Vinyl chloride: Sass et al. respond.

We provided documentation and extensive references to support two claims: industry urged the U.S. Environmental Protection Agency (EPA) to downplay data suggestive of cancer risks in tissues other than the liver, and the U.S. EPA reduced the cancer potency estimate of vinyl chloride in accordance with industry input. The American Chemistry Council (ACC) is a trade association representing over 150 companies that produce and use chemicals, including the Dow Chemical Company (Midland, MI), Georgia Gulf Corporation (Atlanta, GA), and Occidental Chemical Corporation (Los Angeles, CA) (ACC 2005). These three companies are also full members of the Vinyl Institute (Arlington, VA), whose stated goal is to "promote and protect the vinyl industry and the markets it serves" (Vinyl Institute 2005). Price, a lawyer with the ACC, maintains that our commentary is inaccurate because a) studies published since 1997 "reach the opposite conclusion"; b) by demonstrating industry influence on the U.S. EPA assessment of vinyl chloride we are disparaging of U.S. EPA scientists; and c) the pharmacokinetic (PK) model used by the U.S. EPA has been "peer-reviewed, published, and validated."

In response to Price's first point, recent studies confirm earlier findings instead of the opposite. At the time of the U.S. EPA assessment (U.S. EPA 2000) there were over 20 scientific articles and two independent reviews by the International Agency for Research on Cancer (IARC 1979, 1987) suggesting that vinyl chloride is a multisite carcinogen in humans and experimental animals. Recent reviews and data support the IARC conclusions. Of the references listed by Price, three are reviews without new data (Blair and Kazerouni 1997; Boffetta et al. 2003; Bosetti et al. 2003), two describe a PK model (Clewell et al. 2001; Reitz et al. 1996), and two contribute new data that neither refute previous studies nor support ACC claims (Mundt et al. 2000; Ward et al. 2001). One of these is a North American multicenter investigation, discussed in our commentary, which reported modest "excesses of brain cancer" and "cancer of connective and soft tissue" (Mundt et al. 2000). The second new study is a European multicenter investigation that is inconclusive regarding risks of nonliver cancers (Ward et al. 200l). Price also references a meta-analysis that actually reported an excess in brain cancer [standardized mortality ratio (SMR) = 1.26; 95% confidence interval (CI), 0.98-1.62) and soft-tissue sarcomas (SMR = 2.52; 95% CI, 1.56-4.07) (Boffetta et al. 2003); the authors of this meta-analysis conduded that "increased mortality from lung and brain cancers and from lymphatic and hematopoietic neoplasms cannot be excluded." This is consistent with an Italian study that reported increased lung cancer deaths among polyvinyl chloride (PVC) baggers (RR = 3.04; 95% CI, 1.15-7.99) (Gennaro et al. 2003).

Price's letter and the U.S. EPA assessment (U.S. EPA 2000) both reference a review article by National Cancer Institute authors (Blair and Kazerouni 1997). Blair stressed that his findings do not support disregarding possible risks of cancer outside the liver and that potent carcinogens such as vinyl chloride are unlikely to affect only one organ site (Blair A, personal communication). In overall mortality, a slightly increased rate of a common cancer such as lung cancer may lead to more deaths than a more markedly increased rate of a rare cancer such as liver angiosarcoma.

We believe that the U.S. EPA's close relationship with industry compromises credibility. The ACC met with U.S. EPA regulators to discuss a vinyl chloride assessment at least 2 years before public notification of an assessment process. At the urging of the ACC (Price 1999), the U.S. EPA eliminated a statement that there is "suggestive epidemiological evidence that cancer of the brain, lung, and lymphopoietic system" associated with vinyl chloride exposure. The U.S. EPA also removed a 3-fold uncertainty factor that had been included to account for possible tumor induction at such sites, after an ACC letter called the factor "ill advised" (Price 1999). The result is that the U.S. EPA assessment (U.S. EPA 2000) does not adequately warn the public of the potential carcinogenicity of vinyl chloride suggested in the scientific literature, and the risk estimate is weakened 3-fold.

The PK model has not been validated, as stated by Price. The PK model developed by industry consultants and used by the U.S. EPA in its assessment has not been validated because assumptions used in the model have not been tested. Importantly, although the model is limited to liver effects only, the implicit assumption that all metabolism occurs in the liver is incorrect (IARC 1987; McFayden et al. 1998; U.S. EPA 2000).

By using a model limited to liver cancer, the U.S. EPA made a radical departure from its cancer guidelines, recommending that the cumulative risks of all tumor types be included in a cancer assessment (U.S. EPA 1999, 2005). The 1999 carcinogen guidelines under which vinyl chloride was assessed (U.S. EPA 1999) state that

   In the analysis of animal bioassay data on the
   occurrence of multiple tumor types, the cancer
   potencies should be estimated for each relevant
   tumor type that is related to exposure, and the
   individual potencies should be summed for those
   tumors.

This inclusive approach is reconfirmed in the 2005 guidelines (U.S. EPA 2005). This protective approach was not taken by the U.S. EPA in its assessment of vinyl chloride cancer risks.

J.B.S and D.W. are employed by environmental nonprofit organizations with an interest in ensuring that regulations of toxic chemicals are as health protective as feasible. B.C. is an independent consultant in toxic substances control and has no competing financial interests regarding the subject matter of this letter.

REFERENCES

ACC. 2005. American Chemistry Council Homepage. Available: http://www.americanchemistry.com/ [accessed 1 September 2005].

Blair A, Kazerouni N. 1997. Reactive chemicals and cancer. Cancer Causes Control. 8:473-490.

Boffetta P, Matisane MD, Mundt KA, Dell LD. 2003. Meta-analysis of studies of occupational exposure to vinyl chloride in relation to cancer mortality. Scan J Work Environ Health 29(3):220-229.

Bosetti C, LaVecchia C, Lipworth L, McLaughlin JK. 2003. Occupational exposure to vinyl chloride and cancer risk: a review of the epidemiologic literature. Euro J Cancer Prevention 12:427-430.

Clewell H J, Gentry PR, Gearhart JM, Allen BC, Andersen ME. 2001. Comparison of cancer risk estimates for vinyl chloride using animal and human data with a PBPK model. Sci Total Environ 274:37-66.

Gennaro V, Ceppi M, Montanaro F. 2003. Reanalysis of mortality in a petrochemical plant producing vinyl chloride and polyvinyl chloride [in Italian]. Epidemiol Prey 27(4):221-225.

IARC (International Agency for Research on Cancer). 1979. Vinyl chloride, polyvinyl chloride and vinyl chloride-vinyl acetate copolymers. IARC Monogr Eval Carcinog Risk Chem Hum 19:377-438.

IARC (international Agency for Research on Cancer). 1987. Vinyl chloride. IARC Monogr Eval Carcinog Risks Hum Suppl 7:373.

McFayden MC, Melvin WT, Murray GI. 1908. Regional distribution of individual forms of cytochrome P450 mRNA in normal adult human brain. Biochem Pharmacol 55(6):825-30.

Mundt KA, Dell LD, Austin RP, Luippold RS, Noess R, Bigelow C. 2000. Historical cohort study of 10,109 men in the North American vinyl chloride industry, 1942-72; update of cancer mortality to 31 December 1995. Occup Environ Med 57:774-781.

Price CM. 1999. Letter from the Chemical Manufacturers Association to the U.S. EPA regarding the Toxicological Review of Vinyl Chloride. Arlington, VA:Chemical Manufacturers Association.

Reitz R, Gargas M, Andersen ME, Proven WM, Green TL. 1996. Predicting cancer risks from vinyl chloride exposure with a physiologically based pharmacokinetic model. Toxicol Appl Pharmacol 137:253-267.

Sass JB, Castleman B, Wallinga D. Vinyl chloride: a case study of data suppression and misrepresentation. Environ Health Perspect 113:809-812.

U.S. EPA. 1999. Draft Revised Guidelines for Carcinogen Risk Assessment (External Draft, July 1999). Washington, DC:U.S. Environmental Protection Agency, Risk Assessment Forum. Available: http://cfpub.epa.gov/ncea/ cfm/recordisplay.cfm?deid=54932 [accessed 13 June 2005].

U.S. EPA. 2000. Toxicological Review of Vinyl Chloride. Available: http://www.epa.gov/iris/toxreviews/[accessed 15 June 2005].

U.S. EPA. 2005. Guidelines for Carcinogen Risk Assessment and Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens. Available: http:// cfpub2.epa.gov/ncea/raf/recordisplay.cfm?deid=116283 [accessed 13 June 2005].

Vinyl Institute. 2005. Biography of the Vinyl Institute's President, Tim Burns. Available: http://www.vinylinfo.org/ aboutvi/burns.html (accessed 12 June 2005].

Ward E, Boffetta P, Andersen A, Colin D, Comba P, Deddens JA, et al. 2001. Update of the follow-up of mortality and cancer incidence among European workers employed in the vinyl chloride industry. Epidemiology 12:710-718.

Jennifer Beth Sass

Health and Environment Program Natural Resources Defense Council

Washington, DC

E-mail: [e-mail]

Barry Castleman

Environmental Consultant

Garrett Park, Maryland

David Wallinga

Institute for Agriculture and Trade Policy

Minneapolis, Minnesota