TECHNICAL REPORT DATA
fftetu read Instructions on the reverse before completing}
1. REPORT NO.
EPA/600/8-887054
2.
3. RECIPIENT'S ACCESSION NO
PB90-142357/AS
4. TITLE AND SUBTITLE
Health Effects Assessment for Styrene
5. REPORT DATE
«. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
8. PERFORMING ORGANIZATION REPORT NO.
. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
13. TYPE OF REPORT AND PERIOD COVERED
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
14. SPONSORING AGENCY CODE
EPA/600/22
is. SUPPLEMENTARY NOTES
J6. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD$ or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
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Unclassified
21. NO. OF PAGES
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EPA/600/8-88/054
August, 1989
HEALTH EFFECTS ASSESSMENT
FOR STYRENE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
This document has been reviewed 1n accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with styrene.
All estimates of acceptable Intakes and carcinogenic potency presented In
this document should be considered as preliminary and reflect limited
resources allocated to this project. Pertinent toxlcologlc and environ-
mental data were located through on-line literature searches of the TOXLINE,
CANCERLINE and the CHEMFATE/DATALOG data bases. The basic literature
searched supporting this document Is current up to March, 1987. Secondary
sources of Information have also been relied upon In the preparation of this
report and represent large-scale health assessment efforts that entail
extensive peer and Agency review. The following Office of Health and
Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1984b. Health and Environmental Effects Profile for
Styrene. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste, Washington, DC.
EPA/600/X-84/325. NTIS PB88-182175.
U.S. EPA. 1985a. Integrated Risk Information System (IRIS).
Reference dose (RfO) for oral exposure for styrene. Online.
(Verification date 10/09/85.) Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH.
U.S. EPA. 1985b. Reportable Quantity Document for Styrene.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1987. Integrated Risk Information System (IRIS).
Cardnogenlclty Assessment for Lifetime Exposure to Styrene.
Online: Input pending. (Verification date 11/09/87.) Office of
Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH.
U.S. EPA. 1988. Drinking Water Criteria Document for Styrene.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Drinking Water, Washington, DC.
111
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The .Intent 1n these assessments 1s to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope, which tended to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, Is
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants 1n ambient air or water where lifetime
exposure Is assumed. Animal data used for RfD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$i) and oral (RfDso)
exposures.
The RfD (formerly AIC) Is similar 1n concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD 1s route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfDj) exposure with the Implicit assumption that
exposure by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained 1n U.S.
EPA (1984).
For compounds for which there Is sufficient evidence of carclnogenlclty,
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. (1980b). Since cancer 1s a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f
appropriate, based on oral and Inhalation data If available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
The available data Indicate that styrene 1s carcinogenic by the oral
(NCI, 1979) and Inhalation (Jersey et al., 1978) routes In mice and rats,
respectively. U.S. EPA (1987, 1988) derived a q-|* of 3xl(T2
(mg/kg/day) * for oral exposure that Is adopted as the estimate of oral
carcinogenic potency for the purpose of this document. A q-|* of
2.0xlO"3 (mg/kg/day)"1 corresponding to a unit risk for air of 6xlO~7
(vg/m3)"1 was derived for Inhalation exposure to styrene from the
Inhalation study using rats (U.S. EPA, 1987). The appropriateness of this
study for high- to low-dose extrapolation, however, Is being evaluated based
upon pharmacoklnetlc considerations. Styrene 1s placed In U.S. EPA welght-
of-ev1dence Group 82, probable human carcinogen (U.S. EPA, 1987, 1988).
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TABLE OF CONTENTS
Page
1.
2.
3.
4.
5.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
2.2.
ORAL
INHALATION ..........
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS ........
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC ............ ....
3.1.1. Oral. . . . . .
3.1.2. Inhalation. ...... . . . . .
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral. . . o
3.3.2. Inhalation. .......
TOXICANT INTERACTIONS
CARCINOGENICITY .
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
4.1.1. Oral. .
4.1.2. Inhalation
BIOASSAYS. ........ . . . .
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA.
WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA . .
, , . 1
3
. . . 3
, , . 3
, . . 5
... 5
. . . 5
7
, , . 9
... 9
13
14
... 14
... 14
16
, 19
19
... 19
... 19
... 23
... 23
... 26
... 27
... 30
... 32
V1
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TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT ' 34
6.1. SUBCHRONIC REFERENCE DOSE (RfDs) 34
6.2. REFERENCE DOSE (RfD) 34
6.3. CARCINOGENIC POTENCY (q^) 34
6.3.1. Oral. 34
6.3.2. Inhalation. ......... . . 35
7. REFERENCES 41
APPENDIX: Summary Table for Styrene 59
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LIST OF TABLES
No. Title Page
1-1 Selected Physical and Chemical Properties and
Environmental Fate for Styrene 2
3-1 Subchronlc Inhalation Studies of Styrene 8
3-2 Chronic Studies of Styrene 10
3.3 Developmental Toxldty of Styrene by Inhalation to
Laboratory Animals. ..................... 17
6-1 Data Used for the Derivation of q-j* . 36
6-2 Cancer Data Sheet for Derivation of q-|* 37
6-3 Cancer Data Sheet for Derivation of qi* 39
6-4 Cancer Data Sheet for Derivation of q-j* . . . 40
vlll
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LIST OF ABBREVIATIONS
AADI Adjusted acceptable dally Intake
CNS Central nervous system
CS Composite score
DNA Deoxyrlbonuclelc acid
HA Health Advisory
LOAEL Lowest-observed-adverse effect level
MFO Mixed function oxldase
HTD Maximum tolerated dose
NOAEL No-observed-adverse effect level
ppm Parts per million
RBC Red blood cell
RfD Reference dose
RfD$ Subchronlc reference dose
RNA Rlbonuclelc acid
SAP Serum alkaline phosphatase
SGOT Serum glutamlc oxaloacetlc transamlnase
SGPT Serum glutamlc pyruvlc transamlnase
SMR Standard mortality ratio
SNARL Suggested no adverse response level
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected physical and chemical properties and environmental fate of
styrene are presented In Table 1-1.
Zoeteman et al. (1980) estimated the aquatic half-life to be -14 hours.
based on a river reach study. The volatilization half-life has been
estimated to be -3 hours based on a calculated Henry's Law constant of
5.2xlO~3 atm/m3«mol at 25°C. In addition to volatilization, removal by
photochemical degradation, blodegeneratlon and adsorption to sediments (as
Indicated by monitoring data) may be significant removal processes (U.S.
EPA, 1984b). The atmospheric half-life Is based on experimentally deter-
mined rate constants for the reaction of vapor phase styrene with both ozone
and hydroxyl radicals. Considering the reactivity of styrene In air,
physical removal processes are not likely to be Important (U.S. EPA,
1984b). B1odegradat1on screening studies 1n soil Indicate blodegradatlon In
soils may occur. Experimental evidence exists, which Indicates styrene may
persist In certain soils for at least 2 years (U.S. EPA, 1984b). On soil
surfaces, volatilization, oxidation, hydrolysis and acid-catalyzed polymeri-
zation of stryene are expected to reduce Us half-life to a much lower value
than Us half-life 1n subsurface soil.
0115h -1- 04/05/88
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TABLE 1-1
Selected Physical and Chemical Properties
and Environmental Fate for Styrene
Property
Value
Reference
CAS number:
Chemical class:
Molecular weight:
Vapor pressure at 20°C
Water solubility at 20°C:
Log octanol/water
partition coefficient:
B1oconcentrat1on factor:
Half-lives 1n
A1r:
Water:
Soil:
100-42-5
Unsaturated substituted
benzene
104.16
5 mm Hg
300 mg/8.
2.95
13.5, goldfish
(Carasslus auratus)
1-3 hours
3-14 hours, (river)
estimated
4-22 weeks, (subsurface
aquifer) estimated
U.S. EPA, 1984b
U.S. EPA, 1984b
Hansch and Leo,
1985
NLM, 1986
U.S. EPA, 1984b
NLM, 1986;
Zoeteman
et a!., 1980
Wilson et al.,
1983
0115h
04/05/88
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Data regarding the absorption of styrene from the gastrointestinal
tracts of humans could not be located In the available literature. Data
from experiments on rats, however, suggest that absorption Is rapid and
complete. Plotnlck and Welgel (1979) administered a single 20 mg/kg gavage
dose of 14C-styrene 1n corn oil to rats and determined that <10% of the
dose of radioactivity remained 1n the gastrointestinal tract at 8 hours
posttreatment. At the end of 24 hours, fecal excretion accounted for <2% of
the dose and urinary execretlon accounted for -90X of the dose of radio-
activity. In a similar study with somewhat larger doses, Sauerhoff et al.
(1976) determined fecal excretion at 72 hours to account for 4 and 1.5% of
the dose of radioactivity from a 50 and 500 mg/kg dose of 14C-styrene In
corn oil. Urinary excretion accounted for 95 and 90%, and expired air
contained 1 and 9X of the administered dose of radioactivity at the low and
high doses, respectively.
Experiments by WHhey (1976) suggest that the nature of the vehicle
affects the rate of gastrointestinal uptake In rats. When styrene at a dose
of 3.147 mg 1n aqueous solution was given by gavage, blood levels peaked
within 10 minutes and declined rapidly. When 32.61 mg was given In
vegetable oil, blood levels did not peak until ~100 minutes and the rate of
decline was much less rapid, Indicating a prolonged absorption phase.
2.2. INHALATION
The respiratory uptake of styrene has been Investigated In humans and
rats. U.S. EPA (1984b, 1988) summarized the results from several human
Inhalation studies at concentrations ranging from 50-80 ppm (210-340
mg/m3). Rapid absorption from the lungs was suggested by Astrand et al.
OllSh -3- 08/31/89
-------
(1974) who noted that the concentration of styrene In alveolar air plateaued
In ~1 minute after exposure began. Experiments by several Investigators
Indicate that the rate of uptake Increases with exercise (Ramsey et al.,
1980; Wlgaeus et al., 1983; Engstrom et al., 1978). However, Engstrom et
al. (1978) also reports that physical exercise reduces styrene elimination
time considerably. Estimated uptake ranged from 78-125 mg/hour at rest to
~420 mg/hour with strenuous exercise on a stationary bicycle using a mouth-
piece and breathing valve.
The pharmacoklnetlcs of Inhaled styrene has been Investigated In rats at
concentrations higher than those used In humans. Anderson et al. (1984)
exposed adult male F344 rats to 100, 200, 401 or 799 ppm (426, 852, 1710 or
3400 mg/m3) for 6 hours, measured arterial concentrations of styrene and
estimated rates of uptake. Rates of uptake were 6.13, 12.04, 21.12 and
39.26 mg/kg/hour, respectively. The rate of uptake was somewhat dependent
on the rate of metabolism; pretreatment with phenobarbltal or previous
exposure to styrene Induced the metabolism of styrene and Increased the rate
of uptake. Administration of pyrazole Inhibited both metabolism and the
rate of uptake.
0115h -4- 07/23/89
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Several subchronlc oral studies with styrene have been
performed using mice, rats and dogs, and these experiments have been
reviewed In two recent U.S. EPA (1984b, 1988) analyses. For the purpose of
this document, only those studies >90 days In length are discussed.
Ponomarkov and Tomatls (1978) administered a single 1350 mg/kg dose of
styrene In olive oil by gavage to 29 pregnant O-Q mice on day 17 of gesta-
tion. Weaned offspring were treated once weekly with 1350 mg/kg (192.86
mg/kg/day). Vehicle-treated controls consisted of nine pregnant females and
their offspring, which were treated for life. Untreated controls were also
maintained. Treatment with styrene was halted after 16 weeks because of
overt toxldty and high mortality 1n the treated mice compared with
controls. At 20 weeks, mortality had reached 50% 1n treated males and 20%
1n treated females; survival was -100% In untreated controls. The liver was
the most common site of lesions In dead mice, suggesting that this was an
Important target organ; multiple centMlobular liver necrosis was common.
Common lesions In other organs Included hyperplasla of the spleen and severe
lung congestion.
In an Investigation of the effects on neurotransmltter function In the
corpus strlatum, Agrawal et al. (1982) administered styrene In peanut oil by
gavage to six male 8-week-old albino rats at 0, 200 or 400 mg/kg/day for 90
days. There were no effects on rate of body weight gain or the weight of
the corpus strlatum. Binding of 3H-sp1roper1dol to dopamlne reception In
the corpus strlatum was Increased, however, at both treatment levels; the
authors felt this may indicate increased sensitivity of dopamlne receptors
because of the destruction of dopamlne neurons as a result of exposure to
styrene.
OllSh -5- 07/23/89
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To further Investigate the effects on the liver, Srlvastava et al.
(1982) administered styrene In ground nut oil to groups of five young adult
male albino rats at 0, 200 or 400 mg/kg, 6 days/week (0, 171.43 or 342.86
mg/kg/day) for 100 days. There were no statistically significant effects on
rate of body weight gain or liver weights. Significant alterations occurred
1n a number of mltochondrlal and mlcrosomal drug metabolizing enzyme activi-
ties. Activity of benzo[a]pyrene hydroxylase and amlnopyrene-N-demethylase
Increased and glutathlone-S-transferase decreased, all 1n a dose-related
manner. Mitochondria! succlnlc dehydrogenase and S-glucuron1dase activities
were decreased at both treatment levels and add phosphatase activity was
decreased at 400 mg/kg (342.86 mg/kg/day). Glucose-6-phosphatase activity
was unaffected. Evidence of liver damage, Including elevated SGOT and SGPT
activities and focal necrosis (Incidence not reported), was observed at 400
but not at 200 mg/kg.
Results of an earlier study Indicate that female rats may be more resis-
tant than males to the effects of styrene on the liver. Wolf et al. (1956)
administered styrene In a vehicle of olive oil and gum arable to groups of
10 female Hlstar derived rats at 66.7, 133, 400 or 667 mg/kg, 5 days/week
(47.64, 95.64, 285.71 or 476.43 mg/kg/day) for 6 months. The rats were -2
months old at the start of treatment. A group of 20 vehicle-treated females
was maintained as controls. Growth depression and Increased liver and
kidney weights were noted at 400 and 667 mg/kg (285.71 and 476.43 mg/kg/
day), but there was no hlstopathologlcal evidence of liver damage and no
effects on hematology at either of these levels. No adverse effects of any
kind were observed at 66.7 or 133 mg/kg (47.64 or 95.64 mg/kg/day).
A dog study by Quast et al. (1979) clearly defines the NOAEL and LOAEL
for oral toxlclty of styrene. These data have also been summarized In an
OllSh -6- 0//?:VH<)
-------
abstract (Quast et al., 1978). Purebred beagle dogs (4/sex/group) were
administered styrene In peanut on to beagle dogs (sex, number and age not
specified) at 0, 200, 400 or 600 mg/kg/day for 560 consecutive days. There
were no treatment-related effects on body weight, organ weights, urlnalysls
or clinical chemistries (serum urea nitrogen, SGPT, SGOT and SAP) at any
level. Hematologlcal effects Included decreased packed RBC volume at 400
and 600 mg/kg/day and a dose-related Increase In the presence of Heinz
bodies In the RBCs at >400 mg/kg/day. H1stopatholog1cal changes, observed
only In the liver, Included Increased Iron deposits In the retlculoendothe-
llal cells at >400 mg/kg/day and Increased numbers of addophlUc crystal-
line Intranuclear Inclusions In the hepatocytes at 600 mg/kg/day. No
effects were noted at 200 mg/kg/day except for one dog that had slightly
increased Iron deposits In the liver and sporadic low-level occurrence of
He1n^ bodies 1n RHCs. The 200 mg/kg/day level was considered a NOAEL and
400 mg/kg/day a LOAEL for liver and hematologlcal effects In dogs In this
study.
3.1.2. Inhalation. Several subchronlc Inhalation studies have been
performed with styrene In many laboratory species. These studies have been
extensively reviewed by U.S. EPA (1984b, 1988) and are briefly summarized In
Table 3-1. Several studies using rats exposed to 300 ppm, 6 hours/day, 5
days/week for 28-119 days or 145.41 mg/kg/day Indicated transient bio-
chemical alterations (Va1n1o et al., 1979; Savolalnen and Pfaffll, 1977;
Savolainen et al., 1980) or changes In nerve conduction velocity
(Seppalalnen, 19/H) of questionable blologlcnl significance. Of greater
significance Is the observation of hlstopathologlcal alterations In the
liver after exposure for 2 weeks to the above described protocol (Valnlo et
al., 1979).
0115H -7- 07/23/89
-------
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In earlier studies, rats, guinea pigs, rabbits and monkeys were exposed
to 650, 1300 or 2000 ppm (2770, 5540 or 8520 mg/m3), 7-8 hours/day, 5
days/week for 148-360 days (or 313.96, 627.91 or 966.02 nig/kg/day) (Spencer
et al., 1942; Wolf et al., 1956). Rabbits and monkeys appeared to be least
sensitive to styrene vapor as no adverse effects on weight gain, survival,
gross or hlstologlcal appearance of selected major organs and tissue or
hematologlcal parameters were observed. Rats experienced eye and nose
Irritation at >1300 ppm (840.15 mg/kg/day) and weight gain depression at
2000 ppm (1292.53 mg/kg/day). Hlstopathologlcal examinations were not
performed on rats. No effects on body weight gain, organ weights or gross
appearance at necropsy were noted 1n guinea pigs exposed to 650 ppm (313.96
mg/kg/day). At 1300 ppm (627.91 mg/kg/day), mortality from acute lung
Irritation occurred In ~10% of the guinea pigs, and survivors gained weight
slowly. Survival was unaffected In guinea pigs at 2000 ppm (966.02 mg/kg/
day), but depressed rate of body weight gain was noted.
3.2. CHRONIC
3.2.1. Oral. Chronic oral experiments with styrene Include a long-term
study using rats by Ponomarkov and Tomatls (1978), the NCI (1979) bloassay
on rats and mice and a 2-year drinking water study using rats (Belllles et
al., 1985) (Table 3-2). In the Ponomarkov and Tomatls (1978) study, a
single 1350 mg/kg dose was administered to 21 pregnant BO IV rats on gesta-
tion day 17, and 144 male offspring were treated from weaning up to 120
weeks with once weekly doses of 500 mg/kg (71.43 mg/kg/day). Body weight
was unaffected by treatment. Several rats died at 50-60 weeks and exhibited
small necrotlc fod 1n the liver and moderate congestion of the lungs and
kidneys. The liver lesions were not observed in rats that died at >80
weeks. Other common observations were lesions In the forestomach and hyper-
plasla of the epithelium of the renal pelvis.
0115h -9- 07/23/89
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NCI (1979) treated groups of 50 male and 50 female F344 rats by gavage
at 1000 or 2000 mg/kg, 5 days/week (714.29 or 1428.57 mg/kg/day) for 78
weeks followed by a 27-week observation period. Controls consisted of 20
rats/sex. High mortality 1n high-dose rats of both sexes early 1n the
course of treatment led to the establishment of another treatment group at
23 weeks that received 50 mg/kg (35.71 mg/kg/day assuming a similar
treatment regimen) for 103 weeks followed by a 1-week observation period.
Another group of concurrent controls was started at this time. A
dose-related depression In mean body weights was apparent In all treated
groups of males. An early and marked Increase In mortality was observed 1n
high-dose rats of both sexes. Hepatic necrosis was noted 1n several
high-dose rats of both sexes and was considered to be related to the high
mortality observed In this group.
NCI (1979) also treated groups of 50 male and 50 female B6C3F1 mice with
150 or 300 mg/kg, 5 days/week (107.14 or 214.29 mg/kg/day) for 28 weeks
followed by a 13-week observation period. Concurrent vehicle-treated
controls consisted of 20 mice/sex. A dose-related but very slight depres-
sion In mean body weights was observed In female but not male mice.
Survival was decreased In high-dose mice of both sexes, and the Tarone test
Indicated a dose-related trend In decreased survival 1n males but not In
females. H1stopatholog1cal examination revealed no Increase 1n nonneo-
plastlc lesions In treated mice compared with controls.
In a combination chronic toxldty reproduction study (BeHlles et al.,
1985), groups of 50 male and 70 female 35-day-old Charles River C08S(SO)8R
rats were provided drinking water containing styrene at 125 or 250 ppm
nominal concentrations for 2 years. Analysis of styrene 1n drinking water
Indicated that the average concentrations were 112 and 221 ppm (15.68 and
30.94 mg/kg/day). Controls consisted of 76 males and 106 females.
0115h -12- 08/31/89
-------
Treatment had no effect on body weight, food consumption, clinical signs,
survival, ophthalmic examination (conducted at weeks 51 and 104), hemograms,
organ weights, or gross or hlstopathologlcal appearance of many organs and
tissues. The latter three parameters were evaluated for 10 rats/sex/group
at a 52-week Interim sacrifice, at time of natural death or moribund
sacrifice, or at termination. A dose-related decrease In water consumption
was noted 1n both sexes In both treated groups.
3.2.2. Inhalation. Jersey et al. (1978) exposed Sprague-Dawley rats (96
of each sex) to styrene at 0, 600 or 1000 ppm (265.1 and 441.8 mg/kg/day for
female rats and 180.2 and 300.3 mg/kg/day for male rats), 6 hours/day, 5
days/week for up to 18.3 months (549 days) for males and 20.7 months (621
days) for females. The high-dose rats were Initially exposed to 1200 ppm
(530.1 and 360.3 mg/kg/day for females and males, respectively), but the
concentration was reduced to 1000 ppm at 2 months because of narcosis In the
males. Interim sacrifices were performed at 6 months (5/sex/group) and at
12 months (6/sex/group); survivors were sacrificed at 24 months. Survival
In control and high-dose males was markedly reduced, compared with the low
dose, which was due primarily to an outbreak of murlne pneumonia. A depres-
sion In mean body weights was noted In both groups of treated males during
the first 263 days and In high-dose females for the first 506 days of treat-
ment. Sporadic depressions 1n absolute liver and kidney weights were noted
In treated males, but Increased absolute and relative liver weights were
observed In treated females. Neither sex had effects on hematology,
urlnalysls or clinical chemistries. No treatment-related hlstopathologlcal
changes were noted 1n males; minor lesions In the lungs occurred In both
treated groups of females. Neoplastlc changes 1n this experiment are
discussed 1n Section 4.2.2.
0115h -13- 08/31/89
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3.3. TERAT06ENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Murray et al. (1976, 1978a) Investigated the developmental
toxlclty of styrene administered by gavage to groups of 29-39 mated Sprague-
Dawley rats at 0, 180 or 300 mg/kg/day on days 6-15 of gestation. Maternal
toxldty was manifested as decreased body weight gain In both treated
groups. There were no effects on mortality, pregnancy, Implantation/dam,
live or resorbed fetuses/litter or fetal body weights or crown rump lengths.
In addition, examination of fetuses Indicated no Increase 1n the Incidence
of gross external, skeletal or soft tissue malformations.
As a part of the drinking water toxldty study described In Section
3.2.1., Bellies et al. (1985) performed a 3-generat1on reproduction study.
The FQ generation consisted of 10 male and 20 female rats exposed to 0,
125 or 250 ppm (17.5 or 35.0 mg/kg/day) that were mated after -90 days
treatment. Subsequent generations were obtained by mating rats at -110 days
of age. Only one Utter/generation was produced. The Fn parents were
returned to the chronic study after weaning the F. offspring. Although
statistically significant differences were observed sporadically in various
reproductive parameters, no dose-related trends were evident and the
Investigators concluded that there were no treatment-associated effects on
fertility. In addition, there were no effects on relative organ weights,
hlstopathology or cytogenetlcs In any of the generations of offspring.
3.3.2. Inhalation. Tenuous data weakly associate exposure of pregnant
women to styrene with an Increased Incidence of spontaneous abortion.
Hemm1nk1 et al. (1980) analyzed the frequency of spontaneous abortion among
-9000 female chemical workers In Finland from 1973 to 1976. In the Investi-
gators analysis, the number of spontaneous abortions was related to the
number of pregnancies (births > Induced abortions <- spontaneous abortions;
0115h -14- 07/23/89
-------
this 1s referred to as the rate of spontaneous abortion). The ratio of
spontaneous abortions 1n each branch of the chemical Industry refers to the
number of spontaneous abortions related to the number of births. The rate
of spontaneous abortions was 8.54% (p<0.01) 1n the Union of Chemical Workers
with a total of 52 spontaneous abortions, and 15.0% (p<0.01) 1n the subgroup
labeled "styrene production and use" with a total of 6 spontaneous abortions.
The control populations labeled "all women 1n Finland" had 15,482
spontaneous abortions or a 5.52% rate of spontaneous abortion. The ratio of
spontaneous abortions In the Union of Chemical Workers and 1n the styrene
Industry were similarly elevated, 15.57% (p<0.001) and 31.59% (p<0.001),
respectively, 1n relation to 7.98% 1n the control population.
In a smaller scale study, Harkonen and Holmberg (1982) analyzed the
obstetrical histories of 67 plastics lamination workers exposed to styrene,
and 67 age-matched textile and food processing workers. There were no
significant differences 1n the number of pregnant women or 1n the Incidence
of spontaneous abortions between the groups.
Holmberg (1977) Interviewed 43 Finnish mothers of children born with CNS
defects and determined that two had been exposed regularly during pregnancy
to styrene and a number of other chemicals In the reinforced plastics
Industry. The defects 1n the two chemical-exposed Infants were anencephaly
and hydrocephaly. Based on the Finnish fertility rate, the Investigator
estimated that ~12 births should have occurred among reinforced plastics
working women during the study period and that, based on the national
reported rate for anencephaly and hydrocephaly In the population as a whole,
a 300-fold Increase 1n the Incidence of these defects had occurred.
However, a very small sample size was evaluated.
0115h -15- 08/31/89
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Several developmental toxldty studies have been performed using labora-
tory animals exposed by Inhalation (Table 3-3). A teratogenlc response was
not observed In rats (Murray et al., 1978a,b; Ragule, 1974), mice and
hamsters (Kankaanpaa et al., 1980) or rabbits (Murray et al., 1978a,b).
Fetotoxldty (Increased dead and resorbed fetuses) was observed 1n hamsters
at 1000 ppm (4260 mg/m3) (988.96 mg/kg/day assuming a 7 day/week exposure
regimen) 6 hours/day (Kankaanpaa et al., 1980) and In rabbits (marginal
Increase 1n the Incidence of unosslfled fifth sternebrae) at 600 ppm (2556
mg/m3) (392.38 mg/kg/day, assuming a 7 day/week exposure regimen) 7
hours/day (Murray et al., 1978a,b). Ragule (1974) reported resorptlons 1n
rats at 0.35 ppm (1.49 mg/m3) (0.16 mg/kg/day) 4 hours/day throughout
gestation, but this Russian study was not reported In sufficient detail to
permit adequate review. Of the studies reviewed In Table 3-3, only Murray
et al. (1978a,b) evaluated maternal toxldty. There was no evidence of
maternal toxldty In rabbits at 600 ppm (392.38 mg/kg/day), but at 300 and
600 ppm (237.0 and 475.0 mg/kg/day) rats showed decreased food consumption
and reduced body weight gain during days 6-9 of gestation. Exposures In both
species were for 7 hours/day on days 6-15 of gestation.
3.4. TOXICANT INTERACTIONS
Styrene Is rapidly metabolized and eliminated from the body. Toxicant
Interaction studies have focused on the effect of exposure to other chemi-
cals or dietary modifications on the metabolism of styrene. Ikeda et al.
(1972) and Ikeda and Hlrayama (1978) noted that the simultaneous administra-
tion of toluene or trlchloroethylene with styrene (both chemicals given by
1ntraper1toneal Injection or by Inhalation) resulted 1n reduced excretion of
urinary metabolites of styrene, compared with excretion following styrene
administration alone. When given by the IntraperHoneal route, the Inhibi-
tory effect of toluene was reduced by the coadmlnlstratlon of phenobarbltal.
0115h -16- 07/23/89
-------
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In an jn. vUro system, Sato et al. {1980, 1981) observed that mlcrosomes
from rats exposed continuously to low levels of ethanol In the drinking
water for 3 weeks before sacrifice metabolized styrene more rapidly than did
mlcrosomes from control (no ethanol) rats. Removal of. ethanol for as little
as 24 hours before sacrifice resulted In a loss of the effect on mlcrosomal
enzyme Induction. When single graded doses of ethanol were given by gavage
18 hours before sacrifice, maximum enzyme Induction.occurred at 4 g/kg and
less enzyme Induction was noted at 5 g/kg. The enzyme Inducing effects of
ethanol appear to be dose-dependent until a point of diminishing returns Is
reached. Incubation of control mlcrosomes with added ethanol resulted In
depressed styrene metabolism, suggesting that the accelerated metabolism
observed with mlcrosomes from ethanol-treated rats was due to enzyme Induc-
tion rather than to the presence of alcohol In the Incubation system.
Nakajlma et al. (1982) Investigated the effects of dietary changes on
the ability of rat mlcrosomes to metabolize styrene. Decreased food Intake
and decreased dietary sucrose content Increased mlcrosomal metabolism of
styrene. Similar results were obtained with a high protein, high fat diet
free of carbohydrates.
0115h -18- 07/23/89
-------
4. CARCINOGENICITY
4.1. HUMAN DATA
4\1.1. Oral. Pertinent data regarding the carclnogenldty of styrene to
humans by the oral route could not be located In the available literature.
4.1.2. Inhalation. A number of ep1dem1olog1cal Investigations of workers
exposed to styrene have been performed to determine the association of
occupational exposure with cancer (Lemen and Young, 1976; Block, 1976;
Hodgson and Jones, 1985; McMlchael et al.t 1976; Melnhardt et al., 1978,
1982; Ott et al., 1980; Nicholson et al., 1978; Frentzel-Beyme et al., 1978;
Harden et al., 1981). These studies generally are limited by small cohort
size, poorly quantltated duration and Intensity of exposure, exposure to
multiple chemicals and the presence of the healthy worker effect. These
studies have been reviewed 1n detail 1n several recent U.S. EPA (1984b,
1988) analyses, and 1t 1s beyond the scope of this document to repeat that
effort here. Only the conclusions from these analyses are presented.
The National Institute for Occupational Safety and Health (NIOSH, 1976)
held a briefing on April 30, 1976 to review the hazards of styrene-butadlene
production. Five cases of leukemia In a B.F. Goodrich styrene-butadlene
rubber plant were described by Lemen and Young (1976). The leukemlas were
of diverse hlstologlc types and there was no apparent association with a
specific Job classification. Three cases of leukemia In workers In a U.S.
chemical synthetic rubber plant were also described (Lemen and Young, 1976).
Block (1976) described a study of six chemical plants In the Kentucky
area Including one synthetic rubber plant. Of the 72 death certificates
obtained for workers employed between 1950 and 1975, leukemia was Indicated
as the cause of death 1n two cases and Hodgkln's disease was the cause 1n
another two cases. An additional leukemia death was reported for a worker
0115h -19- 07/23/89
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In 1976 (after the study cutoff date). There were three deaths from
leukemia reported 1n the other five chemical plants with no styrene or
butadiene exposure. IARC (1979) reviewed these reports arid concluded the
data were Inadequate to Indicate an association between an Increased risk of
leukemia and styrene or butadiene exposure; however, further study was
justified.
Hodgson and Jones (1985) conducted a mortality study of 622 men who
worked for at least 1 year In the production, polymerization and processing
of styrene at a chemical site In the United Kingdom during the period
1945-1974. This Included 131 men who were potentially exposed to styrene
among other chemicals In laboratories and 491 Individuals who would have had
mixed chemical exposures but had specific potential exposure to styrene In
the production of styrene monomer, the polyerlzatlon of styrene, or the
manufacture of finished products. A significant elevation of lymphoma
deaths 1n the exposed group was reported. However, the number of lymphoma
deaths was small and the workers were exposed to other chemicals In addition
to styrene.
McMlchael et al. (1976) conducted a retrospective cohort study of 6678
male workers 1n a tire manufacturing plant. Workers were placed In one of
six categories based on job classification; only 2-3% were exposed to
styrene-butadlene for >2 years. Risk ratios for deaths from lymphatic and
hematopoletlc cancer, lymphatic leukemia and stomach cancers were calculated
to be 6.2, 3.9 and 2.2, respectively. Although the risk ratio for lymphatic
and hematopoletlc cancer was statistically significant, H was based on only
four deaths, the biological significance of which 1s unclear.
The most extensive Investigation of styrene 1n the workplace was by
Melnhardt et al. (1978) concerning two styrene-butadlene rubber factories
0115h -20- 08/31/89
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(plant A and plant B). Mean styrene concentration In plant A was 0.94 ppm
(4.0 mg/m3) (0.272 mg/kg/day assuming 8-hour workdays, 5 days/week, 70 kg
body weight and 20 mg/m3 breathing rate) and In plant B was 1.99 ppm
(0.577 mg/kg/day assuming 8-hour workdays, 5 days/week, 70 kg body weight
and 20 mVday breathing rate); butadiene was also present at substantially
greater concentrations. These concentrations probably do not reflect past
exposure because changes In the manufacturing processes were expected to
have reduced concentrations. In plant A, 9 deaths from neoplasms of the
lymphatic and hematopoletlc tissues 1n 252 total deaths resulted in an SMR
of 155. Reevaluatlon using a subgroup of white males exposed before changes
were made In the manufacturing process, resulting In reduced exposure,
resulted In an SMR for 212 for overall lymphatic and hematopoletlc neoplasms
and an SMR of 278 for leukemia and aleukemla. In plant B, an SMR of 78 was
calculated for neoplasla of lymphatic and hematopoletlc tissue, which was
attributed to the healthy worker effect. The Investigators noted that the
SMRs calculated for plant A were not statistically significant and that,
because of the high background Incidence of leukemia 1n the general popu-
lation, the observed Incidence would have to be ~4 times larger than the
expected Incidence to be statistically significant using the consecutive
two-sided test ordinarily used by NIOSH. Applying the one-sided test, the
mortality from leukemia and aleukemla for plant A was marginally significant
(p<0.05) and the authors concluded that the findings "suggested" an associa-
tion between styrene-butadlene exposure and mortality from lymphatic and
hematopoletlc cancers.
Ott et al. (1980) reported the results of a retrospective cohort mortal-
ity study of Dow Chemical Co. plants Involved In the manufacture of styrene
products. Statistically significant Increases 1n Incidences of leukemia (6
0115h -21- 08/31/89
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observed, 1.6 expected) and lymphatic leukemia (4 observed, 0.5 expected)
were noted. The largest SMR was determined for workers In one category
exposed to styrene, polystyrene dust, ethylbenzene, ollgomers of styrene.
Inorganic colorants and various solvents.
Nicholson et al. (1978) studied a cohort of 560 male workers exposed for
at least 5 years 1n a styrene-polystyrene factory. For 116 workers, expo-
sure concentration was <1 ppm (<4 mg/m3) (<0.29 mg/kg/day, making usual
assumptions); for the rest of the workers, exposures were generally 5-20 ppm
(20-85 mg/m3) (1.45-5.79 mg/kg/day, making usual assumptions) with some
wide variations. Unspecified levels of benzene and ethylbenzene were also
present. For all causes of death, Including cancer, observed deaths were
fewer than expected, which was attributed to the healthy worker effect.
There appeared to be no differences between high and low exposure groups.
Although there were no specific Increases 1n cause-specific mortality, the
Incidence of leukemia (5/104 deaths) Indicated to the Investigators a need
for further study.
The healthy worker effect was also evident In data from a styrene-
polystyrene factory In Germany. In this study of 1960 workers divided Into
those employed before and after plant modernization reduced exposures, fewer
total deaths occurred than were expected In the exposure groups (Frentzel-
Beyme et al., 1978). There were also fewer cancer-related deaths than
expected, although the Incidences of some rare tumors were Increased
sporadically In single age groups. These Increases were not associated with
extent or duration of exposure and were considered to be artifacts.
Hardell et al. (1981) conducted a matched case-control study of males
aged 25-85 years with malignant lymphomas who were admitted to the Depart-
ment of Oncology In Unea 1n a 4-year period. Exposure histories were
0115h -22- 08/31/89
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obtained by questionnaire. An elevated relative risk (4.6; 95% confidence
limits 1.9-11.4) was noted for a category Including exposure to styrene,
benzene, trlchloroethylene and perchloroethylene.
The U.S. EPA (1984b, 1988) noted the limitations of these epidemiology
studies and declined to draw conclusions regarding the carclnogenldty of
styrene to humans.
4.2. BIOASSAYS
4.2.1. Oral. Oral cancer bloassays with styrene Include the NCI (1979)
study using rats and mice, a 1-year drinking water study using rats (Bellies
et al., 1985) and a long-term study In which the offspring of two strains of
mice and one strain of rats from treated dams were treated once weekly for
life (Ponomarkov and Tomatls, 1978). In the NCI (1979) experiment, (see
Section 3.2.1.), rats were given styrene at 500, 1000 or 2000 mg/kg, 5
days/week for 78-103 weeks (357.14, 714.29 or 1428.57 mg/kg/day). Early
mortality In high-dose rats resulted In Inadequate numbers In these groups
at risk for late developing tumors. Adequate numbers of rats survived 1n
the low and middle groups, however. No tumor Incidence was significantly
elevated In any of these groups compared with controls, nor did time to
tumor appear to be shortened for any tumor type.
Mice were treated at 150 or 300 mg/kg, 5 days/week for 78 weeks (107.14
or 214.29 mg/kg/day) followed by a 13-week observation period (NCI, 1979).
Although survival was reduced In high-dose mice of both sexes, adequate
numbers survived at risk for late developing tumors. No tumor type was
significantly Increased 1n treated female mice compared with controls. In
male mice, a dose-related Increase 1n combined alveolar/bronchlolar
carcinomas and adenomas was noted (0/20 concurrent controls, 6/44 low group,
9/43 high group), which was significant for trend by the Cochran-ArmHage
0115h -23- 07/23/89
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test (p=0.023) and significant at the high group by the Fisher Exact test
(p=0.024). NCI (1979) noted an Incidence of combined adenomas and
carcinomas of the -lung 1n historical untreated controls of 32/271 (12%) and
concluded that the results of this experiment "suggested that the adminis-
tration of styrene may have been associated with the Increased combined
Incidence of alveolar/bronchlolar adenomas or.... carcinomas 1n male mice..."
As part of a chronic toxlclty reproduction study, Bellies et al. (1985)
treated groups of 76 male and 106 female rats with 125 or 250 ppm (17 = 5 or
35.0 mg/kg/day) styrene In the drinking water for 2 years (see Section
3.2.1.). Survival was unaffected and sufficient for observation of late-
developing tumors. Comprehensive gross and hlstopathologlcal examination
performed at Interim sacrifice (10/sex/group at 52 weeks), maternal death or
moribund sacrifice or at termination yielded no evidence of carcinogenldty.
It did not appear that the MID had been reached In this study, since there
were no effects on mortality, body weight or clinical signs.
Ponomarkov and Tomatls (1978) administered single doses of styrene (99%
pure) In olive oil to 29 female 02Q mice at 1350 mg/kg, to 15 females
C57B1 mice at 300 mg/kg and to 21 female BO IV rats at 1350 mg/kg on day 17
of gestation. Following weaning, the offspring of the C57B1 mice were
treated once weekly with 300 mg/kg (42.86 mg/kg/day) and the offspring of
the rats were treated once weekly with 1350 mg/kg (192.86 mg/kg/day) for
life. Offspring of the 02_ mice were treated once weekly with 1350 mg/kg
(192.86 mg/kg/day), but treatment was terminated at 16 weeks because of
overt toxlclty and early mortality. Vehicle-treated progeny controls
consisted of 42 02Q and 25 C57B1 mice and 75 BO IV rats; untreated
controls were also maintained.
OllSh -24- 07/23/89
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Early deaths occurred among the 45 male and 39 female styrene-treated
offspring of the CL0 mice (average age of death was 32 weeks for males and
49 weeks for females compared with 88 and 85 weeks for males and females,
respectively. In the oil-treated controls). Nevertheless, a significant
Increase In the Incidence of lung tumors classified as adenomas and
carcinomas was observed for both sexes (p<0.02 for males and p<0.001 for
females, calculated from study results using Fisher's exact test) when
compared with the olive oil-treated controls. Characteristically, 02Q
mice have a high spontaneous rate of lung adenomas and carcinomas; In this
study, the concurrent control Incidence was 42%-67% (male and female) with
an age at tumor onset ranging from 53-57 weeks. The lung tumor rates (based
on the survivors at the time the first tumor was observed) were 20/23 and
32/32 In treated males and females, respectively, compared with 8/19 and
14/21 1n male and female vehicle-treated controls, and 34/53 and 25/47 In
male and female untreated controls, respectively. Lung tumors were observed
In mice dying at an earlier age 1n the treated group as compared with the
controls. The female treated mice had a much higher ratio of carcinomas to
adenomas than the vehicle controls (1.3 treated compared with 0.4 In the
vehicle controls) but a similar ratio to the untreated controls, perhaps
suggesting vehicle related Inhibition of cardnogenesls. The high sponta-
neous background rate of lung tumors 1n 0_Q mice raises a question as to
how to Interpret this Increase In tumor Incidence. The observed significant
Increase 1n tumor Incidence cannot be dismissed, therefore, and Is thought
to be of a highly suggestive nature given the high statistical significance
of the response and the reduced latency period for tumor Induction 1n terms
of Indicating a tumorlgenlc potential.
0115h -25- 07/23/89
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In C57B1 mice a slight, but Insignificant, Increase In liver carcinomas
was observed In treated animals (3/24). Although this Increase 1s not
statistically significant when compared with male vehicle controls (0/12),
H 1s statistically significant (p=0.022 calculated from study results using
Fisher's exact test) when compared with untreated controls (0/47) and
vehicle controls combined. Pooling both control groups Is acceptable
because there 1s no difference between their tumor responses. No signifi-
cant tumor-related effects were observed 1n BDIV rats.
4.2.2. Inhalation. Jersey et al. (1978) exposed groups of 85 male and 85
female Sprague-Dawley rats to atmospheres containing styrene at 0, 600 or
1200 ppm (0, 2560 or 5110 mg/m3), 6 hours/day, 5 days/week (0, 290.82 or
581.64 mg/kg/day) for ~2 years. After 2 months, the concentration In the
high group was reduced to 1000 ppm (4260 mg/m3, 484.7 mg/kg/day) because
of narcosis In the males. Exposures of each sex were terminated when
mortality reached 50% for that sex In either test group (18.3 and 20.7
months for males and females, respectively). Survivors were sacrificed at
24 months. High mortality from muMne pneumonia 1n control arid 1000 ppm
(484.7 mg/kg/day) males precluded reliable Interpretation of tumor Incidence
data In males. In females, statistically significant Increases In tumor
Incidences Included grossly observed ovarian tumors at 1000 ppm (484,7
mg/kg/day) and mammary adenocarclnomas at 600 ppm (290.82 mg/kg/day). The
Incidence of grossly visible ovarian tumors was 0/85 In controls and 5/85 at
1000 ppm (484.7 mg/kg/day), but microscopic examination resulted In a
reduction In Incidence to 3/85 in the high group. The incidence of mammary
adenocarclnomas was 1/85 In controls and 7/85 at 600 ppm (290.82 mg/kg/day),
but the Investigators noted the Incidence 1n concurrent controls was unusu-
ally low compared with historic controls. A more biologically significant
0115h -26- 07/23/89
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observation was the combined Incidence of leukemia and lymphosarcomas: 1/85
(1.18%) In controls, 6/85 (7.06%) at 600 ppm and 6/85 (7.06%) at 1000 ppm
(484.7 mg/kg/day). Although the Incidence 1n either treated group was not
significantly elevated above concurrent controls, marginal significance
(p=0.04, Fisher Exact test) was obtained when data from the treated groups
were combined. The Investigators presented the Incidence data for leukemla-
lymphosarcoma In historic controls. A total of 11 cases occurred 1n 808
(1.36%) female Sprague-Dawley rats that had been part of 10 other experi-
ments. The Incidence In controls In these experiments ranged from 0-2.64%.
When the Incidence In either treated group (6/85) 1s compared with that of
historic controls, the results are statistically significant by the Fisher
Exact test (p=0.0033, analysis at SRC).
4.3. OTHER RELEVANT DATA
Maltonl et al. (1982) Investigated the ability of styrene to Induce
brain tumors 1n rats exposed by gavage or Inhalation for 52 weeks. In these
experiments, groups of 40 male and 40 female Sprague-Dawley rats were
treated with styrene In olive oil at 0, 50 or 250 mg/kg, 4-5 days/week (0,
35.71 or 178.57 mg/kg/day assuming 5 days/week), or other similar groups
were exposed to 0, 25, 50, 100, 200 or 300 ppm (0, 107, 213, 426, 852 or
1278 mg/m3), 4 hours/day, 5 days/week (0, 8.08, 16.16, 32.31, 64.63 or
96.94 mg/kg/day). The rats were examined at the time of spontaneous death.
In neither study did the Incidence of grossly or hlstologlcally Identified
brain tumors 1n treated rats significantly exceed the Incidence 1n controls.
Styrene oxide, a metabolite of styrene, has been tested for
cardnogenldty by gavage In rats and mice (NTP, 1986). The results of this
bloassay have not yet been published, but an unpublished report from the
contracting laboratory (Ujlnsky, n.d.) Indicates that styrene oxide was
0115h -27- 08/31/89
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associated with stomach tumors In both rats and mice. In an earlier gavage
study with styrene oxide, a dose-related and highly significant Increase In
the Incidence of carcinomas of the forestomach was observed In rats treated
with 50 or 250 mg/kg, 4-5 days/week (35.71 or 178.57 mg/kg/day, assuming 5
days/week) for 52 weeks and observed up to week 156 (Maltonl et al., 1979).
Styrene oxide was negative for skin tumors (Well et al., 1963; Van
Duuren et al., 1963) and for skin and lung tumors (Kotln and Falk, 1963) In
mouse skin painting studies. In the last study, however, malignant lymphoma
occurred 1n 3/20 (16%) of C3H mice painted with a total of 20 ym styrene
oxide. Further Information was not available.
Styrene and some of Us metabolites have been tested for mutagenlclty In
several prokaryotlc, eukaryotlc and mammalian systems. The most comprehen-
sive review and analysis of these studies Is U.S. EPA (1988), from which the
following generalizations are made. Styrene has been uniformly negative In
1n several strains of Salmonella typhlmurlum without metabolic activation,
but both positive and negative results were obtained with metabolic.activa-
tion (Busk, 1979; MHvy and Garro, 1976; De Flora, 1981; Stoltz and WHhey,
1977; Loprleno et al., 1978; De Heester et al., 1977, 1981; Valnlo et al.,
1976; Poncelet et al., 1980; Simmon et al., 1977). Styrene oxide, on the
other hand, yielded consistently positive results 1n S. typhlmurlum strains
TA1535 and TA100 with or without metabolic activation (De Meester et al.,
1977, 1981; Busk, 1979; De Flora, 1981; Glatt et al., 1975; Loprleno et al.,
1978; HHvy and Garro, 1976; Va1n1o et al., 1976; Drlnkwater et al., 1978).
Negative results were obtained with styrene In several forward mutations and
a gene conversion test in yeast (Loprleno et al., 1976; Bauer et al., 1980).
Results In forward mutation tests in V79 human lymphocytes were positive
only 1n the presence of metabolic activation (Loprleno et al., 1976; Belje
0115h -28- 07/23/89
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and Jenssen, 1982). Positive results were obtained for recessive lethal
mutations 1n DrosophUa melanogaster (Donner et al., 1979). In this test,
metabolic Induction with phenobarbltal Increased the frequency of mutation.
Styrene oxide was positive 1n many mutation tests In eukaryotes (Loprleno et
al., 1976; Suglura et al., 1979; Belje and Jenssen, 1982; Amacher and
Turner, 1982; Donner et al., 1979).
H1xed positive and negative results were reported for clastogenlc
effects of styrene In several in vitro and in vivo tests In mammalian
systems (Matsuoka et al., 1979; Ishldate and Yoshlkawa, 1980; Unnalnmaa et
al., 1978a,b; de Raat, 1978; Norppa et al., 1980a,b, 1981; Meretoja et al.,
1978a; Conner et al., 1979, 1980, 1982). Generally, metabolic activation
appeared to be required 1n the \n_ vitro systems. Styrene oxide yielded
positive and dose-related clastogenlc results 1n ]n_ yltrj) systems (de Raat,
1978; Norppa et al., 1980a; Unnalnmaa et al., 1978a,b) and metabolic
activation actually decreased the Intensity of the effect {de Raat, 1978).
Styrene oxide did not produce clastogenlc effects In in vivo systems (Fabry
et al., 1978; McGregor, 1981; Norppa et al., 1979).
U.S. EPA (1988) also summarized several studies In which peripheral
lymphocytes from workers exposed to styrene were examined for chromosomal
damage (Meretoja et al., 1977, 1978b; Flelg and Thless, 1978; Andersson et
al., 1980; Camurrl et al., 1983; Hogstedt et al., 1979; Watanabe et al.,
1981; Thless et al., 1980). Several Investigators reported positive
effects, particularly for concentrations In the workplace >50 ppm (213
mg/m3) (>14.49 mg/kg/day assuming 8-hour workdays, 5 days/week). WHO
(1983) evaluated these studies and concluded that the biological signifi-
cance of these clastogenlc effects 1s unknown.
0115h -29- 08/31/89
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4.4. WEIGHT OF EVIDENCE
Human epldemlologlcal data are Inadequate to either confirm or refute
the carcinogenic activity of styrene; however, the results of three chronic
animal bloassays (Jersey et al., 1978; NCI, 1979; Ponomarkov and Tomatls,
1978) collectively provide sufficient animal evidence. Strong supporting
evidence 1s provided by metabolic and genotoxldty studies, some of which
have been published recently. When the animal bloassay data are considered
collectively along with the metabollsm/genotoxldty data, there Is a
reasonable basis for classifying styrene as having a "sufficient" level of
evidence and therefore as a Group B2 chemical using EPA's Guidelines for
Carcinogen Risk Assessment. The guidelines provide several avenues for
reaching a sufficient level of animal evidence. In this analysis, the
bloassay data alone were considered to be strong enough for at least a
"marginal" call of sufficient animal evidence.
The classification of marginally-sufficient animal evidence comes from
animal bloassays showing statistically significant Increased tumor
Incidences In the B6C31 male mouse (alveolar/bronchlolar adenomas and
carcinomas by multiple dose gavage) (NCI, 1979), 1n male and female 02Q
mice (lung adenomas and carcinomas by dose gavage), 1n male C57B1 mice
(liver carcinomas by gavage) (Ponomarkov and Tomatls, 1978), and 1n female
Sprague-Dawley rats (leukemia/ lymphosarcoma, by Inhalation) Jersey et al.,
1978).
The guidelines encourage the use of additional considerations to support
or limit the strength of the bloassay evidence. In the case of styrene, the
evidence for genotoxldty In short-term animal test systems along with
recent data showing tha styrene and Us epoxlde metabolite form DNA adducts
and the epoxlde has been detected 1n humans exposed to styrene Is very
0115h -30- 08/31/89
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supportive of a carcinogenic potential. Equally Important Is the fact that
the epoxlde metabolite has been tested 1n rodents and found to be clearly
carcinogenic In this blassay. These additional considerations together with
the bloassay data give a collective weight of evidence In the sufficient
category, Group B2.
0115h -31- 08/31/89
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,5. REGULATORY STANDARDS AND CRITERIA
ACGIH (1986a,b) recommends a TWA-TLV for styrene monomer of 50 ppm (~215
mg/m3) and an STEL of 100 ppm (~425 mg/m3) based primarily on the
association of styrene with lymphold or hematopoletlc tumors at 600 and 1000
ppm (290.82 and 484.7 mg/kg/day) In rats In the Jersey et al. (1978) 2-year
Inhalation experiment. OSHA recommended an 8-hour TWA of 100 ppm, an
acceptable celling concentration of 200 ppm (850 mg/m3) and an acceptable
maximum peak of 600 ppm (2560 mg/m3) for <5 minutes In any 3-hour period
(OSHA, 1985).
NAS (1977) derived an ADI of 0.133 mg/kg/day based on the NOAEL of 133
mg/kg/day In the rat gavage study by Wolf et al. (1956). An uncertainty
factor of 1000 was applied and a SNARL of 0.9 mg/l was estimated. U.S.
EPA (1988) derived 1-day HAs for Ingestlon of styrene In drinking water of
22.5 mg/l for a 10 kg child based on a NOAEL of 22.5 mg/kg/day from a
human Inhalation study (Stewart et al., 1968). No data were Identified 1n
the available literature that would be suitable for derivation of a 10-day
HA. It was therefore recommended that the longer-term HA of 20 mg/l for a
child be adopted as the 10-day HA. A lifetime DWEL of 7 mg/l was based on
the NOAEL of 200 mg/kg/day for Hver effects 1n dogs treated by gavage for
560 consecutive days (Quast et al., 1979). An uncertainty factor of 1000
was applied. The same data and uncertainty factor were used by the U.S. EPA
(1984b) to derive an RfD of 0.2 mg/kg/day or 14 mg/day for a 70 kg human.
This RfD Is available on IRIS (U.S. EPA, 1985a).
U.S. EPA (1988) also derived a q^ of 3xlO~2 (mg/kg/day)'1 for
oral exposure to styrene based on the gavage study 1n mice by NCI (1979).
OllSh -32- 07/23/89
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The derivation of this potency factor Is described more completely 1n
Section 6.3. This assessment 1s available on IRIS (U.S. EPA, 1987). In
addition, an Inhalation unit risk of 6xlO~7(vg/m3)~1 based upon the
Jersey et al. (1978) rat Inhalation study Is also described.
OH5h .33. 07/23/89
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
Styrene has been shown to be carcinogenic to laboratory animals by both
oral and Inhalation exposure. RfD<, values, therefore, are not derived.
6.2. REFERENCE DOSE (RfD)
As noted In Chapter 5, recent agency analyses (U.S. EPA, 1984b, 1985a)
have derived an RfD for oral exposure to styrene of 0.2 mg/kg/day or 14
mg/day for a 70 kg human from a NOAEL 1n a 560-day gavage study using dogs
(Quast et a!., 1979). Because styrene has been Identified as a carcinogen,
the RfD value previously derived by U.S. EPA Is not adopted as the RfD for
the purposes of this document. Instead, oral and Inhalation cancer poten-
cies are presented 1n Section 6.3.
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. Ponomarkov and Tomatls (1978) administered styrene by olive
oil gavage to female 0?Q mice, C56B1 mice and BDIV rats once on the 17th
day of gestation and then weekly throughout their offspring's lifetimes. A
statistically significant Increased Incidence and earlier onset of lung
tumors were observed In the 0_n offspring, but the high background tumor
rate (up to 67%) In this strain makes H unsuitable for a potency estimate.
A few rare tumors were observed In the BDIV offspring, but the data are too
sketchy for a reliable potency estimate. In the C57B1 mice, a slight but
Insignificant Increase In Hver carcinomas was observed In treated animals
(3/24). Although this Increase Is not statistically significant when
compared with male vehicle controls (0/12), 1t 1s statistically significant
(p=0.022 calculated from study results using Fisher's Exact Test) when
compared with male untreated controls (0/47) and vehicle controls combined.
OllSh -34- 08/31/89
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Pooling both control groups Is acceptable because there Is no difference
between their tumor responses. Details of this study are summarized 1n
Table 6-1.
NCI (1979) administered styrene at levels of 150 or 300 mg/kg (107.14 or
214.29 mg/kg/day) by corn oil gavage to B6C3F1 mice. Exposure was terminated
after 78 weeks, and the study was terminated after 91 weeks. Statistically
significant Increased Incidences of lung alveolar/bronchlolar adenomas or
carcinomas were observed 1n both exposed groups with a statistically signif-
icant dose-response trend. This study Is summarized In Table 6-2. The
human slope estimate (q,*) from this study Is 3xlO~2 (mg/kg/day). This
slope estimate was chosen 1n both U.S. EPA (1987, 1988) documents to best
characterize the oral carcinogenic potency of styrene. This selection was
based upon the following considerations: that more than one exposure level
was evaluated and that a dose-related trend 1n tumor Incidence was observed.
In addition, the other oral study (Ponomarkov and Tomatls, 1978) utilized a
dosing regimen (one weekly dose) which 1s less appropriate to the prediction
of effects of chronic dally exposure. The Inhalation slope estimates
support the estimate based upon NCI (1979). In this Instance It Is con-
sidered more appropriate to utilize the somewhat stronger study by the route
of Interest rather than attempting to derive a slope estimate based upon
route extrapolation. In conclusion, the q,* (slope) estimate of 3xlO~2
(mg/kg/day)"1 1s proposed as currently the best estimate for the carcino-
genic effects of oral exposure to styrene.
6.3.2. Inhalation. Jersey et al. (1978) observed a small Increase 1n the
Incidence of leukemia and lymphosarcoma In female rats exposed for 20.1
months to styrene at 600 and 1000 ppm (2560 and 4260 mg/m3) (265.1 and
441.8 mg/kg/day) styrene. Incidences were 1/85 (1.18%), 6/85 (7.06%) and
6/85 (7.06%) In concurrent control, low and high groups, respectively.
0115h -35- 08/31/89
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TABLE 6-2'
Cancer Data Sheet for Derivation of q-j*
Compound: styrene
Reference: NCI, 1979
Spec1es/strain/sex: mouse/BCC3F1/male
Route, vehicle: gavage/corn oil
Length of exposure (le) = 91 weeks
Length of experiment (Le) = 78 weeks
Llfespan of animal (L) = 24 months
Body weight = 0.03 kg (assumed)
Tumor site and type: lung alveolar/bronchlolar adenoma/carcinoma
Dose
(mg/kg)
0
150
300
Human q-j* =
Transformed
Animal Dose3
(mg/kg/day)
0
107.1
214.3
3xlO~3 (mg/kg/day)
Human
Equivalent Doseb
(mg/kg/day)
0
8.1
16.2
~i
Incidence
No. Responding/No. Tested
0/20
6/44
9/43
aTWA dose, nominal dose was multlpled by 5 days/7 days and 78 weeks/92
weeks
bBased on surface area approximation animal dose x (WA/WH)I/:}
0115h -37- 07/23/89
-------
The Incidence In either treated group Is not statistically significant when
compared with concurrent controls. When compared with historic controls
(Incidence 11/808, 1.3%), however, the Incidences 1n the treated groups are
statistically significant by the Fisher Exact test (p=0.0033). This
significance reflects the greater statistical power of the larger number of
historic than concurrent controls, rather than a lower Incidence In historic
controls. Because the Incidence In treated rats compared with historic
controls 1s significant, H 1s appropriate to compute a q,* from data In
the Jersey et al. (1978) study. The data used In computation are presented
1n Tables 6-3 and 6-4. Using the multistage model developed by Howe and
Crump (1982), a q^ of 2xlO~3 (mg/kg/day)'1 Is calculated. This
corresponds to a unit risk for air of 6xlO~7 (yg/m3)"1 by assuming a
human ventHatory volume of 20 m3/day, a body weight of 70 kg and complete
absorption. This study (Jersey et al., 1978) may not be appropriate for low
dose extrapolation because of pharmacoklnetlc constraints (U.S. EPA, 1987).
This Issue 1s being evaluated. In the Interim, the slope estimate of
2xlO~3 (mg/kg/day)'1 and the unit risk for air of 6xlO~7
(yg/m3)"1 appear on IRIS (U.S. EPA, 1987).
OllSh -38- 08/31/89
-------
TABLE 6-3
Cancer Data Sheet for Derivation of q-j*
Compound: styrene
Reference: Jersey et a!., 1978
Specles/straln/sex: rat/Sprague-Daw!ey/female
Route, vehicle: Inhalation
Length of exposure (le) = 20.7 months
Length of experiment (Le) = 24 months
Llfespan of animal (L) = 24 months
Body weight = 0.384 kg (control, at end of exposure period)
Tumor site and type: leukemia and lymphosarcoma
Experimental
Doses or Exposure3
0
600 ppmc
1000 ppmd
Human q-|* = 2x1 0~3
Transformed
Animal Doseb
(mg/kg/day)
0
265.1
441.8
(mg/kg/day)'1
Human
Equivalent Dose6
(mg/kg/day)
0
46.75
77.92
Incidence
No. Responding/
No. Tested
1/85
6/85
6/85
Exposures were for 6 hours/day, 5 days/week over a 621-day period:
437/621 days.
transformed doses calculated by expanding to contlnous exposure,
estimating a breathing rate for 0.384 kg rats from the expression [0.105
(body weight/0.113)2'3] and expanding exposure to the full experimental
period (30 hours/week/168 hours/week; 20.7 months/24 months).
cMean measured concentration = 592 ppm (2522 mg/m3)
dHean TWA concentration 1007 ppm (4290 mg/m3) based on 38 days at 1197
ppm and 399 days at 989 ppm.
transformed using a surface area adjustment
0115h -39- 07/23/89
-------
TABLE 6-4
Cancer Data Sheet for Derivation of q-|*
Compound: styrene
Reference: Jersey et al., 1978
Spec1es/strain/sex: rat/Sprague-Dawley/male
Route, vehicle: Inhalation
Length of exposure (le) = 24 months
Length of experiment (Le) = 18.3 months
Llfespan of animal (L) = 24 months
Body weight = 0.565 kg (control, at end of exposure period)
Tumor site and type: leukemia and lymphosarcoma
Experimental
Doses or Exposure3
(ppm)
0
600
1000
Human q-|* = IxlO""3
Transformed
Animal Doseb
(mg/kg/day)
0
180.2
300.3
(mg/kg/day)"1
Human
Equivalent Dosec
(mg/kg/day)
0
36.14
60.23
Incidence
No. Responding/
No. Tested
1/62
5/78
1/78
Exposures were for 6 hours/day, 5 days/week over 549 days out of a
24-month expermental duration.
bBreath1ng rate estimated as [0.105 (0.565 kg/0.113)2/3] and expanding
for continuous exposure by multiplying by 30 hours/week/168 hours/week;
18.3 months/24 months.
transformed using a surface area adjustment
0115h
-40-
07/23/89
-------
7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986a.
Documentation of the Threshold Limit Values and Biological Exposure Indices,
5th ed. Cincinnati, OH. p. 539.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 19865.
TLVs: Threshold Limit Values for Chemical Substance In the Work Environment
Adopted by ACGIH with Intended changes for 1986-1987. Cincinnati, OH.
p. 29.
Agrawal, A.K., S.P. SMvastava and P.K. Seth. 1982. Effect of styrene on
dopamlne receptors. Bull. Environ. Contam. Toxlcol. 29(4): 400-403.
Amacher, D.E. and G.N. Turner. 1982. Mutagenlc evaluation of carcinogens
and noncarclnogens In the L5178Y/TK assay utilizing postmltochondrlal
fractions (S9) from normal rat liver. Mutat. Res. 97(1): 49-65. (Cited 1n
U.S. EPA, 1988)
Andersson, H.C., E.A. Tranberg, A.H. Uggla and G. Zetterberg. 1980.
Chromosomal aberrations and slster-chromatld exchanges In lymphocytes of men
occupationally exposed to styrene In a plastic-boat factory. Mutat. Res.
73(2): 387-402. (Cited 1n U.S. EPA, 1988)
0115h -41- 07/23/89
-------
Anderson, M.E., H.L. Gargas and J.C. Ramsey. 1984. Inhalation pharmaco-
klnetlcs: Evaluating systemic extraction, total In vivo metabolism and the
time course of enzyme Induction for Inhaled styrene In rats based on
arterial blood: Inhaled In concentration ratios. Toxlcol. Appl. Pharmacol.
73: 176-187.
Astrand, I., A. Kllbom, P. Ovrum, I. Wahlberg and 0. Vesterberg. 1974.
Exposure to styrene. I. Concentration In alveolar air and blood at rest and
during exercise and metabolism. Work Environ. Health. 11(2): 69-85.
(Cited 1n U.S. EPA, 1988)
Bauer, C., C. Leporlnl, G. Bronzettl, C. Corsl, R. Nlerl and S. TonarelH.
1980. The problem of negative results for styrene In the j_n vitro mutagene-
sls test with metabolic activation (mlcrosomal assay). 2. Behavior of
epoxlde hydrolase 1n the Incubation mixtures. Boll-Soc. Hal. B1ol. Sper.
56(21): 2200-2205. (Cited In U.S. EPA, 1988)
Belje, B and D. Genssen. 1982. Investigation of styrene 1n the liver
perfuslon/cell culture system. No Indication of styrene 7,8-ox1de as the
principal mutagenlc metabolite produced by the Intact rat liver. Chem.
B1ol. Interact. 39(1): 57-56. (Cited 1n U.S. EPA, 1988)
Bellies, R.P., O.H. Butala, C.R. Stack and S. Makrlss. 1985. Chronic
toxldty and three-generation reproduction study of styrene monomer In the
drinking water of rats. Fund. Appl. Toxlcol. 5: 855-868.
0115h -42- 07/23/89
-------
Block, 3.B. 1976. A Kentucky Study: 1950-1975. in: Proceedings of NIOSH
Styrene-Butadlene Briefing. HEW Publ. No. 77-129. U.S. DHEW, Cincinnati,
OH.
Busk, L. 1979. Mutagenlc effects of styrene and styrene oxide. Mutat.
Res. 67(3): 201-208. (Cited In U.S. EPA, 1988)
CamurM, L., S. Codeluppl, C. Pedronl and L. Scarduelll. 1983. Chromosomal
aberrations and slster-chromatld exchanges In workers exposed to styrene.
Mutat. Res. 119(3-4): 361-367. (Cited In U.S. EPA, 1988)
Conner, M.K., Y. Alarle and R.L. Dombroske. 1979. Sister chromatld
exchange In regenerating liver and bone marrow cells of mice exposed to
styrene. Toxlcol. Appl. Pharmacol. 50(2): 365-367. (CHed In U.S. EPA,
1988)
Conner, M.K., Y. Alarle and R.L. Dombroske. 1980. Sister chromatld
exchange 1n murlne alveolar macrophages, bone marrow, and regenerating liver
cells Induced by styrene Inhalation. Toxlcol. Appl. Pharmacol. 55(1):
37-42. (CHed 1n U.S. EPA, 1988)
Conner, M.K., Y. Alarle and R.L. Dombroske. 1982. Multiple tissue compari-
sons of sister chromatld exchanges Induced by Inhaled styrene. Environ.
Sc1. Res. 24: 433-441. (CHed In U.S. EPA, 1988)
De Flora, S. 1981. Study of 106 organic and Inorganic compounds 1n the
Salmonella/mlcrosome test. Cardnogenesls. 2: 283-298. (Cited in U.S.
EPA, 1985a)
0115h -43- 07/23/89
-------
De Meester, C., F. Poncelet, M. Roberfrold, 0. Rondelet and M. Merder.
1977. MutagenlcHy of styrene and styrene oxide. Mutat. Res. 56(2):
147-152. (Cited In U.S. EPA, 1988)
De Meester, C., M. Duverger-Van Bogaert, M. Lambotte-Vandepaer, M. Mercler
and F. Poncelet. 1981. MutagenlcHy of styrene In the Salmonella typhl-
murlum test system. Mutat. Res. 90(4): 443-450. (Cited 1n U.S. EPA, 1988)
de Raat, W.K. 1978. Induction of sister chromatld exchanges by styrene and
Us presumed metabolite styrene oxide In the presence of rat liver homogen-
ate. Chem.-B1ol. Interact. 20(2): 163-170. (Cited In U.S EPA, 1988)
Donner, M., M. Sorsa and H. Valnlo. 1979. Recessive lethals Induced by
styrene and styrene oxide 1n Drosophlla melanoqaster. Mutat. Res. 67(4):
373-376. (Cited 1n U.S. EPA, 1988)
Drlnkwater, N.R., 3.A. Miller, E.C. Miller and N.C. Yang. 1978. Covalent
Intercalatlve binding to ONA 1n relation to the mutagenlclty of hydrocarbon
epoxldes and N-acetoxy-2-acetylamlnofluorene. Cancer Res. 38(10):
3247-3255. (Cited In U.S. EPA, 1988)
Engstrom, J., R. Bjurstrom, I. Astrand and P. Ovrum. 1978. Uptake, distri-
bution and elimination of styrene In man. Concentration In subcutaneous
adipose tissue. Scand. J. Work Environ. Health. 4(4): 315-323.
Fabry, L., A. Leonard and M. Roberfrold. 1978. MutagenlcHy tests with
styrene oxide In mammals. Mutat. Res. 51(3): 377-381. (Cited 1n U.S. EPA,
1988)
0115h -44- 07/23/89
-------
Flelg, I. and A.M. Thelss. 1978. MutagenlcHy study of workers employed 1n
the styrene and polystyrene processing and manufacturing Industry. Scand.
J. Work Environ. Health. 4 (Suppl.2): 254-258.. (Cited In U.S. EPA, 1988)
Frentzel-Beyme, R., A.M. Thless and R. Wleland. 1978. Survey of mortality
among employees engaged In the manufacture of styrene and polystyrene at the
BASF Ludwlgshafen works. Scand. J. Work. Environ. Health. 4(suppl.2):
231-239.
Glatt, H.R., F. Oesch, A. Frlgerlo and S. Garatt1n1. 1975. Epoxldes
metabollcally produced from some known carcinogens and from some clinically
used drugs. I. Differences 1n mutagenldty. Int. J. Cancer. 16: 787-797.
(Cited In U.S. EPA, 1988)
Hansch, C. and A.J. Leo. 1985. Medchem Project Issue #26. Pomona College,
Claremont, CA.
Hardell, L., M. Eriksson, P. Lenner and E. Lundgren. 1981. Malignant
lymphoma and exposure to chemicals, especially organic solvents, chloro-
phenols and phenoxy acids: A case-control study. Br. J. Cancer. 43(2):
169-176.
Harkonen, H. and P.C. Holmberg. 1982. Obstetric histories of women occupa-
tlonally exposed to styrene. Scand. J. Work Environ. Health. 8(1): 74-77.
Hemmlnkl, K., E. Fransslla and H. Valnlo. 1980. Spontaneous abortion among
female chemical workers In Finland. Int. Arch. Occup. Environ. Health. 45:
123-126.
OllSh -45- 07/23/89
-------
Hodgson, J.T. and R.D. Jones. 1985. Mortality of styrene production,
polymerization and processing workers at a site 1n northwest England. Scan.
J. Work Environ. Health. 11: 347-352,
Hogstedt, B., K. Hedner, E. Mark-Vendel, F. MHelman, A. Schuetz and S.
Skerfvlng. 1979. Increased frequency of chromosome aberrations In workers
exposed to styrene. Scand. J. Work Environ. Health. 5: 333-335. (CHed In
U.S. EPA, 1988)
Holmberg, P.C. 1977. Central nervous defects In two children of mothers
exposed to chemicals In the Reinforced Plastics Industry. Scand. J. Work
Environ. Health. 3: 212-214.
Howe, R.B. and K.S. Crump. 1982. GLOBAL 82, a Computer Program to Extrapo-
late Quantal Animal Toxlclty Data to Low Doses. Prepared for Office of
Carcinogen Standards, OSHA, U.S. Dept. of Labor under Contract No.
41USC252C3.
IARC (International Agency for Research on Cancer). 1979. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Hurnans. Some
Monomers, Plastics and Synthetic Elastomers and Acroleln: Styrene, Poly-
styrene and Styrene-Butadlene Copolymers. 19: 231-274.
Ikeda, M. and T. Hlrayama. 1978. Possible metabolic Interaction of styrene
with organic solvents. Scand. 3. Work Environ. Health. 4(2): 41-46.
0115h -46- 07/23/89
-------
Ikeda, M., H. Ohtsujl and T. Imamura. 1972. In vivo suppression of benzene
and styrene oxidation by coadmlnlstered toluene In rats and effects of
phenobarbHal. Xenoblotlca. 2(2): 101-106.
Ishldate, M. and K. Yoshlkawa. 1980. Chromosome aberration tests with
Chinese hamster cells In vitro with and without metabolic activation: A
comparative study 1n mutagens and carcinogens. ITK Further Studies In the
Assessment of Toxic Actions. Arch. Toxlcol. Suppl* 4: 41-44. (CHed 1n
U.S. EPA, 1988)
Jersey, G., M. Balmer, 3. Quast, et al. 1978. Two-year Chronic Inhalation
Toxlclty and Cardnogenldty Study on Monomerlc Styrene 1n Rats. Dow Chemi-
cal Study for Manufacturing Chemists Association. December 6.
Kankaanpaa, J.T., E. Elovaara, K. Hemmlnkl and H. Varnlo. 1980. The effect
of maternally Inhaled styrene on embryonal and fetal development 1n mice and
Chinese hamsters. Acta. Pharmacol. Toxlcol. 47: 127-129.
Kotln, P. and H.L. Falk. 1963. Organic peroxides, hydrogen peroxide,
epoxldes and neoplasla. Radiation Res. (Supp.) 3: 193-211.
Lemen, R.A. and R. Young. 1976. Investigations of health hazards In
styrene butadiene rubber facilities. IJK Processings of NIOSH Styrene-
Butadlene Briefing. HEW Publ. No. 77-129. U.S. DHEW, Cincinnati, OH.
Lljlnsky, W. n.d. Chronic studies In rodents of vinyl acetate and
compounds related to acroleln. Unpublished data sponsored by NCI, DHHS
Contract No. N01-CO-23909 to LHton B1onet1cs, Inc.
OllSh -47- 07/23/89
-------
L1nna1nmaa, K., T. Meretoja, M. Sorsa and H. Valnlo. 1978a. Cytogenetlc
effects of styrene and styrene oxide on human lymphocytes and A'111 urn cepa.
Scand. J. Work Environ. Health. 4(Suppl.2): 156-162. (CHed 1n U.S. EPA,
1988)
Llnnalnmaa, K., T. Meretoja, M. Sorsa and H. Valnlo. 1978b. Cytogenetlc
effects of styrene and styrene oxide. Mutat. Res. 58: 277-286. (CHed In
U.S. EPA, 1988)
LopMeno, N., A. Abbondandolo, R. Barale, et al. 1976. Mutagenlclty of
Industrial compounds: Styrene and Us possible metabolite styrene oxide.
Mutat. Res. 40(4): 317-324. (Cited In U.S. EPA, 1988)
Loprleno, N., S. Prescu1tt1n1 and I. Shrana. 1978. Mutagenlclty of Indus-
trial compounds and ONA repair Induction analyses. Scand. 3. Work Environ.
Health. 4(Suppl.2): 169-178. (Cited In U.S. EPA, 1988)
Maltonl, C., G. Fallla and G. Kassapldls. 1979. First experimental demon-
stration of the carcinogenic effects of styrene oxide: Long-term bloassays
on Sprague-Dawley rats by oral administration. Med. Lav. 70(5): 358-362.
(Cited In U.S. EPA, 1988)
Maltonl, C., A. C1lbert1 and D. Carr1ett1. 1982. Experimental contribu-
tions In Identifying brain potential carcinogens 1n the petrochemical
Industry. Ann. NY Acad. Scl. 381: 216-249.
OllSh -48- 07/23/89
-------
Matsuoka, A., M. Hayashl and M. Ishldate, Jr. 1979. Chromosomal aberration
tests on 29 chemicals combined with S9 mix In vitro. Mutat. Res. 66(3):
277-Z90. (Cited In U.S. EPA, 1988)
McGregor, D.B. 1981. Report Number 29, Tier II mutagenlc screening of 13.
NIOSH priority compounds. Individual compounds report: Styrene oxide.
Prepared for the National for Occupational Safety and Health, Cincinnati,
OH. NTIS PB83-130203. (Cited In U.S. EPA, 1988)
HcMlchael, A.J., R. Splrtas, J.F. Gamble and P.M. Tousey. 1976. Mortality
among rubber workers: Relationship to specific jobs. J. Occup. Med. 18:
178-185.
Melnhardt, T., R. Young and R. Hartle. 1978. Ep1dem1olog1c Investigations
of styrene-butadlene rubber production and reinforced plastics production.
Scand. J. Work Environ. Health. 4(Suppl.2): 240-246.
Melnhardt, T.J., R.A. Lemen, M.S. Crandall and R.J. Young. 1982. Environ-
mental epidemlologic Investigation of the styrene-butadlene rubber Industry.
Mortality patterns with discussion of the hematopoletlc and lymphatic
malignancies. Scand. J. Work Environ. Health. 8(4): 250-259.
Meretoja, T., H. Vainlo, M. Sorsa and H. Harkonen. 1977. Occupational
styrene exposure and chromosomal aberrations. Mutat. Res. 56(2): 193-197.
(Cited 1n U.S. EPA, 1988)
0115h -49- 07/23/89
-------
Meretoja, T., H. Valnlo and H. Jarventaus. 1978a. Blastogenlc effects of
styrene exposure on bone marrow cells of rats. Toxlcol. Lett. 1(5-6):
815-818. (CHed In U.S. EPA, 1988)
Meretoja, T., H. Jaervantaus, M. Sorsa and H. Valnlo. 1978b. Chromosome
aberrations 1n lymphocytes of workers exposed to styrene. Scand. J. Work
Environ. Health. 4(Suppl.2): 259-264. (CHed 1n U.S. EPA, 1988)
M1lvy, P. and A.J. Garro. 1976. Mutagenlc activity of styrene oxide
(1,2-epoxyethylbenzene) a presumed styrene metabolite. Hutat. Res. 40(1):
15-18. (CHed 1n U.S. EPA, 1988)
Murray, F.J., J.A. John, H.O. Haberstroh, et al. 1976. Teratologlc evalua-
tion of styrene monomers administered to rats by gavage. Dow Chemical Study
for Manufacturing Chemists Association. August 26.
Hurray, F.J., J.A. Jon, M.F. Balmer and B.A. Schwetz. 1978a. Teratologlc
evaluation of styrene given to rats and rabbits by Inhalation or by gavage.
Toxicology. 11(4): 335-343.
Murray, F.J., J.A. Bonn, F.A. Smith, et al. 1978b. Teratologlc evaluation
of Inhaled styrene monomer 1n rats and rabbits. Dow Chemical Study for
Manufacturing Chemists Association. January 30.
Nakajlma, T., Y. Koyama and A. Sato. 1982. Dietary modifications of
metabolism and toxiclty of chemical substances, with special reference to
carbohydrate. Blochem. Pharmacol. 31(6): 1005-1011.
OllSh -50- 07/23/89
-------
NAS (National Academy of Science). 1977. Drinking Water and Health.
Washington, DC. p. 763-765, 836-856.
NCI (National Cancer Institute). 1979. National Cancer Institute Carclno-
genesls Technical Report Series, No. 185: Bloassay of Styrene for Possible
Carclnogenldty. Litton Blonetlcs, Inc., Kensington, MD.
Nicholson, W., I. Sellkoff and H. Seldman. 1978. Mortality experience of
styrene-polystyrene polymerization workers: Initial findings. Scand. 0.
Work Environ. Health. 4(Suppl.2): 247-252.
NLM (National Library of Medicine). 1986. Hazardous Substance Databank
Record #171. On-Hne.
Norppa, H., E. Elovaara, K. Husgafvel-Purslalnen, et al. 1979. Effects of
styrene oxide on chromosome aberrations, sister chromatld exchange and
hepatic drug blotransformatlon In Chinese hamsters JMI vivo. Chem.-Blol.
Interact. 26(3): 305-315. (Cited In U.S. EPA, 1988)
Norppa, H., M. Sorga, P. Pfaeffll and H. Valnlo. 1980a. Styrene and
styrene oxide Induce SCEs and are metabolized In human lymphocyte cultures.
Carclnogenesls. 1(4): 357-361. (Cited 1n U.S. EPA, 1988)
Norppa, H., M. Sorsa and H. Valnlo. 1980b. Chromosomal aberrations In bone
marrow of Chinese hamsters exposed to styrene and ethanol. Toxlcol. Lett.
5(3-4): 241-244. (Cited In U.S. EPA, 1988)
0115h -51- 07/23/89
-------
Norppa, H., H. Va1n1o and M. Sorsa. 1981. Chromosome aberrations \n
lymphocytes of workers exposed to styrene. Am. J. Ind. Med. 2(3): 299-304.
(Cited In U.S. EPA, 1988)
NTP (National Toxicology Program). 1986. Toxicology Research and Testing
Program. Management Status Report 6/10/86.
OSHA (Occupational Safety and Health Administration). 1985. Occupational
Standards. Code of Federal Regulations 29 CFR 1910.1000.
Ott, M.G., R.C. Kolesar, H.C. Scharnweber, E.J. Schneider and J.R. Venable.
1980. A mortality survey of employees engaged In the development of manu-
facture of styrene-based products. 0. Occup. Med. 22(7): 445-460.
Plotnick, H.B. and W.W. Welgel. 1979. Tissue distribution and excretion of
14C-styrene In male and female rats. Res. Commun. Chem. Pathol.
Pharmacol. 24(3): 515-524.
Poncelet, F., C. Oe Meester, M. Duverger-Van Bogaert, M. Lambotte-Vandepaer,
M. Roberfroid and M. Herder. 1980. Influence of experimental factors on
the mutagenlcHy of vlnyllc monomers. Arch. Toxlcol. 4: 63-66. (CHed In
U.S. EPA, 1988)
Ponomarkov, V.I. and L. Tomatls. 1978. Effects of long-term oral adminis-
tration of styrene to mice and rats. Scand. 3. Work. Environ. Health.
4(Suppl.l): 127-135.
0115h -52- 07/23/89
-------
Quast, J.F., R.P. Kalnlns, K.J. Olson, et al. 1978. Results of a toxldty
study In dogs and teratogenlcHy studies 1n rabbits and rats administered
monomerlc styrene. Toxlcol. Appl. Pharmacol. 45: 293-294.
Quast, J.F., C.G. Humlston, R.V. Kalvlns et al. 1979. Results of a
toxldty study of monomerlc styrene administered to beagle dogs by oral
Intubation for 19 months. Toxicology Research Laboratory, Health and
Environmental Services, Dow Chemical Co., Midland, MI. Final report.
Ragule, N. 1974. Embryotoxlc action of styrene. G1g. 1 SanH. 1: 85-86.
(CA 82:81357q)
Ramsey, J.C., J.D. Young, R.J. Karbowskl, M.B. Chenoweth, L.P. McCarty and
W.H. Braun. 1980. Pharmacoklnetlcs of Inhaled sytrene 1n human volunteers.
Toxlcol. Appl. Pharmacol. 53(1): 54-63.
Sato, A., T. Nakajlma and Y. Koyama. 1980. Effects of chronic ethanol
consumption on hepatic metabolism of aromatic and chlorinated hydrocarbons
1n rats. Br. J. Ind. Med. 37(4): 382-386.
Sato, A., T. Nakajlm and Y. Koyama. 1981. Dose-related effects of a single
dose of ethanol on the metabolism In rat liver of some aromatic and chlori-
nated hydrocarbons. Toxlcol. Appl. Pharmacol. 60(1): 8-15.
Sauerhoff, M.W., E.O. Madrid and W.H. Braun. 1976. The Fate of Orally
Administered Styrene In Rats. Toxicology Research Laboratory, Health and
Environmental Research, Dow Chemical U.S.A., Midland, MI.
0115h -53- 07/23/89
-------
Savolalnen, H. and P. Pfaffll. 1977. Effects of chronic styrene Inhalation
on rat brain metabolism. Acta Neuropathol. 40(3): 237-241.
Savolalnen, H., M. Helojokl and M. Tengen-Junnlla. 1980. Behavioral and
gllal cell effects of Inhalation exposure to styrene vapor with special
reference to Interactions of simultaneous peroral ethanol Intake. Acta.
Pharmacol. Toxlcol. 46: 51-56.
Seppalalnen, A.M. 1978. Neurotoxlclty of styrene In occupational and
experimental exposure. Scand. J. Work Environ. Health. 4(Suppl.2): 181-183.
Simmon, V.F., K. Kauhanen and R.G. Tardlff. 1977. Mutagenlc activity of
chemicals Identified In drinking water. Dev. Toxlcol. Environ. Sc1. 2:
249-258. (Cited 1n U.S. EPA, 1988)
Spencer, H.C.-, D.D. Irish, E.M. Adams and V.K. Rowe. 1942. The response of
laboratory animals to monomerlc styrene. J. Ind. Hyg. Toxlcol. 24(10):
295-301. (Cited In U.S. EPA, 1988)
Srlvastava, S.P., M. Das, M. Mushtaq, S.V. Chandra and P.K. Seth. 1982.
Hepatic effects of orally administered styrene In rats. J. Appl. Toxlcol.
2(4): 219-222.
Stewart, R.D., H.C Dodd, E.G. Baretta and A.W. Schaffer. 1968. Human
exposure to styrene vapor. Arch. Environ. Health. 16(5): 656-662.
0115h -54- 07/23/89
-------
Stoltz, O.R. and R.G. WHhey. 1977. Mutagenlclty testing of styrene and
styrene oxide 1n Salmonella typhlmuMum. Bull. Environ. Contam. Toxlcol.
17(6): 739-742. (Cited In U.S. EPA, 1988)
Suglura, K., A. Maeda and M. Goto. 1979. SubstUutlonal effects of styrene
oxides on survival and mutation Induction In cultured Chines hamster cells
(V-79)+. Chemosphere. 8(6): 369-372. (Cited In U.S. EPA, 1988)
Thless, A.M., H. Schwegler and I. Flelg. 1980. Chromosome Investigations
In lymphocytes of workers employed 1n areas In which styrene-contalnlng
unsaturated polyester resins are manufactured. Am. J. Ind. Hed. 1(2):
205-210. (Cited 1n U.S. EPA, 1988)
U.S. EPA. 1980. Guidelines and Methodology Used 1n the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
U.S. EPA. 1984a. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Tox1c1ty Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1984b. Health and Environmental Effects Profile for Styrene.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid
Waste, Washington, DC. EPA/600/X-84/325. NTIS PB88-182175.
0115h -55- 08/31/89
-------
U.S. EPA. 1985a. Integrated Risk Information System (IRIS). Reference
dose (RfO) for oral exposure for Styrene. Online. (Verification date
10/09/85.) Prepared by the Office of Health and Environmental Assess- ment,
Environmental Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1985b. Reportable Quantity Document for Styrene. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH for the Office of Emergency and
Remedial Response, Washington, DC.
U.S. EPA. 1987. Integrated Risk Information System (IRIS). Cardno-
genldty Assessment for Lifetime Exposure to Styrene. Online: Input
pending. (Verification date 11/09/87.) Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH.
U.S. EPA. 1988. Drinking Water Criteria Document for Styrene. Prepared by
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Drinking Water,
Washington, DC.
Valnlo, H., R. Paakkonen, K. Ronnholm, V. Raunlo and 0. Pelkonen. 1976. A
study on the mutagenlc activity of styrene and styrene oxide. Scand. J.
Work Environ. Health. 3: 147-151. (Cited 1n U.S. EPA, 1988)
Valnlo, H., J. Jarvlsalo and E. Tasklnen. 1979. Adaptive changes caused by
Intermittent styrene Inhibition on xenoblotlc blotransformatlon. Toxlcol.
Appl. Pharmacol. 49(1): 7-14. (CUed 1n U.S. EPA, 1988)
0115h -56- 08/31/89
-------
Van Duuren, B.L., N. Nelson, L. Orris, E.D. Palmes and F.L. Schmltt. 1963.
CarclnogenlcHy of epoxldes, lactones and peroxy compounds. J. Natl. Cancer
Inst. p. 41-55.
Watanabe, T., A. Endo, K. Sato, et al. 1981. Mutagenlc potential of
styrene 1n man. Ind. Health. 19(1): 37-45. (Cited 1n U.S. EPA, 1988)
Well, C.S., N. Condra, C. Haun and J.A. Strlegel. 1963. Experimental
cardnogenlclty and acute toxlclty of representative epoxldes. Am. Ind.
Hyg. Assoc. 3. 24: 305-325.
WHO (World Health Organization). 1983. Styrene Environmental Health
Criteria 26. IPCS International Programs on Chemical Safety. WHO, Geneva,
Switzerland.
Wlgaeus, E., A. Lof, R. Bjurstrom, M.B. Nordqvlst. 1983. Exposure to
styrene: Uptake, distribution, metabolisms and eliminations 1n man. Scand.
0. Work. Environ. Health. 9: 479-488.
Wilson, J.T., G.F. McNabb, R.H. Wilson and M.J. Moonan. 1983. Blotrans-
formatlon of selected organic pollutants In groundwater. Devel. Ind.
M1crob1ol. 24: 225-233.
WHhey, J.R. 1976. Quantitative analysis of styrene monomer In polystyrene
and foods Including some preliminary studies of the uptake and pharmaco-
dynamlcs of the monomer In rats. Environ. Health Perspect. 17: 125-133.
0115h -57- 07/23/89
-------
Wolf, M.A., V.K. Rowe, D.D. McColllster, R.L. HolUngsworth and F. Oyen.
1956. Tox1colog1cal studies of certain alkylated benzenes and benzene.
Arch. Ind. Health. 14: 387-398.
Zoeteman, B.C.J., K. Harmsen, J.B.H.J. Llnders, C.F.H. Morra and W. Slooff.
1980. Persistent organic pollutants In river water and groundwater of The
Netherlands. Chemosphere. 9: 231-249*
0115h -58- 07/23/89
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