3

Independent Assessment of Styrene

The committee’s task had two parts. The first was to review the styrene substance profile as it was presented in the National Toxicology Program (NTP) 12th Report on Carcinogens (RoC) (NTP 2011a). In Chapter 2 of this report, the committee considered only literature that was available to NTP (literature published by June 10, 2011). It reviewed the primary literature, assessed NTP’s description and analysis of that literature, and determined whether NTP’s arguments support the conclusion that styrene is “reasonably anticipated to be a human carcinogen”.

To address the second part of its task, the committee carried out an independent assessment of styrene carcinogenicity, which is the focus of the present chapter. The committee used its peer review in Chapter 2 and the background document that supports the styrene profile in the 12th RoC as a starting point. The present chapter provides a brief summary of informative studies and highlights key data that informed its independent assessment of styrene. The reader is also referred to the background document (NTP 2008) for a more detailed discussion of study methodologies, strengths, and weaknesses for literature published prior to 2011 and to the primary literature.

The committee’s independent assessment of styrene carcinogenicity was based on literature that included primary data; however, the committee used published peer-reviewed review articles and reviews by other authoritative bodies to ensure that relevant literature was not missed and that all plausible interpretations of primary data were considered. The committee also considered comments and arguments that were presented during its first meeting, comments received from outside stakeholders during the study process, and independent literature searches carried out by National Research Council staff. The goal of the literature searches was to identify relevant literature that may have missed inclusion in the 12th RoC and relevant literature that was published after the release of the 12th RoC. Each search began on January 1, 2008, the year in which the background document for styrene was published (Bucher 2013). The search was first run on May 28, 2013, and it was updated on November 13,



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3 Independent Assessment of Styrene The committee’s task had two parts. The first was to review the styrene substance profile as it was presented in the National Toxicology Program (NTP) 12th Report on Carcinogens (RoC) (NTP 2011a). In Chapter 2 of this report, the committee considered only literature that was available to NTP (literature pub- lished by June 10, 2011). It reviewed the primary literature, assessed NTP’s de- scription and analysis of that literature, and determined whether NTP’s argu- ments support the conclusion that styrene is “reasonably anticipated to be a human carcinogen”. To address the second part of its task, the committee carried out an inde- pendent assessment of styrene carcinogenicity, which is the focus of the present chapter. The committee used its peer review in Chapter 2 and the background document that supports the styrene profile in the 12th RoC as a starting point. The present chapter provides a brief summary of informative studies and high- lights key data that informed its independent assessment of styrene. The reader is also referred to the background document (NTP 2008) for a more detailed discussion of study methodologies, strengths, and weaknesses for literature pub- lished prior to 2011 and to the primary literature. The committee’s independent assessment of styrene carcinogenicity was based on literature that included primary data; however, the committee used published peer-reviewed review articles and reviews by other authoritative bod- ies to ensure that relevant literature was not missed and that all plausible inter- pretations of primary data were considered. The committee also considered comments and arguments that were presented during its first meeting, comments received from outside stakeholders during the study process, and independent literature searches carried out by National Research Council staff. The goal of the literature searches was to identify relevant literature that may have missed inclusion in the 12th RoC and relevant literature that was published after the release of the 12th RoC. Each search began on January 1, 2008, the year in which the background document for styrene was published (Bucher 2013). The search was first run on May 28, 2013, and it was updated on November 13, 57

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58 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens 2013.1 Databases searched were PubMed, Medline (Ovid), Embase (Ovid), Sco- pus, and Web of Science. The search strategy for each database and the exclu- sion criteria are described in greater detail in Appendix D. After identifying the relevant body of literature up to November 13, 2013, the committee reviewed the primary data and applied the RoC listing criteria to human, experimental animal, and mechanistic studies. It then integrated the evidence to develop its own independent listing recommendation for styrene. Consideration was given to all relevant information, including “dose response, route of exposure, chemi- cal structure, metabolism, pharmacokinetics, sensitive sub-populations, genetic effects, or other data relating to mechanism of action or factors that may be unique to a given substance” (NTP 2011b). In accordance with the listing criteria, expert judgment was used to inter- pret and apply the RoC listing criteria to evidence in human and animal studies. A substance can be classified in the RoC as “known to be a human carcinogen” if “there is sufficient evidence of carcinogenicity from studies in humans, which indicates a causal relationship between exposure to the agent, substance, or mix- ture, and human cancer” (NTP 2008, p. v). A substance can be classified in the RoC as “reasonably anticipated to be a human carcinogen” if at least one of the following three criteria are fulfilled (NTP 2008, p. v):  “There is limited evidence of carcinogenicity from studies in humans, which indicates that causal interpretation is credible, but that alternative explanations, such as chance, bias, or confounding factors, could not adequately be excluded.”  “There is sufficient evidence of carcinogenicity from studies in experi- mental animals, which indicates there is an increased incidence of ma- lignant and/or a combination of malignant and benign tumors (1) in multiple species or at multiple tissue sites, or (2) by multiple routes of exposure, or (3) to an unusual degree with regard to incidence, site, or type of tumor, or age at onset.”  “There is less than sufficient evidence of carcinogenicity in humans or laboratory animals; however, the agent, substance, or mixture belongs to a well-defined, structurally related class of substances whose mem- bers are listed in a previous Report on Carcinogens as either known to be a human carcinogen or reasonably anticipated to be a human carcin- ogen, or there is convincing relevant information that the agent acts through mechanisms indicating it would likely cause cancer in hu- mans.” 1 The cut-off date for the literature search was chosen to allow the committee time to review the literature within the time constraints of the project schedule.

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Independent Assessment of Styrene 59 As discussed in Chapter 2, the type of information needed to meet the criterion for sufficient evidence in experimental animals is clear and transparent. The type of information needed to meet the criterion for limited or sufficient evidence in hu- mans required more interpretation and expert judgment on behalf of the commit- tee. In its evaluation of the epidemiology literature, the committee described the information it used to identify informative studies and to evaluate those studies. This chapter begins with a section on metabolism and toxicokinetics. It then reviews cancer studies in humans, cancer studies in experimental animals, and mechanistic data. The chapter ends with a section that summarizes the evi- dence and provides a final conclusion and listing recommendation for styrene that is based on the listing criteria published in the 12th RoC. METABOLISM AND TOXICOKINETICS The absorption, distribution, metabolism, and excretion of styrene have been reviewed by several organizations (Sumner and Fennell 1994; IARC 2002; Vodicka et al. 2006; NTP 2008). In brief, as expected for a lipid-soluble hydro- carbon, styrene is absorbed after inhalation, ingestion, or dermal exposure. In- creased blood concentrations of styrene or styrene metabolites have been ob- served in experimental subjects and workers exposed to styrene. Concentrations of styrene in the blood increase rapidly after the onset of exposure and decay over the course of several hours after termination of the exposure (see the back- ground document for styrene [NTP 2008] for more information). Styrene is ex- tensively metabolized, and metabolites are excreted in urine. Humans and ro- dents differ quantitatively in whole-body metabolism and excretion, but styrene metabolic pathways are qualitatively similar in rodents and humans (IARC 2002; Vodicka et al. 2006). Several pharmacokinetic and physiologically based pharmacokinetic models of inhaled styrene absorption and metabolism have been developed (Filser et al. 2002; Sarangapani et al. 2002; Chen et al. 2008; NTP 2008; Verner et al. 2012). Metabolic activation is thought to be essential for styrene toxicity and car- cinogenicity (IARC 2002; Vodicka et al. 2006; NTP 2008, 2011a). The balance between the metabolic activation rate and the detoxification rate in a specific target tissue is critical in determining the ultimate response. This section pro- vides information on styrene phase I metabolism (metabolic activation), infor- mation on phase II (detoxification) pathways, and then a summary. Multiple target sites are relevant to the carcinogenic hazard posed by sty- rene. In humans, styrene exposure is associated with cancer of the lymphohema- topoietic system, esophagus, pancreas, and kidney (see the section “Epidemio- logic Studies” below). In mice, styrene causes lung tumors, but statistically significant increases in tumor burden were not observed for other sites. The metabolic pathways that are likely to be important in the carcinogenic response are fairly well defined (and described below), but there is no comprehensive information on activation and detoxification rates in potential target tissues in the human.

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60 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens Phase I: Metabolism Styrene is metabolically activated by cytochrome P450 monooxygenase (CYP450)-dependent oxidation on the side chain to form styrene-7,8-oxide (see Figure 3-1). Because this molecule contains an asymmetric carbon, there are two enantiomers, R- and S-styrene-7,8-oxide. Styrene aromatic ring metabolites are also formed, including 4-vinylphenol (presumably through styrene-1,2-oxide) and 2-vinylphenol (presumably through styrene-2,3-oxide). Of those pathways, sty- rene-7,8-oxide and 4-vinylphenol have been the most studied. It is possible that styrene-7,8-oxide and its initial detoxification products are further metabolized, perhaps through ring oxidation, and that 4-vinylphenol is also metabolized (Carl- son et al. 2001; Carlson 2004, 2012; Cruzan et al. 2012, 2013). In the rodent, 14C- labeled CO2 is exhaled after 14C-styrene administration; this suggests that aromatic ring–opened metabolites are formed (Boogaard et al. 2000a). The precise struc- tures and toxicologic roles of those downstream metabolites are not fully charac- terized. In humans, styrene-7,8-oxide-based metabolic products form over 90% of the excreted metabolites of styrene (see below). That is clear evidence that sty- rene-7,8-oxide is the primary phase I metabolite in humans. Ring oxidation to 4- vinylphenol also occurs but to a much smaller extent. Sulfate and glucuronide conjugates of 4-vinylphenol have been identified in urine of humans but at low concentrations (less than 1% of the excreted metabolites) (IARC 2002; Vodicka et al. 2002a; NTP 2008). Aromatic ring metabolites may be critical with respect to cytotoxic or genotoxic effects in specific target organs even though they con- stitute only a minor pathway with respect to whole-body metabolism of styrene. Multiple forms of human CYP450 are reported to catalyze styrene oxida- tion, albeit with different activities, including CYP1A2, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2E1, CYP2F1, CYP2S1, CYP3A3, CYP3A4, CYP3A5, and CYP4B1 (Nakajima et al. 1994; Vodicka et al. 2006; Carlson 2008; Fukami et al. 2008; NRC USCG 2008; Bui and Hankinson 2009). Multi- ple recent studies have shown associations of polymorphisms in selected CYPs with the pattern of urinary styrene metabolite excretion; although the studies suggest a role of CYPs in styrene metabolism, they did not examine associations with disease outcome. Two CYP2E1 binding sites with allosteric interactions result in a shift to more efficient metabolism as styrene concentration increases. Many of the aforementioned CYPs are expressed in nonhepatic tissues, and this indicates that styrene may be metabolically activated in multiple organs in hu- mans. Because styrene produces lung tumors in mice, a focus of investigation has been on pulmonary metabolism in mice. Styrene is extensively metabolized in the mouse liver and lung (primarily in Clara cells) by multiple forms of CYP, including CYP2E1 and CYP2F2 (Carlson 2004, 2008, 2012; Shen et al. 2010; Cruzan et al. 2012, 2013). Both side chain and aromatic ring metabolites are probably formed in the lung. In the mouse, CYP2F2 may be particularly im- portant in activation of styrene (Cruzan et al. 2012, 2013). Investigations of the role of CYP2F2 in the pulmonary response to styrene have focused solely on

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Independent Assessment of Styrene 61 cytotoxicity and short-term cell proliferation, and its role is critical in both these processes in the mouse lung. It is important to consider, however, that cytotoxi- city and short-term cell proliferation responses may not be the sole determinants of the ultimate tumorigenic response and, in this context, the role of this CYP in lung tumorigenicity in mice remains uncertain. OH Conjugates CH CH3 1-Phenylethanol CH CH2 CH CH2 CH CH2 H2O O + H H Styrene CH2 CH2OH O H 2-Phenylethanol Styrene-1,2-oxide Styrene-3,4-oxide H H CH CH2 CH CH2 C CH2 CH2 C O O OH HO 2-Vinylphenol 4-Vinylphenol Styrene-7,8-oxide Phenylacetaldehyde ? GS OH CH2 COOH CH CH2 CH CH2 OH + GS N OH Phenylacetic acid C CH2 GSH conjugate 1 GSH conjugate 2 OH Phenylethylene glycol O 1-Phenyl- 2-Phenyl- (styrene glycol) 2-hydroxy 2-hydroxy CH2 C N CH2 COOH ethylmercapturic ethylmercapturic acid acid Glucuronide acetate H H Phenylaceturic acid C COOH COOH OH O Mandelic acid Benzoic acid C N CH2 COOH H Hippuric acid O C COOH Phenylglyoxilic acid FIGURE 3-1 Primary metabolic pathways of styrene. Main pathways are indicated by thick arrows. Metabolites that have been extensively studied are highlighted in the boxes. This figure is not a complete depiction of all known metabolites. A similar figure can be found in the background document for styrene (NTP 2008). GSH, glutathione. Source: Adapted from IARC (2002).

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62 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens Styrene-7,8-oxide is genotoxic (see below). Metabolites derived from sty- rene-7,8-oxide are excreted in urine after styrene exposure; this is a clear indica- tion that it is formed in humans. Moreover, styrene-7,8-oxide is detected in ve- nous blood in humans and rodents after styrene exposure (NTP 2008), so it can probably migrate from the organ in which it was formed. The presence of sty- rene-7,8-oxide in the blood indicates widespread exposure to this genotoxic me- tabolite throughout the body. In humans, styrene-7,8-oxide–hemoglobin adducts and styrene-7,8-oxide–DNA adducts in lymphocytes have been observed, possi- bly because of circulating styrene-7,8-oxide or the generation of styrene-7,8- oxide in circulating blood cells (NTP 2008, 2011a). Nonenzymatic epoxidation of styrene, perhaps via oxyhemoglobin, may occur in erythrocytes (Tursi et al. 1983). As in the human, styrene-7,8-oxide is present in blood of both rats and mice exposed to styrene. Styrene exposure does not induce tumors in the rat and a statistically significant increase in tumors was only observed in the lungs of mice. The reasons for this are unclear. Styrene-7,8-oxide-based DNA adducts are formed in mouse lung after styrene exposure (Boogaard et al. 2000b), but their role in lung tumorigenesis in mice is not known. The amount of DNA ad- ducts found in the lung vs liver in the mouse or in the rat lung vs mouse lung does not correlate with the target organ or a specific-species tumor response (Cruzan et al. 2009). However, inasmuch as adduct formation is the first of mul- tiple steps of tumor development, a direct relationship between adduct concen- trations and tumor response among species or organs is not necessary. The lack of direct concordance between styrene-7,8-oxide-adduct concentrations and tu- mor formation does not exclude the potential role of these adducts in the pulmo- nary carcinogenic response in mice. Styrene is also metabolized via oxidation of its aromatic ring. Although a minor component, 4-vinylphenol-derived metabolites are present in urine after styrene exposure (NTP 2008, 2011a; Linhart et al. 2010, 2012). The aromatic ring–derived metabolite 4-vinylphenol is more potent than styrene or styrene- 7,8-oxide in inducing pulmonary toxicity (Carlson 2002, 2004; Cruzan et al. 2005). This metabolite is thought to be formed by CYP2E1 and CYP2F2 in ro- dents (Carlson et al. 2001). 4-Vinylphenol is further metabolized by epoxidation in the rodent liver and lung (Zhang et al. 2011). Although it is not known with absolute certainty, aromatic ring–derived metabolites are likely important in the pneumotoxicity of styrene in mice (Cruzan et al. 2009, 2012, 2013). Information is not available on target organ–specific formation of aromatic ring metabolites in humans. The genotoxicity of these metabolites has not been extensively in- vestigated. Phase II: Detoxification The side-chain–based or aromatic ring–based phase I metabolic oxidative products of styrene can be detoxified by hydrolysis via epoxide hydrolase or gluta- thione conjugation. Styrene-7,8-oxide is metabolized by epoxide hydrolase to

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Independent Assessment of Styrene 63 form styrene glycol, which can be converted to mandelic acid and phenylglyoxylic acid (Figure 3-1). Those two products are excreted in urine and account for more than 90% of the excreted styrene metabolites in humans (Vodicka et al. 2006; NTP 2008, 2011a). Information is not available on the pharmacogenetics of epox- ide hydrolase relative to styrene disposition in humans; however, microsomal epoxide hydrolase knockout mice are more sensitive to styrene-induced cytotoxi- city, and this highlights its potentially important role (Carlson 2010b, 2011a). Glu- tathione-based conjugates of styrene metabolites are also formed; they account for less than 10% of the excreted metabolites in humans but may account for more than 30% of the excreted metabolites in rodents (NTP 2008; Vodicka et al. 2006). Studies in mice that are deficient in glutathione-S-transferase P1P2 (-/-) suggest that this form is not important in styrene detoxification, but other forms of gluta- thione-S-transferase may still have a role in detoxification (Carlson 2011b). Some evidence suggests that expression of glutathione-S-transferase M1 and T1 in hu- mans may contribute to individual variability in the fraction of styrene-7,8-oxide that is conjugated to glutathione (Haufroid et al. 2002; Teixeira et al. 2004; Fusti- noni et al. 2008; Vodicka et al. 2006). Further information on the precise phase II activities of styrene in critical target cells is not available. Summary of Styrene Metabolism and Toxicokinetics Metabolism of styrene is key to its toxic and carcinogenic responses. The organ-specific tumorigenic responses to styrene will depend, in large part, on the balance between the rate of activation and the rate of detoxification in each or- gan. Thorough information on styrene activation and detoxification rates specif- ic to target sites, particularly in the human, is not available. Given the wide array of CYP450 isozymes that can oxidize styrene, including forms that are known to be expressed in extrahepatic tissues (for example, CYP2E1 and CYP2A13), it is not possible to exclude the possibility that styrene bioactivation can occur in multiple target tissues. The presence of styrene-7,8-oxide in blood indicates that there is widespread tissue exposure to this genotoxic metabolite even in tissues that have low capacity for styrene activation. That highlights the importance of cellular detoxification capacities relative to organ-specific effects of styrene. In tissues that have low activity of epoxide hydrolase or glutathione-S-transferase, it might take only low levels of oxidation of styrene to produce cellular effects. The absence of marked toxicity in organs other than the liver or lung of mice (see the “Cytotoxicity” section) suggests detoxification capacities in that species are sufficient to prevent overt toxicity, except in the liver and lung. However, specific information on capacities for detoxification of styrene metabolites (such as epoxide hydrolase and glutathione-S-transferase) in critical target tissues in humans is not available. Therefore, the available information on styrene metabo- lism is insufficient to exclude any tissue from being a plausible target for sty- rene-induced cytotoxicity, which could contribute to carcinogenesis.

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64 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens EPIDEMIOLOGIC STUDIES The literature was searched to identify relevant epidemiologic studies that had been published by November 13, 2013 (see Appendix D). The committee established exclusion criteria for the literature search and identified studies that were most informative for determining whether an association exists between styrene exposure and carcinogenesis. The committee then reviewed and evaluat- ed the methods and results of those informative studies and applied the RoC listing criteria to the evidence. Identification of Informative Studies The committee established a set of attributes for identifying the most in- formative cohort and case–control studies. The most informative cohort studies were ones that had  Large cohorts that were exposed to high and varied concentrations of styrene.  Systematically assigned exposure estimates (such as the years in which exposure began and ended or job exposure matrices that coupled work- er histories with exposure estimates according to occupation).  Styrene exposures that could be assessed apart from exposures to other potentially carcinogenic chemicals.  Systematically and reliably assigned cancer end points.  Internal comparisons, for example incidence rate ratios (IRRs) and mortality rate ratios (MRRs) that compared workers with different lev- els of exposure in the same cohort. The most informative case–control studies were ones that had  Relatively large numbers of cases and controls.  Reliable assessments of styrene exposure based on specific job histories or other sources of information.  Interviews of cases and controls or their next of kin to collect occupa- tional histories and data related to lifestyle (for example, smoking) and other important potential confounders. On the basis of those attributes, the committee identified what it judged to be the 11 informative publications: six studies that used four cohorts in the rein- forced-plastics industry that were conducted in Europe (Kogevinas et al. 1994; Kolstad et al. 1994, 1995) and the United States (Wong et al. 1994; Ruder et al. 2004; Collins et al. 2013) and five case–control studies conducted in Europe (Scélo et al. 2004; Seidler et al. 2007; Cocco et al. 2010; Karami et al. 2011) and

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Independent Assessment of Styrene 65 Canada (Gerin et al. 1998). See Table 3-1 for descriptions of the studies, includ- ing the salient strengths and weaknesses of each study. It should be noted that approximately one-third of the Kolstad et al. (1994) cohort in Denmark was in- cluded in the Kogevinas et al. (1994) European cohort. However, the two studies assessed different cancer outcomes (incidence and mortality, respectively), and the Kolstad et al. (1994) study only included male workers whereas the Kogevi- nas et al. (1994) study included male and female workers. It should also be not- ed that the Collins et al. (2013) study was an extension of the study by Wong et al. (1994). However, Wong et al. (1994) assessed somewhat different exposure metrics and necessarily focused on mortality that occurred closer to the time of high exposure. The committee reviewed all epidemiologic studies that reported human exposure to styrene and an assessment of cancer end points and it identified sev- eral epidemiologic studies that it judged to be less informative compared to the 11 studies listed above. Reasons why the studies were judged as less informative studies and were excluded from Chapter 3 include small numbers of subjects, low concentrations of exposure to styrene, and simultaneous exposure of cohorts to other chemicals in addition to styrene (especially 1,2-butadiene), which pre- vented a clear characterization of styrene exposures. For an in-depth description of all epidemiology studies that were reviewed by NTP, see NTP (2008). Evaluation of Informative Studies After identifying studies that it deemed most informative, the committee evaluated the study data to inform its judgment of whether the evidence of car- cinogenesis in humans after exposure to styrene is sufficient, limited, or incon- clusive. The following factors were judged by the committee to increase the credibility of evidence on human carcinogenicity of styrene:  High estimates of MRRs, IRRs, standardized mortality ratios (SMRs), standardized incidence ratios (SIRs), or odds ratios (ORs). The commit- tee considered a study to be particularly credible if a relative risk or its surrogate was ≥2.0 in an entire study cohort or a subset with high expo- sure (that is, a doubling of cancer mortality or incidence compared to the less exposed or unexposed comparison group). However, a relative risk estimate ≥1.5 also added credibility to the overall body of evidence, par- ticularly if the relative risk was unlikely to be due to chance on the basis of the confidence interval (CI) around the estimate.  Exposure–response relationships for any reliably established exposure metric.  Consistency of the above two types of observations among independent cohort studies of the reinforced-plastics industry or between cohort and case–control studies. Some inconsistencies among findings in different populations is typical in the epidemiologic literature and can be the

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66 TABLE 3-1 Summary of Most Informative Epidemiologic Studies Related to Styrene Exposure and Cancer Study Design, Population, Outcomes, Exposure Assessment and Exposure Metrics Strengths and Limitations and Analytic Strategy Kogevinas et al. 1994 Cumulative exposure and average exposure assessed Strengths for each worker on the basis of individual job histories  Large cohort with many workers involved (Included approximately one-third of subjects and country-, period-, and job-specific exposure in lamination. from Kolstad et al. 1994). estimates from personal sampling measurements and  Relatively long duration of followup urine measurements. (period of followup and employment varied A retrospective cohort of 40,688 male and by country, average followup = 13 years, female workers ever employed in 660  16,500 personal sampling measurements from 539,479 person–years at risk), with little reinforced-plastics plants in six countries 1955 to 1990. loss to followup (3.0% of the cohort). (Denmark, Finland, Italy, Norway, Sweden,  18,500 measurements of styrene metabolites in  Cumulative exposure computed with and United Kingdom). urine conducted in the 1980s. without a 5-year lag period.  Internal comparisons made—Poisson Mortality from all causes and specific causes. Cumulative exposure (<75, 75–199, 200–499, ≥500 regression models included cumulative ppm–years). exposure, age, sex, calendar period, and SMRs and 95% CIs: External comparisons time since first exposure. based on data from WHO, standardized by Average exposure (<60, 60–99; 100–119; 120–199; sex, age (5-year age groups), and calendar ≥200 ppm). Limitations period (5-year periods).  About 60% of the cohort was employed in Longest-held job collapsed into 5 job groups the reinforced-plastics industry for <2 Rate ratios and 95% CIs from Poisson (laminators, n = 10,629; workers with unspecified years. regression: Internal comparisons limited to tasks, n = 19,408; workers in other exposed jobs, n =  No information on smoking, alcohol use, or exposed subjects. 5,406; workers not exposed to styrene, n = 4,044; and other lifestyle factors. workers with unknown job titles, n = 1,201). Duration of exposure (assessed by combining data from payroll records and plant records showing the dates of production of reinforced plastics [in Denmark, pension- fund records were used]). Time since first exposure (<10, 10–19, ≥20 years).

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Kolstad et al. 1994 Pension-fund records were used to determine duration Strengths of employment (for exposed workers, only payments  Large cohort with relatively long followup A retrospective cohort study of 36,525 male recorded during exposed employment were included). (followup during 1970–1989, range of workers in 386 reinforced-plastics plants ever followup 0 to 20 years, mean = 10.9 years, employed during 1964–1988 in Denmark and Type of company (ever producing reinforced plastics, 584,556 person–years at risk) and little loss 14,254 workers not exposed to styrene in 166 never producing reinforced plastics, and unknown (<2%) to followup. industries not producing reinforced plastics, or production) and years since first employment (<10 vs  Outcome of interest was cancer incidence company unknown. ≥10 years). instead of mortality, which avoids the issues related to cause of death Incidence of all cancers and specific For workers employed in plants producing reinforced categorization and different lengths of lymphohematopoietic cancers. plastics (n=36,525): survival after cancer diagnosis.  Internal comparisons made and yielded SIRs and 95% CIs: External comparisons  First year of employment (1964–1970, 1971–1975, similar results. based on national incidence rates standardized 1976–1988) and years since first employment (<10 for sex, age, and year of diagnosis. vs ≥10). Limitations  Years since first employment (<10 vs ≥10) and  Exposure assessment at plant level, with SIRs and 95% CIs from Poisson regression years of employment (<1 vs ≥1). 12,837 workers from 287 companies in (internal comparisons to unexposed workers; which it was estimated that ≥50% of authors reported that results were similar to Analyses of a subset of workers in plants with styrene workers were involved in reinforced- results based on external comparisons but data measurements (9,335 workers employed during the plastics production (included in Kogevinas were not provided). years of sampling). 2,473 personal air samples (not et al. 1994) and 23,748 workers from 99 linked to workers or job titles) collected during companies in which 1–49% of the 1964–1988; 1,814 of which were sampled in the 128 workforce produced reinforced plastics); companies included in the study. These were averaged 60% of workers employed <1 year. by company and dichotomized as follows: <50 ppm vs  Personal sampling data available on a ≥50 ppm. subset of the cohort, but not linked to workers or job titles.  No information on smoking, alcohol use, or other lifestyle factors. (Continued) 67

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