The Cancer Chronicles

by George Johnson

  15. sheep grazing in the mountains: The story of cyclopamine is told in Philipp Heretsch, Lito Tzagkaroulaki, and Athanassios Giannis, “Cyclopamine and Hedgehog Signaling: Chemistry, Biology, Medical Perspectives,” Angewandte Chemie (international ed. in English) 49, no. 20 (May 3, 2010): 3418–27. [http://www.ncbi.nlm.nih.gov/pubmed/20429080]

  16. holoprosencephaly: Max Muenk, “Translational Concepts to Disease: Holoprosencephaly as an Example,” lecture presented July 22, 2011 at the Society for Developmental Biology Seventieth Annual Meeting, Chicago, IL.

  17. one of every 250 early embryos: Erich Roessler, Maximilian Muenke, et al., “Mutations in the Human Sonic Hedgehog Gene Cause Holoprosencephaly,” Nature Genetics 14, no. 3 (November 1996): 357–60. [http://dx.doi.org/10.1038/ng1196-357]

  18. can drive the formation of malignancies: For an overview of sonic hedgehog and cancer see Lee L. Rubin and Frederic J. de Sauvage, “Targeting the Hedgehog Pathway in Cancer,” Nature Reviews Drug Discovery 5, no. 12 (December 2006): 1026–33 [http://dx.doi.org/10.1038/nrd2086]; and Jennifer M. Bailey, Pankaj K. Singh, and Michael A. Hollingsworth, “Cancer Metastasis Facilitated by Developmental Pathways: Sonic Hedgehog, Notch, and Bone Morphogenic Proteins,” Journal of Cellular Biochemistry 102, no. 4 (November 1, 2007): 829–39. [http://onlinelibrary.wiley.com/doi/10.1002/jcb.21509/abstract]

  19. Gorlin syndrome: Ervin H. Epstein, “Basal Cell Carcinomas: Attack of the Hedgehog,” Nature Reviews Cancer 8, no. 10 (October 2008): 743–54. [http://dx.doi.org/10.1038/nrc2503]

  20. a cream containing cyclopamine: Sinan Tabs and Oktay Avci, “Induction of the Differentiation and Apoptosis of Tumor Cells in Vivo with Efficiency and Selectivity,” European Journal of Dermatology 14, no. 2 (April 2004): 96–102. [http://www.ncbi.nlm.nih.gov/pubmed/15196999]

  21. another hedgehog inhibitor: “FDA Approval for Vismodegib,” National Cancer Institute. [http://www.cancer.gov/cancertopics/druginfo/fda-vismodegib]

  22. might help control the genetic switches: More specifically, Dmrt5 is a transcription factor, a molecule that binds to the genome and regulates the output of a gene.

  23. “zinc fingers,” “Dmrt5,” and “Emma Farley”: Emma K. Farley et al., “Novel Transcription Factor Involved in Neurogenesis,” Developmental Biology 344, no. 1 (2010): 493. [http://www.researchgate.net/publication/47383131_Novel_transcription_factor_involved_in_neurogenesis]

  24. so many new scraps of information: Venugopala Reddy Bommireddy Venkata, Cordelia Rauskolb, and Kenneth D. Irvine, “Fat-Hippo Signaling Regulates the Proliferation and Differentiation of Drosophila Optic Neuroepithelia,” Developmental Biology 344, no. 1 (2010): 506 [http://www.researchgate.net/publication/47383178_Fat-Hippo_signaling_regulates_the_proliferation_and_differentiation_of_Drosophila_optic_neuroepithelia]; and Thomas L. Gallagher and Joshua Arribere, “Fox1 and Fox4 Regulate Muscle-specific Splicing in Zebrafish and Are Required for Cardiac and Skeletal Muscle Functions,” Developmental Biology 344, no. 1 (2010): 491–92. [http://www.researchgate.net/publication/47383123_Fox1_and_Fox4_regulate_muscle-specific_splicing_in_zebrafish_and_are_required_for_cardiac_and_skeletal_muscle_functions]

  25. a whimsical turn: Cristina L. Walcher and Jennifer L. Nemhauser, “1 + 1 = 3: When Two Hormones Are Better Than One,” Developmental Biology 344, no. 1 (2010): 487; [http://www.researchgate.net/publication/47383110_113_When_two_hormones_are_better_than_one] and Nowlan Freese and Susan C. Chapman, “Where’d My Tail Go?” Developmental Biology 344, no. 1 (2010): 441. [http://www.researchgate.net/publication/47382941_Where’d_my_tail_go]

  26. six little words: The full title was “How Heart Cells Embrace Their Fate in the Chordate Ciona Intestinalis” by Stacia Ilchena and James Cooley, Developmental Biology 344, no. 1 (2010): 502–3. [http://www.researchgate.net/publication/47383162_How_heart_cells_embrace_their_fate_in_the_chordate_Ciona_intestinalis]

  CHAPTER 7 Where Cancer Really Comes From

  1. excavating a canal: Love Canal’s history is described in Allan Mazur, A Hazardous Inquiry: The Rashomon Effect at Love Canal (Cambridge, MA: Harvard University Press, 1998), 8–15.

  2. some 22,000 tons of toxic waste: “Love Canal: A Special Report to the Governor & Legislature,” April 1981, New York Department of Health website. [http://www.health.state.ny.us/environmental/investigations/love_canal/lcreport.htm]

  3. “The odors penetrate your clothing”: “Chemical Waste at Love Canal, October 18, 1977,” Ecumenical Task Force of the Niagara Frontier Records, 1946–1995 (MS 65), University at Buffalo Libraries, Love Canal Collections website. [http://library.buffalo.edu/specialcollections/lovecanal/collections/etf.php]

  4. incorporated the saga into a novel: Joyce Carol Oates, The Falls: A Novel (New York: Ecco, 2004).

  5. the EPA estimated: “U.S. Finds Risk of Cancer High for Residents Near Love Canal; Three Families Inside Fence,” New York Times, November 11, 1979.

  6. admitted to a mathematical error: Irvin Molotsky, “Rep. LaFalce Says Draft Report Inflated Love Canal Cancer Risk; Mathematical Errors Conceded,” New York Times, November 20, 1979.

  7. Another EPA report found: Irvin Molotsky, “Damage to Chromosomes Found in Love Canal Tests,” New York Times, May 17, 1980. The findings were in D. Picciano, “Pilot Cytogenetic Study of the Residents Living Near Love Canal, a Hazardous Waste Site, Mammalian Chromosome Newsletter 21 (1980): 86–93.

  8. dismissed by a panel: Richard J. Meislin, “Carey Panel Discounts 2 Studies on Love Canal Health Problems,” New York Times, October 11, 1980.

  9. A later study for the Centers for Disease Control: Clark W. Heath Jr. et al., “Cytogenetic Findings in Persons Living Near the Love Canal,” JAMA: The Journal of the American Medical Association 251, no. 11 (March 16, 1984): 1437–40. [http://jama.ama-assn.org/content/251/11/1437]

  10. a thirty-year retrospective: “Love Canal Follow-up Health Study,” New York Department of Health website, October 2008. [http://www.health.ny.gov/environmental/investigations/love_canal/docs/report_public_comment_final.pdf] For a critique of the report see appendix T, “Public Comments and Responses, Love Canal Follow-up Health Study,” especially the comments by epidemiologist Richard Clapp, 145–47.

  11. Almost half of the 6,026 residents: Demographic details are described in table 20, page 97 of the “Love Canal Follow-up.”

  12. the birth defect rate: “Love Canal Follow-up,” 42–43. Altogether there were thirty-seven congenital malformations reported among 1,767 singleton births (those not including twins and triplets) between 1960 and 1996. For comparing incidence rates, the study counted only “consistently and reliably reported” cases as defined by the New York State Congenital Malformation Registry, which had complete records only beginning in 1983. Earlier information came from local hospitals and was not considered solid enough to use in the comparisons. (See pages 29–30 of the report for details. Also see table 19, page 96, and appendix A on page 103.)

  13. higher than for the rest of the state: That excluded New York City.

  14. slightly more girls had been born: “Love Canal Follow-up,” 41–43.

  15. no convincing evidence: “Love Canal Follow-up,” 2.

  16. overall cancer rate was actually a little lower: That was compared with both the county and the state. See “Love Canal Follow-up,” 39–41.

  17. Rachel Carson’s elegant warning: Silent Spring (Boston: Houghton Mifflin Company, 1962).

  18. scathing polemics: Samuel S. Epstein, The Politics of Cancer (San Francisco: Sierra Club Books, 1978) and The Politics of Cancer Revisited (Fremont Center, NY: East Ridge Press, 1998).

  19. a modern epidemic of cancer: The historian Robert N. Proctor captures the zeitgeist in Cancer Wars: How Politics Shapes What We Know and Don’t Know About Cancer (New York: Basic Books, 1995). See particularly 54–74.

  20. “the plague of the twentieth century”: Epstein, Politics of Cancer Revisited, 14.

  21. “a grim game of chemical roulette”: Russell Train in a speech to the National Press Club, February 26, 1976.
The story was picked up by the Associated Press and appeared the next day in newspapers, including The Morning Record (Meriden, CT) and the Sarasota Herald-Tribune. [http://news.google.com/newspapers?nid=2512&dat=19760227&id=_KNHAAAAIBAJ&sjid=d_8MAAAAIBAJ&pg=1388,3515703]

  22. “the Great Cancer Wars”: Proctor, Cancer Wars, 74.

  23. Ninety percent of cancer is environmental: For an account of the origin of the misconception, see Proctor, Cancer Wars, 55–57; and (keeping in mind its libertarian bias) Edith Efron, Apocalyptics: Cancer and the Big Lie: How Environmental Politics Controls What We Know About Cancer (New York: Simon & Schuster, 1984), 429–32.

  24. known and suspected agents: See National Toxicology Program, Report on Carcinogens, 12th ed. (Research Triangle Park, NC: U.S. Department of Health and Human Services, 2011). [http://ntp-server.niehs.nih.gov/?objectid=03C9AF75-E1BF-FF40-DBA9EC0928DF8B15]

  25. To get a sense of how strongly cancer was influenced: The migrant studies are summarized in R. Doll and R. Peto, “The Causes of Cancer: Quantitative Estimates of Avoidable Risks of Cancer in the United States Today,” Journal of the National Cancer Institute 66, no. 6 (June 1981): 1191–1308, reference on 1200–01; Proctor, Cancer Wars, 24–26; and Efron, Apocalyptics, 430–32.

  26. seemed to be escalating abruptly: The numbers were published in Earl S. Pollack and John W. Horm, “Trends in Cancer Incidence and Mortality in the United States, 1969–76,” Journal of the National Cancer Institute 64, no. 5 (May 1, 1980): 1091–103 [http://jnci.oxfordjournals.org/content/64/5/1091]; and in Toxic Chemicals and Public Protection: A Report to the President by the Toxic Substances Strategy Committee (Washington, DC: Council on Environmental Quality, May 1980), which is available online through the Hathi Trust Digital Library. [http://catalog.hathitrust.org/Record/007413257]

  27. appeared to be the vindication: For a description of the controversy see Doll and Peto, “Causes of Cancer,” 1279–81; and Efron, Apocalyptics, 434–36.

  28. warned that the comparisons were invalid: Doll and Peto, “Causes of Cancer,” 1280–81; and Efron, Apocalyptics, 435.

  29. commissioned a study: Doll and Peto, “Causes of Cancer.”

  30. accomplished scientists in their field: Doll’s later work was called into question when it was revealed after his death that he had accepted consulting fees from chemical companies. In defending his colleague, Peto said that Doll was open about the connections and gave the money to Green College, Oxford, which he helped found. See Sarah Boseley, “Renowned Cancer Scientist Was Paid by Chemical Firm for 20 Years,” The Guardian, December 7, 2006. [http://www.guardian.co.uk/science/2006/dec/08/smoking.frontpagenews] In the letters section of the next day’s edition other prominent scientists defended Doll’s impartiality (see “Richard Doll Still Deserves Our Respect”). [http://www.guardian.co.uk/science/2006/dec/09/guardianletters?intcmp=239] They included the chief executive of the Medical Research Council, the director of Wellcome Trust, and Martin Rees, the president of the Royal Society.

  31. which numbers to trust: Doll and Peto, “Causes of Cancer,” appendix C, 1270–81.

  32. The situation improved: Doll and Peto, “Causes of Cancer,” 1281.

  33. In 30 percent of cancer deaths, tobacco was a cause: Doll and Peto, “Causes of Cancer,” table 20, 1256.

  34. “most of the types of cancer that are common today”: Doll and Peto, “Causes of Cancer,” 1212.

  35. Any specific case of cancer will have multiple causes: For the dilemmas involved in sorting out the environmental and genetic factors of a disease, see Kenneth J. Rothman and Sander Greenland, “Causation and Causal Inference in Epidemiology,” American Journal of Public Health 95 suppl. 1 (2005): S144–50. [http://www.ncbi.nlm.nih.gov/pubmed/16030331]

  36. They were a component: For a recent assessment see Paolo Boffetta and Fredrik Nyberg, “Contribution of Environmental Factors to Cancer Risk,” BMJ: British Medical Journal 68, no. 1 (December 1, 2003): 71–94 [http://bmb.oxfordjournals.org/content/68/1/71.abstract]; and Richard W. Clapp and Molly M. Jacobs, “Environmental and Occupational Causes of Cancer: New Evidence, 2005–2007,” October 2007, Lowell Center for Sustainable Production website. [http://www.sustainableproduction.org/downloads/EnvandOccCausesofCancer-2007Update-DownloadVersion.pdf]

  37. “there is too much ignorance”: Doll and Peto, “Causes of Cancer,” 1251.

  38. cancer mortality among people under sixty-five: Doll and Peto, “Causes of Cancer,” 1256. For details see 1281–85 and tables D1 and D3.

  39. largely true for older Americans: Doll and Peto, “Causes of Cancer,” 1256. See table D2 for the overall rate and D4 for specific cancers. There appeared to be an increase in brain cancer deaths and smaller increases in other nonrespiratory cancers, but the authors attributed these mostly to better record keeping.

  40. not because we were getting much better: Doll and Peto, “Causes of Cancer,” 1256.

  41. Two smaller studies: J. Higginson and C. S. Muir, “Environmental Carcinogenesis: Misconceptions and Limitations to Cancer Control,” Journal of the National Cancer Institute 63, no. 6 (December 1979): 1291–98; [http://www.ncbi.nlm.nih.gov/pubmed/390201] and E. L. Wynder and G. B. Gori, “Contribution of the Environment to Cancer Incidence: An Epidemiologic Exercise,” Journal of the National Cancer Institute 58, no. 4 (April 1977): 825–32. [http://www.ncbi.nlm.nih.gov/pubmed/321795]

  42. began challenging the report: Samuel S. Epstein and Joel B. Swartz, “Fallacies of Lifestyle Cancer Theories,” Nature 289, no. 5794 (January 15, 1981): 127–30. [http://www.nature.com/nature/journal/v289/n5794/abs/289127a0.html]

  43. When lung cancer rates began rising: David G. Hoel, Devra L. Davis, et al., “Trends in Cancer Mortality in 15 Industrialized Countries, 1969–1986,” Journal of the National Cancer Institute 84, no. 5 (March 4, 1992): 313–20. [http://jnci.oxfordjournals.org/content/84/5/313.abstract]

  44. While epidemiologists kept watch: Bruce Ames’s story is told in Proctor, Cancer Wars, 136–52.

  45. the Ames test: Bruce N. Ames et al., “Carcinogens Are Mutagens: A Simple Test System Combining Liver Homogenates for Activation and Bacteria for Detection,” Proceedings of the National Academy of Sciences 70, no. 8 (August 1973): 2281–85. [http://www.pnas.org/content/70/8/2281.abstract]

  46. By killing esophagus cells: Alcohol may also increase cancer risk by breaking down into carcinogenic acetaldehyde and through other mechanisms. For a summary see “Alcohol Use and Cancer,” American Cancer Society website, last revised January 27, 2012. [http://www.cancer.org/Cancer/CancerCauses/DietandPhysicalActivity/alcohol-use-and-cancer]

  47. a paper in Science: B. N. Ames, “Dietary Carcinogens and Anticarcinogens,” Science 221, no. 4617 (September 23, 1983): 1256–64. [http://www.ncbi.nlm.nih.gov/pubmed/6351251]

  48. In 1997, he reported: B. N. Ames and L. S. Gold, “Environmental Pollution, Pesticides, and the Prevention of Cancer: Misconceptions,” FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology 11, no. 13 (November 1997): 1041–52. [http://www.ncbi.nlm.nih.gov/pubmed/9367339]

  49. In fact he doubted: Ames and Gold, “Environmental Pollution, Pesticides, and the Prevention of Cancer.”

  50. Half of everything tested: B. N. Ames and L. S. Gold, “Chemical Carcinogenesis: Too Many Rodent Carcinogens,” Proceedings of the National Academy of Sciences 87, no. 19 (October 1990): 7772–76. [http://www.pnas.org/content/87/19/7772.abstract]

  51. an experiment costing tens of millions of dollars: Cancer and the Environment (Washington, DC: U.S. Department of Health and Human Services, March 2003), 25.

  52. mitogenesis increases mutagenesis: Ames and Gold, “Chemical Carcinogenesis.”

  53. Toxicologists defended the tests: P. J. Infante, “Prevention Versus Chemophobia: A Defence of Rodent Carcinogenicity Tests,” Lancet 337, no. 8740 (March 1991): 538–40; [http://www.lancet.com/journals/lancet/article/PII0140-6736(91)91310-Q/fulltext] P. F. Infante, “Use of Rodent Carcinogenicity Test Results for Determining Pote
ntial Cancer Risk to Humans,” Environmental Health Perspectives 101, suppl. 5 (December 1993): 143–48 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1519448]; and I. Bernard Weinstein, “Cell Proliferation: Concluding Remarks,” Environmental Health Perspectives 101, suppl. 5 (December 1993): 159–61. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1519446]

  54. diverting attention from a genuine problem: See, for example, Clapp and Jacobs, “Environmental and Occupational Causes of Cancer”; Devra Lee Davis and Joel Schwartz, “Trends in Cancer Mortality: U.S. White Males and Females, 1968–83,” Lancet 331 (March 1988): 633–36 [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(88)91426-2/abstract]; and Devra Davis, The Secret History of the War on Cancer (New York: Basic Books, 2007).

  55. recent report by a White House advisory group: Reducing Environmental Cancer Risk: What We Can Do Now, 2008–2009 Annual Report (Washington, DC: National Cancer Institute, April 2010). [http://deainfo.nci.nih.gov/advisory/pcp/annualreports/pcp08-09rpt/PCP_Report_08-09_508.pdf]

  56. The alternative would be to administer: Reducing Environmental Cancer Risk, 11.

  57. “has been grossly underestimated”: Reducing Environmental Cancer Risk, introductory letter, unpaginated.

  58. many scientists criticized the report: David C. Holzman, “President’s Cancer Panel Stirs Up Environmental Health Community,” Journal of the National Cancer Institute 102, no. 15 (August 4, 2010): 1106–13. [http://jnci.oxfordjournals.org/content/early/2010/07/28/jnci.djq297.extract]

  59. The National Academy of Sciences has described: “Toxicity Testing in the 21st Century: A Vision and a Strategy (Washington, DC: National Academies Press, 2007). These ideas are beginning to be embodied in the Environmental Protection Agency’s Computational Toxicology Research program. [http://epa.gov/ncct]

  60. death rates from cancer did rise gradually: Ahmedin Jemal et al., “Annual Report to the Nation on the Status of Cancer, 1975–2009, Featuring the Burden and Trends in Human Papillomavirus (HPV)–Associated Cancers and HPV Vaccination Coverage Levels,” Journal of the National Cancer Institute (January 7, 2013). See table 2. A summary with a link to the full report is available on the National Cancer Institute’s SEER (Surveillance, Epidemiology, and End Results) website. [http://seer.cancer.gov/report_to_nation]