Angiosarcoma of the liver

Most toxicity problems associated with the finished product arise from the nature of the additives and seldom from the polymer. Mention should, however, be made of poly(vinyl carbazole) and the polychloroacrylates which, when monomer is present, can cause unpleasant effects, whilst in the 1970s there arose considerable discussion on possible links between vinyl chloride and a rare form of cancer known as angiosarcoma of the liver. 

The hazards of chemicals are commonly detected in the workplace first, because exposure levels there are higher than in the general environment. In addition, the exposed population is well known, which allows early detection of the association between deleterious health effects and the exposure. The toxic effects of some chemicals, such as mercury compounds and soot, have been known already for centuries. Already at the end of the eighteenth century, small boys who were employed to climb up the inside of chimneys to clean them suffered from a cancer of the scrotum due to exposure to soot. This was the first occupational cancer ever identified. In the viscose industry, exposure to carbon disulfide was already known to cause psychoses among exposed workers during the nineteenth century. As late as the 1970s, vinyl chloride was found to induce angiosarcoma of the liver, a tumor that was practically unknown in ocher instances. ... 

In male and female rats exposed to 10, 50, 250, or 12 50 ppm vinyl bromide in a lifetime inhalation study, there was a dose-related increase in angiosarcomas of the liver in both sexes. A significant increase in hepatocellular neoplasms was also seen in male rats exposed at 250ppm and in female rats exposed at 10, 50, and 250ppm. The lack of increase in hepatocellular neoplasms in rats at the 12 50 ppm level was probably due to their early mortality and termination at 72 weeks. In limited mice studies, no local tumors were produced by skin application or subcutaneous administration. Vinyl bromide is mutagenic in bacterial assays and Drosophilas It is activated via a P-450-dependent pathway to its epoxide that can covalently bind to DNA. ... 

Toxicology. Occupational exposure to vinyl chloride is associated with an increased incidence of angiosarcoma of the liver and other malignant tumors, acroosteolysis, Raynaud syndrome, scleroderma, thromhocytopenia, circulatory dismrbances, and impaired liver function. Very high concentrations cause central nervous system (CNS) depression. 

Lloyd JW Angiosarcoma of the liver in vinyl chloride/polyvinyl chloride workers. J Occup Med 17 333-334, 1975... 

Three workers in a Goodrich poly(vinyl chloride) plant in Louisville developed a rare angiosarcoma of the liver. This started the investigation of vinyl chloride as a possible carcinogen. 

Baxter PJ, Anthony PP, Macsween RNM, et al. 1980a. Angiosarcoma of the liver Annual occurrence and aetiology in Great Britain. Br J Ind Med 37 213-221. 

Kojiro M, Nakashima T, Ito Y, et al. 1985. Thorium dioxide-related angiosarcoma of the liver. Pathomorphologic study of 29 autopsy cases. Arch Pathol Lab Med 109 853-857. 

Fig. 6.4 Distribution of death from angiosarcomas of the liver in relation to time after onset of exposure, in persons exposed occupationally to vinyl chloride and persons injected intravenously with Thorotrast (thorium dioxide) (reproduced from Spirtas et al., 1983).

For chemicals, the situation is usually even more complex. In the case of someone who has developed angiosarcoma of the liver, however, the tumor is rare enough so that if the person is known to have been exposed to any one of the three known causes, Le., vinyl chloride monomer, arsenic, or Thorotrast (thorium dioxide), attribution is relatively reliable. In the case of vinyl chloride, the relative risk ratio in exposed workers was 80 hence, the attributed risk in such a worker would be 98-99 percent. 

Inhalation exposure studies on VC, VB and VDC showed that all three compounds produced angiosarcoma of the liver. 

The most notable effect of vinyl chloride is its carcinogenicity. It causes a rare angiosarcoma of the liver in chronically exposed individuals, observed particularly in those who cleaned autoclaves... 

Chronic animal studies report increased mortality and weight loss, as well as effects on the liver, kidney, and CNS at levels as low as 1.3 mg kg day Animal studies have shown increased testicular damage as well as decreased male fertility in rats exposed to low levels of vinyl chloride for 12 months. In addition, some animal studies have shown decreased fetal weights and increased terata at maternally toxic inhalation exposure levels of vinyl chloride. Animal studies have also reported that inhaled vinyl chloride increases the incidence of angiosarcoma of the liver. 

Epidemiological studies conducted on humans exposed to inhaled vinyl chloride have shown increases in angiosarcoma of the liver. Hepatocellular carcinoma of the liver as well as some brain tumors... 

Anonymous. Epidemiologic notes and reports Angiosarcoma of the liver among polyvinyl chloride workers—Kentucky. Morb Mortal Wldy Rep 1997 46 99-101. 

Angiosarcoma of the liver is a rare tumor associated with previous exposure to vinyl chloride. Patients with such a tumor may have serum alkaline phosphatase values within the reference interval or many times the upper reference limit (FI). Makk et al. (M5) screened over 1000 apparently well workers at a polyvinyl chloride factory and found hyper-phosphatasemia in 32. In 15 of these cases, the circulating enzyme was predominantly of hepatic origin. Makk et al. (M5) stated that a relative elevation of liver functions could be detected in workers exposed to... 

Vinyl chloride (VC) has been reported to induce angiosarcoma of the liver in exposed animals and workers [e.g., Gehring et al. (1978, 1979)]. The dose-response... 

Vinyl chloride Plastic industry Angiosarcoma of the liver... 

In the mid 1970 s, a number of publications appeared that demonstrated that vinyl chloride induced angiosarcoma of the liver in workers in the polyvinyl chloride manufacturing industry [5,7]. Subsequently, a number of biochemical studies, focussing on vinyl chloride metabolism in the liver, were published. Barbin et al. [8] demonstrated that, in Ihe presence of oxygen and NADPH, vinyl chloride was transformed to... 

Visceral involvement due to toxic damage of liver, kidney, nervous system and muscles, or angiosarcoma of the liver... 

Leukopenia, as well as angiosarcoma of the liver, drew attention to the carcinogenic and mutagenic properties of VC. Whether other kinds of malignancies are caused by VC was questioned by Fox and Collier (1977) based on an extensive epidemiological study. The relationship between VC disease and SSc is shown in Table 9. 

The hazards associated with VCM are not only angiosarcoma of the liver. There are recent studies that indicate a higher incidence of cancer of the lung, brain, and bone marrow among workers exposed to VCM. The effect of VCM may not be evident until 15 or more years after the beginning of exposure. Particularly severe exposure used to be experienced by workers who had to climb into polymerization reactors to scrape PVC residues from the walls, agitators, and so on. 

Also during 1973, three doctors treating separate workers at one PVC plant found each with angiosarcoma of the liver (ASL). The incidence rate of ASL in the general population is quite low, about 1 death per 100,000 annually and is associated with only a small number of assignable causes. Therefore the probability was extremely small that three workers at the same plant contracted this rare cancer only by happenstance. The connection of ASL to exposure to VCM in the workplace was confirmed after examination of death certificates of other plant workers. In Jan. 1974, the apparent human carcinogenicity of VCM was reported in the medical literature. 

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