Plastic debris pervades our environment. Some breaks down into microplastics (MPs) that can enter and distribute in living organisms causing effects in multiple target organs. MPs have been demonstrated to harm animals through environmental exposure. Laboratory animal studies are still insufficient to evaluate human impact. And while MPs have been found in human tissues, the health effects at environmental exposure levels are unclear.

We reviewed and summarized existing evidence on health effects from occupational exposure to MPs. Additionally, the diverse effects documented for workers were organized by MP type and associated co-contaminants. Evidence of the unique effects of polyvinyl chloride (PVC) on liver was then highlighted.

We conducted two stepwise online literature reviews of publications focused on the health risks associated with occupational MP exposures. This information was supplemented with findings from animal studies.

Our analysis focused on 34 published studies on occupational health effects from MP exposure with half involving exposure to PVC and the other half a variety of other MPs to compare. Liver effects following PVC exposure were reported for workers. While PVC exposure causes liver toxicity and increases the risk of liver cancers, including angiosarcomas and hepatocellular carcinomas, the carcinogenic effects of work-related exposure to other MPs, such as polystyrene and polyethylene, are not well understood.

The data supporting liver toxicity are strongest for PVC exposure. Overall, the evidence of liver toxicity from occupational exposure to MPs other than PVC is lacking. The PVC worker data summarized here can be useful in assisting clinicians evaluating exposure histories from PVC exposure and designing future cell, animal, and population exposure-effect research studies.

Plastic particles in the nanometer range-called nanoplastics-are environmental contaminants with growing public health concern. As plastic particles are present in water, soil, air and food, human exposure via intestine and lung is unavoidable, but possible health effects are still to be elucidated. To better understand the Mode of Action of plastic particles, it is key to use experimental models that best reflect human physiology. Novel assessment methods like advanced cell models and several alternative approaches are currently used and developed in the scientific community. So far, the use of cancer cell line-based models is the standard approach regarding in vitro nanotoxicology. However, among the many advantages of the use of cancer cell lines, there are also disadvantages that might favor other approaches. In this review, we compare cell line-based models with stem cell-based in vitro models of the human intestine and lung. In the context of nanoplastics research, we highlight the advantages that come with the use of stem cells. Further, the specific challenges of testing nanoplastics in vitro are discussed. Although the use of stem cell-based models can be demanding, we conclude that, depending on the research question, stem cells in combination with advanced exposure strategies might be a more suitable approach than cancer cell lines when it comes to toxicological investigation of nanoplastics.

Vinyl chloride (VC) is a common industrial organic chlorine and environmental pollutant. In recent years, the dietary structure of residents especially Chinese has gradually shifted to western dietary patterns. VC aggravates dietary fatty acid-induced hepatic steatosis, but its mechanism is still unclear. And if the risk factors for steatosis persist, more severe diseases such as fibrosis and cirrhosis will occur. Therefore, we studied the effects and mechanisms of VC (160 and 800 mg/m³ ) and its metabolite (chloroacetaldehyde, 2.25, 4.5, and 9 μM) on hepatic steatosis of high-fat diet (HFD)-fed mice and palmitic acid (PA, 100 μM) treated HepG2 cells. Liver and serum biochemical indicators and pathological staining of the liver showed that the hepatic steatosis of VC combined with HFD groups was more severe than that of single-exposure groups (HFD group, low-dose VC group, and high-dose VC group). Moreover, VC enhanced HFD-induced oxidative stress (OS) and endoplasmic reticulum stress (ERS) and further upregulated the expression of sterol regulatory element-binding protein 1 (SREBP-1) and FAS. Besides, antioxidants and ERS inhibitors reduced the steatosis of HepG2 cells induced by VC metabolites and PA. These results suggest that VC exposure can enhance the degree of hepatic steatosis in HFD-fed mice. VC combined with HFD led to OS and ERS and upregulated the expression of de novo lipogenesis-related proteins, which may be related to the occurrence of hepatic steatosis. And the increased expression of CYP2E1 induced by VC combined with HFD may be the cause of OS.

The understanding of the relationship between exposure to carcinogenic vinyl chloride (VCM) and ethylene dichloride (EDC) and liver fibrosis is limited.

This study aimed to investigate the associations between the urinary metabolite levels of VCM and EDC and the risk of liver fibrosis in residents living near a petrochemical complex.

Our study comprised 447 adult residents of two townships with questionnaire survey and health examination near the largest petrochemical complex in central Taiwan. The urinary levels of thiodiglycolic acid (TdGA), the metabolite of VCM and EDC, were detected in study subjects. We utilized fibrosis-4 (FIB-4) as the noninvasive liver fibrosis index. Adjusted linear model was applied to evaluate the associations between the distance from the complex and the urinary TdGA levels. Adjusted logistic regression model was applied to evaluate the associations between the urinary TdGA levels and the risk of liver fibrosis.

The study subjects living in the closer township had significant higher urinary TdGA levels than those living in the more distant township (269.6 ± 200.7 vs. 199.2 ± 164.7 μg/g creatinine) (p < 0.001). It showed that urinary TdGA levels were decreased 0.53-fold when the distances from the complex were increased 1-fold after adjusting for confounding factors. It demonstrated that the study subjects with the highest TdGA levels (>343.3 μg/g creatinine) had a higher risk of FIB-4>1.29 (OR = 2.09; 95% CI: 1.17, 3.78), and those with higher TdGA levels (232.7 to 343.3 μg/g creatinine) had a marginally higher risk of FIB-4>1.29 (OR = 1.65; 95% CI: 0.94, 2.90).

The residents living closer to the VCM/PVC plant in the petrochemical complex had higher urinary TdGA levels, which were associated with an increased risk of fibrosis. This confirmed that the EDC and VCM potentially emitted from the petrochemical industry may have an impact on the liver health of nearby residents.

Vinyl chloride (VC) is a common industrial organochlorine, shown to cause hepatic angiosarcoma and hepatic steatosis. However, the role of endoplasmic reticulum stress (ERS) and oxidative stress (OS) in hepatic steatosis after subchronic exposure to VC in mice, is unclear. Based on body weight, forty healthy SPF male C57BL/6 J mice were randomly divided into a control group and three VC exposure groups (57.3, 286.7, and 1433.6 ppm) (n = 10 each). VC was administered by static inhalation in a 50 L sealed plexiglass inhalation chamber for 2 h per day, five days per week for 16 weeks. Serum and liver tissues were analyzed for liver enzymes and lipids. Hepatic cytochrome P450 2E1 (CYP2E1) and OS related indicators malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were measured. The mRNA expressions of ERS downstream genes, including glycoregulatory protein-78 (GRP-78), sterol regulatory element binding protein-1 (SREBP-1), Acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) were detected by real-time PCR (RT-PCR) and their protein levels examined by western blotting. The CYP2E1 levels increased after VC administration in a dose-dependent manner. MDA levels increased (P < .05) and SOD and GSH levels decreased (P < .05) in the liver of each group with the increase in the dose of VC. ERS and expressions of downstream genes (GRP-78, SREBP-1, ACC, and FAS) were enhanced after VC administration. These results suggested that OS and ERS could be induced by VC, which may lead to an increase in fatty acid synthesis in the liver, further aggravating hepatic steatosis.

Occupational and experimental studies have revealed that high vinyl chloride monomer (VCM) exposure is associated with non-alcoholic fatty liver disease (NAFLD). Epidemiological study reported that children living near a petrochemical complex have elevated exposure levels of urinary thiodiglycolic acid (TDGA), a potential VCM biomarker. However, no studies on the association of urinary TDGA exposure with NAFLD in children are available.

To assess the association of pediatric NAFLD with urinary TDGA exposure in school-aged children living near a petrochemical complex.

In total, 261 school-aged children (aged 6-13 years) living near a petrochemical complex were recruited during October 2013 to September 2014. First morning spot urine was sampled for analyzing urinary TDGA through liquid chromatography-tandem mass spectrometry. Ultrasonography and serum alanine aminotransferase (ALT) were examined in each participant. NAFLD was diagnosed as recommended by the North American and European Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN and ESPGHAN). Risk for NAFLD with urinary TDGA exposure in children was evaluated using a multivariate logistic regression model.

The percentage of children with NAFLDNASPGHAN and NAFLDESPGHAN were 9.6% and 11.5%, respectively. Median levels (μg/g creatinine) of urinary TDGA of children with NAFLDNASPGHAN (vs non-NAFLDNASPGHAN) and NAFLDESPGHAN (vs non-NAFLDESPGHAN) were 118.0 (vs 96.6) and 113.1 (vs 96.5), respectively. Participants in the highest urinary TDGA quartile (Q4: ≥160.0 μg/g creatinine) had a significantly increased risk (odds ratio [OR] = 4.95; 95% confidence interval [CI] = 1.15-21.38; P = 0.032) and dose-response trend (Ptrend = 0.045) for NAFLDNASPGHAN compared with those in the lowest urinary TDGA quartile (Q1: <35.4 μg/g creatinine) after adjustment for age, gender, BMI, triglycerides, HOMA-IR and distance of elementary schools from the petrochemical complex. Participants in the Q4 had borderline significantly increased risk (OR = 3.45; 95% CI = 0.89-13.42; P = 0.074) correlated with NAFLDESPGHAN compared with those in the Q1 after adjustment for confounders.

Our findings support the hypothesis that children exposed to higher urinary TDGA levels significantly increased pediatric NAFLD risk. Serum ALT levels can be a useful predictor for screening children's NAFLD in field studies. Large and longitudinal studies are warranted to elucidate the association.

Portal hypertension, liver fibrosis, and angiosarcoma of the liver (ASL) have been reported among workers exposed to vinyl chloride monomer (VCM) since the 1970s. In 2007, the International Agency for Research on Cancer established the association of VCM with hepatocellular carcinoma (HCC), though only on the basis of the few cases available. Thereafter, recent reports from the United States cohort and a European sub-cohort of vinyl chloride workers provided compelling evidence of a strong association between cumulative VCM exposure and HCC risk. Further areas of research include the risk of liver cancer at lower levels of exposure and different patterns of risk of ASL and HCC with the time since exposure. The evidence of interaction between VCM exposure and other known liver carcinogens such as alcohol and chronic viral infection provides clues for the health surveillance of exposed workers. Notably, also the risk of VCM-associated chronic liver disease is modulated by alcohol consumption, viral infection, and genetic polymorphism. A counter-intuitive finding from cohort studies of exposed workers is the lower mortality from liver cirrhosis with respect to the general population; this can be attributed to the healthy worker effect and to the selection of liver cancer as the cause of death in the presence of concomitant chronic liver disease. Studies designed to overcome these intricacies confirmed an association between cumulative VCM exposure and the risk of liver cirrhosis.

Vinyl chloride (VC) is a noninfective occupational risk factor. It is found in industrial chemicals, volatile organic compounds, cigarette smoke ingredients, etc. It is a kind of toxic gas that causes many diseases. VC exposure causes an increased risk of liver fibrosis and can result in angiosarcoma of the liver. Previous studies have shown that high-doses of VC exposure in mice resulted in acute death with marked tubular necrosis of the renal cortex. In this study, we assessed the nephrotoxicity of VC in vitro and in vivo. As a result, we demonstrated that VC induced fibrosis-associated protein expression, such as connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1) and collagen 1, and autophagy-associated protein expression, such as Beclin 1 and LC3-II, in kidney cells. The beclin1 siRNA experiments found that autophagy inhibited VC-induced fibrosis. Blood urea nitrogen (BUN) and creatinine levels were increased after VC treatment. Furthermore, VC caused glomerulosclerosis and tubular injury in mouse kidney tissues. Kidney tissue sections showed that VC induced fibrosis and autophagy in mouse kidney tissues. In summary, the results of VC-induced fibrosis suggest that autophagy plays an important role in kidney damage. VC may cause nephrotoxicity, and the results illustrate the importance of considering the toxicological hazards of VC in kidney cells.

The effect of exposure to vinyl chloride monomer (VCM) on susceptibility to hepatotoxicity in children is unknown, although experimental studies have demonstrated a significantly increased risk of hepatocellular carcinoma in rodents exposed to VCM in early life. Epidemiological studies have revealed a high prevalence of liver fibrosis and abnormal liver function in workers exposed to high VCM levels. We aimed to assess the association among urinary thiodiglycolic acid (TDGA) level, abnormal liver function, and hepatic fibrosis in school-aged children living near a petrochemical complex. A total of 303 school-aged (6-13 years) children within 10 km nearly a petrochemical complex was recruited in central Taiwan. First-morning urine and blood samples were collected from each subject, and urinary TDGA level was analyzed through liquid chromatography-tandem mass spectrometry. Liver function was determined by serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Hepatic fibrosis was assessed using the AST to platelet ratio index (APRI) and fibrosis-4 score (FIB-4). Risk of hepatotoxicity induced by TDGA exposure was estimated using multivariate logistic regression. The median (range, subclinically abnormal %) AST and ALT levels of all subjects were 26.0 (17.0-99.0, 25.7%) and 15.0 (7.0-211.0, 5.9%) IU/L, respectively. Children in the highest urinary TDGA quartile (≥160.0 μg/g creatinine) exhibited significantly elevated median AST levels compared with those in the lowest quartiles (<35.4 μg/g creatinine, p = 0.033). After adjustment for potential confounding factors, children in the highest quartiles (Q4) of TDGA level had significantly increased odds ratio (OR) of subclinically abnormal AST (OR = 3.86; 95% confidence interval: 1.54-9.67) compared with those in the lowest quartile. A dose-response trend (p = 0.004) was observed. Our findings support the hypothesis that elevated urinary TDGA level in children living near petrochemical complex is associated with susceptibility to hepatotoxicity.

Non-alcoholic fatty liver disease is a major cause of chronic liver pathology in humans. Fatty liver disease involves the accumulation of hepatocellular fat in hepatocytes that can progress to hepatitis. Steatohepatitis is categorized into alcoholic (ASH) or non-alcoholic (NASH) steatohepatitis based on the etiology of the insult. Both pathologies involve an initial steatosis followed by a progressive inflammation of the liver and eventual hepatic fibrosis (steatohepatitis) and cirrhosis. The involvement of pharmaceuticals and other chemicals in the initiation and progression of fatty liver disease has received increased study. This review will examine not only how xenobiotics initiate hepatic steatosis and steatohepatitis but also how the presence of fatty liver may modify the metabolism and pathologic effects of xenobiotics. The feeding of a high fat diet results in changes in the expression of nuclear receptors that are involved in adaptive and adverse liver effects following xenobiotic exposure. High fat diets also modulate cellular and molecular pathways involved in inflammation, metabolism, oxidative phosphorylation and cell growth. Understanding the role of hepatic steatosis and steatohepatitis on the sequelae of toxic and pathologic changes seen following xenobiotic exposure has importance in defining proper and meaningful human risk characterization of the drugs and other chemical agents.

Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures.

Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS² analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed.

613 unique named metabolites were identified. Of these, 189 metabolites were increased in the VC exposure group while 94 metabolites were decreased. Random Forest analysis indicated that the metabolite signature could separate the groups with 94% accuracy. VC exposures were associated with increased long chain (including arachidonic acid) and essential (including linoleic acid) fatty acids. Occupational exposure increased lipid peroxidation products including monohydroxy fatty acids (including 13-HODE); fatty acid dicarboxylates; and oxidized arachidonic acid products (including 5,9, and 15-HETE). Carnitine and carnitine esters were decreased, suggesting peroxisomal/mitochondrial dysfunction and alternate modes of lipid oxidation. Differentially regulated metabolites were shown to interact with extracellular-signal-regulated kinase 1/2 (ERK1/2), Akt, AMP-activated protein kinase (AMPK), and the N-Methyl-d-aspartate (NMDA) receptor. The top canonical pathways affected by occupational exposure included tRNA charging, nucleotide degradation, amino acid synthesis/degradation and urea cycle. Methionine and homocysteine was increased with decreased cysteine, suggesting altered 1-carbon metabolism.

Occupational exposure generated a distinct plasma metabolome with markedly altered lipid and amino acid metabolites. ERK1/2, Akt, AMPK, and NMDA were identified as protein targets for vinyl chloride toxicity.

Vinyl chloride monomer (VCM) is widely used in the production of polyvinyl chloride (PVC) plastics. VCM is recognized as a confirmed human and animal carcinogenic compound. Recent studies have reported poor health of plastic workers, even having exposure at concentrations below the permissible limit to VCM. There has not been any study regarding exposed workers to VCM in Iran. Similarly, no information exists as to the biological monitoring of such workers. The main purpose of this study was to conduct a thorough occupational and biological monitoring of Iranian plastic workers exposed to VCM.A total of 100 workers from two plastic manufacturing plants (A and B) in Tehran along with 25 unexposed workers as controls were studied. The personal monitoring of all nonsmoking workers exposed to VCM at two plastic manufacturing plants (A and B) was performed in the morning shift (8 a.m. to 4 p.m.) according to the National Institute For Occupational Safety And Health method no. 1007.Biological monitoring of workers was carried out through collection of exhaled breath of all exposed and control workers in Tedlar bags and with a subsequent analysis using gas chromatography-flame ionization detector.Not only the mean occupational exposure of workers to VCM at plant A was higher than the respective threshold limit value but also the statistical significance was higher than workers at plant B. Similarly, VCM concentration in exhaled breath of workers at plant A was also statistically significantly higher than at plant B. Correlation of occupational exposure of all workers to vinyl chloride with its concentration in exhaled breath was statistically significant.This is the first study on biological monitoring for exposed plastic workers to VCM using exhaled breath. On the basis of the results in this study, a novel method of biological monitoring of plastic workers was proposed.

Occupational diseases may be defined only medically or scientifically, and even then, their definition is not simple. However, compensable occupational diseases involve the additional layer of legal systems and social welfare policies as well. Their multifaceted nature makes determining the work-relatedness of these diseases more complex. Korea has established standards for the recognition of occupational diseases in Schedule 5 of the Enforcement Decree of the Labor Standards Act, and specific criteria for the recognition of occupational diseases are listed in Schedule 3 of the Enforcement Decree of the Industrial Accident Compensation Insurance Act. The new list of compensable occupational diseases comprises 13 articles as an open-ended system. The newly added articles pertain to lymphohematopoietic (Article 5) and infectious diseases (Article 9), as well as diseases of other target organs. Furthermore, the article on liver diseases (Article 8) has been partially revised. The new act has been changed to clarify the meaning as it has been presented in recent research. It is necessary to achieve agreement among concerned parties, including experts from the legal, medical, and social domains to resolve the issues of work-relatedness, causation, notion of aggravation, and so on for preparing a list and a process that are more reasonable.

Hepatotoxicity is the most common organ injury due to occupational and environmental exposures to industrial chemicals. A wide range of liver pathologies ranging from necrosis to cancer have been observed following chemical exposures both in humans and in animal models. Toxicant-associated fatty liver disease (TAFLD) is a recently named form of liver injury pathologically similar to alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Toxicant-associated steatohepatitis (TASH) is a more severe form of TAFLD characterized by hepatic steatosis, inflammatory infiltrate, and in some cases, fibrosis. While subjects with TASH have exposures to industrial chemicals, such as vinyl chloride, they do not have traditional risk factors for fatty liver such as significant alcohol consumption or obesity. Conventional biomarkers of hepatotoxicity including serum alanine aminotransferase activity may be normal in TASH, making screening problematic. This article examines selected chemical exposures associated with TAFLD in human subjects or animal models and concisely reviews the closely related NAFLD and ALD.

Liver disease is a major health issue characterized by several pathological changes, with steatosis (fatty liver) representing a common initial step in its pathogenesis. Steatosis is of critical importance because prevention of fatty liver can obviate downstream pathologies of liver disease (eg, fibrosis). Recent studies have shown a strong correlation between chemical exposure and steatosis. The work described here identifies chemicals on the US Environmental Protection Agency's Integrated Risk Information System (IRIS) that induce steatosis and investigates putative mechanisms by which these chemicals may contribute to this pathological condition. Mitochondrial impairment, insulin resistance, impaired hepatic lipid secretion, and enhanced cytokine production were identified as potential mechanisms that could contribute to steatosis. Taken together, this work is significant because it identifies multiple mechanisms by which environmental chemicals may cause fatty liver and expands our knowledge of the possible role of environmental chemical exposure in the induction and progression of liver disease.

Nonalcoholic steatohepatitis (NASH) is defined histopathologically by the presence of macrovesicular steatosis, cellular ballooning, and inflammation. NASH represents a complex multifactorial disease that typically occurs within the context of the metabolic syndrome. NASH lacks homogeneity, and other forms of NASH can present atypically. Less than 50% of patients with NASH respond to pharmacologic treatment, which speaks to this heterogeneity. The authors discuss drugs, disease entities, and nutritional states that can cause or exacerbate underlying NASH indirectly through worsening insulin resistance or directly by interfering with lipid metabolism, promoting oxidative injury, or activating inflammatory pathways.

The use of Di-2-ethylhexyl phthalate (DEHP) plasticised polyvinyl chloride (DEHPPPVC) in medical devices persists despite evidence suggesting that DEHP migration can be harmful. Researchers have shown that a simple surface sulfonation process can retard the migration of DEHP, which may reduce the associated inflammatory response. The present study is designed to investigate the effects of surface sulfonation on DEHP migration and blood contact activation using in vitro and rodent models.

The study was carried out in two phases: phase 1, in which the migration rate of DEHP from DEHPPPVC and sulfonated DEHP plasticised PVC (SDEHPPPVC) was measured; phase 2 of the study, in which the materials were incorporated into a rat recirculation biomaterial test model and blood samples taken to assess CD11b expression on neutrophils, IL-6 and Factor XIIa.

The initial DEHP concentration washed from the surface after storage was 37.19 +/- 1.17 mg/l in the PPVC group and 5.89 +/- 0.81 mg/l in the SPPVC group (p<0.0001). The post-wash migration rate was 3.07 +/- 0.32 mg/l/hour in the PPVC group compared to 0.46 +/- 0.038 mg/l/hour in the SPPVC group (p<0.0001). In phase 2 of the study, CD11b expression increased by 228.9% +/- 37% over the test period in the PPVC group compared to 118.3% +/- 46% in the SPPVC group (p<0.01). IL-6 levels rose from 3.1 +/- 1.4 pg/ml to 263 +/- 26 pg/ml in the PPVC group and 2.2 +/- 1.6 pg/ml to 161 +/- 29 pg/ml in the SPPVC group (p<0.01). Factor XIIa levels rose from 0.22 +/- 0.13 g/ml to 3.7 +/- 0.32 microg/ml and 0.28 +/- 0.09 to 2.71 +/- 0.21 microg/ml in the PPVC and SPPVC groups, respectively (p<0.05 at 90 minutes).

The simple sulfonation process significantly retards the migration of DEHP and is associated with the moderation of contact activation processes.

Although nonalcoholic steatohepatitis (NASH) is typically associated with obesity, it has also been reported to occur in lean individuals exposed to industrial chemicals. Occupational exposure to vinyl chloride (VC) is a well-documented risk factor for hemangiosarcoma, but has not previously been associated with steatohepatitis. Here we evaluate liver biopsies from 25 nonobese, highly exposed VC workers for steatohepatitis. Next, we evaluate associated metabolic and cytokine abnormalities in affected workers controlled by 26 chemical workers with no to minimal VC exposures, and 11 unexposed, healthy volunteers. Among highly exposed VC workers the prevalence of steatohepatitis was 80%. Of these, 55% had fibrosis and four had hemangiosarcoma. We have coined the term toxicant-associated steatohepatitis (TASH) to describe this condition, which was not explained by obesity or alcohol. Although mean serum transaminases were normal in TASH, total cytokeratin 18, but not the caspase-cleaved fragment, was elevated. Despite the absence of obesity, workers with TASH had insulin resistance with reduced adiponectin levels. TASH was also associated with markedly elevated serum tumor necrosis factor alpha and interleukins 1beta, 6, and 8. Serum antioxidant activity was reduced in TASH.

TASH occurred frequently in these nonobese VC workers with high cumulative exposures and normal liver enzymes. Elevated total cytokeratin 18 suggested the presence of necrotic cell death in TASH and may be a useful serologic biomarker. TASH was further characterized by insulin resistance, elevated proinflammatory cytokines, and impaired antioxidant defenses. The threshold VC exposure and the role of other chemical agents in TASH are as yet unknown.

Vinyl chloride monomer is a known cause of angiosarcoma of the liver. It also has other toxic effects on the liver, and it has recently been suggested that exposure to vinyl chloride also causes hepatocellular carcinoma. However, the data on which this conclusion is based is incomplete. There is inadequate ascertainment of unequivocal diagnoses. In the largest studies lack of data meant that confounding diseases such as viral hepatitis or alcoholic liver disease could not be assessed. At best, the increase in risk is minimal, based on more than 22,000 exposed workers and more than 640,000 person years of observation. However, based on the available data the hypothesis that vinyl chloride causes or contributes to the development of hepatocellular carcinoma remains unproven.

Although a relationship between vinyl chloride monomer (VCM) and liver cirrhosis has been reported, the underlying mechanisms are not clear. Cytochrome P450 2E1 (CYP2E1), aldehyde dehydrogenase 2 (ALDH2) and glutathione S-transferase theta 1 (GSTT1) enzymes are involved in activation and detoxification of VCM, and thus may be important determinants of interindividual susceptibility to VCM-induced liver damage, including liver cirrhosis. The objective of this study was to evaluate if metabolizing genetic polymorphisms could modify individual susceptibility to liver fibrosis of the VCM exposure. CYP2E1, ALDH2, and GSTT1 polymorphisms were determined by the PCR-RFLP method among 320 workers who were employed in five polyvinyl chloride manufacturing plants. Cumulative VCM exposure levels for study subjects were calculated using a job exposure matrix model. Thirteen workers were diagnosed as having liver fibrosis by using ultrasonography. We observed a dose-response trend between VCM exposure and liver fibrosis. Regarding the results on genetic polymorphisms, CYP2E1 c2c2 genotype showed a significant increase in the risk of liver fibrosis as compared to those with CYP2E1 c1c1 or c1c2 genotypes. No differences were observed between GSTT1 and ALDH2 genotypes and liver fibrosis. In summary, our result suggests that genetic polymorphism in CYP2E1 may be responsible for individual differences in susceptibility to liver fibrosis with regard to chronic VCM exposure. Thus, polymorphism analysis of metabolizing enzymes might be useful in the risk assessment of liver damage in workers with VCM exposure.

To investigate liver function in vinyl chloride workers and assess its relation with current/past occupational exposure to vinyl chloride monomer (VCM).

A medical examination including the execution of liver function tests (LFTs) and liver ultrasonography was executed in a group of 757 workers with a long-standing service in the production of VCM/polyvinylchloride (PVC). Cumulative and maximum VCM exposures were calculated. History of viral hepatitis and alcohol intake were carefully investigated. Regression analysis explored the association between abnormal LFTs and a group of possible determinants (VCM cumulative and maximum exposure, BMI, age, history of viral hepatitis, alcohol and triglyceride levels). Also, synergistic effect between VCM and a history of hepatitis was analysed, as well as the possible association between VCM exposure and aspartate aminotransferase/alanine amino transferase (AST/ALT) ratio >1. Distribution of abnormal LFTs was also assessed in relation to the results provided by liver ultrasonography.

The most frequently abnormal serum parameters were, in decreasing order: total cholesterol (27.3%), triglycerides (12.2%), total bilirubin (9.1%), gamma glutamil transpeptidase (GGT; 9.0%) and ALT (8.2%). The AST/ALT ratio >1 was present in 28.1% of workers. Abnormal LFTs were not found to be associated with current or past VCM exposure. High ALT resulted positively associated with BMI, AST with alcohol intake, GGT with alcohol intake and triglycerides. No synergistic effect on LFTs of exposure to VCM and a history of hepatitis was observed. The AST/ALT ratio >1 was not found to be associated with VCM exposure. The prevalence of abnormal LFTs was higher in case of liver steatosis (ALT) or periportal fibrosis (GGT), but not in case of pure hepatomegaly, as documented by ultrasonography.

Liver function assessment only including LFTs is not able to detect VCM-induced liver damage, but reveals alterations due to non-occupational factors, such as dietary and/or metabolic disfunctions. The LFTs are however of importance to detect conditions that could recommend avoidance of exposure to VCM and are useful for medical counselling and health promotion purposes.