Our literature search identified an initial 3961 publications of which 92 duplicate articles were removed. We excluded 3329 articles based on title and abstract screening. We retrieved the 546 remaining articles for detailed full article screening for specific inclusion and exclusion criteria as well as for overlapping data. For duplicate reports, we selected the studies with larger sample size and longer follow-up time. A total of 50 studies met full eligibility criteria to be included in qualitative data synthesis and 35 studies were included in meta-analysis (Fig. 1). Fifteen studies were not included in the meta-analysis because the described exposures or occupations were not studied in any other study.
Exposure to phenoxy herbicides and chlorophenols
We included 17 case–control [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38] and 10 cohort studies [38,39,40,41,42,43,44,45,46,47] that provided data on occupational exposures to phenoxy herbicides and chlorophenols. We presented the characteristics of individual studies in Tables 2 and 3 and the findings of these studies in supplementary tables 2 and 3.
The earlier study conducted in 1979 by Hardell et al. in Northern Sweden demonstrated a six-fold increased risk of STS with exposure to phenoxy herbicides . A southern Swedish case-referent study  with a large number of histologically proven cases (n = 110) confirmed the earlier findings of an increase of the same magnitude in the risk for STS after exposure to phenoxy herbicides and chlorophenols. The third Swedish study  also concluded that occupations which may imply exposure to phenoxy herbicides and chlorophenols, such as gardeners and railroad and wood workers, had an increased risk of STS.
Studies from New Zealand  and Australia  failed to confirm the Swedish findings. This study in New Zealand was conducted on a similar scale as the Swedish studies with regard to the number of STS cases. However, the study design differed from the Swedish studies by the control group consisting of other cancers. In a large population-based study conducted in six Canadian provinces with diverse agricultural practices Pahwa et al. also came to conclusion that STS was not associated with exposure to phenoxy herbicides . The study limitations were low response rate and potential for exposure recall-bias. In a population-based study from Northern Italy, Vineis et al. found an increased risk of STS in female rice weeders, but not in male . In another study from Italy, which was hospital-based, Franceschi et al. found no significant association of STS risk with exposure to herbicides . Both Italian studies were limited by low statistical power and possible recall-bias. Two population-based studies undertaken in Kansas (Hoar et al., 1986) and Western Washington (Woods et al., 1987), states with high use of herbicides, found no association between agricultural herbicide use and the occurrence of STS [26, 30].
In contrast, the results of the largest US population-based study (Hoppin et al., 1998) that included 295 male STS cases from eight population-based cancer registries supported the hypothesis of an association of sarcoma with exposure of chlorophenols in cutting oils and wood preservation . The findings of two-nested case controlled studies (Kogevinas et al., 1995) within a large international cohort including 21,183 workers, with substantial exposure to herbicides in production workers and sprayers also reported excess risk of STS .
As for Agent Orange, in a hospital-based study, Kang et al. concluded that there was no significant association of STS and previous military service in Vietnam . However, the authors noted that the absence of positive association might be due to insufficient observation time. Another study from the same group of researchers compared a total of 217 STS cases to 599 controls for Vietnam Service . The study revealed that Vietnam veterans in general did not have an increased risk of STS when compared to those men who had never been in Vietnam. However, an increased risk of STS was observed in the subgroups of veterans, such as combat veterans, combat veterans with MOSC (military occupational specialty category), and those who served within military region III, the area where Agent Orange spray was reported to be excessive.
In a cohort study of workers in manufacture of phenoxy herbicides in Denmark, findings of Lynge et al. supported the earlier Swedish observations of an excess risk of STS following exposure to herbicides . In contrast, in the Swedish study with 15% estimated risk of exposure to phenoxy herbicides in agricultural or forestry workers with large numbers of STS cases (n = 331), Wiklund et al. reported no increased risk of STS . The findings from two other cohort studies of Swedish licensed pesticide applicators  and Swedish female farmers , presented by the same group of authors, were consistent with the hypothesis that exposure to these compounds does not increase risk of STS. These studies were limited by lack of information on exact exposure to herbicides and consisted of cohorts with assumed occupational exposure to phenoxy acids. Data from ongoing large prospective cohort study of farmers and pesticide applicators in North Carolina and Iowa called the Agricultural Health Study also did not show increased risk of STS . Similarly, Fleming et al. found no cases of STS in a large retrospective cohort study of 33,658 pesticide applicators from Florida .
Increased mortality from STS was on the border of statistical significance among workers at a plant in Alabama manufacturing agricultural and other chemicals, based on small numbers (n = 3) . Similarly, in the study of rice growers in Northern Italy Gambini et al. were unable to come to any firm conclusion as there was only one case of death from STS with SMR as high as 1808.5 due to the very low expectation in this category .
In a large international cohort of chemical workers from ten courtiers in manufacturing agricultural and other chemicals, set up by the IARC, Saracci et al. found a six-fold excess of STS in the cohort as a whole and a nine-fold excess among sprayers 10–19 years from first exposure .
Exposure to dioxins
We included 4 cohort studies that provided data on occupational exposures to dioxins [51,52,53,54]. The studies evaluating non-occupational exposures and industrial accidents were not included. We presented the characteristics of the individual studies in Table 4 and the findings of these studies in supplementary table 4.
The largest study was a historical cohort of 21,863 male and female workers from 12 countries coordinated by the IARC and followed for 70 years . In this study, Kogevinas et al. observed twofold excess mortality for STS among workers exposed to herbicides contaminated with dioxins, subjects with a long duration of exposure, and persons first employed before 1965. The validity of this study may have been influenced by a possibility of exposure misclassification and inaccurate STS diagnosis on death certificates. Steenland et al. found excess mortality in the highest exposed chemical workers at 12 US plants . Bodner et al. reported a greater than expected rate for STS in another US cohort of chemical production workers exposed to substantial levels of dioxin . Collins et al. also observed an increased mortality rate from STS with dioxin exposure in the latest update from the largest single plant cohort study of workers at the Dow Chemical Company in Michigan with a follow-up period of 62 years . Limitations of this study were the potential for misclassification of sarcoma diagnosis and the small number of sarcoma cases.
Exposure to vinyl chloride monomers
We included 5 cohort studies [55,56,57,58,59] observing the relationship to mortality from ASL. Three of these studies also evaluated the association between VCM and other STS. Two multicenter epidemiologic studies combined populations of exposed workers included in previous investigations and extended the follow-up. We presented the characteristics of the individual studies in Table 5 and the results of these studies in supplementary table 5.
The European multicenter study (Ward et al., 2001)  was an extended follow-up of a cohort organized by Simonato et al.  and included the population previously studied in the UK [61, 62], Sweden , and Norway . The results were generally consistent with the original findings in which the excess from liver cancer was related to time since first exposure, duration of employment and estimated quantitative exposures. A strong relation was observed between cumulative exposure to VCM and occurrence of liver cancer. The relationship was even more evident when only ASL was analyzed.
Mundt et al. aimed to evaluate exposure–response relationships for mortality from ASL and hepatocellular carcinoma (HCC) in the North American cohort mortality data for men engaged in the manufacture of VC or PVC resin at any of 35 factories in the US . The association between VCM and ASL reported in this cohort 44 years ago persisted in the updated study and was strongest among most highly exposed workers. These findings were consistent with those reported in the European study (Ward et al., 2001). The median latency for ASL deaths was 36 years.
Collins et al. reported 15 cases of ASL in the most recent update of the Dow chemical company diseases registry for ASL . Thirteen ASL cases were at a single plant with high VCM exposure before 1974, which could indicate that exposures were higher at this location than the other locations. Fedeli et al. reported 9 deaths from ASL in a cohort of 1658 workers involved in VCM production and polymerization in northeastern Italy . Latency among ASL cases was 32 years and the risk continued to increase through the highest levels of cumulative exposure. Wong et al. found increased mortality from HCC but no death caused by ASL in the retrospective cohort study from Taiwan . This could be due to much lower levels of VCM exposure in Taiwanese workers compared to North American and Western European workers.
Other occupation exposures
We included 6 cohort studies [66,67,68,69,70,71] and 12 case–control studies [31, 33, 37, 72,73,74,75,76,77,78,79] that provided data on various other occupational exposures and sarcoma incidence and mortality. We presented the characteristics of the individual studies in Tables 6 and 7and the results of these studies in supplementary tables 6 and 7.
Zahm et al. demonstrated an association between woodworking occupations and increasing risk of STS in a population-based case–control study in Kansas. Hoar et al. found increased risk of STS with exposure to insecticides used on animals but not on crops . Similarly, Pahwa et al. observed a statistically significant increased risk of STS with exposure to insecticides—aldrin and diazinon in Canadian population-based case–control study . STS risk was higher among the farmers with longer duration of exposure, farmers who themselves mixed or applied insecticides to animals and failed to use any protective equipment.
In a large historical cohort of Danish paper mill workers, Rix et al. found an increased risk of STS female workers with a high risk among paper sorters employed in manual sorting and packing . Another cohort form the same authors found an excess risk of STS in Danish sulfite pulp workers .
In a large case–control study from six Canadian provinces, Hossain et al. found an increased risk for STS associated with an exposure to radium, longest-held job as a machinist, short-term job as chicken farm worker, pulp and paper industry worker, and apartment complex worker .
A large population-based study from the US reported by Hoppin et al. demonstrated excess risk of different sarcoma subtypes from various occupational exposures . In this study, self-reported herbicide use and exposure to chlorophenols and cutting oil was associated with malignant fibrohistiocytic sarcoma and leiomyosarcoma, wood-related exposures with leiomyosarcoma, and meatpacking with dermatofibrosarcoma protuberans. In another large population-based case–control study from the US, Briggs et al. showed that exposure to wood dust was associated with increased risk of STS in African American men but not in white men . Race-specific occupational risk factors evident only among African American men may represent racial disparities in levels of exposures to carcinogens.
In a case–control study from Sweden, Wingren et al. demonstrated that gardeners, railroad workers, unspecified chemical workers, workers in contact with wood, and construction workers with exposure to asbestos and pressure impregnating agents had an increased risk of STS . In a case–control study from Northern Italy, Franceschi et al. came to the conclusion that workers with exposure to chemical agents, benzene, or other solvents had higher risk of developing STS . Excess mortality in bone and soft tissue sarcomas was detected in a large cohort of US and Russian “Mayak” nuclear facility workers exposed to plutonium . In a series of case-referent studies from the New Zealand, Pearce et al. observed that the risk for STS was elevated in meat workers . In the study conducted in England and Wales, Balarajan et al. found no increased risk of STS among farmers and allied workers. However, when each occupational subgroup was analyzed separately, the excess risk found was limited to farmers, farm managers, and market gardeners . In the largest international case–control study, conducted in nine European countries, Merletti et al. found increased risk of bone sarcoma in woodworkers (particularly carpenters), blacksmiths, toolmakers and machine-tool operators, workers employed in manufacture of equipment and machinery industry, construction workers, and workers who ever used pesticide .
Results of meta-analysis
Exposure to phenoxy herbicides and chlorophenols
We conducted a meta-analysis of 16 case–control studies, involving 2254 sarcoma cases and 24,148 con1trols (Fig. 2). The pooled OR was 1.85 (95% CI 1.22, 2.82), P = 0.008, indicating significant positive association between exposure to phenoxy herbicides and chlorophenols and incidence of sarcoma. There was significant heterogeneity across the individual studies I2 = 79.0%, P ≤ 0.001.
Four cohort studies involving 11 sarcoma cases and 59,289 participants assessed the association between exposure to phenoxy herbicides and chlorophenols and sarcoma mortality (Fig. 3). The pooled SMR was 40.93 (95% CI 2.19, 765.90), P = 0.013, indicating a statistically significant positive association. However, there was significant heterogeneity across the individual studies I2 = 93.7%, P ≤ 0.001.
Based on meta-analysis of 3 cohort studies, involving 379,864 participants and 343 sarcoma cases, assessing exposure to phenoxy herbicides and chlorophenols and sarcoma incidence, the pooled RR was 0.90 (95% CI 0.81, 1.00), P = 0.0489, indicating no association (Fig. 4). There was no evidence of heterogeneity across the included studies, I2 0.0%, P = 1.00. Two studies included in this meta-analysis, Wiklund et al. and Wiklund et al. , that showed no association between exposure to phenoxy herbicides and chlorophenols and STS were much larger in size and tended to drive the results of meta-analysis. One explanation for the lack of any excess of sarcoma in these studies might be that both studies were register-based studies consisted of cohorts of agricultural and forestry workers and pesticide applicators with assumed occupational exposures to phenoxy acids and lacked individualized exposure data.
Based on 2 cohort studies, involving 103,078 participants and 31 cases of sarcoma, the pooled SIR was 0.63 (95%CI 0.44, 0.89), P = 0.010, indicating no association between exposure to phenoxy herbicides sarcoma incidence (Fig. 5). There was no evidence of heterogeneity across the included studies, I2 0.0%, P ≤ 0.001.
Exposure to dioxins
A meta-analysis of 4 cohort studies involving 30,797 participants evaluated the association between exposure to dioxins and STS mortality (Fig. 6). There were 14 deaths due to STS in these studies. The pooled SMR was 2.56 (95% CI 1.60, 4.10), P ≤ 0.001, indicating a statistically significant positive association between exposure to dioxins and STS mortality. There was no evidence of heterogeneity across the included studies, I2 0.0%.
Exposure to vinyl chloride monomers
We conducted a meta-analysis of 3 cohort studies, including 12,816 participants. There were 110 deaths from STS in these studies. The RR of ASL was increased in all studies included in meta-analysis. The pooled RR was 19.23 (95% CI 2.03, 182.46, P = 0.010), indicating a statistically significant positive association between exposure to VCM and ASL mortality (Fig. 7). There was significant heterogeneity across the individual studies I2 = 94.4%, P ≤ 0.001.
Excess death due to connective and soft tissue cancer was observed and was strongest amongst highly exposed workers in tree cohort studies including 12,816 participants (Fig. 8). There were 20 deaths due to connective and soft tissue cancer in these studies. The pooled SMR was 2.23 (95 CI 1.55, 3.22), P < 0.001, indicating statistically significant positive association between VCM exposure and STS. The study results were adequately similar, as I2 = 0.0%.
Other occupational exposures
With regard to other occupational exposures, population-based studies reported increased sarcoma incidence with exposure to insecticides used on animals, benzene, radium, cutting oil, and wood dust, in female paper sorters, gardeners, railroad workers, farmers, farm managers, long-term jobs as a machinist, short-term jobs as chicken farm workers, temporary jobs at apartment complexes, pulp and paper industry workers, meatpacking and woodworking occupations, and sulfite mill and nuclear facility workers.
Meta-analysis of 4 case–control studies with 8593 participants assessed the association between STS incidence and occupational exposure to woodworking and wood dust (Fig. 9). The pooled OR was 2.16 (95% CI 1.39, 3.36), P < 0.001, indicating a statistically significant positive association. There was no significant heterogeneity across the studies, I2 = 0.0%.