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Final Report on Carcinogens Background Document for Styrene.

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Rep Carcinog Backgr Doc.2008 Sep ; (8-5978):i-398.
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Executive Summary: Introduction: Styrene is a viscous, highly flammable liquid used worldwide in the production of polymers, which are incorporated into products such as rubber, plastic, insulation, fiberglass, pipes, automobile parts, food containers, and carpet backing. Styrene was nominated for possible listing in the Report on Carcinogens by a private individual based on its widespread use and exposure and evidence of carcinogenicity from studies in humans and experimental animals. Human Exposure: The primary use of styrene is in the manufacture of polystyrene, which is used extensively in the manufacture of plastic packaging, thermal insulation in building construction and refrigeration equipment, and disposable cups and containers. Styrene also is used in styrene-butadiene rubber, other polymers, and resins that are used to manufacture boats, shower stalls, tires, automotive parts, and many other products. U.S. production of styrene has risen steadily over the past 70 years, with 11.4 billion pounds produced in 2006 (domestic production capacity for 2006 was estimated at 13.7 billion pounds). Styrene and styrene metabolites in blood and urine, and styrene-7,8-oxide-DNA adducts and styrene-7,8-oxide-hemoglobin adducts are generally accepted biological indices of exposure to styrene. The primary source of exposure to the general public is inhalation of indoor air; however, exposure can also occur from inhalation of outdoor air, ingestion of food and water, and potentially from skin contact. Tobacco smoke also can be a major source of styrene exposure for both active smokers and individuals exposed to environmental tobacco smoke. Outdoor and indoor air levels (including air levels in most other occupational settings) are generally below 1 ppb [0.001 ppm], although higher levels have been reported. Workers in certain occupations, including the reinforced-plastics , styrene-butadiene, and styrene monomer and polymer industries, are potentially exposed to higher levels of styrene than the general public. Air levels in the reinforced-plastics industry are generally lower than 100 ppm, [although much higher levels have frequently been measured], while levels in the styrene-butadiene industry and the styrene monomer and polymer industries have rarely been reported to exceed 20 ppm. Numerous Federal agencies have established regulations for styrene, including the Department of Homeland Security, DOT, EPA, FDA, and OSHA, and both ACGIH and NIOSH have established guidelines to limit occupational exposure to styrene. Human Cancer Studies: Numerous epidemiological studies have evaluated the relationship between styrene and cancer in humans. Most of the studies are cohort studies of workers in three major industries: (1) the reinforced-plastics industry, (2) the styrene-butadiene rubber industry, and (3) the styrene monomer and polymer industry. Two additional cohort studies (one on biomonitored workers, and the second on environmental exposure to styrene-butadiene), several case-control studies, and an ecological study have also been published. The limitations of these studies include potential misclassification of styrene exposure and disease, small numbers of long-term workers, inadequate follow-up, and the potential for co-exposure to other chemicals. Thus, although more than a hundred thousand workers have been studied to assess a possible carcinogenic effect of styrene exposure, only a small fraction of well-characterized, high-level, and long-term styrene-exposed workers have been followed for a sufficiently long time. In addition, most of the available studies of occupational cohorts have focused only on male workers (who constitute the majority of exposed workers) or have not performed gender-specific risk analyses. [Thus, comparatively few data are available on cancer incidence or mortality among exposed female workers, limiting the ability to evaluate breast cancer or cancers at tissue sites specific for females.] Workers in the reinforced-plastics industry have the highest levels of exposure and few other potentially carcinogenic exposures, but many of the workers in this industry have short-term exposure, often of less than a year. Cancer mortality or incidence was studied in the following four populations of reinforced-plastics workers: (1) in Washington state in the United States (Ruder et al. 2004), (2) in 30 manufacturing plants in unspecified U.S. locations (Wong et al. 1994), (3) in Denmark (Kolstad et al. 1994), and (4) in Europe (Denmark, Finland, Italy, Norway, United Kingdom, and Sweden) (Kogevinas et al. 1994a). (The Danish and the European populations were partly overlapping, as 13,682 Danish male workers were included among the 36,610 male workers making up the European cohort.) In the styrene-butadiene industry, the cohort studies are among the largest, with the longest follow-up times. The principal methodological challenge is to separate the potentially independent or synergistic effects of butadiene, a known human carcinogen, which is highly correlated with styrene in this industry. Two independent (non-overlapping populations) are available, a small cohort of 6,678 male workers at a rubber tire manufacturing plant (a subset of the workers were engaged in the production of styrene-butadiene and other rubbers) (McMichael et al. 1976a) and a larger cohort established by Delzell and colleagues (Delzell et al. 1996, 2006) of 13,130 to 16,610 styrene-butadiene rubber industry workers from multiple plants in the United States and Canada. The cohort established by Delzell includes most (but not all) of the workers from two cohorts - a 2-plant cohort (Texas) (Meinhardt et al. 1982) and an 8-plant cohort originally established by Matanoski and colleagues (United States and Canada) and reported in a series of previous publications (7 of the 8 plants were included in the Delzell cohort). Thus, there is considerable overlap between these populations. Two nested case-control studies (Matanoski et al.1997, Santos-Burgoa et al. 1992) of a single group of cases with lymphohematopoietic cancers were available from the Matanoski cohort. The Delzell cohort expanded the previous cohorts to include workers employed from 1943 to January 1, 1991 and followed to 1998, whereas the earlier cohort included workers employed until 1976 and followed until 1982. In addition, the individual study populations were established by different procedures and exclusion criteria (which may partly explain the lack of complete consistency in the number of study subjects across the published studies) and often used different exposure assessments, selection of study subjects, and types of analysis. Two types of analyses were conducted on the Delzell cohort: external analyses reporting on standardized mortality ratios (SMRs) for the total cohort or subsets of the cohorts for multiple cancers sites (Sathiakumar et al. 1998, 2005), and, secondly, internal analyses of relative risk (RR) estimates for quantitative exposure to styrene and lymphohematopoietic cancers (Delzell et al. 2001, 2006, Macaluso et al. 2006, Graff et al. 2005). (Dimethyldithiocarbamate [DMDTC] was also included as a potential confounder in some analyses of lymphohematopoietic cancer in the Delzell cohort, according to the authors, because of its potential immunosuppressant activity in CD4+ lymphocytes, although its carcinogenicity has not been evaluated outside of this series of studies). Workers in the styrene monomer and polymer industry may be exposed to a variety of chemicals, including benzene, toluene, ethylbenzene, and various solvents, and the cohorts are smaller, with many short-term workers, and few cancer outcomes. The potential effect of styrene on lymphohematopoietic cancers has been studied most extensively. Findings for lymphohematopoietic cancer and other tumor sites of interest are discussed below. Lymphohematopoietic cancers: Statistically significant increases were observed for all lymphohematopoietic cancers combined and leukemia among rubber-tire manufacturing workers (McMichael et al. 1976) and statistically nonsignificant increases were observed for combined lymphohematopoietic cancers and some specific lymphohematopoietic cancers in the Meinhardt and Matanoski cohorts, but the potentially confounding effects of butadiene and other exposures were not analyzed. Two nested case-control studies (using different types of analyses and exposure assessments and the same group of cases) from the Matanoski cohort attempted to evaluate the relative contribution of styrene and butadiene to lymphohematopoietic cancer mortality. Santos-Burgoa et al. (1992) found no significant excess risks for combined and specific lymphohematopoietic cancers and mean exposure after controlling for butadiene exposure. Matanoski et al. (1997) calculated risks for both average and cumulative exposure to styrene. Taking into account butadiene exposure, and demographic and employment variables in step-down regression analyses, these models found, for an average exposure of 1 ppm vs. no exposure, significant associations for all lymphohematopoietic cancers combined, lymphomas, and myeloma, but not leukemia. For cumulative exposure, significant positive associations between styrene exposure and combined lymphohematopoietic cancers, leukemia, and myeloma were found, with butadiene exposure dropping out of each of the final models except for leukemia. Specific lymphohematopoietic cancers have been studied more extensively in the Delzell cohort. With respect to leukemia, statistically significant increases have been reported among subgroups of workers with longer durations of employment and longer latency, with the highest cumulative exposure, and in certain specific job groups (Sathiakumar et al. 2005, Delzell et al. 2006). Internal analyses by Delzell et al. involving single-chemical (styrene only), 2-chemical (styrene and butadiene), and 3-chemical (styrene, butadiene, and DMDTC) models of cumulative exposure have shown increased relative risks of leukemia with increasing cumulative styrene exposure. However, the response was attenuated when controlling for exposure to butadiene and was no longer apparent (RRs were less than or equal to one) after additionally controlling for DMDTC. Elevated risks for leukemia were also observed with increasing exposure to styrene peaks in single-chemical, 2-chemical and 3-chemical models (although it was attenuated somewhat in the 2- and 3-chemical models) (Graff et al. 2005, Delzell et al. 2006). No statistically significant increased risks were found for other lymphohematopoietic cancers in all employees of the Delzell cohort, but statistically significant risks of NHL and CLL combined were found among workers with higher exposure in an external (SMR) analysis, and in internal analyses among ever-hourly workers, ever-hourly workers with 10+ years of employment and 20 to 29 years or 30 years since first hire, and among specific job groups. Risks of NHL or NHL and CLL combined appeared to increase with increasing cumulative styrene exposure; the risks increased when butadiene was added to the model, and were somewhat attenuated in models that included DMDTC. Exposure to butadiene did not appear to be related to NHL and CLL combined or NHL risk. [However, it should be noted that no trend analyses were performed on these data.] (Graff et al. 2005, Delzell et al. 2006). No associations were found for other types of lymphohematopoietic cancers and styrene exposure in the Delzell cohort. In the reinforced-plastics industry, among the highest-exposure groups, the total number of observed versus expected deaths or cases across the four cohorts were comparable for all lymphohematopoietic (52 observed vs. 52.8 expected), lymphomas (14 vs. 15.1), or leukemia (19 vs. 19.8), and were slightly higher than expected for Hodgkin's disease (11 observed vs. 7.9 expected) and multiple myeloma (4 vs. 3.4). Significantly increased risks for leukemia incidence were reported in the Danish study among workers with earlier first date of exposure, and who had worked at least 10 years since first employment, but not for workers employed for 1 year or more (Kolstad et al. 1994). In the European multi-country cohort (which overlaps with the Danish study), no excess of leukemia mortality was found, and no exposure-response relationships with cumulative or average exposure were observed, although a non-significant trend was observed with time since first exposure (Kogevinas et al. 1994a). With respect to other lymphohematopoietic cancers, non-significantly increased risks for non-Hodgkin's lymphoma were found in the Danish and European multi-country cohorts. Positive exposure-response relationships with average styrene exposure and time since first exposure was observed for lymphohematopoietic cancers (P = 0.019 and 0.012, respectively) and for malignant lymphoma (P = 0.052 and 0. 072, respectively) in the European multi-country cohort, but no relationship with cumulative exposure was observed (Kogevinas et al. 1994a). No excesses in mortality from any lymphohematopoietic cancers were observed in the two smaller cohort studies (Ruder et al. 2004 and Wong et al. 1994). In the styrene monomer and polymer industries, the risk of lymphohematopoietic malignancies was also increased in most of the studies (as well as the total number of observed cases across studies), but these workers might also have been exposed to benzene. Pancreatic cancer: Among the highest styrene-exposed group in the reinforced-plastics industry, there was an excess in the total number of observed cases of pancreatic cancer across the four cohort studies compared with the total number of expected cases [corresponding to an SMR of 1.77 (95 % CI = 1.23 to 247)]. Increases in pancreatic cancer risk were observed in three of the four reinforced-plastics industry cohorts (one of which was statistically significant [Kolstad et al. 1995], and the other two of which were nonsignificant [Kogevinas et al. 1994a, Ruder et al. 2004]). The risk of pancreatic cancer was slightly higher among the Danish workers with longer term employment and earlier start date, and increased with cumulative exposure in the multi-plant cohort. No indications of exposure-response relationships were found in the smaller U.S. cohorts. Statistically nonsignificant increased risks were also observed in one study in the styrene monomer and polymer industry (Frentzel-Beyme et al. 1978), and among biomonitored workers (10 years after the first measurement) (Anttila et al. 1998). However, no increased risk of pancreatic cancer was reported among styrene-butadiene workers (Sathiakumar et al. 2005). Esophageal cancer: Among workers with high potential exposure to styrene, increases in esophageal cancer risk were reported in three of the four cohorts (statistically significant increases in mortality were observed among all exposed workers in the two U.S. studies of reinforced-plastics workers [Ruder et al. 2004, and Wong et al. 1994] and a statistically nonsignificant increase among a subset of laminators in the European cohort [Kogevinas et al. 1994a]). Risks were not elevated among the Danish reinforced-plastics workers (Kolstad et al. 1994). Across the industry, an approximately 2-fold excess of esophageal cancer was observed among high-exposed groups (laminators and others). A nonsignificant trend with cumulative exposure was reported in the European multi-country study. No increases in risk were reported among styrene-butadiene rubber workers or among styrene monomer and polymer workers. Other sites: Findings were less consistent for cancer at other sites. Significantly increased risks were observed for cancers of the lung, larynx, stomach, benign neoplasms, cervix and other female tumors, prostate, rectum, and urinary system in either a single study or two studies. There were some supporting exposure-response data for cancers of the urinary system and rectum. A significant increase in breast cancer mortality was observed in a case-control study of occupational exposures among adult females (Cantor et al. 1995), although there was no evidence of increased risk between low- and high-exposure categories. An ecological study reported a significant increase in the risk of invasive breast cancer in the general population, but exposure estimates were based on environmental releases of styrene, which are the least precise measures of exposure. Studies in Experimental Animals The carcinogenicity of styrene in rats and mice has been investigated by several routes of exposure. Other relevant studies in experimental animals include studies of mixtures (beta-nitrostyrene and styrene) and studies of the major metabolite of styrene, styrene-7,8-oxide (styrene oxide). Mice: Three strains of mice were exposed to styrene by gavage. In male B6C3F1 mice, exposure to styrene for 5 days per week for 78 weeks was associated with a significantly increased incidence of alveolar/bronchiolar adenoma and carcinoma (combined) in high-dose (300 mg/kg) animals, and a significant positive dose-response trend was observed (NCI 1979a). NCI questioned the significance of these lung tumors because the incidence in the control group was unusually low compared with historical untreated controls, and only small numbers of vehicle historical controls were available from the same testing laboratory. [However, a larger number of vehicle (corn oil)-treated historical controls from this same time period (prior to 1979), with similar study duration, and from the same source as the styrene study were available from a different testing laboratory. Results from these historical vehicle controls indicated that the concurrent vehicle controls in the NCI study were not unusually low and the lung tumor incidence in the high-dose group was significantly increased compared with those historical controls.] There also was a significant dose-response trend for hepatocellular adenomas in female B6C3F1 mice, but no significant pair-wise comparisons were observed. The other gavage study included a single dose of styrene administered to pregnant dams on gestation day 17 and weekly exposures of the pups after weaning (Pomomarkov and Tomatis 1978). O20 mice (a strain with a high spontaneous incidence of lung tumors) were dosed at 1,350 mg/kg and C57Bl mice were dosed at 300 mg/kg. A significantly higher incidence and earlier onset of lung tumors (adenoma and carcinoma combined) occurred in both male and female O20 mice compared with vehicle controls. Tumor incidence was not significantly increased in C57Bl mice. Significantly increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) occurred in male CD-1 mice at inhalation exposure concentrations of 40 to 160 ppm over a period of 104 weeks and in female mice at exposure concentrations of 20, 40, and 160 ppm over a period of 98 weeks (Cruzan et al. 2001). Female mice in the high-dose (160-ppm) group also had increased incidences of alveolar/bronchiolar carcinoma. No increased incidences of tumors were observed in female A/J mice (also a strain susceptible to lung tumors) treated with 20 intraperitoneal injections of styrene over 7 weeks (total dose of 200 mumol [approximately 100 mg/kg b.w.]) and evaluated 20 weeks after the last injection (Brunnemann et al. 1992). Rats: Several of the studies in rats were limited because of short duration, high mortality, incomplete histopathology, or incomplete reporting. None of the carcinogenicity studies reviewed in rats showed evidence of lung tumors, and none of the gavage (NCI 1979a, Pomomarkov and Tomatis 1978, Conti et al. 1988), or intraperitoneal or subcutaneous injection studies (Conti et al. 1988) reported an increased incidence in any tumor type. An oral gavage study in F344 rats (NCI 1979a) and an inhalation study in Sprague-Dawley rats (Cruzan et al. 1998) were the most robust and most completely reported carcinogenicity studies. Neither study showed an increase in tumor incidences in styrene-exposed rats, although Sprague-Dawley rats exhibited a negative trend in pituitary and mammary gland tumors and a positive trend for testicular interstitial-cell tumors. In another inhalation study in Sprague-Dawley rats, there was a dose-related increase in the incidences of malignant mammary gland tumors; treatment-related and statistically significant incidences of these tumors were seen in the top three dose groups (Conti et al. 1988). A drinking-water study did not report any dose-related carcinogenic effects (Beliles et al. 1985). However, statistical reanalyses of study data indicated a marginal increase in the incidence of mammary fibroadenoma in high-dose female rats and a significant dose-related trend. Another inhalation study (Jersey et al. 1978) [unpublished but reviewed in several published reports] indicated that styrene was associated with a statistically significant increase in incidence of mammary adenocarcinoma in the low- (600-ppm) but not high-dose (1000-ppm) group and a significant increase (when compared with historical but not concurrent controls) in the combined incidence of lymphosarcoma and leukemia in female rats in both the 600-ppm and 1000-ppm dose groups. The authors did not consider the mammary adenocarcinomas to be causally associated with styrene exposure because the incidence of mammary adenocarcinoma was low compared with historical controls and there was no incidence of mammary adenocarcinoma in the high-dose group. Elevated incidences of leukemia/lymphosarcoma were observed in both treatment groups of female Sprague Dawley rats in this inhalation study. Mixtures and Metabolite Studies: No increase in tumor incidence was observed in rats exposed by gavage (3 days per week) to a mixture of 70% styrene and 30% beta-nitrostyrene over 78 weeks (NCI 1979b), but an increased incidence of lung tumors was observed in male mice in the 175 mg/kg dose group, but not in the 350 mg/kg dose group exposed to this styrene/beta-nitrostyrene mixture. [However, because of poor survival of the high-dose male mice there were substantially fewer animals at risk for late-occurring tumors.] The styrene metabolite, styrene-7,8-oxide, was previously evaluated for carcinogenicity and is listed in the Report on Carcinogens [first listed in the 10th Report on Carcinogens, 2002] as reasonably anticipated to be a human carcinogen based on forestomach tumors in rats and mice and liver tumors in male mice. Absorption, Distribution, Metabolism, and Excretion: Styrene can be absorbed through inhalation, ingestion, or skin contact, but the most important route of exposure in humans in occupational settings is by inhalation, which results in rapid absorption and distribution of approximately 60% to 70% of inhaled styrene; the highest tissue concentrations are in subcutaneous fat. Food is also an important source of exposure for the general population. Metabolic activation of styrene results in formation primarily of the genotoxic metabolite styrene-7,8-oxide, which can be detoxified by glutathione conjugation or conversion to styrene glycol by microsomal epoxide hydrolase. Styrene is metabolized in both the liver and the lung, and the Clara cells in the lung are regarded as the major cell type in styrene activation following inhalation exposure. The initial step in styrene metabolism is catalyzed by cytochromes P450; CYP2E1 and Cyp2f2 are the predominant enzymes in humans and experimental animals. In animals, CYP2E1 predominates in liver, while Cyp2f2 is the primary enzyme in mouse lung. CYP2A13, CYP2F1, CYP2S1, CYP3A5, and CYP4B1 are preferentially expressed in the lung compared with liver in humans, and the human CYP2F1 has been shown to be capable of metabolizing styrene when expressed in vitro. Because styrene-7,8-oxide contains a chiral carbon, this and some subsequent styrene metabolites can exist as either R- or S-enantiomers. A second metabolic pathway through styrene-3,4-oxide results in formation of 4-vinylphenol, which has been detected in humans, rats, and mice in vivo, but the importance of 4-vinylphenol in styrene toxicity has not been well characterized. Almost all absorbed styrene is excreted as urinary metabolites, primarily mandelic acid and phenylglyoxylic acid. Species differences exist among rats, mice, and humans in the metabolism and toxicity of styrene, which may be related, at least in part, to interspecies differences in the stereochemistry of metabolism. The R-enantiomer, which has been suggested by some reports to be more toxic than the S-form, has been reported to be produced in relatively larger amounts in mouse lung than in rat lung, but the difference was less pronounced when microsomal preparations were used. In mice, the R-isomer of styrene-7,8-oxide was significantly more hepatotoxic than the S-isomer; the toxicity of the R-isomer also was greater in the lung, but the difference was not statistically significant. Toxicity: Styrene exposure has been associated with numerous health effects in humans and laboratory animals. The acute toxicity of styrene is low to moderate with an oral LD50 of 320 mg/kg and an inhalation LC50 of 4,940 ppm (4-hour exposure) in mice and an oral LD50 of 5,000 mg/kg and an inhalation LC50 of 2,770 ppm (2-hour exposure) in rats. The primary effects of acute exposure to styrene in experimental animals and humans include irritation of the skin, eyes, and respiratory tract and CNS effects. Drowsiness, listlessness, muscular weakness, and unsteadiness are common signs of systemic styrene intoxication. Several studies have reported effects on color vision, hearing threshold, reaction time, and postural stability following long-term occupational exposure to styrene at concentrations ranging from about 20 to 30 ppm. Reports of ischemic heart disease and hepatic, renal, hematological, and immunological effects have been inconsistent. Human data are insufficient to determine whether styrene is a reproductive or developmental toxicant, but effects of styrene to increase serum prolactin levels in humans have been reported. Styrene toxicity in experimental animals is similar to that reported in humans. Exposure to styrene vapors can cause eye and respiratory tract irritation, CNS depression, and death. Clara cells are the main target of styrene pneumotoxicity, and the available data indicate increased susceptibility in the mouse. Glutathione depletion as a result of styrene exposures has been reported to be associated with damage to lung, liver, and kidney tissues. The cytotoxicity of styrene in the mouse lung, a tissue high in CYP2F isoforms, could be prevented by CYP2F inhibitors. Some studies have reported reproductive and developmental effects, but these effects were seen mostly at doses associated with maternal toxicity. Reported effects have included embryonic, fetal, and neonatal death, skeletal and kidney abnormalities, decreased birth weight, neurobehavioral abnormalities, and postnatal developmental delays. The possibility of polystyrene dimer and trimer extracts from food containers mimicking the physiological effects of estrogen have also been investigated, but with a mixture of positive and negative results. Genetic Damage: In vitro studies show that styrene-7,8-oxide forms DNA adducts and causes single-strand breaks in a dose-related manner. Several studies have shown a correlation between single-strand breaks and DNA adducts and indicate that the strand breaks, which are not generally regarded as significantly lethal or mutagenic lesions, are efficiently repaired within several hours after exposure has stopped. Adducts are formed primarily at the N7-, N2-, and O6-positions of guanine. N7-adducts are formed in the greatest amount but are the least persistent, while O6-adducts are formed in the least amount but are the most persistent. Styrene-7,8-oxide was mutagenic without metabolic activation in all in vitro mutagenicity test systems reported and caused mutations in some studies in the presence of metabolizing enzymes. Both styrene and styrene-7,8-oxide caused cytogenetic effects (sister chromatid exchange [SCE], chromosomal aberrations, and micronuclei) in human lymphocytes or other mammalian cells in vitro. DNA adducts have been detected in liver and lung cells of mice and rats exposed to styrene in vivo, although the levels varied across studies. The majority of studies in experimental animals demonstrated an effect of both styrene-7,8-oxide and styrene exposure on single-strand breaks, while both positive and negative results for cytogenetic or clastogenic effects of styrene were reported. DNA adducts, primarily N7- and O6-adducts, were reported in white blood cells in all studies of styrene-exposed workers employed mainly in hand-lamination plants. In most studies in workers, single-strand breaks showed exposure-related increases; however, two studies gave negative results. The limited data on mutation frequencies in HPRT and GPA in styrene-exposed workers are inconclusive. More than half the studies measuring chromosomal aberrations have reported an increase in chromosomal aberrations in styrene-exposed workers (or subgroups of workers), and several studies have reported a positive exposure-response relationship with styrene air levels or urinary metabolites. A meta-analysis of 22 studies found a positive association between styrene exposure level and chromosomal aberration frequency when exposure levels were dichotomized as greater than or less than a threshold value of 30 ppm for an 8-hour time-weighted average. Studies of other cytogenetic markers in humans are conflicting. About half of the studies that evaluated micronucleus and SCE frequency in styrene workers were positive, and a few studies have reported significant dose-response relationships with styrene exposure. A meta-analysis of 10 micronucleus studies was inconclusive, and a meta-analysis of 14 SCE studies indicated a slight increase in SCE frequency but, again, was too small to be conclusive. A number of studies have been published on the possible modulating role of genetic polymorphisms, mainly in xenobiotic metabolism enzymes and DNA-repair genes, at the level of various biomarkers. Some authors have suggested that genetic susceptibility (probably at many loci) may be important in styrene-mediated genotoxicity. Mechanistic Data: The proposed mechanisms for the carcinogenicity of styrene include both genotoxic and epigenetic pathways. These mechanisms, which are not necessarily mutually exclusive, include: (1) metabolic conversion of styrene to styrene-7,8-oxide and subsequent induction of DNA damage in the target tissue and (2) cytotoxic effects of styrene metabolites in the mouse lung. A variety of DNA adducts (including some at base-pairing sites on nucleotides) induced by styrene and styrene-7,8-oxide has been identified in human cells, experimental animals, and occupationally exposed workers, but the covalent binding indices for both molecules are relatively low in rats and mice. The DNA damage induced by styrene exposure, including single-strand breaks, was found to correlate significantly with markers of styrene exposure in some studies of styrene workers. Styrene is mutagenic through the formation of styrene-7,8-oxide (in vitro). A number of studies reported a positive association between occupational exposure to styrene and the frequency of chromosomal aberrations, with some studies reporting exposure-response relationships. Some authors have suggested that polymorphisms in DNA-repair genes could put some individuals at higher risk for styrene genotoxicity or carcinogenicity. Many researchers have tried to explain why lung tumors were observed in mice but not in rats in long-term inhalation exposure studies. Some researchers have proposed that styrene exposure causes pulmonary hyperplasia in the mouse lung, which may play a role in the development of lung tumors. Effects of repeated styrene exposure observed in the lungs of mice, but not in rats, included focal crowding of bronchiolar cells, bronchiolar epithelial hyperplasia, and bronchiolo-alveolar hyperplasia. The Harvard Center for Risk Analysis (Cohen et al. 2002) considered three factors as possible explanations for the greater susceptibility of mouse lung than rat lung to development of hyperplasia leading to tumors with exposure to styrene are: (1) the presence of the styrene-metabolizing cytochromes in mouse lung tissues, (2) greater formation of the R-enantiomer of styrene-7,8-oxide, and (3) the susceptibility of mouse lung tissue to glutathione depletion. However, they concluded that although toxicokinetic models generally predict higher rates of metabolism by mice and rats than by humans, the models do not consistently predict a difference between the rodent species. An alternative mechanism is that interspecies differences in styrene toxicity are most likely explained through CYP2F-generated metabolites (2f2 in mice, 2F4 in rats, and 2F1 in humans) in the mouse lung. This is based on data showing that most of the effects of cytotoxicity and tumor formation were seen in mouse respiratory tissues, which are high in CYP2F isoforms, and that CYP2F inhibitors prevented cytotoxicity. Moreover, metabolites formed from ring oxidation, including 4-vinylphenol, are about 6-fold higher in mice compared with rats, and 4-vinylphenol is more potent than styrene-7,8-oxide as a pneumotoxicant.
PMID: 20737009 [PubMed - as supplied by publisher]
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