Styrene has not been previously evaluated for an acceptable daily
    intake for man by the Joint FAO/WHO Expert Committee on Food


         Styrene is also known as ethenylbenzene, vinylbenzene,
    vinylbenzol, styrolene, styrol, styropol, styropor, styrone,
    cinnamene, cinnamol, phenethylene, phenylethylene and phenylethane. It
    is a colourless, viscous liquid with a melting point of -30.6°C and a
    boiling point of 145.2°C. It is insoluble in water, soluble in
    ethanol, ether and acetone and very soluble in benzene and petroleum
    ether. Its uses include intermediate in the manufacture of plastics,
    elastomers and resins which in turn are used in packaging foods, food
    products and various other processes in the food industry. It is also
    used as a synthetic flavouring substance and adjuvant.



    Absorption, distribution and excretion

         Studies with laboratory animals have shown that styrene is
    readily absorbed from the gastrointestinal tract following oral
    administration (Plotnick & Weigel, 1979; Sauerhoff et al., 1976).

         The distribution and excretion of a single oral dose of 20 mg
    14C-styrene/kg b.w. was studied in male and female Charles-River
    rats. The peak tissue levels occurred four hours after administration,
    with the kidneys exhibiting the highest concentration of 14C per unit
    weight, followed by the liver and pancreas. The primary route of
    elimination was via urinary excretion with 90% of the dosage detected
    in the urine within 24 hours, while less than 2% was detected in the
    feces (Plotnick & Weigel, 1979).

         The disposition of orally administered styrene was studied in
    mature Sprague-Dawley rats (Spartan substrain) in which doses of 50 or
    500 mg/kg 14C-styrene were administered via gavage. Approximately 95
    and 90% of the 50 and 500 mg/kg b.w. doses, respectively, were
    eliminated in the urine as styrene metabolites. The pulmonary route of
    elimination accounted for 1.3% of the lower dosage and 8.9% of the
    higher dosage. There was a distinct sex difference in the pulmonary
    elimination of styrene with males expiring twice as much styrene as
    the females. The fecal route of elimination accounted for only about
    4% of the administered dose (Sauerhoff et al., 1976).


         A number of metabolic studies in laboratory animals which have
    utilized a variety of routes of administration have shown that styrene
    is metabolized by the mixed function oxidase (MFO) system to
    styrene-7, 8-oxide, and that this occurs not only in the liver but in
    a number of other tissue types and organs (Leibman & Ortiz, 1970;
    Salmona et al., 1976; Cantoni et al., 1978). The metabolic activation
    by the microsomal system depends on the presence of necessary
    cofactors for a NADPH generating system and oxygen (Kappus et al.,
    1971; Bartsch et al., 1975; Salmona et al, 1976). The oxide can be
    metabolized further to styrene glycol by the action of epoxide
    hydrolase (Leibman & Ortiz, 1969 and 1970; Ryan & Bend, 1977).
    Generally the greatest activity for the MFO and hydrolase have been
    detected in the liver with the activity of the latter being greater
    than that of the former (Cantoni et al., 1978). The glycol in turn can
    be converted to mandelic acid, phenylglyoxylic acid and finally to
    hippuric acid or it can be conjugated to glucuronic acid (Ryan & Bend,
    1977; El Masri et al., 1958; Sauerhoff et al., 1976; James & White,
    1967; Ikeda et al., 1974; Astrand et al., 1974; Gotell et al., 1972).
    The oxide can also be conjugated with glutathione to form three
    mercapturic acid   derivatives, N-acetyl-s-(1-phenyl-2-hydroxyethyl)
    cysteine and N-acetyl-s-(phenylacetyl) cysteine. Other metabolites
    which have been identified include mercapturic acids, benzoic acid,
    4-vinylphenol,  2-phenylethanol, phenaceturic acid and phenylglycol
    all of which may be excreted as conjugates of glucuronic acid or
    glutathione (Sauerhoff et al., 1976; Bakke & Scheline, 1970;
    Delbrassine et al., 1981; El Masri et al., 1958). Studies in rats have
    shown that the opening of the epoxide ring of styrene by glutathione
    5-transferase is stereospecific with a preference for the R-isomer
    (Delbrassine et al., 1981).

         There has also been evidence generated that styrene is converted
    to an arene oxide, since an intermediate, styrene-3,4-oxide, undergoes
    isomerization to 4-vinylphenol which has been isolated in the urine of
    both animals and men who have been exposed to styrene (Pantarotto et
    al., 1978; Bakke & Scheline, 1970; Pfäffli et al., 1981; James &
    White, 1967; Pachecka et al., 1979). However, this route of metabolism
    is considered to be a minor one, since much more mandelic acid is
    detected in the urine as compared to the 4-vinylphenol.

         In vitro preparations of human erythrocytes and lymphocytes
    have been shown to catalyze the oxidation of styrene to styrene oxide.
    This reaction is inhibited by the presence of CO, but not by
    superoxide dismutase, catalase and scavengers of hydroxyl radicals,
    and it required the presence of oxygen. These data indicate that
    oxyhemoglobin and not free oxygen radicals can be involved in styrene
    oxidation (Tursi et al, 1983; Belvedere & Tursi, 1981).


    Special studies on carcinogenicity

         Carcinogenicity data on styrene and styrene oxide were reviewed
    by the International Agency for Research on Cancer (IARC) in 1979.


         A lifetime study following in utero exposure was conducted with
    C57B1 black mice. Fifteen dams were administered a single dose of
    300 mg of styrene/kg b.w. dissolved in olive oil via intubation on the
    17th day of gestation. A vehicle (olive oil) treated group of 57 males
    and 49 females served as a control group. Styrene was then given
    weekly at the same dose level and via the same route to 27 male and 27
    female offspring from weaning up to 120 weeks of age. A group of 12
    males and 13 females which were the offspring of five dams treated
    with olive oil on the 17th day of gestation received olive oil on a
    weekly basis after weaning. The incidence of neonatal mortality of the
    styrene-treated group was 35%. In the parental generation lymphomas
    were noted in 10 of 12 styrene-treated animals as compared to 3 of 5
    of the vehicle treated animals.  In the male progeny hepatocellular
    carcinomas were found in 3 of 4 animals. This compares to an occurence
    of 1 to 12 of vehicle-treated controls and 1 of 47 untreated controls
    (P>0.05). The incidences of all other tumor-types were similar in the
    styrene-treated and control animals (Ponomarkov & Tomatis, 1978).

         A group of 29 pregnant O20 mice received a single dose of
    1350 mg/kg b.w. of styrene by gavage (dissolved in olive oil) on the
    17th day of gestation, while a control group received olive oil alone.
    This same dosage of styrene was administered to the offspring
    (39 females and 45 males) from weaning to 16 weeks of age. Treatment
    was terminated at this point because of excessive mortality. The most
    frequently observed lesions in the styrene-treated offspring which
    expired before the twentieth week were multiple centrilobular necrosis
    of the liver, hypoplasia of the spleen and severe congestion of
    the lungs. In those animals that expired after the forty-fifth
    week multiple abscess-like cavities in the liver filled with
    polymorphonuclear leukocytes were noted. The study was terminated when
    the last animal had expired at 100 weeks.  There were no differences
    in tumor incidences between the dams treated with styrene and those
    treated with olive oil.  In the progeny pulmonary adenomas and

    adenoearcinomas were noted in 20/23 males and 32/32 females treated
    with styrene and in 8/19 males and 14/21 females in these animals
    treated with olive oil alone (P>0.01, P<0.01). However, in untreated
    controls 34/53 males and 25/42 females were found to also have
    pulmonary adenomas and adenocarcinomas (P<0.05, P<0.01). The average
    age at death of the pulmonary tumor-bearing, styrene-treated mice was
    32 and 49 weeks for the males and females, respectively. In contrast,
    the olive oil-treated males and females exhibited an average age of 88
    and 85 weeks, while the average age of mortality of the untreated
    control males and females was 94 and 99 weeks, respectively. No other
    differences in tumor incidences were noted between the various groups
    (Ponomarkov & Tomatis, 1978).

         Groups of 50 male and 50 female B6C3F1 mice were dosed daily by
    gavage five days per week with styrene dissolved in corn oil at dose
    levels equivalent to 150 and 300 mg/kg b.w. Treatment was for 78 weeks
    and was followed by a 13 week observation period. A group of 20
    animals of each sex served as a vehicle corn oil control group. In the
    males, but not females, there was a significant positive relationship
    between mortality and dosage. A slight, dose-related mean body weight
    depression was noted in the females, but not the males, while no other
    clinical annormalities were noted. There were adequate numbers of both
    males and females at risk for late-developing tumors. In the low
    dosage group 92 percent (46/50) and 80 percent (40/50) of the males
    and females, respectively, survived on test until the termination of
    the study. The percentages of survival for the high dosage group was
    78 and 76 for the males and females, respectively, and for the
    controls 100 and 90 percent for the respective sexes.

         During the course of the study, five low dose females were found
    missing. A variety of neoplastic lesions were found in both the
    styrene-treated and control animals, however, with the exception of
    pulmonary tumors, the incidences neoplastic lesions were unrelated to
    the administration of styrene. There was a significant increase in the
    incidence of a combination of pulmonary adenomas and carcinomas in the
    styrene-treated male mice with 0/20, 6/45 and 9/49 of the control, low
    dosage and high dosage animals demonstrating these lesions (P = 0.024
    for Fischer exact test comparing high dose and control). However, a
    definitive conclusion on the carcinogenicity of styrene could not be
    drawn because of the high variability of the incidence of these
    neoplasia in historical control mice at the laboratory which performed
    the study. The historical incidence of the combination of alveolar/
    bronchiolar adenomas and aleolar/bronchiolar carcinomas in male mice
    in this laboratory is 12 percent (32/271). The authors concluded that
    there was no convincing evidence for carcinogenicity of styrene in the
    mouse study. (National Cancer Institute, 1978)


         A group of 21 BD IV rats were given 1350 mg of styrene/kg b.w.
    in olive oil orally on the 17th day of gestation. Their offspring (73
    males and 71 females) then received 500 mg/kg b.w. styrene weekly from
    weaning for 120 weeks. Ten dams and their offsprings (36 males and 39
    females) received olive oil and served as controls. The average litter
    sizes of the different groups were similar. The mortality of the
    offspring of styrene-treated dams (10%) was greater than that of
    the controls (2.5%), but not significantly. There was no evidence
    of a difference in body weight gain and survival between the
    styrene-treated and control offspring. The incidence of survival were
    8/73 and 20/71 of the male and female, styrene-treated animals and
    14/36 and 18/39 male and female control animals. The incidence of
    tumor-bearing dams was greater in the styrene-treated group than
    the control group, but the difference was not significant. Three
    neurogenic and three stomach tumors were observed in the
    styrene-treated progeny that were not observed in the controls
    (Ponomarkov & Tomatis, 1978).

         A study was carried out with Fischer 344 rats in which groups of
    50 males and 50 females were administered styrene dissolved in corn
    oil five days per week by gavage at doses equivalent to 500, 1000 and
    2000 mg/kg b.w. Treatment was for 103 weeks for the low dosage group
    and 78 weeks for the medium and high dosage groups. This was followed
    by an observation period of one week for the low dosage groups and
    twenty-seven weeks for the medium and high dosage groups. A group of
    40 animals of each sex served as vehicle controls (corn oil). The
    highest dosage resulted in a significantly earlier and higher
    mortality in both sexes, wherein, an additional dosed group of each
    sex was included in the bioassay. The survival of the other dosage
    groups were not adversely affected by styrene administration. By week
    53 only 12 percent (6/50) of the males had survived, while only 14
    percent (7/50) of the females had survived by week 70. The survival
    incidences for the other groups were 88 percent (44/59), 94 percent
    (47/50) for the low and medium dose males and 92 percent (46/50) for
    the low and medium dose females. The various control groups
    demonstrated survival incidences which varied from 85 to 90 percent
    and 75 to 90 percent for the male and female controls. Adequate
    numbers of animals were at risk in the low and medium dosage groups
    from late-developing tumors. A dose-related reduction in the mean body
    weight was observed in the treated males, however, the relevance of
    this observation is questionable considering the decreased survival in
    the high dosage group. No other compound-related clinical signs were
    observed. None of the statistical tests for any site of tumors in rats
    of either sex showed a significant positive association between the
    administration of styrene and an increased tumor incidence (National
    Cancer Institute, 1978).

         In a two-year study in Sprague-Dawley rats styrene was
    administered in the drinking water at intended concentrations of
    125 and 250 ppm which resulted in approximate intakes of 7.7 and
    14 mg/kg b.w./day for the males and 12 and 21 mg/kg b.w./day for the
    females. Each treatment group was initially comprised of 50 males and
    70 females, and a group of 76 males and 106 females served as
    controls. The following parameters were assessed during the course of
    the study; body weight gain, food and water intake, hemograms,
    clinical chemistry, urinanalysis, clinical signs, mortality and gross
    necropsy and histological examination at interim and terminal
    sacrifices and of those animals which died during the course of the
    study or were sacrificed in a moribund condition. Styrene did not
    produce any changes in the above parameters with the exception that
    the terminal bodyweights of the high dosage females were less than
    that of the controls. Mortality throughout the study was no different
    in the three groups with 34 (control), 23 (low dose) and 19 (high) of
    the males and 46 (control), 30 (low dose) and 26 (high dose) of the
    females expiring before termination of the study. Styrene did not
    produce either gross or histological changes, nor was there an
    apparent styrene-related increase in tumor incidence. All tumors noted
    were common, spontaneously occuring tumors for this strain of rat or
    rare tumors that occurred without regard to treatment group (Chemical
    Manufacturers Association, 1980).

         The long-term effects of styrene were assessed in two groups of
    Wistar rats. Groups each consisted of 15 male and 15 male Wistar rats
    and received a fatty solution of the monomer in dosages of either 1 or
    5 mg/kg b.w. by mouth for a period of 10 months. The treatment was
    then discontinued and the animals were periodically followed for up to
    10 months. A postmortum examination was performed on all animals which
    expired during the study and on those animals which were sacrificed at
    the end of the 20th months. Two tumors were identified in the inquinal
    region in females which received the highest dosage of styrene with
    one tumor appearing at five months post-exposure and the other at ten
    months post-exposure. Histological evaluation of the tumors revealed
    that they were well developed fibroadenomas. The authors concluded
    that the appearance of the tumors was associated with administration
    of the styrene (Radeva & Krustev, 1982).

         Groups of 40 male and 40 female Sprague-Dawley rats were
    administered styrene oxide in olive oil by gavage at dosages
    equivalent to 0, 50 and 250 mg/kg b.w. four or five days per week for
    52 weeks, whereupon, the treatment was terminated and the animals were
    permitted to live until their deaths. The numbers of males which
    survived until the fifty-first week of the study were 37/40, 31/40 and
    28/40 of the control, low and high dosage groups. The incidences of
    survival for the females were 28/40, 31/40 and 30/40 of the control,
    low and high dosage groups. The histological analysis revealed that
    both dosages of the oxide elicited a higher, dose-related incidence of
    papillomas and carcinomas of the forestomach than the control animals

    with 19.3% of the low dosage animals and 50% of the high dosage
    animals demonstrating these lesions. Many of the carcinomas were
    observed to have metastasized to the liver, and in addition, many of
    the oxide-treated animals were noted to have precursor lesions
    (Maltoni et al., 1979).

    Special studies on mutagenicity

         Styrene and styrene epoxide were studied in spot tests and plate
    incorporation assays for activity agains S. typhimurium straing
    TA-98, 100, 1535, 1537 and 1538 with and without hepatic metabolizing
    systems from Arochlor 1254 - pretreated rats and hamsters. Styrene was
    not mutagenic for any of the tester strains, whereas, the epoxide was
    active in strains TA-100 and 1535 in the spot and plate assays without
    activation. Activity in these strains indicate that the epoxide acted
    as a base substituted mutagen (Stoltz & Withey, 1977; Busk, 1979).

         In other studies styrene was shown to be mutagenic to strains
    TA-100 and 1535, but only after metabolic activation. Styrene oxide in
    these studies was mutagenic, with and without metabolic activities
    (Vainio et al., 1976; de Meester et al., 1977; Watabe et al., 1978a,
    1978b; Loprieno et al., 1978; Milvy & Garro, 1976; Greim et al.,

         The putative styrene intermediate, 1-vinylbenzene-3,4-oxide,
    which has a half-life of 4.3 seconds at pH 7.4 in aqueous solution
    proved to be a potent mutagen toward S. typhimurium, TA-100, but not
    TA-98. This intermediate also demonstrated potent cytotoxicity to both
    His + revertant colonies. The final metabolite, 4-vinylphenol, which
    is the metabolite to which the oxide is converted proved to be neither
    mutagenic or cytotoxic in these studies (Watabe et al., 1982).

         The two enantiomers of styrene 7,8-oxide and various thioether
    conjugates of racemic styrene 7,8-oxide were tested for mutagenic
    activity in S. typhimurium TA-100. The results of these studies
    suggested that the (R) enantiomer is more mutagenic than the (S)
    enantiomer, with the racemic mixture demonstrating intermediate
    activity and the conjugates exhibiting no activity (Pagano et al.,

         The activities of epoxide hydrolase and monoxygenase were studied
    in incubation mixtures for liver microsomal assays with S-9 metabolic
    activation in the absence or presence of styrene from rats and mice.
    The results of this study showed that the activity of the hydrolase is
    more stable than that of the monoxygenase. This is further evidence
    that in the S. typhimurium mutagenic assay system styrene shows
    equivocal results because the styrene epoxide is being hydrolyzed at a
    fairly constant rate while its formation from styrene is occurring at
    decreasing rates (Bauer et al., 1980).

         In a metabolizing, D7 strain of Saccharomyces cerevisiae
    styrene induced an increase in the frequency of cross-over, gene
    conversion and point mutation (Del Carratore et al., 1983). In a
    series of mutagenic assays which measured forward mutations in
    Schizosaccharomyces pombe and V-29 Chinese hamster cells and gene
    conversions in S. cerevisiae in the diploid strain D4, styrene oxide
    was active in the forward mutation experiments with yeast and Chinese
    hamster cells and the production of gene-conversion in yeast. In
    contrast, styrene was inactive in these assays, even in the presence
    of purified mouse - liver microsomes. In a host-mediated assay which
    utilized S. pombe both compounds were active in the production of
    gene conversion, but not for forward mutation (Loprieno et al., 1976).
    In subsequent studies styrene oxide, but not styrene, was shown to
    have mutagenic activity in unscheduled DNA synthesis (UDS) studies in
    a human heterploid cell line and in the induction of chromosomal
    aberrations in the bone marrow of CD-1 mice treated by gavage with a
    0.5 ml of solution 66% in olive oil. The UDS studies also utilized a
    mouse liver homogenate, but styrene still failed to demonstrate
    activity (Loprieno et al., 1978).

         Styrene oxide in Chinese hamster ovary cells was a potent inducer
    of sister chromatid exchanges (SCF), while styrene did not increase
    the number of SCF per metaphase. The effect of the oxide was
    diminished by the presence of a rat S9 metabolic activation system,
    whereas, it had no effect on the lack of activity of styrene. In
    contrast, when an inhibitor of epoxide hydrolase, cyclohexene oxide,
    was used the induction of SCF by styrene with metabolic activation
    became evident (de Raat, 1978).

         Styrene oxide was tested in a mutagenic test screening programme
    which involved a sperm abnormality test and dominant lethal test in
    male mice exposed to atmospheric concentrations of 15 or 100 ppm for
    7 hours per day for 5 days, a cytogenic test in bone marrow celles of
    male and female rats exposed in a manner as described previously or a
    single exposure of 7 hour duration and a sex-linked recessive lethal
    test in Drosophila melanogaster with exposure to atmosphere of
    100 ppm for 150 minutes. The results of these studies showed that
    styrene oxide had no activity on the frequency of chromosomal
    aberrations and sex-linked recessive lethal mutation frequency in
    D. melanogaster. In the dominant lethal test a small reduction in
    pregnancy frequency and total number of implantations was attributed
    to styrene oxide. The highest dosage of the oxide, also resulted in a
    slight increase in the frequency of sperm abnormality (McGregor,

         Additional studies with Drosophila melanogaster showed that
    both styrene and styrene oxide induce recessive lethal mutations and
    that the frequency of their occurence is increased by pretreatment
    with either sodium phenobarbitone or trichloropropane oxide (Donner et
    al., 1979).

         The mutagenic potential of styrene and its 7,8-oxide were studied
    in the isolated perfused rat liver as the metabolizing system and
    Chinese hamster V79 cells as genetic target cells. The 7,8-oxide was
    rapidly metabolized by the liver, and therefore, failed to elicit a
    mutagenic effect. In contrast, styrene produced an increase in V79
    mutants which seemed not to be due to the formation of the 7,8-oxide,
    since simultaneous analysis of its concentration in the perfusion
    medium did not correlate with the mutagenic effect (Beije & Jenssen,

         The in vivo exposure of Chinese hamsters to atmospheric
    concentrations of styrene oxide from 25 to 100 ppm did not affect the
    incidence of chromosomal aberrations and sister chromatid exchanges in
    bone marrow cells. To alter the rate of chromosomal aberrations
    required the administration of lethal concentrations of the oxide by
    the intraperitoneal route (Norppa et al., 1979, 1983).

         The daily oral administration of 500 mg of styrene kg/b.w. for
    four days or 200 mg of styrene/kg b.w. failed to induce chromosomal
    aberrations in the bone marrow cells of CD-1 male mice. Concurrent
    pharmacokinetic studies performed on the same animals failed to show
    the presence of styrene-7,8-oxide in the blood (at the nanogram level)
    (Sbrana et al., 1983).

         Styrene produced chromosomal breaks in in vitro preparations of
    human lymphocytes, whereas, the oxide was responsible for the
    formation of micronuclei and nuclear birdges (Linnainmaa et al.,
    1978). In a mutagenic assay in human diploid fibroblasts styrene oxide
    failed to elicit an increase in unscheduled DNA synthesis (McGregor,

         Cultures of periphenal lymphocytes of workers employed in
    industries with styrene exposure levels which ranged from 30 to
    400 mg/mc showed significantly greater frequencies of chromosomal
    aberrations than those of a matched (sex, age, age and smoking habit)
    control group ( Camurri et al., 1983).

         A micronucleus test based on the analysis of lymphocytes with
    preserved cytoplasm revealed an increased frequency of micronuclei in
    workers exposed to a time-weight average of styrene concentration
    between 1 and 36 ppm. These ambient concentrations correlated with low
    urinary levels of mandelic acid (Hogstedt et al., 1983).

         Styrene and styrene-7,8-oxide induce pronounced dose response
    increases in the occurences in sister chromatid exchanges in human
    lymphocytes and whole blood cultures. The effect of styrene was
    greater in the presence of erythrocytes indicating that styrene must
    be converted to the 7,8-oxide for its capability to induce an increase
    in the incidence of sister chromatid exchanges (Norppa et al., 1980a,

    Special studies on teratogenicity

         The toxicity of styrene and styrene oxide chicken embryos was
    studied by injecting from 2 to 100 umol of either compound in 50 ml
    of an olive oil-ethanol mixture into the air sacs of eggs from
    White-Leghorn SK12 chickens. Malformations were noted in 15% of the
    styrene embryos and 7% of the styrene oxide treated embryos. The
    embryos were most susceptible on the day of, and the day after the
    beginning of incubation (Vainio et al., 1977).

         Sprague-Dawley rats in groups of 39, 30 and 29 animals were given
    0, 180 and 300 mg styrene/kg b.w./day by gavage from days 6 through 15
    of gestation. The styrene was administered as a peanut oil solution at
    a volume of 2 mg/kg b.w. as twice daily doses of 90 or 150 mg/kg b.w.
    There were no significant differences between the treated-animals and
    the controls during gestation except for a diminished weight gain on
    days 6 through 9 of gestation that was attributed to a reduction in
    food intake. Dams were sacrificed prior to parturition and the fetuses
    were examined. The incidence of external visceral and skeletal
    malformations in the treated animals did not differ from either the
    matched or historical controls. A compound-related effect on the
    embryo and fetus was not observed, as was no teratogenic effect.
    Styrene at both dosages did induce a decrease in body weight gain and
    decreased food consumption in the dams (Murry et al., 1978).

    Special studies on reproduction

         Water and milk extracts of CNP-2p grade plastics which were
    subjected to a vacuum process and contained 80 to 110 ppm styrene were
    given every 24 hours to 741 rats in a multi-generation study which was
    22 months in duration. A group of animals which received water and
    milk served as controls. The parental generation received the extracts
    from 1.5 to 13 months of age, while the F1 and F2 generations
    were given the extracts from weaning to 8 and 2 months-of-age,
    respectively. The administration of the extracts continued throughout
    pregnancy and lactation.  The animals which received the extracts
    demonstrated a statistically reliable decrease in the number of red
    blood cells and activity of cholinesterase after a two day fast. A
    histological analysis revealed that the extract-treated animals
    demonstrated dystrophic changes in the superficial, cortical renal
    tubules and a catarrhal state in the duodenum. No other hematological
    or histological parameters were found to be adversely altered by the
    administration of the extracts. A large number of still-born, poorly
    developed and deformed pups were noted to have been born to the
    parental and F1 dams which were treated with the extracts as compared
    to the control animals. In addition, it was noted that there was a
    delay in the growth of fur in the F1 and F2 generations which were
    treated with the extracts (Chernova, 1971).

         A three-generation reproduction study was conducted as part of a
    combined chronic two-year reproduction study in which styrene was
    administered in the drinking water of rats. From each group (125 and
    250 ppm groups) of the chronic study at least 10 males and 20 females
    were mated to produce F1 pups and then subsequent F2 and F3
    generations were produced. The following reproductive and
    toxicological indices monitored in this study; mean litter size,
    live-to-total pup ratios, pup survival indices at intervals from birth
    to weaning were evaluated as well as liver and kidney weights of
    representative pups necropsied at weaning, cytogenetic evaluation of
    bone marrow samples of other weanlings, gross necropsy of F1 and F2
    parents, organ weigths and histopathologic examinations of liver and
    kidneys of weanlings and of tissues of representative F1 and F2
    parents.  Styrene had no deleterious effects on the reproductive
    capacity of rats through the three generations and on other
    toxicological parameters measured (Chemical Manufacturers Association,

    Special studies on enzyme systems

         The effect of styrene on carbohydrate balance was studied in
    Wistar rats which received a dosage by gavage of 2.5 g/kg b.w. which
    was equivalent to 1/2 the LD50. The results indicated that glucose
    absorption and hepatic glycogen content were reduced after styrene
    administration (Delag et al., 1976).

         The effect of orally administered styrene on hepatic mixed
    function oxidase enzyme activities, glutathione-S-transferase activity
    and glutathione content was studied in male rats. Doses of 250, 450
    and 900 mg/kg b.w. were administered for seven days to groups of 15
    animals. The two highest dosages enhanced the activity of aryl
    hydrocarbon hydroxylase and aniline hydroxylase, while the highest
    dosage alone, significantly lowered the activity of glutathione-
    S-transferease and glutathione content. In a subsequent study in which
    an identical protocol was followed with the exception that only the
    two highest dosages were used (450 and 900 mg/kg b.w.) effects on
    renal MFO activity and glutathione activity were noted. An increase in
    MFO activity was assessed as an increase in the activity of ary
    hydrocarbon hydroxylase, aniline hydroxylase ethylmorphine-N-
    demethylase and benzphetamine N-demethylase. In addition, the activity
    of glutathione-S-transferase was decreased along with the levels of
    renal glutathione (Das et al., 1981, 1983).

         The intubation of 1 ml/kg b.w. of styrene daily for 15 days to
    adult male albino rats elicited a significant increase in serotonin
    and noradrenalin levels in the brain without a change in dopamine
    content. These changes coincided with a significant decrease in the
    activity of monoamine oxidase, however, no change in acetyl
    cholinesterase activity was observed (Husain et al., 1980).

         Groups of male rats were administered styrene in ground nut oil
    by gavage at dosages of 200 and 400 mg/kg b.w. six days per week for
    100 days. A dose-dependent increase in hepatic benzo(a)pyrene 
    hydroxylase and aminopyrine-N-demethylase activities were noted, while
    a decrease in the activity of glutathione-S-transferase, mitochondrial
    succinic dehydrogenase and B-glucoronidase and no change in glucose-6-
    phosphatase were observed (Srivastava et al., 1982).

    Special studies on immune function

         The effects of styrene on immunological function were studied in
    a series of three experiments in 36 rabbits. The animals used in the
    study were immunized with lamb erythrocytes for a period of 7 to 8
    days beginning with the initiation of dosing with styrene. Styrene was
    administered 5 times per week in the form of an emulsion (vegetable
    oil and potato starch) according to three different dosing schedules.
    These were 250 mg/kg b.w. for 58 days, 5 mg/kg b.w. for 216 days and
    0.5 mg/kg b.w. for 202 days. The results of these studies established
    that the higher dosages of styrene produced acute variations in the
    titer of complement and antibodies. The phagocytic activity of the
    leucocytes were also observed to be depressed. These changes were
    noted to have occured prior to other indications of styrene
    intoxication at the highest dosage. These included a reduction of
    appetite and hyperemia of the conjunctiva of the eye (Sinitskii,

    Acute toxicity


    Species     Route        LD50           Reference

    Rat         oral      5.0 g/kg b.w.     Wolf et al., 1956
    Rat         oral      5.5 g/kg b.w.     Ogleznev, 1963

    Short-term studies


         A subchronic study was performed as a range finding study for the
    NCI chronic mouse bioassay. Five males and five females were placed in
    groups which received dosages of 0, 147, 215, 316, 464 and 681 mg of
    styrene/kg b.w. which was administered as a corn-oil gavage five days
    per week for seven weeks. A reduced mean body weight gain was noted in
    the groups which received 316 and 464 mg/kg b.w., but not the highest
    dosage of 681 mg/kg b.w. No other clinical abnormalities were noted to
    be related to the exposure to styrene (National Cancer Institute,

         In a one month study in 75 mice styrene at a dosage of 1/10 of
    the LD50, 0.55 g/kg b.w., had no effect on the growth of the treated
    animals. No other details of the study were provided (Ogleznev, 1963).


         Rats were dosed by gavage with dosages of 0.1, 0.5, 1.0 and 2.0 g
    of styrene/kg b.w. emulsified in olive oil with gum arabic. Dosing was
    five days per week for 4 weeks. There was an increase in mortality and
    pronounced esophageal and gastric irritation in the groups which
    received the two highest dosages. Slight esophageal and gastric
    irritation were also observed at the next lowest dosage of 0.5 g/kg
    b.w., along with poor weigth gains in the five males which survived
    the 28-day testing period. The animals which received the lowest
    dosage of 0.1 g/kg b.w. were found to be in generally good condition
    (Spencer et al., 1942).

         Matched groups of ten female rats were dosed by gavage with
    dosages of 0, 66.7, 133, 400 and 667 mg of styrene/kg b.w./day five
    days per week for six months. The test compound was administered as an
    olive-oil solution. The two lowest dosages had no effects on the
    animals. However, the two higher dosages did produce, in a
    dose-related manner, a slight reduction in the rate of growth and
    slight depressions in hepatic and renal weights. Although blood cell
    counts were made after 20, 40, 80 and 130 doses no compound related
    effects were noted (Wolf et al., 1956).

         Groups of five male and five female Fischer 344 rats received
    styrene in corn-oil via gavage five days per week for seven weeks at
    dosages of 0, 681, 1000, 1470, 2150 and 3160 mg/kg b.w. This was
    followed by a one week observation period. The treated males,
    particularly at the higher dosages, tended to have lower mean body
    weight gains than the controls.  At the conclusion of the study no
    other compound-related clinical abnormalities were demonstrated
    (National Cancer Institue, 1978).

         Groups of adult, male rats were administered (six days/week)
    styrene in ground nut oil by gavage dosages of 200 or 400 mg/kg b.w.
    for a period of 100 days. No overt signs of toxicity were noted in the
    treated animals. Weight gain and absolute and relative liver weights
    were not different in the control and treated animals. The highest
    dose of 400 mg/kg b.w. was associated with tiny areas of focal
    necrosis in the liver which consisted of degenerated hepatocytes and
    inflammatory cells (Srivastava et al., 1982).


         Groups of four female and male Beagle hounds were administered
    styrene by gavage at dosages of 0, 200, 400 or 600 mg/kg b.w./day for
    up to 561 days. The styrene was provided as a 50/50 mixture in peanut

    oil. The two highest dosages elicited Heinz bodies in the erythrocytes
    of the males and occasionally in the females on the lowest dosage.
    There were other sporadic changes in various hematological parameters
    (decreased packed cell volume, erythrocyte counts and sedimentation
    rates and hemoblogin levels and increased incidence of anisocytosis
    and hypochromia of erythrocytes, hemosiderin in hepatic
    reticuloendothelial cells and numbers of hepatocellular intranuclear
    acidophilic crystalline inclusions) which quickly disappeared when the
    administration of styrene was terminated. Although body weights, food
    consumption, clinical chemistry determinations and organ weights
    (brain, heart, liver, kidneys and testes) were studied none were
    adversely effected by the administration of styrene (Quast et al.,


    Epidemiological and clinical studies

         Experimental exposures to concentrations of styrene from 50 to
    800 ppm for varying periods of time have shown depression of the
    central nervous (CNS) system. These include reports of listlessness, 
    drowsiness, incoordination, decrements of manual dexterity, feeling of
    intoxication and changes in visual evoked response and EEG amplitude
    (Carpenter et al., 1944; Gamberale & Hultengren, 1974; Oltramare et
    al., 1974). In contrast other studies have shown that styrene exposure
    of from 50 to 350 ppm and again for varying periods of time did not
    have effects on CNS function (Stewart et al., 1968; Gamberale &
    Hultengren, 1974; Oltramare et al., 1974). In the workplace exposure
    to styrene has been attributed to cause increased reaction times,
    abnormal EEGs, headache, fatigue, malaise and dizziness (Seppalainen &
    Harkonen, 1976; Harkonen et al., 1978; Nicholson et al., 1978; Lorimer
    et al., 1976; Rosen et al., 1978; Cherry et al., 1980). There have
    also been reports of styrene - induced peripheral neuropathy in the
    workplace. In several studies reductions in nerve condition velocites
    and mild sensory neuropathy have been noted (Lilis et al., 1978; Rosen
    et al., 1978).

         Styrene exposure has also resulted in irritation of the eyes,
    respiratory tract, throat, and epidermis (Stewart et al., 1968; Gotell
    et al., 1972; Araki et al., 1971; McLaughlin, 1946; Rosen et al.,
    1978; Oltramare et al., 1974; Lorimer et al., 1976).

         There are studies which suggest that styrene exposure in the
    workplace has adverse effects on hepatic function. These changes have
    included elevated serum enzyme activities, serum uric acid and glucose
    tolerance (Lorimer et al., 1976; Axelson & Gustavson, 1978; Chmieleski
    et al., 1973; Chmielewski, 1976). This link between styrene exposure
    and hepatic dysfunction, however has not been definitively
    established. The issue of styrene-induced reproductive and/or
    teratogenic effects was raised in a study of congenital defects in
    children whose mothers were occupationally exposed to styrene

    (Holmberg, 1977) and in a study in which styrene was measured in
    umbilical cord blood suggesting the ability of styrene to cross the
    placenta (Dowty et al., 1976). In addition, an increased rate of
    spontaneous abortions was noted in a study of styrene workers
    (Hemminki, 1980). In contrast to these observations another study of
    occupationally exposed women failed to establish a link between the
    incidence of spontaneous abortions and styrene exposure (Harkonen &
    Holmberg, 1982).

         Several studies have examined whether styrene can induce a
    carcinogenic response in humans. Several mortality studies of
    occupationally exposed individuals have failed to show an excess of
    deaths due to cancer (Ott et al., 1980; Frentzel-Beyme et al., 1978;
    Nicholson et al., 1978). In a proportionate mortality study of 560
    styrene-polystyrene polymerization workers over an approximately 15
    year period showed a deficit of deaths as compared to the general
    population was noted. Among the deaths of the workers were one
    leukemia, one lymphoma and an additional death accompanied by leukemia
    (Nicholson et al., 1978). There have been only limited epidemiological
    studies performed on the possible styrene-induced carcinogenicity in
    humans. A mortality study of employees engaged in the development or
    manufacture of styrene-based products revealed a statistically
    significant increase in the number of leukemias in comparison to other
    company employees, however, when the comparison was made with national
    statistics the difference was not statistically significant (Ott et
    al., 1980). In a study of styrene and polystyrene plant workers in
    which 24 deaths certificates were examined there was no evidence of an
    association between exposure to styrene and an excess of cancer
    (Frentzel-Beyme et al., 1978).


         Styrene readily crosses epithelial surfaces and therefore is
    absorbed from the gastrointestinal tract. Once absorbed styrene can be
    eliminated unchanged via expiration or it can be converted to a number
    of metabolites, including mandelic acid, phenylglyooxylic acid and
    hippiuric acid, which in turn are excreted via the urine. The proposed
    intermediate in this metabolic scheme is an epoxide, styrene oxide,
    however its existence has been established solely in in vitro
    experimentation and has never been isolated in vivo.

         In studies in laboratory animals styrene has generally been shown
    to elicit adverse effects only at high dose levels. These effects
    include reductions in body weight gains, generation of Heinz bodies in
    erythrocytes, sporadic changes in several hematological parameters,
    variations in the titer of complement and antibodies and focal
    necrosis in the liver. It is reported to have no teratogenic effect
    nor to have adverse consequences on reproductive performance.
    Mutagenic studies have generally shown styrene to be inactive,
    although under some test conditions chromosomal effects were produced.

    However, its metabolite, styrene oxide, has pronounced mutagenic
    activity. Lifetime studies in rats have failed to demonstrate a
    styrene-induced carcinogenic effect. One in three studies in the mouse
    involving in utero exposure provided "limited evidence" of a
    carcinogenesis. In contrast, one preliminary study has shown that
    styrene oxide has carcinogenic potential.

         In humans, styrene has been reported to have depressive effects
    on CNS function and is an irritant to epithelial surfaces. There has
    been some evidence generated in clinical studies that indicate that
    styrene is hepatotoxic, however, the evidence is not conclusive. Data
    from human studies have presented suggestive evidence that styrene is
    teratogenic, however, the animal studies have not borne this out.
    Human clinical and epidemiological studies performed to data have
    generally shown that styrene is not carcinogenic and failed to
    establish a link between styrene exposure and carcinogenesis.


    Level causing no toxicological effects

         Rat: 125 ppm in drinking water, equal to 7.7 mg/kg b.w./day for 2

    Estimate of a provisional maximum tolerable daily intake for man

         0.04 mg/kg bw.


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    See Also:
       Toxicological Abbreviations
       Styrene (EHC 26, 1983)
       Styrene (ICSC)
       STYRENE (JECFA Evaluation)
       Styrene (PIM 509)
       Styrene (IARC Summary & Evaluation, Volume 60, 1994)
       Styrene (IARC Summary & Evaluation, Volume 82, 2002)