPCS, 2001). Some neurological effects, including kernicterus in children and
19 infants, have been suggested to be secondary to hemolytic effects of naphthalene (ATSDR, 2005).
20 Effects in rodents, including decreases in absolute brain or accumulation of ammonia, have been
21 noted by ECA (2003).
22 Systematic review question: Integrating the human, animal, and mechanistic evidence,
23 what is the potential for naphthalene exposure to result in neurological effects in humans?
24
25
26 Ocular effects
27 Ocular effects were noted in humans and animals in reviews by CDC (2010), UK HPA
28 (2007), ECA (2003), ATSDR (2005), IPCS (2001), IARC (2002), and U.S. EPA (2008). IARC (2002),
29 ECA (2003), UK HPA (2007), CDC (2010), and U.S. EPA (2003 & 2008) have summarized data on
30 occupational exposure resulting in cataract formation, retinal hemorrhaging, chorioretinitis, eye
31 irritation, lens opacity, decreased vision, corneal damage, and optical neuritis. Animal studies
32 reviewed by U.S. EPA (2003, 2008), UK HPA (2007), ECA (2003), IPCS (2001), and IARC (2002) in
33 rats, mice, and rabbits have shown similar effects as those exhibited in humans, specifically cataract
34 formation, lens opacity, irritation, focal lesions, and increased ocular density. Some of these
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Scoping and Problem Formulation Materials for Naphthalene
1 reviews have noted other ocular effects in animal models, such as ocular discharge, retinal
2 degeneration, yellowing of eye fluids, conjunctival reddening and swelling, and retinal damage (U.S.
3 EPA 2003, 2008; ATSDR, 2005).
4 Systematic review question: Integrating the human, animal, and mechanistic evidence,
5 what is the potential for naphthalene exposure to result in ocular effects in humans?
6
7 Reproductive/Developmental Effects
8 IARC (2002), ATSDR (2005), and EGA (2003) have summarized reproductive and
9 developmental toxicity studies via the oral or inhalation route. Several studies have documented
10 hemolytic anemia as the primary adverse effect in newborns following gestational exposure
11 although sensorineural hearing loss and severe neonatal jaundice have also been reported (IARC,
12 2002; ATSDR, 2005; EGA, 2003. It was noted that in some of these cases the child or mother was
13 glucose-6-phosphate dehydrogenase deficient (IARC, 2002; EGA, 2003). IARC (2002), ATSDR
14 (2005), IRIS (1998), and U.S. EPA (2003, 2008) reviewed adverse effects in animal developmental
15 and reproductive studies that included reductions in the number of live pups per litter and
16 decreased maternal and fetal body weight in rodent species following oral exposure. IPCS (2001)
17 reviewed studies that found accelerated onset of spermatogenesis in male offspring in rats orally
18 administered naphthalene and reproductive abnormalities in cattle, pigs, and sheep exposed to
19 PCNs. An increased percentage of adversely affected implants per litter and increased incidence of
20 visceral malformations, especially enlarged ventricles of the brain, were reported in rats by IARC
21 (2002). IARC (2002) also reported a study that documented lowered glutathione levels in the
22 testes and epididymides in rats intraperitoneally injected with naphthalene. U.S. EPA (2003)
2 3 reviewed a study that documented increases in delayed cranial ossification and heart development
24 in rat fetuses following gestational exposure to naphthalene. ATSDR (2005) and U.S. EPA (2003)
25 summarized studies in rabbits that reported increases in fused sternebrae in female pups,
26 increased maternal mortality, increased rates of abortions, and other signs of maternal toxicity that
27 included lethargy and bloody vaginal discharge.
28 Systematic review question: Integrating the human, animal, and mechanistic evidence,
29 what is the potential for naphthalene exposure to result in developmental effects in humans?
30
31 Respiratory effects
32 EPA's 1998 IRIS assessment derived a reference concentration (RfC) for noncancer effects
33 based on nasal effects (hyperplasia and metaplasia in respiratory and olfactory epithelium) in a
34 chronic mouse inhalation study (NTP, 1992). Since that time, NTP (2000) has conducted a
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Scoping and Problem Formulation Materials for Naphthalene
1 comprehensive chronic inhalation bioassay in rats. Respiratory effects in humans and animals
2 were summarized and reported by IARC (2002), ATSDR (2005), CalEPA (2004), EGA (2003), UK
3 HPA (2007), and U.S. EPA (2003, 2008). ATSDR (2005) and U.S. EPA (2008) reviewed reports of
4 rhinopharyngolaryngitis observed in humans exposed to naphthalene via inhalation. Inhalation
5 and oral exposure reportedly also produced hypoxia or pulmonary edema in humans, although
6 these respiratory effects were stated as being secondary to hemolysis. Reports summarized by NTP
7 (1992, 2000) illustrated pulmonary necrosis and necrosis of bronchial epithelial cells following
8 intraperitoneal (ip) injection in mice. IARC (2002) evaluated studies done in mice, rats, and
9 hamsters that documented swelling, vacuolization, exfoliation, and/ or necrosis of tracheobronchial
10 epithelium following i.p. injection of naphthalene. Additionally, IARC (2002) reviewed studies done
11 in mice observing pulmonary neuroendocrine-cell hyperplasia and injury to distal and proximal
12 conductivity airways. Reviews of respiratory effects in rodent species orally exposed to
13 naphthalene noted increase in lung weight, lung injury, slow respiration, periods of apnea, and
14 necrosis and exfoliation in nasal olfactory epithelium (UK HPA, 2007; ECA, 2003). ECA (2003) also
15 reviewed studies showingvacuolation in lobar bronchus cells and necrosis of olfactory epithelium
16 in hamsters. Several animal studies observing respiratory effects following inhalation exposure
17 have been summarized by IARC (2002), ATSDR (2005), CalEPA (2004), ECA (2003), UK HPA
18 (2007), and U.S. EPA (2003, 2008). The nose and lungs are commonly reported to be the most
19 sensitive toxicity targets in rodent species. Nonneoplastic lesions of the nose included chronic
20 inflammation, metaplasia of the olfactory epithelium, atypical hyperplasia, atrophy, hyaline
21 degeneration of the olfactory epithelium, hyperplasia of the respiratory epithelium of the nose,
2 2 squamous metaplasia, hyaline degeneration, and goblet cell hyperplasia of the respiratory
23 epithelium, glandular hyperplasia, and loss of Bowmans' glands as reported by IARC (2002), ATSDR
24 (2005), CalEPA (2004), ECA (2003), UK HPA (2007), and U.S. EPA (2003, 2008). IARC (2002),
25 CalEPA (2004), ECA (2003), UK HPA (2007) and U.S. EPA (2003, 2008) reviewed reports of lung
26 injury including chronic inflammation, injury to the proximal and distal conducting airways,
27 damage to ciliated and Clara cells of bronchial epithelium, alveolar epithelial hyperplasia,
28 interstitial fibrosis, necrosis of Clara cells in proximal airways, and the formation of granuloma. No
29 reviews identified studies of respiratory effects in humans from oral or dermal exposure to
30 naphthalene.
31 Systematic review question: Integrating the human, animal, and mechanistic evidence,
32 what is the potential for naphthalene exposure to result in respiratory tract effects in humans?
33
34
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Scoping and Problem Formulation Materials for Naphthalene
i 3.4. Key Issues
2
3 Toxicokinetics of Naphthalene
4 ATSDR (2005), IARC (2002), Cal EPA (2004) have reviewed the absorption, distribution,
5 metabolism and excretion (ADME) of naphthalene. Briefly, exposure to naphthalene occurs mainly
6 through inhalation, oral and dermal routes. Naphthalene is readily absorbed into the systemic
7 circulation following exposure by any of these routes. Absorbed naphthalene and its metabolites
8 are distributed by the blood throughout the body. Naphthalene is rapidly metabolized in a number
9 of tissues to a wide array of metabolites, including epoxide and quinone intermediates that may
10 react with cellular macromolecules such as proteins and DNA. Two major metabolic pathways have
11 been identified: one dependent on cytochrome P450 (GYP) and another involving glutathione
12 conjugation. Multiple metabolites have been identified in urine and blood of workers exposed to
13 naphthalene and in experimental animal studies.
14 Studies are available comparing the rate and extent of metabolism of naphthalene in
15 different tissues and in different animal species; and these are important for evaluating differences
16 across tissues and across species in naphthalene-related toxicity. For instance, lung specific
17 expression patterns of cytochrome P450 enzymes, particularly CYP2F, have been investigated as
18 potential explanations for differences in respiratory tract toxicity and cancer. In human tissues
19 (based on in vitro metabolism studies of liver microsomes) other enzymes may be involved.
20 Overall, inter- and intraspecies differences in metabolism could impact the extrapolation of rodent
21 bioassay data to humans and the identification of potential susceptible subpopulations.
22 Based on the available data, some key issues EPA will evaluate regarding the toxicokinetics
23 of naphthalene include:
24 • The chemical form (naphthalene or a metabolite) responsible for the various toxicities
25 reported.
26 • Available information on inter- and/or intraspecies differences in the toxicokinetics relevant to
27 naphthalene or its metabolites.
28 • The availability, evaluation, and further development (within assessment resources and time
29 constraints) of PBPK models for reliable route-to-route, interspecies, and/or intraspecies
3 0 extrapolation.
31
32 Mode of Action for Respiratory Tract Tumors
33 As discussed previously, several reviews have discussed mechanistic studies investigating
34 the role of mutagenicity and/or genotoxicity in inducing respiratory tract tumors in rodents (IARC,
35 2002; ATSDR, 2005). For instance, the potential for mutagenicity and/or genotoxicity of
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Scoping and Problem Formulation Materials for Naphthalene
1 naphthalene metabolites such as 1,2- and 1,4-naphthaquinone has been noted. Others have
2 suggested a dual mode of action involving mutation and sustained cytotoxicity-induced,
3 regenerative cell proliferation and hyperplasia for naphthalene-induced nasal tumors in rats
4 (Bogen etal., 2008). Based on EPA's Cancer Guidelines and Supplemental Guidance (U.S. EPA,
5 2005a,b), the current understanding of biology of cancer indicates that mutagenic chemicals are
6 expected to exhibit a greater effect in early life exposure versus later life exposure. If a
7 determination were made that a mutagenic mode of action were operative for naphthalene-induced
8 respiratory tract tumors, then Age-Dependent Adjustment Factors would be applied to the cancer
9 toxicity values to account for early-life susceptibility. Therefore, as for all IRIS assessments,
10 evaluation of a potential mutagenic mode of action for naphthalene-induced rodent respiratory
11 tract tumors has important implications.
12 Several investigators have evaluated other potential modes of action for chemically-induced
13 mouse lung tumors such as those observed from naphthalene exposure (NTP, 1992; Bogen et al.,
14 2008; Cruzan, 2009, Rhomberg et al., 2010). In addition, mode of action workshops (see below)
15 and a peer-consultation workshop1 have been conducted previously on the topic of mode of action
16 of naphthalene-induced carcinogenicity. Because of the importance of evaluating all existing
17 information on this topic, recently EPA conducted a "State-of-the-science workshop on chemically-
18 induced mouse lung tumors: applications to human health assessment" on January 7-8, 2014, RTF,
19 NC. The focus of this workshop was to discuss the available data and interpretation of results from
20 studies of mouse bronchiolar-alveolar adenomas and carcinomas (lung tumors) following exposure
21 to naphthalene, styrene or ethylbenzene, and the relevance of such tumors in mice to human cancer
22 risk. Several panels of scientists discussed the available studies of human cancer epidemiology and
23 pathophysiology, comparative pathology, biological mechanisms and evidence for cellular, genetic
24 and molecular toxicology. The panelists included experts from academia, industry, government and
25 nongovernmental organizations. The aim of the workshop was not to have the panel reach
26 consensus on any particular topic, but to foster discussion across the different areas of expertise
27 and viewpoints so that both EPA and the public could become better informed of the issues.
28 Workshop materials can be obtained at http://www.epa.gov/iris/irisworkshops/mltw/. The
29 workshop materials and topics discussed during this meeting will be used to inform the
30 development of the naphthalene assessment. In addition, another similar workshop was conducted
31 recently by the Styrene Information and Research Center to highlight mode of action research
32 related to mouse lung tumors and human relevance (http://styrene.org/2013-mode-of-action-
33 workshop).
1 http://www.epa.gov/EPA-MEETINGS/2005/March/Dav-08/m4472.htm
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Scoping and Problem Formulation Materials for Naphthalene
1 Toxicogenomic data are available on naphthalene that might inform naphthalene
2 toxicokinetics and/or toxicodynamics (Thomas et al., 2009, 2011). As discussed in U.S. EPA (2009),
3 gene and protein expression, and other transcriptional and translational data can provide
4 important information on absorption, distribution, metabolism, and excretion (ADME), mechanism
5 of action, and human relevance information in the weight of evidence analysis. Specifically for
6 naphthalene, types and levels of gene expression in the toxicogenomics data may inform species
7 and gender differences in tissues such as nose and lung. Lastly, evaluations of the available mode of
8 action information have recently been conducted, including a hypothesis-based weight-of-evidence
9 analysis that was used as a tool for evaluating strengths and uncertainties associated with the mode
10 of action data for naphthalene (Rhomberg et al., 2010, Piccirillo etal., 2012)
11 Based on the available data, the key issues for naphthalene mode of action include (but are
12 not limited to):
13 • Identification of key events leading to the development of tumors in rats (nose) and mice (lung)
14 • Role of reactive metabolites (epoxides, quinones and/or ROS) in naphthalene-induced tumors
15 • The potential role of genotoxicity and/or mutagenicity in the mode of action of naphthalene-
16 induced tumors, including site-specific DNA damage
17 • Role of cytotoxicity and sustained regenerative cell proliferation in the mode of action of
18 naphthalene-induced tumors
19 • Role of cytochrome P-450 enzymes in the development of tumors
20 • Exceedance of detoxification capacity (e.g., GSH depletion) and the potential for covalent
21 modification of key proteins
22 • Role of species differences observed in the development of naphthalene-induced tumors. For
23 example,
24 o increased incidence of nasal tumors following inhalation exposure in rats but not mice,
25 whereas both rats and mice exhibit nasal cytotoxicity and degeneration of the nasal
26 olfactory epithelium
27 o increased incidence of nonneoplastic lung lesions (e.g. clara cell necrosis) and lung
2 8 tumors in mice but not in rats
29 • Species differences in enzyme activities (e.g., epoxide hydrolase, aldo-keto reductases) and
3 0 naphthalene toxicity
31 Based on the U.S. EPA (2005) Cancer Guidelines framework for evaluation of mode of
3 2 action, the following will be considered after a systematic review:
33 • Identification of mode of action hypotheses to be considered in the assessment
34 • Identification of the key events for each hypothesized mode of action
35 • Evaluation of experimental support for each hypothesized mode of action
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Scoping and Problem Formulation Materials for Naphthalene
1 • Sufficient support for each hypothesized mode of action in test animals
2 • Human relevance of hypothesized modes of action
3 • Populations or lifestages that are particularly susceptible to each hypothesized mode of action
5 Human Susceptibility
6 Human susceptibility has already been discussed above in the context of toxicokinetics and
7 mode of action, but in addition, several reviews have identified deficiency in glucose-6-phosphate
8 dehydrogenase (G6-PD) as a potential susceptibility factor for the toxic effects of naphthalene
9 (IARC, 2002; ATSDR 2005; EGA 2003; UK HPA 2007; U.S. EPA 2008). Therefore, an additional key
10 issue regarding susceptibility is to identify the end points (and related evidence) for which G6-PD
11 deficiency is associated with increased susceptibility to naphthalene toxicity.
12 CalEPA (2004) noted thathematological effects following naphthalene exposure are
13 frequently seen in neonates and infants, who are seemingly more susceptible to hematological
14 crises than adults due to their lower capacity for methemoglobin reduction.
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Scoping and Problem Formulation Materials for Naphthalene
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