Vinyl Chloride

Vinyl Chloride
By Dan South

Vinyl chloride is classified by the U.S. Environmental Protection Agency (USEPA) as a Class A - known human carcinogen, but how did it get so classified and why? It is a widely used chemical, being critical in the production of polyvinyl chloride (PVC). Unfortunately, it is a powerful carcinogen that many people are exposed to every day. Having been around for many years and used so commonly, vinyl chloride is a relatively well-studied and well-understood chemical compound.

Vinyl chloride was first produced in the 1920’s, but became widely used after the introduction of PVC in the 1930’s (Kielhorn, 2000). Since then, its production has grown tremendously until approximately 15 billion pounds were reported produced in the United States in 1995 (ATSDR, 2009). Its primary use remains in the production of PVC, although it is also used in the production of other chlorinated solvents such as 1,1,1-trichloroethane (Kielhorn, 2000). It is also found in groundwater as a breakdown product of these chlorinated solvents at sites such as industrial facilities and landfills where the contaminants have been released to the aquifers (Kielhorn, 2000).

Vinyl chloride, with molecular weight 62.5 grams per mole, is a sweet-smelling, colorless gas at room temperature and 1 atmosphere of pressure. The chemical formula for this chlorinated solvent is C2H3Cl.

The carcinogenicity of vinyl chloride has been established through both human cohort studies and animal testing (USEPAIRIS, 2009). The data from these two systems agrees quite well.
Several independent studies of cohorts of workers in PVC plants have documented significant increases in rates of angiosarcoma, a rare cancer of the liver lining, and less commonly, cancers of the brain and lung for people exposed to vinyl chloride. The USEPA IRIS document at http://www.epa.gov/iris/subst/1001.htm goes into great detail about these different studies. A brief overview of the findings, however, is in order. The first clear linking of vinyl chloride to liver cancer came in 1974 when scientists named Creech and Johnson studied workers in a PVC plant (USAEPAIRIS, 2009). They found an unusually high number of incidents for a very rare form of cancer (angiosarcoma). Since then other studies throughout the world have found the same results, confirming the link. Always, the most common cancer linked to vinyl chloride is angiosarcoma. These studies are considered reliable by USEPA because the methods were well-documented and the cohort sizes were generally large. The size of the cohorts ranged from hundreds to more than 7,000 in one German study (USEPAIRIS, 2009).

With possible links to cancer in humans reported, the next step was to conduct testing on animals. Tests have been conducted on Wistar rats as well as Sprague-Dawley rats that have resulted in significant increases in liver and other cancers by both ingestion and inhalation delivery methods. These results were confirmed with other species including mice and hamsters. As with the human studies, the sample sizes for these animal experiments were appropriate. The USEPA rated the different studies to assess the quality of the data. For example it reports:
“Confidence in the study of Til et al. (1983, 1991) is high because it used adequate numbers of animals, was well controlled, and reported in detail on the histological effects on the liver. Bi et al. (1985) and Sokal et al. (1981) both give corroborative information on liver effects following inhalation exposure. Because of the close similarity of the pharmacokinetics via the inhalation and oral routes and the use of a PBPK model, inhalation data can be used to fill gaps in the inhalation database and vice versa” (USAEPAIRIS, 2009).

These tests included different methods of delivering the vinyl chloride. Some studies used inhalation for exposure, others used ingestion. For the ingestion exposures, the scientists mixed very specific amounts of the chemical in the form of PVC in the food or water for the test subjects. Being long-term studies, the researchers generally used doses well below the level that causes significant effect such as 0.014 mg VC/kg bw/day to 14.1 mg VC/kg-day. At least one study exposed Sprague-Dawley rats to 0, 1, 5, 10, 25, 50, 100, 150, 200, 250, 500, 2500, 6000, or 10,000 ppm VC by inhalation for 4 hours/day, 5 days/week for 52 weeks to see if the number of tumors was concentration dependent (USAEPAIRIS, 2009). He concluded that it was.

The primary exposure route for humans for vinyl chloride is through inhalation (ATSDR, 2007). A secondary, but much less significant route of exposure is through ingestion of contaminated well water.

Vinyl chloride is rapidly and well absorbed after inhalation or oral exposure (UN World Health Organization, 1999). In studies of both animals and humans, under steady-state conditions, it was calculated that approximately 40% of inspired vinyl chloride is absorbed after exposure by inhalation. Animal studies indicated that more than 95% of vinyl chloride was absorbed after oral exposure (UN World Health Organization, 1999). Absorption of vinyl chloride in the gaseous state through the skin is not significant when compared to the amount entering the body from inhalation (UN World Health Organization, 1999). Prior to 1974 and the establishment of tighter standards, workers in the plastic industry were the population most at risk for exposure to vinyl chloride. Currently with the existing PEL in place, exposure to workers and nearby residents in the United States and Western Europe is low. In less developed countries, however, such as China and Croatia, residents and neighbors of facilities have been shown to have been exposed to excessive levels of airborne vinyl chloride (Kielhorn, 2000).

The USEPA IRIS document has dose-response data for ingestion and inhalation routes of entry that do not copy well to the blog. I encourage you to view them at: http://www.epa.gov/iris/subst/1001.htm
There is a 1 in 10,000 chance that someone exposed to 2.4 micrograms per liter per day since birth to vinyl chloride will develop cancer.

Results from several studies on the metabolism of vinyl chloride by rats indicate that the primary route of metabolism is believed to be by Cytochrome P450 (Reitz, 1996). The Phase I reaction oxidizes vinyl chloride to chloroethylene oxide (C2H3ClO). This highly reactive epoxide is inherently unstable and reforms to 2-chloroacetaldehyde (C2H3ClO) (Reitz, 1996 and Kielhorn, 2000). These two metabolites are further metabolized through a phase II process of conjugation binding with glutathione (Reitz, 1996) resulting in excretion through the urine (Reitz, 1996). Two of the urinary metabolites are N-acetyl-S-(2-hydroxyethyl)cysteine and thiodiglycolic acid (Reitz, 1996). The metabolism of a person can be saturated with high enough concentrations (~3000 parts per million according to Reitz, 1996) that the body then eliminates the compound in other ways, especially through exhalation of the parent compound (Reitz, 1996).

The mechanism for carcinogenicity of vinyl chloride again involves the metabolites chloroethylene oxide and chloroacetaldehyde. These short-lived, highly reactive compounds are believed to react with the body’s deoxyribonucleic acid (DNA) which leads to a mistranscription during cell division (Reitz, 1996). This causes a loss of information for the daughter cell. The major DNA adduct induced by vinyl chloride reportedly was 7-(2-oxoethyl)guanine (Bolt, 2005). However, 7-(2-oxoethyl)guanine is not mutagenic and it may be lesser adducts that cause the miscoding (Dogliotti, 2006). It is proposed that these mutations on the tumor-suppressor genes prevent the body from opposing the growth of tumors (Bolt, 2005).

Due to its carcinogenic nature, the permissible exposure limit (PEL) from the Occupational Health and Safety Administration (OSHA, 2009) is 1 part per million (ppm) per 8 hour period. The short term exposure limit (STEL) for vinyl chloride is 5 ppm per 15 minute period (OSHA, 2009). Since the odor of vinyl chloride becomes detectable at approximately 3,000 ppm, the odor threshold is too high to be of use (ATSDR, 2009). If a person can smell vinyl chloride, then that person has already been exposed above the PEL. As with the PEL, the carcinogenic nature of vinyl chloride has caused the maximum contaminant level (MCL) in drinking water set by the USEPA to be very low. The MCL for vinyl chloride is 0.002 milligrams per liter (mg/L) (USEPA, 2009).

We have learned a lot about vinyl chloride from both human case studies of workers exposed to the compound as well as well-documented, carefully controlled animal studies. Each source of information adds to the overall understanding of how this powerful carcinogen damages the body. Hopefully the study of vinyl chloride can serve as a guide for the study of other potential carcinogens.

References
Bolt, H.M., (2005), Vinyl chloride-a classical industrial toxicant of new interest. Critical Reviews in Toxicology, v.35(4):307-323

Environmental Protection Agency . (2009). "Environmental protection agency drinking water standards". Retrieved on March 18, 2009, from http://www.epa.gov/.

Environmental Protection Agency Integrated Risk Information System (EPAIRIS, 2009), Retrieved on March 18, 2009 from http://www.epa.gov/iris/subst/1001.htm .

Dogliotti, E. (2006). Molecular mechanisms of carcinogenesis by vinyl chloride. Annali dell'Istituto Superiore di Sanita, 42(2), 163-169.

Kielhorn, Janet, Melber, Christine, Wahnschaffle, Ulrich, Aitio, Antero, Mangelsdorf, Inga. (2000) Vinyl chloride: still a cause for concern. Environmental Health Perspectives, V.108, n.7.

Occupational Safety and Health Administration. (2007). Permissible Exposure Limits. Retrieved from http://www.osha.gov/ on March 18, 2009.

Reitz, R. H., Gargas, M. L., Anderson, M. E., Provan, W. M., & Green, T. L. (1996). Predicting cancer risk from vinyl chloride exposure with a physiologically based pharmacokinetic model. Toxicology and Applied Pharmacology, 137, 253-267.

Toxicological profile vinyl chloride. (2009). Agency for Toxic Substances & Disease Registry (ATSDR), retrieved on March 18, 2009 from http://www.atsdr.cdc.gov/.

United Nations Environment Programme, World Heath Organization. (1999) Vinyl chloride. Health and Safety Guide, No. 109,