Vinyl Chloride Toxicity

Etiology

Vinyl chloride toxicity primarily results from occupational exposure during the polymerization of vinyl chloride monomer into polyvinyl chloride; however, community exposures secondary to industrial spills have been reported, particularly during vinyl chloride monomer transport between processing facilities, with the most recent incident reported in the United States in 2023.[10][11][12] In addition, there are case reports of significant chronic exposure associated with aerosol propellant use during the 1960s and early 1970s, although vinyl chloride monomer is no longer used in this manner.[3] In developed nations, significant occupational exposures are now rare. However, in developing economies, hepatic angiosarcoma has been documented in workers exposed over the past 10 to 20 years—the typical latent period for hepatic angiosarcoma—suggesting that significant occupational exposures have continued in some settings.[13][14]

In addition to its role in polyvinyl chloride production, trace levels of vinyl chloride monomer are found in cigarette smoke. Moreover, environmental bacteria can degrade polyvinyl chloride waste into vinyl chloride monomer, contributing to potential exposure.[14][15] Persistent low levels can be detected in groundwater near waste sites.[14][16] However, no hepatic angiosarcoma cases have been linked to such low-level exposures.[14]

According to the Agency for Toxic Substances and Disease Registry's (ATSDR) 2006 vinyl chloride toxicology profile, vinyl chloride monomer, as a volatile compound, rapidly disperses into the air, limiting its accumulation in environmental reservoirs such as groundwater. A 1996 train derailment resulting in a vinyl chloride monomer spill led to detectable concentrations of 0.06 to 8 ppm in surrounding residential areas. Urine samples from residents, rescue workers, and control groups showed no difference in thiodiacetic acid concentrations, one of the urine biomarkers of vinyl chloride monomer exposure. [IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Chemical Agents and Related Occupations. Vinyl Chloride. 2012.]

Epidemiology

The United States Environmental Protection Agency estimates that 10 to 20 billion lbs (4.5 to 9 billion kg) of vinyl chloride are produced annually in the United States at 15 to 20 locations, many of which are near Baton Rouge, Louisiana. Among exposed workers worldwide, there were reports of 197 cases of vinyl chloride monomer-related hepatic angiosarcoma between 1974 and 2000, with an average latency of 20 years.[14][14] Incidence peaked in the mid-to-late 1970s amongst reactor vessel cleaners believed to have suffered exposure to vinyl chloride monomer levels as high as 3000 ppm.[17]

Pathophysiology

Vinyl chloride monomer is readily absorbed across all body compartments, resulting from acute central nervous system (CNS) and respiratory effects, such as lightheadedness and bronchial irritation at low concentrations. At high concentrations, death can result from CNS and respiratory depression due to a general anesthetic effect.[18]

Chronic exposure among polymerization vessel cleaners is known to cause acroosteolysis, a condition characterized by Raynaud phenomenon and osteolysis in the terminal phalanges of the fingers that is believed to be mediated through obstructive lesions of small peripheral arteries in the distal extremities.[19][20]

The chronic hepatic mutagenic effects of vinyl chloride monomer on hepatocytes and sinusoidal cells are propagated by metabolic activation of vinyl chloride monomer to form chloroethylene oxide, which subsequently binds DNA, thereby exhibiting effects on proto-oncogene and tumor suppressor gene expression. This effect demonstrates causal links to the development of hepatic angiosarcoma, a rare and aggressive cancer, in humans and animal models.[14] Vinyl chloride monomer exposure can increase the risk of cirrhosis and brain, lung, and hematologic cancers.[21]

Toxicokinetics

Vinyl chloride monomer is a highly volatile compound, and inhalation is the primary route of exposure. Vinyl chloride monomer rapidly distributes across all body compartments and undergoes metabolism through CYP2E1 to form epoxide intermediates, which are subsequently detoxified via glutathione conjugation and excreted renally.[22] Animal studies suggest that metabolites are also widely distributed throughout the body but do not accumulate in the tissue, even with chronic exposure. Metabolism follows Michaelis-Menten kinetics.[23][24][25] At low doses, excretion is primarily renal; at higher doses, with enzyme saturation, exhalation of unmetabolized vinyl chloride monomer occurs.[23]

History and Physical

A detailed occupational and environmental exposure history greatly aids the treating clinician but should not delay the treatment of acute, life-threatening toxicity. A detailed history should determine toxin exposure, dose, route, time of exposure, and use of personal protective equipment, including respiratory protection. In acute exposure, symptoms may vary by the degree of exposure, ranging from dizziness, shortness of breath, and headaches to CNS depression, respiratory arrest, and death with severe exposure.[26][27]

Individuals with a history of significant vinyl chloride monomer exposure, whether remote or ongoing, may present with mild acute symptoms or nonspecific systemic symptoms such as malaise, night sweats, and weight loss if malignancy is present.[28] Individuals with vinyl chloride monomer-related hepatic angiosarcoma may not necessarily present with the signs and symptoms of liver failure.[2][7]

Physical examination findings may represent vinyl chloride monomer-induced complications. In acute exposures, respiratory distress or somnolence may be a presenting sign. Complications from significant chronic exposure may manifest as thickened skin over the hands and forefingers, Reynaud phenomenon, acroosteolysis, abdominal distension, ascites, or cachexia in those with advanced hepatic angiosarcoma.

Evaluation

Workers involved in the production and polymerization of vinyl chloride monomer to polyvinyl chloride should undergo routine screening to monitor their level of ongoing exposure. OSHA standard 1910.1017 requires annual occupational medical surveillance of workers exposed to vinyl chloride monomer over the actionable level of 0.5 ppm. The standard mandates laboratory monitoring of total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine transaminase, and gamma-glutamyltransferase at least annually. However, derangements of standard measurements of hepatic function may not be observable until late in the course of hepatic angiosarcoma, and other markers may be more sensitive. A major metabolite of vinyl chloride monomer, thiodiglycolic acid, can also be detected in the urine of workers with occupational exposure.[21] Liver biopsy is the most accurate test for the characteristic pattern of vinyl chloride-induced damage, but it is an invasive procedure with risks that may limit its utility.[29]

Treatment / Management

During suspected or confirmed acute exposures, management begins with the cessation of ongoing exposure by removing the individual from the contaminated area and performing external decontamination. There should be no delay in the movement to fresh air and away from poorly ventilated areas. Gaseous vinyl chloride monomer is denser than air, and low-lying areas may accumulate vinyl chloride monomer gas. Rescue personnel may need Level B or Level A protective gear with a self-contained breathing apparatus to protect themselves during emergency response to industrial accidents or train derailments.[10] According to the ATSDR, contaminated patients can off-gas vinyl chloride monomer in high-volume exposures, and their clothing should be removed to prevent further acute exposure to medical staff. [Agency for Toxic Substances and Disease Registry (US). Toxicological Profile for Vinyl Chloride. Health Affects. 2024] Patients with severe respiratory or CNS depression require critical care management during the period of acute intoxication. As a halogenated hydrocarbon, vinyl chloride monomer can sensitize the myocardium to catecholamines, resulting in life-threatening arrhythmias.[26] Therefore, in severe cases, cardiac monitoring is prudent, and adrenergic medications such as epinephrine should be used cautiously.(B3)

Workers presenting with the signs and symptoms of hepatic dysfunction or chronic systemic illness should undergo a specialized evaluation by an occupational medicine physician or medical toxicologist to assess occupational exposure. In addition, a referral to a hepatologist is advised for the evaluation and treatment of vinyl chloride-induced hepatic injury and hepatic angiosarcoma. Treatment options for hepatic angiosarcoma are limited. Thus, prevention of vinyl chloride monomer exposure should be the initial focus of employers.

Differential Diagnosis

The signs and symptoms of mild-to-severe acute vinyl chloride monomer exposure include shortness of breath, cough, dizziness, headaches, respiratory depression, and CNS depression. These symptoms may be due to any number of industrial toxins, particularly other volatile halogenated hydrocarbons. A detailed occupational history can help guide the diagnosis.

The signs and symptoms of chronic occupational exposure to vinyl chloride monomer, including Raynaud phenomenon, thickening of the skin of the hands and forearms, and acroosteolysis of the distal phalanges, collectively can resemble systemic sclerosis. The diagnosis can be differentiated based on the absence of antinuclear antibodies and a history of vinyl chloride monomer exposure. Raynaud phenomenon may also be secondary to mechanical arterial obstruction, hyperviscosity of the blood, or exposure to some chemotherapeutics, environmental conditions, or vibrating tools.[30][31]

The diagnosis of hepatic angiosarcoma should prompt the suspicion of a history of significant vinyl chloride monomer exposure. This rare tumor has also been linked to chronic arsenic exposure, copper sulfate, and a thorium-based radiocontrast, which has not been used for many decades.[32]

Prognosis

Single acute exposures to vinyl chloride monomer typically result in mild symptoms such as dizziness and headaches and have not been clearly associated with long-term effects.[14] In reactor vessel cleaners routinely exposed to elevated vinyl chloride monomer levels before the 1975 OSHA standard, the progression of acroosteolysis slowed with removal from the exposure, with improvement in some cases.[19][33] 

A 1973 retrospective cohort study of 1294 highly exposed polymerization workers identified 11 cases of hepatic angiosarcoma, indicating an incidence among these workers many thousands of times higher than in the general population.[34][35] There is no standardized treatment regimen for hepatic angiosarcoma, although partial hepatectomy, liver transplant, and chemotherapy are all used. However, despite intervention, the 2-year survival rate remains as low as 3%.[36][37]

Complications

Minimal complications are the norm from single, mild occupational or environmental exposures. Significant acute exposures can cause respiratory and CNS depression and death. Long-term occupational exposure in workers exposed before the 1975 OSHA standard has been linked to acroosteolysis and hepatic angiosarcoma. Cirrhosis, hepatocellular carcinoma, brain cancer, and lung cancer also have correlations with vinyl chloride monomer exposure in these workers, but causation remains controversial.[4] In developing countries with poor regulation of the polyvinyl chloride industry, hepatic angiosarcoma continues to be documented in plant workers, suggesting significant ongoing exposure.[13][14]