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EPA/635/R-14/198
Scoping and Problem Formulation Materials
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Scoping and Problem Formulation for the Identification of Potential
Health Hazards for the Integrated Risk Information System (IRIS)
Toxicological Review of Ethylbenzene
[CASRN 100-41-4]
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 Ethylbenzene
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 3
3. PROBLEM FORMULATION 4
3.1. Preliminary Literature Survey 4
3.2. Health Outcomes Identified by the Preliminary Literature Survey 6
3.3. Hazard Questions for Systematic Review 8
3.4. Key Issues 12
REFERENCES 17
11
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Scoping and Problem Formulation Materials for Ethylbenzene
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 ethylbenzene, 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 Ethylbenzene
1. BACKGROUND
i 1.1. Production and Use
2
4 Figure 1. Chemical structure of ethylbenzene (NLM, 2005).
5
6 Ethylbenzene (CAS# 100-41-4), also known as phenylethane, is a colorless, flammable, and
7 aromatic hydrocarbon that is present in crude petroleum and gasoline. In addition, it is used in
8 industry primarily as a chemical intermediate in the production of styrene monomer (IPCS, 1996).
9 Ethylbenzene has also been used as an industrial solvent and as a diluent in the paint industry as
10 well as in the manufacture of synthetic rubber, acetophenone, and cellulose acetate (CalEPA, 1997).
11 Ethylbenzene is present in naphtha, asphalt, and as an impurity in xylene solvents (CalEPA, 1997).
12 Ethylbenzene production volumes in the US range from 7-13 billion pounds per year, which
13 is among the highest for chemicals manufactured in the US (ATSDR, 2010). The production and use
14 of ethylbenzene in industry result in the potential for contamination of air, soil, and water (CalEPA,
15 1997). The presence of ethylbenzene in gasoline, as well as its use as a solvent, result in potential
16 for release to air. Soil contamination may occur through fuel spillage, solvent disposal, or storage
17 tank leakage. Water has the potential to become contaminated by ethylbenzene from industrial
18 discharges, fuel spillage, leaking petroleum pipelines and underground storage tanks, landfill
19 leachate, and improper disposal of wastes containing ethylbenzene.
20 According to the U.S. EPA's Toxics Release Inventory (TRI) Program, the environmental
21 release of ethylbenzene in the US from facilities required to report in 2012 was approximately 2.7
22 million pounds into the atmosphere from fugitive emissions and point sources; 0.8 million pounds
23 to land from landfills, land treatment, underground injection and other land disposal sources; and
24 4,531 pounds to surface waters (U.S. EPA, 2014). This is a decline of roughly 9.3 million pounds
25 from the total release in 1994.
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Scoping and Problem Formulation Materials for Ethylbenzene
1
2 1.2. Environmental Fate
3 Ethylbenzene is not expected to be especially persistent in environmental media. With a Koc
4 value of 240, the mobility of ethylbenzene in soil is expected to be moderate. Volatilization from
5 water and soil is likely to be an important environmental fate process for ethylbenzene, based on its
6 vapor pressure (ATSDR, 2010). When released to the atmosphere, ethylbenzene is expected to
7 exist predominantly in the vapor phase (ATSDR, 2010). In the atmosphere, ethylbenzene may
8 adsorb to suspended particles and be removed along with the particles by precipitation or dry
9 deposition (IPCS, 1996). The atmospheric half-life of gaseous ethylbenzene has been estimated at
10 around 15 hours (IPCS, 1996).
11 Due to the contributions from tobacco smoke and attached garages, indoor air levels of
12 ethylbenzene in residential settings are likely to be higher than outdoor levels, and have been
13 reported to range from 1.00-110 ng/m3 (ATSDR, 2010; U.S. EPA, 1987; U.S. EPA, 2010).
14 Ethylbenzene air concentrations reported in occupational settings range from 365-2,340 |ig/m3
15 (ATSDR, 2010). Generally, ambient air concentrations of ethylbenzene are lower in rural areas than
16 in urban areas, where vehicle emissions are thoughtto be a major contributor. ATSDR (2010)
17 reports median levels of 0.62 ppb (2.7 |J.g/m3) in urban and suburban locations and 0.01 ppb (0.056
18 [ig/m3) in rural locations.
19 Water has the potential to become contaminated by ethylbenzene from industrial
20 discharges, boat fuel, and storage tank leakage. Thus, there is a higher potential for drinking water
21 sources near leaking gasoline storage tanks to become contaminated (CalEPA, 1997).
22
23 1.3. Human Exposure Pathways
24 Individuals who are likely to have higher exposures are those living near hazardous waste
25 sites where ethylbenzene has been detected or those using well water downgradient from leaking
26 underground storage tanks. Ethylbenzene inhalation and ingestion estimates were higher in a
27 household that used groundwater contaminated by gasoline from a leaking underground storage
28 tank, compared to an unexposed cohort (ATSDR, 2010).
29 Inhalation is expected to be an important route of ethylbenzene exposure for the general
30 population, particularly while pumping gasoline or driving, and by cigarette smoking. Median
31 blood ethylbenzene levels prior to and after pumping gasoline were reported to be 0.10 |ig/L and
32 0.16 [J.g/L, respectively (ATSDR, 2010). In the US, the median and 95thpercentile blood levels are
33 approximately 0.035 |ig/L and 0.14 |ig/L, respectively (CDC, 2013).
34
35
36
37
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Scoping and Problem Formulation Materials for Ethylbenzene
2. SCOPE OF THIS ASSESSMENT
1 A previous IRIS assessment on ethylbenzene was completed in 1991. Reference values
2 were derived for oral and inhalation exposure. At that time, ethylbenzene was not classified in
3 regard to its potential to cause cancer in humans due to a lack of animal and human data. Since
4 then, a number of relevant studies on ethylbenzene toxicity have been conducted and new data are
5 available. Ethylbenzene and naphthalene bioassays with mice have both resulted in lung tumors
6 and raised similar questions of relevance to human health. An EPA workshop on mouse lung
7 tumors associated with exposure to several compounds, including naphthalene and ethylbenzene,
8 was conducted in January 2014. The IRIS program is evaluating these two chemicals
9 simultaneously due to their having some similar toxicological issues.
10 Ethylbenzene has been identified as a concern at contaminated sites, as an air pollutant and
11 a contaminant in drinking water. It has been listed under a number of environmental statutes that
12 are implemented by EPA, including the Clean Water Act (CWA), Federal Insecticide Fungicide and
13 Rodenticide Act (FIFRA), Clean Air Act (CAA), Safe Drinking Water Act (SDWA), Emergency
14 Planning and Community Right-to-Know Act (EPCRA), Toxic Substances Control Act (TSCA),
15 Resource Conservation and Recovery Act (RCRA), and the Comprehensive Environmental
16 Response, Compensation, and Liability Act (CERCLA). The chemical is on ATSDR's 2013 substance
17 priority list
18 A new IRIS assessment will evaluate all potential human health hazards associated with
19 ethylbenzene exposure through oral and inhalation routes of exposure. An assessment for the
20 dermal route of exposure is not planned at this point because oral and inhalation exposure are
21 generally considered the major routes of exposure and evaluating risk from dermal exposure was
22 not identified as a priority need. Furthermore, no dermal-only exposure studies in humans or
23 experimental animals were identified.
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Scoping and Problem Formulation Materials for Ethylbenzene
3. PROBLEM FORMULATION
i 3.1. Preliminary Literature Survey
2 A preliminary literature survey was performed to identify health outcomes whose possible
3 association with ethylbenzene has been investigated. This survey consisted of a search for health
4 assessment information produced by other federal, state, and international health agencies, and an
5 additional broad search of PubMed to locate more recent studies. The review of health assessment
6 information results was used to narrow the list of potential health endpoints for consideration in
7 the IRIS assessment and was supplemented by the PubMed search covering dates after the health
8 assessments' publication. The PubMed search was not intended to be a comprehensive search of
9 the available literature, but was intended to identify ethylbenzene health outcomes that had not
10 been previously evaluated (i.e., they were not a part of previous study designs) or were not
11 observed in previous studies evaluated in prior health assessments. In addition, the preliminary
12 literature survey was used to identify key scientific issues, including potential mode of action
13 hypotheses that warrant evaluation in the assessment
14 The following assessments, in addition to EPA's 1991 IRIS assessment
15 [http://www.epa.gov/iris/subst/0051.htm], are available from several federal, state, and
16 international health agencies (in reverse chronological order):
17
18 1. Occupational Safety and Health Administration. OSHA (2012). Chemical Sampling
19 Information, Ethyl Benzene.
20 https://www.osha.gov/dts/chemicalsampling/data/CH 240000.html
21 2. Agency for Toxic Substances and Disease Registry. ATSDR (2010). Toxicological profile for
22 ethylbenzene. http://www.atsdr.cdc.gov/ToxProfiles/tpllO.pdf
23 3. National Institute for Occupational Safety and Health. NIOSH (2010). NIOSH pocket guide to
24 chemical hazards. RTECS. Benzene, ethyl-.
25 http://www.cdc.gov/niosh/npg/npgd0264.html
26 4. California Environmental Protection Agency. Cal/EPA (2008). No significant risk levels
27 (NSRLs) for the proposition 65 carcinogen ethylbenzene.
28 http://www.oehha.ca.gov/Prop65/law/pdf zip/EthylbenzeneNSRL032808.pdf
29 5. California Environmental Protection Agency. Cal/EPA (2007). Long-term health effects of
30 exposure to ethylbenzene.
31 http://oehha.ca.gov/air/hot spots/pdf/Ethvlbenzene SRP082707.pdf
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Scoping and Problem Formulation Materials for Ethylbenzene
1 6. International Agency for Research on Cancer. IARC (2000). IARC Monographs on the
2 Evaluation of Carcinogenic Risks to Humans. Volume 77, Some Industrial Chemicals.
3 http://monographs.iarc.fr/ENG/Monographs/vol77/mono77-10.pdf
4 7. International Programme on Chemical Safety. IPCS (1996). Ethylbenzene. Volume 186.
5 http://www.inchem.org/documents/ehc/ehc/ehcl86.html
6
7 The additional PubMed search was limited to publication dates between November, 2010
8 and July, 2014 in order to identify studies released after the publication of ATSDR's 2010
9 Toxicological Profile for ethylbenzene (ATSDR, 2010). Search terms focused on each of the health
10 outcomes shown in Table 1 and included a range of related terms. For instance, musculoskeletal
11 effects search terms included ethylbenzene in conjunction with muscle, bone, muscular system,
12 skeletal system, locomotion, locomotor system, cartilage, tendons, ligaments, or joints. All results of
13 the PubMed search were screened by title and abstract to identify those appropriate for health
14 assessment The primary sources in the PubMed search included the following:
15
16 1. Billionnet C, Gay E, Kirchner S etal. 2011. Quantitative assessments of indoor air
17 pollution and respiratory health in a population-based sample of French dwellings.
18 Environ Res. 111(3): 425-434.
19 2. Martins PC, Valente J, Papoila AL et al. 2012. Airways changes related to air pollution
20 exposure in wheezing children. Eur Respir 39(2): 246-253.
21 3. Wallner P, KundiM, Moshammer H etal. 2012. Indoor air in schools and lung function of
22 Austrian school children. J Environ Monit 14(7): 1976-1982.
23 4. Wang YR, Yand DY, Zhang M etal. 2011. The changes of blood neurotransmitter levels in
24 workers occupationally exposed to ethylbenzene. Zhonghua Lao Dong Wei Sheng Zhi Ye
25 Bing Za Zhi [Chinese journal of industrial hygiene and occupational diseases]. 29(2):
26 125-127.
27 5. Zhang M, Wang Y, Wang Q et al. 2013. Ethylbenzene-induced hearing loss,
28 neurobehavioral function, and neurotransmitter alterations in petrochemical workers. J
29 Occup Environ Med 55(9): 1001-1006.
30 6. Zhang M, Wang YR, Yang DY et al. 2011. The neurobehavioral effects of population
31 occupationally exposed to ethylbenzene. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za
32 Zhi [Chinese journal of industrial hygiene and occupational diseases]. 29(2): 128-130.
33
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Scoping and Problem Formulation Materials for Ethylbenzene
1
2 3.2. Health Outcomes Identified by the Preliminary Literature Survey
3 The preliminary literature survey identified human, animal, and in vitro studies related to
4 multiple health outcomes, mechanism of action, mode of action hypotheses, pharmacokinetics, and
5 susceptible lifestages or subpopulations. Each row in Table 1 summarizes whether data are
6 available on a particular health outcome or other toxicologically-relevant information, with each
7 column indicating the types of studies that are available with respect to test system (human,
8 animal, or in vitro] and exposure route (oral or inhalation, for in vivo studies). In addition, the table
9 indicates whether animal studies of subchronic or chronic design are available, and whether the
10 human studies are in an occupational, community, or clinical exposure setting. Studies that do not
11 fall into any of these categories are indicated by checkmarks without an associated descriptor.
12
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Scoping and Problem Formulation Materials for Ethylbenzene
Table 1. Ethylbenzene studies
Human Studies
Oral
Inhalation
Animal Studies
Oral
Inhalation
In Vitro Studies
Health Outcomes
Body Weight
Effects
Cancer
Cardiovascular
Dermal
Developmental
Endocrine
Gastrointestinal
Hematological
Hepatic
Immunological
Metabolic disease
Musculoskeletal
Neurological and
Sensory
Renal
Reproductive
Respiratory
•/
(Occupational)
•/
(Occupational)
^
(Occupational)
•/
(Community)
•/
(Chronic)
,/
(Subchronic)
•/
(Subchronic)
•/
(Subchronic)
^
(Subchronic)
^
(Subchronic)
,/
(Subchronic)
,/
(Subchronic)
•/
(Subchronic)
•/
(Chronic)
,/
(Subchronic, Chronic)
•/
(Chronic)
,/
(Subchronic)
•/
(Subchronic, Chronic)
,/
(Subchronic, Chronic)
,/
(Subchronic, Chronic)
•/
(Subchronic, Chronic)
,/
(Subchronic)
•/
(Subchronic, Chronic)
•/
(Subchronic)
^
(Subchronic, Chronic)
,/
(Subchronic)
,/
(Subchronic, Chronic)
^
Other Data and Analyses
ADME1
Toxicokinetic
models 2
Mode of action
hypotheses
Susceptibility data
Genotoxicity
Other mechanistic
data
•/
^
•/
•/
•/
•/
•/
•/
^
•/
^
1 Absorption, distribution, metabolism and excretion (ADME) data also exists for dermal exposure for human and animals
2 Inhalation PBPKs included
3 Individuals that may be more susceptible to toxic effects include those with pre-existing hearing loss and diseases of the
respiratory system, liver, kidney, or skin; fetuses; young children; pregnant women; and those taking certain medications,
such as hepatotoxic medications or drugs (ATSDR 2010).
Adverse outcome models of carcinogenesis and benchmark dose
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Scoping and Problem Formulation Materials for Ethylbenzene
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 endocrine, hematological, immunological, hepatic, renal, neurological and sensory effects (including
7 otological and ocular effects), respiratory, and reproductive and developmental effects. The
8 summaries reflect characterizations provided by the other assessments and may differ from the
9 final IRIS assessment's conclusions. The end points identified form the basis for developing the
10 systematic review questions for a revised IRIS assessment The systematic reviews would include
11 analysis of available human, experimental animal, and in vitro studies. Systematic review questions
12 were only developed where effects were noted.
13
14 Body Weight Effects
15 ATSDR (2010) identified transitory decreases in body weight gain in one study, while other
16 studies show no changes in body weight
17 Systematic review question: Integrating the human, animal, and mechanistic evidence,
18 what is the potential for ethylbenzene exposure to result in body weight effects in humans?
19
20 Cancer
21 EPA's 1991 IRIS assessment classified ethylbenzene as "Group D - not classifiable as to
22 human carcinogenicity" (U.S. EPA, 2011). Consequently, IARC (2000) classified ethylbenzene as
23 "Group 2B - possibly carcinogenic to humans." The National Toxicology Program (NTP, 1999)
24 conducted a two year inhalation study in rodents demonstrating increased incidence of renal tubule
25 neoplasms in rats and an increased incidence of alveolar/bronchiolar neoplasms and hepatocellular
26 neoplasms in mice. NTP (1999) indicated that there was clear evidence of carcinogenic activity of
27 ethylbenzene in male F344/N rats based on increased incidences of renal tubule neoplasms.
28 Additionally, the incidences of testicular adenomas were increased. NTP also determined that there
29 was some evidence of carcinogenic activity of ethylbenzene in female F344/N rats based on
30 increased incidences of renal tubule adenomas, in male B6C3F1 mice based on increased incidences
31 of alveolar/bronchiolar neoplasms, and in female B6C3F1 mice based on increased incidences of
32 hepatocellular neoplasms.
33 EPA's 1991 assessment of ethylbenzene found no studies suitable for determination of an
34 oral qualitative or quantitative cancer value (U.S. EPA, 2011). CalEPA (2008) developed oral human
35 cancer potencies based on the 1999 NTP inhalation study. No chronic oral ethylbenzene studies
36 have been found in the literature.
37 Systematic review question: Integrating the human, animal, and mechanistic evidence,
38 what is the potential for ethylbenzene exposure to result in carcinogenesis in humans?
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Scoping and Problem Formulation Materials for Ethylbenzene
1 Is ethylbenzene exposure associated with genotoxic and/or mutagenic effects related to its
2 potential carcinogenicity? And if so, under what conditions?
3
4 Cardiovascular Effects
5 ATSDR (2010) identified a study which evaluated histologically the effects of ethylbenzene
6 exposure on cardiac tissue. According to ATSDR (2010), no histological effects were noted in the
7 study.
8
9 Dermal Effects
10 No dermal effects were identified following an inhalation exposure in rats or mice (ATSDR,
11 2010).
12
13 Developmental Effects
14 Increases in the incidence of extra ribs were noted in the offspring of rats exposed to
15 ethylbenzene at various concentrations depending on the exposure period. In addition, significant
16 reductions in fetal body weight have been observed (ATSDR 2010).
17 Systematic review question: Integrating the human, animal, and mechanistic evidence,
18 what is the potential for ethylbenzene exposure to result in developmental effects in humans?
19
20 Endocrine Effects
21 Long-term exposure to ethylbenzene has been shown to produce hyperplasia of the thyroid
22 and pituitary glands (ATSDR 2010).
23 Systematic review question: Integrating the human, animal, and mechanistic evidence,
24 what is the potential for ethylbenzene exposure to result in endocrine effects in humans?
25
26 Gastrointestinal Effects
27 No adverse effects have been reported following subchronic and chronic inhalation of
28 ethylbenzene in laboratory animals (ATSDR, 2010).
29
30 Hematological Effects
31 Studies in animals reporting hematological findings are unclear. One study reported
32 significant decreases in platelet counts in female rats and significant increases in mean total
33 leukocyte counts in male rats, while others report no effects. A decrease in platelet counts and an
34 increase in mean corpuscular volume was noted in rats exposed orally for 13 weeks (ATSDR 2010).
35 Wang et al. (2011) reported no significant difference in hematologic indexes including white blood
36 cell, red blood cell, hemoglobin, and platelet counts in 246 workers occupationally exposed to
37 ethylbenzene. In the same study it was reported that ethylbenzene decreased blood
38 neurotransmitter (dopamine and acetylcholinesterase) levels in workers (Wangetal., 2011).
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Scoping and Problem Formulation Materials for Ethylbenzene
1 Systematic review question: Integrating the human, animal, and mechanistic evidence,
2 what is the potential for ethylbenzene exposure to result in hematological effects in humans?
3
4 Hepatic Effects
5 EPA's 1991 IRIS assessment (U.S. EPA, 2011) derived an oral reference dose based on liver
6 and kidney toxicity from a 182 day gavage study in female rats reported in 1956. Since that time, a
7 number of other studies have been identified by ATSDR (2010) as well as other agencies. A number
8 of studies in laboratory animals have reported hepatic effects consistent with induction of
9 microsomal enzymes (increase in liver weight, induction of hepatic drug metabolizing enzymes, and
10 changes in the ultrastructure of the liver). Other effects include moderate to marked hypertrophy
11 of the periportal hepatocytes, enlarged hepatocytes with multiple nuclei, hepatocellular
12 hypertrophy and necrosis, and eosinophilic foci. A gavage study (13 week) in rats showed an
13 increase in serum liver enzymes, increased absolute and relative liver weights, and increased
14 incidence of centrilobular hepatocyte hypertrophy. In another study, increased liver weight and
15 cloudy swelling of the parenchymal liver cells were noted in rats exposed for 6 months (ATSDR
16 2010).
17 Systematic review question: Integrating the human, animal, and mechanistic evidence,
18 what is the potential for ethylbenzene exposure to result in hepatic effects in humans?
19
20 Immunological Effects
21 Absolute and relative spleen weights were increased in pregnant rats during pre-mating
22 and gestation or gestation alone, however no histopathological changes were noted (ATSDR 2010).
23 Systematic review question: Integrating the human, animal, and mechanistic evidence,
24 what is the potential for ethylbenzene exposure to result in immunological effects in humans?
25
26 Metabolic Disease
27 No studies were identified that evaluated the effects of ethylbenzene on metabolic diseases
28 (ATSDR, 2010).
29
30 Musculoskeletal Effects
31 No musculoskeletal effects have been reported in laboratory animals following subchronic
32 or chronic inhalation exposures.
33
34 Neurological and Sensory Effects
35 Acetylcholinesterase activity was significantly decreased (p < 0.05) in ethylbenzene-
36 exposed petrochemical workers compared to control (office personnel). A negative correlation was
37 also shown between acetylcholinesterase and neurobehavioral function (Zhang et al., 2013).
10
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Scoping and Problem Formulation Materials for Ethylbenzene
1 NeurobehavioralJunction: Scores of neurobehavioral function relating to memory and
2 learning were significantly decreased (p < 0.05) in petrochemical workers compared to control
3 (office personnel) (Zhang etal., 2013). According to Zhang etal. (2011), score of emotion, or vigor,
4 was significantly lower (p < 0.05), while scores of fatigue and mean reaction time were significantly
5 higher for occupationally exposed workers compared to control. It was also stated that scores of
6 digital span, manual dexterity, visual retention and target tracking were significantly decreased
7 compared to control (office workers). Furthermore, it was observed that for several
8 neurobehavioral endpoints workers exposed to ethylbenzene for three years or longer differed
9 significantly from workers exposed to ethylbenzene for 2 years or less, which suggests that workers
10 exposed for three years to ethylbenzene may be a susceptible population of neurobehavioral
11 function impairment (Zhang et al., 2011).
12 Systematic review question: Integrating the human, animal, and mechanistic evidence,
13 what is the potential for ethylbenzene exposure to result in neurobehavioral effects in humans?
14 Otological effects: Deterioration in auditory thresholds and alterations of cochlear
15 morphology have been observed in laboratory animals exposed to ethylbenzene via inhalation
16 (ATSDR 2010). Additionally, ethylbenzene-induced hearing loss has been observed in
17 petrochemical workers. Hearing loss was significantly greater (p < 0.05) in ethylbenzene-exposed
18 workers compared to groups exposed to noise and office personnel (Zhang et al., 2013).
19 Systematic review question: Integrating the human, animal, and mechanistic evidence,
20 what is the potential for ethylbenzene exposure to result in otological effects in humans?
21 Ocular effects: Eye irritation, a burning sensation, and profuse lacrimation have been
22 observed in humans exposed to 1,000 ppm ethylbenzene. Ocular irritation and lacrimation have
23 also been observed in rats, mice, and guinea pigs following acute exposure to > 1,000 ppm
24 ethylbenzene. Lacrimation was observed in rats exposed to 382 ppm for four weeks, while no
25 ocular effects were documented in rats or mice after a 13-week exposure to 975 ppm ethylbenzene.
26 Systematic review question: Integrating the human, animal, and mechanistic evidence,
27 what is the potential for ethylbenzene exposure to result in ocular effects in humans?
28
29 Renal Effects
30 EPA's 1991 IRIS assessment (U.S. EPA, 2011) derived an oral reference dose based on liver
31 and kidney toxicity from a 182 day gavage study in female rats reported in 1956. Since that time, a
32 number of other studies have been identified by ATSDR (2010) as well as other agencies. Exposure
33 to ethylbenzene results in renal effects including increases in kidney weights, induction of drug
34 metabolizing enzymes, accumulation of alpha 2u-globulin, nephropathy, renal tubule hyperplasia,
35 and renal carcinogenesis. An increase in hyaline droplet nephropathy was noted in rats exposed
36 orally for 13 weeks. A different study found increased kidney weight and cloudy swelling of the
37 kidney tubular epithelium in rats exposed for 6 months (ATSDR 2010).
11
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Scoping and Problem Formulation Materials for Ethylbenzene
1 Systematic review question: Integrating the human, animal, and mechanistic evidence,
2 what is the potential for ethylbenzene exposure to result in renal effects in humans?
3
4 Reproductive Effects
5 No adverse effects on reproduction were observed following ethylbenzene exposure in
6 laboratory animals (ATSDR, 2010). Rare histological changes had been reported but most studies
7 are negative.
8 Systematic review question: Integrating the human, animal, and mechanistic evidence,
9 what is the potential for ethylbenzene exposure to result in reproductive effects in humans?
10
11 Respiratory Effects
12 Human studies have reported throat and nasal irritation and a feeling of chest constriction
13 during brief inhalation exposures and the severity of the symptoms increased with increased
14 concentration. Subchronic to chronic inhalation studies in animals have reported no
15 histopathological findings of the respiratory tissue (ATSDR, 2010). More recent studies have
16 shown a negative association between ethylbenzene exposure and forced expiratory vital capacity,
17 or FVC, (Wallner et al., 2012) and forced expiratory volume in one second, or FEV(l), in children
18 (Wallner et al., 2012; Martins et al., 2012). Increasing exposure to ethylbenzene was also
19 associated with acidity of exhaled breath condensate in children (Martins et al., 2012). In a
2 0 different study ethylbenzene was significantly associated with rhinitis, or inflammation of the
21 mucous membrane of the nose (38.3%) (Billionnet et al., 2011).
22 Systematic review question: Integrating the human, animal, and mechanistic evidence,
23 what is the potential for ethylbenzene exposure to result in respiratory effects in humans?
24
25 3.4. Key Issues
26
27 Toxicokinetics of Ethylbenzene
28 The absorption, distribution, metabolism and excretion (ADME) of ethylbenzene have been
29 reviewed by ATSDR (2010). Briefly, ethylbenzene is readily absorbed from a variety of exposure
30 routes and is rapidly cleared from the blood in 60 minutes or less. Inhaled ethylbenzene
31 accumulates in adipose tissue with concentrations of ethylbenzene in mesenteric adipose being 20-
32 60 times higher than blood concentrations at steady state. The metabolism of ethylbenzene is
33 mainly through hydroxylation and subsequent conjugations. Qualitative and quantitative metabolic
34 differences exist between humans and laboratory animals and these differences may ultimately
35 provide a basis for defining the relevance of adverse ethylbenzene endpoints in humans, but to
36 date, mechanistic data have been lacking.
37 Studies are available comparing the rate and extent of metabolism of ethylbenzene in
38 different tissues and in different animal species; and these are important for evaluating differences
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Scoping and Problem Formulation Materials for Ethylbenzene
1 across tissues and across species in ethylbenzene-related toxicity. For instance, lung specific
2 expression patterns of cytochrome P450 enzymes, particularly CYP2F, have been investigated as
3 potential explanations for differences in respiratory tract toxicity and cancer. In human tissues
4 (based on in vitro metabolism studies of liver microsomes) other enzymes may be involved.
5 Overall, inter- and intraspecies differences in metabolism could impact the extrapolation of rodent
6 bioassay data to humans and the identification of potential susceptible subpopulations.
7 Based on the available data, some key issues EPA will evaluate regarding the toxicokinetics
8 of ethylbenzene include:
9 • The chemical form (ethylbenzene or a metabolite) responsible for the various toxicities
10 reported.
11 • Available information on inter- and/or intraspecies differences in the toxicokinetics relevant to
12 ethylbenzene or its metabolites.
13 • The availability, evaluation, and further development (within assessment resources and time
14 constraints) of PBPK models for reliable route-to-route, interspecies, and/or intraspecies
15 extrapolation.
16 Mode of Action for Carcinogenicity
17 Rat kidney tumors
18 While rat renal tumors have been reported following exposure the ethylbenzene, there are
19 varying perspectives on whether humans could be expected to develop the same type of tumor.
2 0 Controversy exists around the MOA of these tumors and whether or not they are related to chronic
21 progressive nephropathy (CPN); an age related condition found in rats, or are the tumors from a
22 different mechanism. In 2002 Hard (2002) reevaluated the NTP histological findings and
2 3 concluded that the increased incidence of renal tubule tumors was related to chemically-induced
24 exacerbation of chronic progressive nephropathy (CPN), suggesting that because humans do not
25 show a similar age-related renal pathology, these rat tumors are not relevant to humans. Seely et
26 al. (2002) analyzed the association between CPN and renal tubule neoplasms in male F344 rats and
27 concluded thatthe association between the two was marginal. Hard et al. (2012) expanded on the
28 reanalysis by examining all control rats from 24 long-term NTP studies and concluded that
29 advanced stages of CPN represent a risk for the development of a low incidence of renal tubule
30 adenomas.
31
32 Mouse lung tumors
3 3 Mouse lung tumors following ethylbenzene inhalation have been investigated by several
34 authors seeking to define the mode or modes of action (MOA) (Cruzan et al., 2009; Chanetal., 1998;
35 Saghiretal., 2009; Saghiretal., 2010; Stottetal., 2003). The relevance of chemically-induced
36 mouse lung tumors to human health has not been determined. While humans can develop lung
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Scoping and Problem Formulation Materials for Ethylbenzene
1 tumors, differences in the types of tumors, their location, metastatic propensities, cell of origin, and
2 cell metabolism can affect the relevance of mouse lung tumors to human health.
3 Because of the importance of evaluating all existing information on this topic, recently EPA
4 conducted a "State-of-the-science workshop on chemically-induced mouse lung tumors:
5 applications to human health assessment" on January 7-8, 2014, RTF, NC. The focus of this
6 workshop was to discuss the available data and interpretation of results from studies of mouse
7 bronchiolar-alveolar adenomas and carcinomas (lung tumors) following exposure to naphthalene,
8 styrene, or ethylbenzene, and the relevance of such tumors in mice to human cancer risk. Several
9 panels of scientists discussed the available studies of human cancer epidemiology and
10 pathophysiology, comparative pathology, biological mechanisms and evidence for cellular, genetic
11 and molecular toxicology. The panelists included experts from academia, industry, government and
12 nongovernmental organizations. The aim of the workshop was not to have the panel reach
13 consensus on any particular topic, but to foster discussion across the different areas of expertise
14 and viewpoints so that both EPA and the public could become better informed of the issues.
15 Workshop materials can be obtained at httpi//www.epa.gQY/ins/insjvQH{shops/rnlt\v/. The
16 workshop materials and topics discussed during this meeting will be used to inform the
17 development of the ethylbenzene assessment In addition, another similar workshop was
18 conducted recently by the Styrene Information and Research Center to highlight mode of action
19 research related to mouse lung tumors and human relevance (http://styrene.org/2013-mode-of-
20 action-workshop).
21
2 2 Evaluation of Potential Mutagenic Mode(s) of Action
23 Ethylbenzene research and workshops have evaluated and discussed the potential for
24 certain ethylbenzene metabolites, e.g., 2,5-ethylquinone and 3,4-ethylquinone, to be mutagenic or
25 exhibit other types of genotoxicity. The comparative metabolism of mice versus humans may
26 inform the relevance of mouse tumors to potential human carcinogenesis. It is expected that the
27 ethylbenzene re-assessment will require interpretation and analysis of mode of action research to
28 inform the relevance of the observed ethylbenzene-induced mouse lung tumors.
29 The IRIS Program follows the Supplemental Cancer Guidelines (U.S. EPA, 2005b) that
30 recommend an analysis of the available data for all carcinogenic chemicals to determine whether a
31 mutagenic mode of action may be operational. This recommendation stems from a determination
32 by the Agency that there is increased susceptibility for cancer when exposures occur early in life. If
33 it is determined that ethylbenzene has human cancer potential by the oral or inhalation routes of
34 exposure, then a specific determination regarding the mode of action as per the Supplemental
35 Cancer Guidelines will be made.
36
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Scoping and Problem Formulation Materials for Ethylbenzene
1 Key issues related to mode of action for carcinogenicity
2 Based on the available data, the key issues for ethylbenzene mode of action for
3 carcinogenesis include (but are not limited to):
4 • Identification of key events leading to the development of tumors in rats (kidney) and mice
5 (lung)
6 • Role of metabolites in ethylbenzene-induced tumors
7 • Role of genotoxicity or mutagenicity in the mode of action of ethylbenzene-induced tumors
8 • Role of cytotoxicity and sustained regenerative cell proliferation in the mode of action of
9 ethylbenzene-induced tumors
10 • Role of cytochrome P-450 enzymes in the development of lung tumors
11 • Role of CPN in the development of kidney tumors
12 • Species differences in enzyme activities and ethylbenzene toxicity
13 Based on the U.S. EPA (2005a,b) Cancer Guidelines framework for evaluation of mode of
14 action, the following will be considered after a systematic review:
15 • Identification of mode of action hypotheses to be considered in the assessment
16 • Identification of the key events for each hypothesized mode of action
17 • Evaluation of experimental support for each hypothesized mode of action
18 • Sufficient support for each hypothesized mode of action in test animals
19 • Human relevance of hypothesized modes of action
20 • Populations or lifestages that are particularly susceptible to each hypothesized mode of action
21 Mechanisms of neurotoxicity, including ototoxicity
22 Studies have also demonstrated that ethylbenzene may exert detrimental effects on animal
23 (Tegeris and Balster, 1994; Ethylbenzene Producers Association, 1986; Molnar et al., 1986; Cragg et
24 al., 1989), as well as human (Yant et al., 1930) central nervous systems. In vivo studies of
25 ethylbenzene toxicity in animals indicate that alterations in dopamine levels and other biochemical
26 changes in the brain, as well as in evoked electrical activity in the brain may play a role in nervous
27 system ethylbenzene-induced toxicity (Andersson et al., 1981; Frantik et al., 1994; Mutti et al.,
28 1988; Romanelli et al., 1986).
29 Various in vitro studies on the mechanism of ethylbenzene induced-toxicity have paid
30 particular attention to the chemical's effect on cell membranes, especially that of the astrocyte
31 (Vaalavirta and Tahti, 1995a, 1995b; Sikkema et al., 1995; Naskali et al., 1993; Engelke etal., 1993).
32 According to Sikkema et al. (1995), alterations in cell membrane integrity and structure following
3 3 partitioning of ethylbenzene in to the lipid bilayer is a potential mechanism of toxicity. Additionally,
34 as an in vitro model for the membrane mediated effects of solvents on the central nervous system,
3 5 various studies have investigated ethylbenzene's effect on the membrane of rat astrocytes
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Scoping and Problem Formulation Materials for Ethylbenzene
1 (Vaalavirta and Tahti, 1995a, 1995b; Naskali et al., 1993,1994). Cultured astrocytes of the cerebella
2 were sensitive to ethylbenzene's effects, measured by inhibition of Na+, K+-ATPase, and Mg++-
3 ATPase (Vaalavirta and Tahti, 1995a, 1995b). The effect was determined to be dose-dependent
4 (Naskali et al., 1994). Perhaps, the cells' ability to maintain homeostasis is disrupted by inhibition of
5 membrane-bound enzymes, which regulate membrane ion channels (ATSDR, 2010)
6 Animals have shown persistent hearing deficits following the cessation of ethylbenzene
7 exposure and a recovery period, but it is unknown if humans would respond in a similar fashion.
8 The slow or lack of recovery observed in animals could have significant health effect implications
9 for humans exposed to ethylbenzene. The mechanisms of ototoxicity due to ethylbenzene exposure
10 remain unclear; however, an in vitro study has suggested that low concentration ethylbenzene-
11 induced ototoxicity may be mediated via nicotinic acetylcholine receptors. Under conditions of low
12 receptor occupancy, ethylbenzene inhibited acetylcholine-mediated ion currents in human
13 heteromeric a9 alO nicotinic acetylcholine receptors, which were expressed in Xenopus oocytes
14 (van Kleefetal, 2008).
15 Based on the available data, some key issues EPA will evaluate regarding the neurotoxicity
16 and ototoxicity of ethylbenzene include:
17 • Reversibility, persistence and potential for progression of the neurobehavioral effects after
18 humans are removed from ethylbenzene exposure
19 • Reversibility of the ototoxic effects in humans removed from ethylbenzene exposure
20 • The relevance of ototoxicity to humans at lower exposure levels
21 Human Susceptibility
2 2 Human susceptibility has already been discussed above in the context of toxicokinetics and
23 mode of action. No other potential susceptibility factors have been identified for the toxic effects of
24 ethylbenzene.
25
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Scoping and Problem Formulation Materials for Ethylbenzene
2
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