Styrene - PSL1

3.0 Assessment of "Toxic" Under CEPA

3.1 CEPA 11(a) Environment

Styrene is produced and used in large quantities in Canada, which results in its release to the environment, primarily the atmosphere. Once in the environment, styrene does not persist in air, water or soil. Measurable concentrations are found in ambient air in Canada and in some industrial and municipal effluents. Much of the data that were identified on the concentrations of styrene in other media, including surface water and biota, are limited primarily to those generated in the late 1970s and early 1980s.

Estimation of exposure based on these older data suggests that styrene in food and water may have contributed significantly to the overall intake of aquatic-based wildlife, such as mink, to the substance at that time. Because of the lack of recent data on concentrations in these media, their current contribution to overall exposure cannot be evaluated. It was, however, possible to estimate the intake of styrene from air. The lowest lowest-observed-effect-level (LOEL) for meaningful effects in laboratory animals was 60 ppm (260 mg/m³) air, in a study by Kishi et al. (1992a, 1992b), in which female rats were exposed to styrene through inhalation during pregnancy. In offspring, body weight was significantly reduced and reflex responses were abnormal. Based on a net factor of 100 (10 to account for interspecies differences and to extrapolate from the laboratory to the field, and 10 to extrapolate a NOEL from a LOEL), the effects threshold for wild mammals was estimated to be 2.6 mg/m³. The highest concentration measured at Walpole Island (3.2 mg/m³), a rural site located near an industrial region, is over 800 times less than this threshold.

The toxicological data identified for aquatic biota were limited to acute studies for various trophic levels. In each case, the study protocols did not adequately address the volatility of styrene and, therefore, the actual concentrations that caused effects were much lower than reported.

The data that were identified on the extent of exposure of most biota to styrene, and on the effects that may result, were insufficient to conclude whether styrene is entering the environment in quantities or under conditions that may be harmful to the environment.

3.2 CEPA 11(b): Environment on which Human Life Depends

Although styrene is volatile at tropospheric temperatures and absorbs infrared radiation in wavelengths ranging from 7 to 13 mm (a range associated with trace gas warming of the troposphere), this substance is removed from the atmosphere by photooxidation (half-life £ 9 hours), resulting in low steady-state concentrations in the atmosphere (Canadian urban air average = 0.59 mg/m³). As such, styrene is not expected to contribute to global warming or depletion of stratospheric ozone.

Therefore, on the basis of the available data, it has been concluded that styrene is not entering the environment in quantities or under conditions that constitute a danger to the environment on which human life depends.

3.3 CEPA 11(c): Human Life or Health

3.3.1 General Population Exposures

Estimated daily intakes of styrene from various media, for different age groups of the Canadian general population, are presented in Table 2. Indoor air contributes a substantial fraction of exposure for non-smokers in the general population (estimated daily intake for various age classes ranges from 0.07 to 0.10 mg/kg bw/day). The estimated daily intake of styrene from ambient air ranges from 0.004 to 0.17 mg/kg bw/day for various age classes. Intakes of styrene from drinking water and from soil are estimated to be negligible, ranging from < 0.001 to 0.03 mg/kg bw/day and from < 0.000003 to < 0.00005 mg/kg bw/day, respectively. Food may also make a substantial contribution to the intake of styrene by the general population, although the available data on styrene levels in the Canadian food supply are limited by analytical sensitivity. Based on the limits of detection in a 1992 survey, in which styrene was not detected in samples of 34 food groups purchased in Windsor, Ontario (ETL, 1992), the estimated intakes of styrene via food range from < 0.11 to < 0.58 mg/kg bw/day for various age classes. These estimated intakes in food are obviously uncertain, but are within the range of estimates based on other data, as noted in the footnotes to Table 2.

Based on the above estimates, the total estimated daily intakes for the non-smoking general population range from < 0.20 to < 0.79 mg/kg bw/day overall. Estimated intakes are maximum values, since the intakes from food and soil are upper limits for potential exposure from these media. On the other hand, the mean concentrations in indoor air reported from limited Canadian and extensive United States surveys of homes in urban areas are severalfold higher than those used here.

The estimated daily intake of styrene from cigarettes ranges from 2.86 to 3.51 mg/kg bw/day for adults and teens, respectively, based on data on amounts of styrene in mainstream cigarette smoke in a United States report (U.S. Department of Health and Human Services, 1989).

Table 2 Estimated Daily Intake (µg/kg bw) of Styrene by Canadians for Various Media

Medium	Estimated Daily Intake (µg/kg bw/day)
	0-6 moa	7 mo-4 yrb	5-11 yrc	12-19 yrd	20-70 yre
Assumed to weigh 7 kg, breathe 2 m3 of air per day, drink 0.75 L of water per day and ingest 35 mg soil per day (EHD, 1992). Assumed to weigh 13 kg, breathe 5 m3 of air per day, drink 0.8 L of water per day and ingest 50 mg soil per day (EHD, 1992). Assumed to weigh 27 kg, breathe 12 m3 of air per day, drink 0.9 L of water per day and ingest 35 mg soil per day (EHD, 1992). Assumed to weigh 57 kg, breathe 21 m3 of air per day, drink 1.3 L of water per day and ingest 20 mg soil per day (EHD, 1992). Assumed to weigh 70 kg, breathe 23 m3 of air per day, drink 1.5 L of water per day and ingest 20 mg soil per day (EHD, 1992). Based on range of mean concentrations of styrene reported in 24-h samples of ambient air from 18 Canadian sites in 5 provinces (0.09 to 2.35 mg/m3) [Dann, 1990], assuming 4 of 24 hours are spent outdoors daily (EHD, 1992). Based on mean concentration of styrene (0.28 mg/m3) reported in a national pilot study of indoor air of 757 homes across Canada (Concord Environmental, 1992), assuming 20 of 24 hours are spent indoors daily (EHD, 1992). The average concentration determined in this study is similar to or slightly lower than those from most other more limited Canadian and from extensive U.S. studies. Based on range of mean concentrations of styrene (< 0.050-0.250 mg/L) in treated water from 80 drinking water supplies in Ontario's 1990 Drinking Water Surveillance Program (Lachmaniuk, 1991). Findings were similar in a survey from Alberta, in which styrene was detected at only trace levels in one of 1 081 samples from 220 locations (Halina, 1992). Based on analysis of a limited number of samples of urban soils removed from point sources, in Port Credit and Oakville/Burlington, Ontario, in which the soils analyzed contained less than 10 mg/kg (Golder Associates, 1987). Based on a 1992 survey in Windsor, Ontario, in which styrene was not detected in retail samples of 34 food groups (each a composite of individual food items, combined in proportion to their consumption by the Canadian general population) [ETL, 1992]. Limits of detection were 0.005 and 0.001 mg/g for solid and liquid foods, respectively; estimates were made by assuming that the food groups contained styrene at less than the limit of detection. These estimated intakes are within the range of those based on monitoring of raw agricultural commodities in the U.S. (MRI, 1992), assuming that the styrene levels in specific food items in this survey were representative of their food groups as a whole (0.026 to 0.132 mg/kg bw/day), of foods packaged in styrene-based polymers and copolymers in the U.K. (average and maximum of 1 mg/day and 4 mg/day, respectively [0.014 to 0.057 mg/kg bw/day for a 70 kg person]) [MAFF, 1983], and on modelling of migration of styrene monomer from styrene-based polymers and copolymers in the U.S. (9.1 mg/day [or 0.15 mg/kg bw/day for a 60 kg adult]) [Ad Hoc Styrene Migration Task Group, 1992]. Based on the styrene content in the mainstream cigarette smoke (10 mg/cigarette) from a U.S. report (U.S. Department of Health and Human Services, 1989). Approximately 20 cigarettes per day are smoked by Canadians aged 15 years or older as of 1990 (Kaiserman, 1992).
Air Ambientf	0.004-0.11	0.006-0.15	0.007-0.17	0.006-0.14	0.005-0.13
Indoorg	0.07	0.09	0.10	0.09	0.08
Drinking Waterh	< 0.005-0.03	< 0.003-0.02	< 0.002-0.008	< 0.001-0.006	< 0.001-0.005
Soili	< 0.00005	< 0.00004	< 0.00001	< 0.000004	< 0.000003
Foodj	< 0.58	< 0.53	< 0.30	< 0.15	< 0.11
Total Intake (not including cigarettes)	< 0.66- < 0.79	< 0.63- < 0.79	< 0.41- < 0.58	< 0.25- < 0.39	< 0.20- < 0.33
Intake by cigarette smokersk	-	-	-	3.51	2.86

3.3.2 Effects

Based on available data, carcinogenicity and heritable mutations are potentially the most sensitive end-points for assessment of "toxic" for styrene under CEPA. The weight of evidence for the carcinogenicity and potential to induce heritable mutations of styrene has been assessed, therefore, on the basis of the classification schemes developed for this purpose (EHD, 1992).

The results of chronic studies in rodents exposed to styrene provide only limited evidence that styrene is carcinogenic. Borderline increases in the combined incidence of leukaemias and lymphosarcomas have been observed in female Sprague-Dawley rats following inhalation (Jersey et al., 1978), although it is currently considered inappropriate to combine these tumour types (McConnell, 1986). An increase in malignant mammary tumours occurred in female Sprague-Dawley rats exposed to styrene by inhalation; however, it was not dose-related and its relevance to exposure to styrene could not be assessed, owing to inadequate documentation of non-neoplastic effects in this study (Conti et al., 1988). There have also been two reports of marginal increases in lung tumours in male B6C3F₁ mice exposed to styrene orally (NCI, 1979) and in both sexes of O₂₀ mice with combined in utero and oral exposure (Ponomarkov and Tomatis, 1978).

There is consistent evidence (observed in two studies), therefore, only for small increases in lung tumours in mice associated with exposure to styrene. It should be noted, however, that there are limitations in all of the studies conducted to date that complicate the assessment of the weight of evidence of carcinogenicity. For example, in the NCI (1979) bioassay in B6C3F₁ mice, there was an apparent deficit in the incidence of lung tumours in the small concurrent control group, in which no lung tumours were observed, and the increase in the high-dose group was within the range observed for these tumours in historical controls. The study in O₂₀ mice by Ponomarkov and Tomatis (1978) is also limited in that only a single-dose level was administered and lung tumours also occurred at relatively high frequencies in controls. Increases in the incidences of other types of tumours have not been consistently observed and have been marginal, even at relatively high exposures.

In epidemiological studies conducted to date, mortality from lymphatic and haematopoietic cancers has been significantly increased in some studies of workers from several industries with mixed exposures to styrene and other chemicals (i.e., those manufacturing styrene-butadiene rubber, styrene/polystyrene, and fibrous glass products). In the most sensitive study conducted to date, there were small but significant excesses of mortality from several lymphopoietic malignancies in styrene-butadiene copolymer industry production workers (Matanoski et al., 1990). In a follow-up nested case-control study in which exposure to styrene and butadiene was ascertained, multivariate analysis indicated that there was excess leukaemia risk related to butadiene, whereas the increase for styrene was not significant. There was little evidence of excess risk of other lymphopoietic cancers (Matanoski et al., 1989; Santos-Burgoa et al., 1992). Small increases in mortality from lymphatic and haematopoietic cancers have also been reported in studies of workers from a number of other cohorts (McMichael et al., 1976; Meinhardt et al., 1982; Hodgson and Jones, 1985; Bond et al., 1992), although most of these reports have been based on very small numbers of deaths. In some case-control studies, nonsignificant excesses of various lymphatic and haematopoietic cancers have been associated with exposure to styrene (Flodin et al., 1986; Ott et al., 1989; Siemiatycki, 1991), although these observations were all based on very small numbers of cases (i.e., between 1 and 4) for any specific type of malignancy.

The results of several earlier epidemiological studies that did not reveal a significant excess of these neoplasms in workers exposed to styrene (Nicholson et al., 1978; Frentzel-Beyme et al., 1978; Okun et al., 1985) do not contribute to the weight of evidence, as they were seriously limited by one or more of very small numbers of subjects/deaths, inadequate reporting or the passage of insufficient time since exposure to styrene. Even in more powerful studies of workers with relatively high exposures (Coggon et al., 1987; Wong, 1990), in which significant excesses of mortality from these neoplasms have not been identified, insufficient time may have elapsed for their development. In the cohort studied by Wong (1990), however, the mortality from leukaemia and aleukaemia was increased, although not significantly, in groups of workers with relatively high exposure to styrene, but not in those with lower exposure. This observation, in the largest cohort from an industry where exposures would have been relatively high, is suggestive of a dose-response relationship in the association between exposure to styrene and deaths from these malignancies. The results of a recent update of this study were not available at the time of completion of this assessment.

In most cases in these studies, mortality due to these cancers has not been related to either the duration or intensity of exposure (Hodgson and Jones, 1985; Coggon et al., 1987; Matanoski et al., 1990; Bond et al., 1992). With the exception of some recent studies in the fibrous glass industry, however, exposures have generally been poorly characterized, and historical exposures, particularly in the styrene/polystyrene and styrene-butadiene industries, are unknown.

It could be argued that the lack of consistency in the subtypes of lymphatic and haematopoietic cancers that are increased does not support a causative role for styrene in their development; however, because these neoplasms all arise from cells that are derived from a common multipotential progenitor cell in the bone marrow, it is possible that a carcinogenic agent that affected this tissue could give rise to more than one type of lymphatic and/or haematopoietic cancer.

Interpretation of all of the available epidemiological studies is complicated by the fact that, in each case, there were concomitant exposures to a number of other substances, although styrene was the principal common agent to which workers were exposed in the variety of industries studied (styrene-butadiene rubber, styrene/polystyrene, and fibrous glass products). In particular, the frequent concomitant exposure to benzene (a leukaemogen) is problematic, and Matanoski et al. (1989; Santos-Burgoa et al., 1992) reported that an observed increase in leukaemia was significantly associated with exposure to butadiene, but not with styrene. Largely as a consequence of these concurrent exposures, and in combination with the weakness of the associations and the uncertainties concerning the lack of specificity and of a dose-response relationship, the evidence that exposure to styrene has caused the observed increases in mortality from lymphatic and haematopoietic cancers in these populations of workers is considered to be limited.

The weight of evidence indicates that styrene is genotoxic in animals following metabolic activation. Thus, the results of short-term tests (Section 2.5.1) indicate that, following metabolic activation, styrene is an in vitro clastogen capable of inducing chromosomal aberrations and micronuclei in mammalian test systems. The observed ability of styrene to bind to DNA and to induce SCE and DNA single-strand breaks supports the conclusion that styrene is genotoxic in vitro. In in vivo tests, styrene has induced SCE and chromosomal aberrations in mice following inhalation, and was clastogenic following intraperitoneal injection to mice and rats.

The weight of evidence in cytogenetic studies of workers exposed to styrene and other compounds (Section 2.5.2) indicates that exposure to high levels (i.e., approximately 50 to 100 ppm [217 to 433 mg/m³]) may be associated with chromosomal abnormalities (most often aberrations) in the peripheral lymphocytes of exposed workers. There is also some limited indication that exposures to concentrations in the range of 10 to 25 ppm (43 to 108 mg/m³) are able to induce chromosomal effects [micronuclei]. (It should be noted, however, that there are inconsistencies in the results of the available studies, probably attributable to such limitations as small population size, uncertainty with respect to current and historical exposures, the high and variable background levels of chromosomal aberrations or inadequate control for potential clastogenic effects of smoking and exposure to other chemicals.)

There is, therefore, only limited evidence of the carcinogenicity of styrene to both animals and humans; however, there are limitations of all of the epidemiological studies and carcinogenesis bioassays in animal species conducted to date, which may have contributed to a lack of sensitivity of these investigations to detect increases in tumour incidence. Moreover, the weight of the available evidence from in vitro and in vivo investigations in experimental animals indicates that styrene is genotoxic following metabolic activation. On the other hand, limited available data indicate that humans may be less sensitive to the carcinogenic and genotoxic effects of styrene than experimental animals, owing to interspecies differences in metabolism and detoxification of the putatively toxic metabolite. On the basis of in vitro studies of tissue from 5 human subjects, it appears that humans form less styrene-7,8-oxide, and hydrolyze it more quickly than rats and mice, the species in which the carcinogenesis and genotoxicity assays have been conducted (Mendrala et al., 1993). Styrene-7,8-oxide has been detected, however, at low levels in the blood of humans exposed to styrene (Wigaeus et al., 1983; Löf et al., 1986a, 1986b), and there is some (albeit weak and inconsistent) evidence of the carcinogenicity and clastogenicity of styrene in occupationally exposed populations. On this basis, styrene has been classified in Group III ("possibly carcinogenic to humans") of the classification scheme for carcinogenicity developed for the determination of "toxic" under CEPA (EHD, 1992).

On the basis of the data summarized above, there is sufficient evidence of the genotoxicity of styrene to somatic cells in animal species; evidence in humans is suggestive. There is also evidence from studies in animals that germ cells are exposed in vivo, based on the observed styrene-induced effects on testicular histopathology and biochemistry and on sperm count in rodents exposed by the oral route (Section 2.5.1). An increased frequency of sperm head shape abnormalities in workers exposed to styrene at a reinforced plastics factory in an inadequately designed study (Jelnes, 1988) suggests that this may also be the case in humans. On this basis, styrene has also been classified in Group III ("possible human germ cell mutagens") of the classification scheme developed for mutagenicity in germ cells under CEPA (EHD, 1992).

For compounds classified in Group III of the classification schemes for carcinogenicity and heritable mutations developed for assessment of "toxic" under paragraph 11(c) of CEPA (EHD, 1992), in most cases, a tolerable daily intake (TDI) is derived on the basis of a no- or lowest-observed-(adverse)-effect-level (NO(A)EL or LO(A)EL) in humans or animal species (by the most relevant route of exposure) divided by an uncertainty factor.

Owing to limitations of the available data on concentrations in the general environment, the principal route of exposure to styrene for the general population in Canada is not clear (Section 3.3.1). Ambient and indoor air are estimated to contribute a substantial portion of the total daily intake of styrene for all age classes, but the limited available information suggests that intake via food may also contribute a substantial amount of the total exposure, although intake in food has been overestimated in this assessment due to the need to rely on detection limits for calculation of intakes from this medium. (Styrene was not detected in foodstuffs in Canada in the survey (ETL, 1992) on which estimated intake from food is based.) Therefore, TDIs have been developed for both oral and inhalation exposures, for comparison to the estimated intakes derived in Section 3.3.1.

Although workers are exposed to styrene primarily by inhalation, the available data on non-neoplastic effects (principally neurological) in human populations are considered to be inadequate to serve as the basis for the development of a TDI, due to such factors as the lack of precise exposure data, the small numbers of subjects in many studies and simultaneous exposures to other chemicals. The available clinical studies of neurological effects are also considered inadequate to serve as the basis for development of a TDI, because they are limited to short-term investigations of neurological and behavioural effects in very small numbers of subjects. It should be noted, however, that a TDI derived on the basis of neurotoxic effects in cross-sectional epidemiological studies and clinical studies in human volunteers would not vary greatly from that derived below on the basis of studies in animal species.

The available data, although limited, indicate that neurological development is among the most sensitive of end-points to the effects of styrene exposure. Kishi et al. (1992a) reported that the offspring of Wistar rats exposed to 60 and 293 ppm (260 and 1 270 mg/m³) styrene for 6 h/day during days 7 to 21 of gestation had significantly lower body weights at day 1 of age at both concentrations. In addition, the levels of serotonin and 5-hydroxytryptamine (5-HT) were reduced in the cerebrum of the pups at both concentrations, although this reduction was not statistically significant at 60 ppm. Neither dose significantly affected maternal body weight. These researchers also conducted behavioural tests on the pups, and reported (the results were only available in an abstract at the time of completion of this assessment) that exposure to 60 ppm (260 mg/m³) styrene during gestation delayed the development of righting reflex and auditory startle reflex, while exposure to 293 ppm (1 270 mg/m³) induced alterations in a wider range of behavioural measures (Kishi et al., 1992b). Another group of Japanese researchers also reported that the timing of developmental milestones (pinna detachment, incisor eruption) was delayed, and exploratory and avoidance behaviour altered, in rat pups exposed post-natally (7 h/day, 6 days/week, from birth to 48 days of age) to 25 ppm (108 mg/m³) and 50 ppm (217 mg/m³) styrene, respectively (Shigeta et al., 1989). [These authors observed, however, that pup body weight was reduced on the first day of exposure, suggesting that the neonates may not have been at a comparable stage of development at the start of the experiment.]

Similar neurotoxic effects have been observed in rodents following subchronic exposure to higher levels of styrene (i.e., approximately 300 ppm [1 299 mg/m³]), including alterations in the cellular composition of the brain (Rosengren and Haglid, 1989) and in brain chemistry (Savolainen and Pfaffli, 1977), and decrements in performance in visual discrimination tests (Kulig, 1988). In addition, the numerous reports of neurophysiological and neurobehavioural effects in volunteers and workers exposed to styrene (Section 2.5.2) suggest that studies of neurological end-points in animals exposed to styrene are an appropriate model for assessing potential risks to humans. A range of other non-genotoxic effects has been observed in rodents following subchronic exposure to approximately 300 ppm (1 299 mg/m³) styrene, including glutathione depletion in the liver and lung (Vainio et al., 1979), histopathological alterations in the bronchiolar epithelium (Morisset et al., 1979) and effects on the haematopoietic system (Seidel et al., 1990).

Thus, the lowest reported levels inducing meaningful effects fall within a similar range; indeed, there is no clearly superior critical study, and TDIs derived on the basis of the lowest effect levels from several studies reported above would be similar. For this assessment, the study by Kishi et al. (1992a, 1992b) has been selected for the derivation of a TDI, since it leads to the most conservative value and since observed effects included both body weight changes and manifestations of neurotoxicity (including biochemical and behavioural effects). Thus, the lowest LOEL for neurotoxic (and other) effects in animals following inhalation of styrene in an adequately conducted study is 60 ppm (260 mg/m³) in Wistar rats exposed to the compound in utero (Kishi et al., 1992a, 1992b). The TDI for inhalation exposure is therefore derived as follows:

where:

• 260 mg/m³ is the LOEL for effects on body weight, the results of behavioural testing, and neurotransmitter levels (the latter not statistically significant) in the cerebrum of rat pups exposed to styrene on days 7 to 21 of gestation in the study by Kishi et al. (1992a, 1992b), which leads to development of the most conservative TDI;
• 0.11 m³/day is the assumed volume of air inhaled daily by rats (EHD, 1992);
• 0.35 kg is the assumed body weight of a rat (EHD, 1992);
• 6/24 is the conversion of 6 h/day to continuous exposure; and
• 500 is the uncertainty factor (× 5 for use of a LOEL (the effects observed at this concentration were not clearly adverse); × 10 for interspecies variation, × 10 for intraspecies variation). An additional factor for limited evidence of carcinogenicity was not incorporated since the observed effects in the critical study are not related to carcinogenesis and occur at concentrations considerably less than those that induce small increases in tumour incidence. Limited available data also indicate that humans form less of the putative toxic metabolite, styrene-7,8-oxide, and hydrolyze it more quickly than experimental animals; however, available data were insufficient to take these differences into account in the development of the uncertainty factor, and the relevance of this metabolite to developmental and neurotoxic effects is not clear.
  
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The most suitable study on which to base a TDI for the oral route of exposure is that conducted by Beliles et al. (1985), in which exposure of Sprague-Dawley rats to styrene in drinking water at 250 mg/L, but not 125 mg/L, over three generations, was embryo/foetotoxic. (Based on levels of styrene in the water, the mean doses estimated by the authors in a parallel chronic study, in which the exposure regimen was similar, were 21 and 12 mg/kg bw/day, respectively, in females.) The specific effects observed (reduced gestational survival, pup survival, or pup body weight) differed across generations, but in all instances were observed at the higher dose only. (A variety of other effects, including enzyme induction, histological changes in the liver or testes, and neurochemical or behavioural alterations, have been observed in animals following subchronic exposure to styrene, but at considerably higher doses, i.e., between 200 and 500 mg/kg bw/day [Section 2.5.1]). In addition to yielding the lowest LOAEL among the available studies, the study by Beliles et al. (1985) is also the one in which the exposure regimen is most relevant to humans, in that it included transplacental and lactational exposures. (Transfer of styrene across the placenta has been shown to occur in experiments with animals [Section 2.4], and the compound has been detected in the breast milk of women in the United States [Section 2.3.2].)

The lowest NOAEL for non-neoplastic effects in animals following oral exposure in an adequately conducted study is 12 mg/kg bw/day for reproductive effects in a three-generation study in Sprague-Dawley rats (Beliles et al., 1985). The TDI for oral exposure is, therefore, derived as follows:

where:

• 12 mg/kg bw/day is the NOAEL for reproductive effects (decreased gestational survival, pup survival, pup weight at the next highest dose) in rats exposed to styrene in drinking water in the three-generation study by Beliles et al. (1985); and
• 100 is the uncertainty factor (× 10 for interspecies variation, × 10 for intraspecies variation). An additional factor for limited evidence of carcinogenicity was not incorporated since the observed effects in the critical study are not related to carcinogenesis and occur at concentrations considerably less than those which induce small increases in tumour incidence. Limited available data also indicate that humans form less of the putative toxic metabolite, styrene-7,8-oxide, and hydrolyze it more quickly than experimental animals; however, available data were insufficient to take these differences into account in the development of the uncertainty factor and the relevance of this metabolite to effects on reproduction is not clear.

The estimated total average daily intake of styrene for various age groups in the Canadian general population ranges from < 0.20 to < 0.79 mg/kg bw/day overall. These estimates are from > 50- to > 200-fold less than the TDI derived above, based on inhalation studies in experimental animals exposed in utero, and from > 150- to > 600-fold less than the TDI derived from studies in which animals were exposed to styrene over 3 generations by the oral route. In addition, it should be noted that, due to the need to rely on detection limits for calculation of intakes from food, intake from this medium has been overestimated.

On the basis of the available data, it has been concluded that concentrations of styrene present in the Canadian environment do not constitute a danger in Canada to human life or health.

3.4 Conclusion

It has been concluded that the available information is insufficient to determine whether styrene is entering the environment in quantities or under conditions that may be harmful to the environment. It has, however, been concluded that styrene is not entering the environment in quantities or under conditions that may constitute a danger to the environment on which human life depends, or to human life or health.