Getting Risk Right

4. Wald’s insight is reminiscent of techniques that artists have long used to free themselves from the rote and therefore deadening habits that we all fall into. We are so used to the objects around us—the human figure, a chair—that it is difficult not to substitute our idea of the figure or chair for what is actually there. One trick artists use to circumvent these preconceptions is to draw what is not the figure or not the chair—what is referred to as the “negative space” surrounding the object.

When I told the story about Abraham Wald in a Forbes column (http://www.forbes.com/sites/geoffreykabat/2013/01/17/making-room-for-the-unseen-in-tackling-complex-problems/), an immunologist colleague, Lawrence Silbart of the University of Connecticut, wrote to me, “I had never heard about this before! This is of course how our immune repertoire is shaped. We subtract out self-reactive lymphocytes while they are immature and can’t do any harm. Thus, only lymphocytes that react with other shapes (i.e., foreign intruders) are allowed to reach maturity. Presumably this system evolved since our immune systems can’t anticipate what these new shapes are going to look like (since new pathogens emerge and old ones evolve)… so it’s nature’s Wald.”

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1. Hormann AM et al. Holding thermal receipt paper and eating food afterward using hand sanitizer results in high serum bioactive and urine total levels of bisphenol A (BPA). PLoS ONE 2014 Oct. 22. doi:10.1371/journal.pone.0110509.

2. Associated Press. American Ebola doc: “I’m thrilled to be alive.” New York Times 2014 Aug. 21.

3. I am referring to the paper by Andrew Wakefield published in the Lancet in 1998 claiming that there is a link between administration of the measles, mumps, and rubella vaccine and the appearance of autism and bowel disease in children. Twelve years later, owing to the efforts of a persistent investigative journalist, the work was shown to be fraudulent and the paper was retracted.

4. Centers for Disease Control and Prevention. U.S. Multi-state measles outbreak 2014–2015. http://www.cdc.gov/measles/multi-state-outbreak.xhtml; Nagourney A, Goodnough A. Measles cases linked to Disneyland rise, and debate over vaccinations intensifies. New York Times 2014 Jan. 21; Xia R, Lin RG. Measles outbreak at 149 cases in eight states, Canada and Mexico. Los Angeles Times 2015 Feb. 20.

5. Satel SL. Will the F.D.A. kill off e-cigs (op-ed). New York Times 2015 Jan. 18; Fairchild AL, Bayer R. Smoke and fire over e-cigarettes. Science 2015;347:375–76.

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7. Offit P. Do You Believe in Magic? The Sense and Nonsense of Alternative Medicine. New York: Harper, 2013; Navarro VJ et al. Liver injury from herbals and dietary supplements in the U.S.—drug-induced liver injury network. Hepatology 2014 60(4):1399–1408. doi:10.1002/hep.27317. Epub 2014 Aug. 25.

8. Geller AI et al. Emergency department visits for adverse events related to dietary supplements. New England Journal of Medicine 2015;15(373):1531–40. doi:10.1056/NEJMsa1504267.

9. Patel CJ, Cullen MR, Ioannidis JPA, Butte AJ. Systematic evaluation of environmental factors: persistent pollutants and nutrients correlated with serum lipids. International Journal of Epidemiology 2012;41:828–43.

10. Konkel L. Data Stretching back to 1959 may explain link between environment and breast cancer. Scientific American 2015 Apr. http://www.scientificamerican.com/article/data-stretching-back-to-1959-may-explain-link-between-environment-and-breast-cancer/; Cohn BA et al. DDT exposure in utero and breast cancer. Journal of Endocrinology and Metabolism 2015. doi:10.1210/jc.2015–1841.

11. Young SS, Karr A. Deming, data, and observational studies: a process out of control and needing fixing. Significance 2011;8:116–20. http://onlinelibrary.wiley.com/doi/10.1111/j.1740–9713.2011.00506.x/abstract.

12. World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer. 2007.

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14. Taubes G. Epidemiology faces its limits. Science 1995;269:164–69; Kabat GC. Hyping Health Risks: Environmental Hazards in Everyday Life and the Science of Epidemiology. New York: Columbia University Press, 2008; Boffetta P, McLaughlin JK, La Vecchia C, Tarone RE, Lipworth L, Blot WJ. False positive results in cancer epidemiology: a plea for epidemiologic modesty. Journal of the National Cancer Institute 2008;100:988–95; Young, Karr. Deming, data and observational studies; Bhopal R. Seven mistakes and potential solutions in epidemiology, including a call for a World Council of Epidemiology and Causality. Emerging Themes in Epidemiology 2009;6:6. doi:10.1186/1742–7622–6-6; Rothman KJ. Six persistent research misconceptions. Journal of General Internal Medicine 2014;29:1060–64. doi:10.1007/s11606–013–2755-z.

15. Ioannidis JPA. Why most research findings are false. PLoS Medicine 2005;2:e124. doi:10.1371/journal.pmed.0020124.

16. Freedman DH. Lies, damned lies, and medical science. Atlantic 2010 Nov. 20.

17. Ioannidis JPA. Contradicted and initially stronger effects in highly cited clinical research. JAMA 2005;294:218–28.

18. Tsilidis KT, Papatheordorou SI, Evangelou E, Ioannidis JPA. Evaluation of excess statistical significance in meta-analyses of 98 biomarker associations with cancer risk. Journal of the National Cancer Institute 2012;104:1867–75.

19. Ioannidis JP. How to make more published research true. PLoS Medicine 2014;11(10):e1001747. doi:10.1371/journal.pmed.1001747. eCollection 2014.

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21. Rothman KJ, Greenland S. Causation and causal inference in epidemiology. American Journal Public Health 2005;95:S144–S150. doi:10.2105/AJPH.2004.059204; Gee D. Late lessons from early warnings: toward realism and precaution with endocrine-disrupting substances. Environmental Health Perspectives 2006;114 Suppl.:152–60.

22. Phillips CV, Goodman KJ. The missed lessons of Sir Austin Bradford Hill. Epidemiologic Perspectives and Innovations. 2004;1:3. http://www.ncbi.nlm.nih.gov/pubmed/15507128.

23. Rothman, Greenland. Causation and causal inference in epidemiology.

27. Kabat G. After 40 years of research, what do we know about preventing breast cancer? Forbes 2013 Feb. 24.

28. “Circular epidemiology can be defined as the continuation of specific types of epidemiologic studies beyond the point of reasonable doubt of the true existence of an important association or the absence of such an association.” Kuller L. Circular epidemiology. American Journal of Epidemiology 1999;150:897–903.

29. Savitz D. The etiology of epidemiologic perseveration: when enough is enough. Epidemiology 2010;21:281–83. doi:10.1097/EDE.0b013e3181d77b5f.

30. Platt JR. Strong inference. Science 1964;146:347–53.

31. Chamberlin TC. The method of multiple working hypotheses. Science 1890;15:92–96.

32. “When multiple hypotheses become coupled to strong inference, the scientific search becomes an emotional powerhouse as well as an intellectual one.” Platt. Strong inference.

1. Latour B. We Never Have Been Modern, trans. Catherine Porter. Cambridge, Mass.: Harvard University Press, 1993.

2. Kabat GC. Hyping Health Risks: Environmental Hazards in Daily Life and the Science of Epidemiology. New York: Columbia University Press, 2008.

3. Chang K. Debate continues on hazards of electromagnetic waves. New York Times 2014 July 7.

4. “Even today, though the caveat that the occurrence of two events (association) does not indicate causality is widely recognized, Hume’s identification of this limitation in the search for causal relationships is often ignored. The seduction of inductive reasoning is a trap that easily catches the unwary.” Rabins PV. The Why of Things: Causality in Science, Medicine, and Life. New York: Columbia University Press, 2013, 14.

5. Jordan VC. Avoiding the bad and enhancing the good of soy supplements in breast cancer (editorial). Journal of the National Cancer Institute 2014;106:dju233. doi:10.1093/jnci/dju233.

6. Quoted in Taubes G. Epidemiology faces its limits. Science 1995;269:164–69.

7. Boffetta P, McLaughlin JK, La Vecchia C, Tarone RE, Lipworth L, Blot WJ. False-positive results in cancer epidemiology: a plea for epidemiologic modesty. Journal of the National Cancer Institute 2008;100:988–95; McLaughlin JK, Tarone RE. False positives in cancer epidemiology. Cancer Epidemiology Biomarkers and Prevention 2013;22:11–15. doi:10.1158/1055–9965.EPI-12–0995; Ioannidis JPA. Why most published research findings are false. PLoS Medicine 2005. doi:10.1371/journal.pmed.0020124; Kabat. Hyping Health Risks; Collins FS, Tabak LA. NIH plans to enhance reproducibility. Nature 2014;505:612–13; Dawn K et al. Systematic review of the empirical evidence of study publication bias and outcome reporting bias. PLoS ONE 2008;3:e3081.

8. Kabat. Hyping Health Risks.

9. Kabat G. Having it both ways on what causes cancer: IARC’s flawed paradigm. Forbes 2015 Nov. 19. http://www.forbes.com/sites/geoffreykabat/2015/11/19/having-it-both-ways-on-what-causes-cancer/.

10. According to IARC’s own “Preamble” to the monographs series setting out its mission, “A cancer ‘hazard’ is an agent that is capable of causing cancer under some circumstances, while a cancer ‘risk’ is an estimate of the carcinogenic effects expected from exposure to a cancer hazard” (emphasis added). The preamble goes on to state, “The Monographs are an exercise in evaluating cancer hazards, despite the historical presence of the word ‘risks’ in the title. The distinction between hazard and risk is important, and the Monographs identify cancer hazards even when risks are very low at current exposure levels, because new uses or unforeseen exposures could engender risks that are significantly higher” (emphasis added). http://monographs.iarc.fr/ENG/Preamble/CurrentPreamble.pdf.

11. Plummer B. The bacon freak-out: why the WHO’s cancer warnings cause so much confusion. Vox 2015 Oct. 26. http://www.vox.com/2015/10/26/9617928/iarc-cancer-risk-carcinogenic.

12. Gupta N, Stopfer M. Negative results need airing too. Nature 2011;470. doi:10.1038/470039a; Yong E. Replication studies: bad copy. Nature 2012 485:298–300. doi:10.1038/485298a; Nyhan B. To get more out of science, show the rejected research. New York Times 2014 Sept. 18.

13. The magnifying glass effect is very much in line with the kinds of biases described by Kahneman and Tversky, especially the availability heuristic.

14. Slovic P, ed. The Perception of Risk. London: Earthscan, 2000.

15. Phalen R. California Air Resources Board PM 2.5 Mortality Symposium, Sacramento Calif., Feb. 26, 2010. https://www.youtube.com/watch?v=CIGFgyhaw2o.

16. Cope MB, Allison DB. White hat bias: examples of its presence in obesity research and a call for renewed commitment to faithfulness in research reporting. International Journal of Obesity 2010;34:84–88; Atkinson RL, Macdonald I. White hat bias: the need for authors to have the spin stop with them (editorial). International Journal of Obesity 2010;34:83.

17. Kabat G. The crisis of peer review. Forbes 2015 Nov. 23. http://www.forbes.com/sites/geoffreykabat/2015/11/23/the-crisis-of-peer-review/.

18. Wakefield AJ et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998 Feb 28;351(9103):637–41; retraction in Lancet 2010 Feb 6;375(9713):445; partial retraction in Murch SH et al. Lancet 2004 Mar 6;363(9411):750; Deer B. How the case against MMR was fixed. BMJ 2011;342. doi:http://dx.doi.org/10.1136/bmj.c5347.

19. Rothman KJ. Conflict of interest: the new McCarthyism in science. Journal of the American Medical Association 1993;269:2782–84; Conflict of interest policies: protecting readers or censoring authors? In reply. Journal of the American Medical Association 1993;270:2684.

20. Trinquart L, Johns DM, Galea S. Why do we think we know what we know? A metaknowledge analysis of the salt controversy. International Journal of Epidemiology 2016;45:251–60.

21. Feynman R. Cargo cult science: some remarks on science, pseudoscience, and learning how to not fool yourself. Commencement address, California Institute of Technology, 1974. http://calteches.library.caltech.edu/51/2/CargoCult.htm.

22. Quoted in Taubes. Epidemiology faces its limits.

23. The precautionary principle. https://commons.wikimedia.org.

24. Sunstein CR. Beyond the precautionary principle. John M. Olin Law & Economics Working Paper no. 149 (2nd series), Public Law and Legal Theory Working Paper no. 38 (January 2003): 8. http://ssrn.com/abstract_id=307098 p. 8.

25. Ibid., 2. Sunstein goes so far as to argue that the precautionary principle is useless because “it leads in no direction at all. The reason is that risks of one kind or another are on all sides of regulatory choices and it is therefore impossible, in most real-world cases, to avoid running afoul of the principle” (42). He explains the enormous appeal of the principle and its incorporation into legal and political discourse by its conformity with cognitive biases, such as loss aversion and the availability heuristic (5–7).

26. To name just a few instances: IARC’s questionable assessments of cells phones, coffee, formaldehyde, and glyphosate; NIEHS’s program supporting research on BPA; and DOE’s and NIEHS’s earlier program on EMFs.

27. Trinquart, Johns, Galea. Why do we think we know what we know?

28. Kahneman D, Tversky A. Judgment under uncertainty: heuristics and biases. Science 1974;185:1124–31; Kahneman D. Thinking Fast and Slow. New York: Farrar, Straus, and Giroux, 2011.

29. Kuran T, Sunstein CR. Availability cascades and risk regulation. Working Paper Series, 685. http://www.law.uchicago.edu/Lawecon/index.xhtml, and at Public Law and Legal Theory Working Paper Series. http://www.law.uchicago.edu/academics/publiclaw/index.xhtml, and Social Science Research Network Electronic Paper Collection. http://ssrn.com/abstract_id=1019644.

31. Ibid., 691–97. George Johnson situates the Love Canal incident in the context of ideas about cancer and the environment that were prevalent in the 1970s, in The Cancer Chronicles: Unlocking Medicine’s Deepest Mystery. New York: Knopf, 2013.

32. Kuran, Sunstein. Availability cascades and risk regulation, 713.

33. Ibid., 716–17, 726.

1. Park RL. Cellular telephones and cancer: how should science respond? Journal of the National Cancer Institute 2001;93:166–67. Resorting to a form of magical thinking, Reynard went on to say, “The tumor was exactly in the pattern of the antenna.” Mukherjee S, Do cellphones cause brain cancer? New York Times magazine 2011 April 13.

2. Linet MS, Inskip PD. Cellular (mobile) telephone use and cancer risk. Reviews on Environmental Health 2010;25:51–55.

3. Park. Cellular telephones and cancer.

4. For an account of the rise and fall of the controversy surrounding the health effects of exposure to EMFs, see Kabat GC. Hyping Health Risks: Environmental Hazards in Daily Life and the Science of Epidemiology. New York: Columbia University Press, 2008, chap. 4.

5. Rothman KJ. Health effects of mobile telephones (editorial). Epidemiology 2009:20(5):653–55.

6. American Cancer Society. Cancer Facts and Figures 2014. http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2014/.

7. Ahlbom A, Green A, Kheifets L, Savitz D, Swerdlow A. Epidemiology of health effects of radiofrequency exposure. Environmental Health Perspectives 2004;112:1741–54; Linet, Inskip. Cellular (mobile) telephone use.

8. Ahlbom et al. Epidemiology of health effects.

10. Kabat. Hyping Health Risks, chap. 4.

11. INTERPHONE Study Group. Brain tumours risk in relation to mobile telephone use: results of the INTERPHONE international case-control study. International Journal of Epidemiology 2010;39:675–94.

12. Ahlbom A, Feychting M, Green A, Kheifets L, Savitz DA, Swerdlow AJ, International Commission for Non-Ionizing Radiation Protection (ICNIRP) Standing Committee on Epidemiology. Epidemiologic evidence on mobile phones and tumor risk: a review. Epidemiology 2009;20:639–52.

13. Repacholi MH et al. Systematic review of wireless phone use and brain cancer and other head tumors (review). Bioelectromagnetics 2012;33:187–206; Lagorio S, Röösli M. Mobile phone use and risk of intracranial tumors: a consistency analysis. Bioelectromagnetics 2014;35:79–90; Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR). Potential Health Effects of Exposure to Electromagnetic Fields (EMF). 2015, 72–84.

14. Hardell L, Carlberg M. Mobile phones, cordless phones and the risk for brain tumours. International Journal of Oncology 2009;35:5–17; Hardell L, Carlberg M, Hansson MK. Pooled analysis of case-control studies on malignant brain tumours and use of mobile and cordless phones including living and deceased subjects. International Journal of Oncology 2011;38:1465–74.

15. Ahlbom A, Feychting M. Mobile telephones and brain tumors (editorial). BMJ 2011;343.d6605. doi:10.1136/bmj.d6605.

16. Deltour I, Johansen C, Auvinen A, Feychting M, Klaeboe L, Schüz J. Time trends in brain tumor incidence rates in Denmark, Finland, Norway, and Sweden, 1974–2003. Journal of the National Cancer Institute 2009;101:1721–24; Deltour IU et al. Mobile phone use and incidence of glioma in the Nordic countries 1979–2008: consistency check. Epidemiology 2012;23:301–307; De Vocht F, Burstyn I, Cherrie JW. Time trends (1998–2007) in brain cancer incidence rates in relation to mobile phone use in England. Bioelectromagnetics 2011;32:334–39; Little MP et al. Mobile phone use and glioma risk: comparison of epidemiological study results with incidence trends in the United States. BMJ 2012;344:e114. doi:10.1136/bmj.e1147.

17. Repacholi et al. Systematic review of wireless phone use; Lagorio, Röösli. Mobile phone use.

18. http://www.bioinitiative.org.

19. Goldberg P. Peers puzzled by Herberman’s stance on cell phone while believers rally. Cancer Letter 2008;34, Aug. 1.

20. Cell Phones and Brain Tumors: 15 Reasons for Concern. http://www.radiationresearch.org/pdfs/reasons_us.pdf; Environmental Working Group. Cell Phone Radiation: Science Review on Cancer Risks and Children’s Health. http://static.ewg.org/reports/2012/cellphones/2009-cellphoneradiation-fullreport.pdf?_ga=1.222126232.1202499323.1425218899.

21. Cell Phones and Brain Tumors.

22. Ibid.; Environmental Working Group. Cell Phone Radiation.

23. Khurana VG, Teo C, Kundi M, Hardell L, Carlberg M. Cell phones and brain tumors: a review including the long-term epidemiologic data. Surgical Neurology 2009;72:205–14; discussion 214–15. Epub 2009 Mar. 27.

24. Myung SK et al. Mobile phone use and risk of tumors: a meta-analysis. Journal of Clinical Oncology 2009;27:5565–72. Epub 2009 Oct. 13.

25. Davis D. Brain cancer and cell phones: the jury is still out. Huffington Post 2009 Dec. 7. http://www.huffingtonpost.com/devra-davis-phd/brain-cancer-and-cell-pho_b_379601.xhtml.

26. Kabat. Hyping Health Risks, chap. 3.

27. Davis DL, Bradlow HL, Wolff M, Woodruff T, Hoel DG, Anton-Culver H. Medical hypothesis: xenoestrogens as preventable causes of breast cancer. Environmental Health Perspectives 1993;101:372–77.

28. Davis. Brain cancer and cell phones; Davis D. Disconnect: The Truth About Cell Phone Radiation, What the Industry Has Done to Hide It, and How to Protect Your Family. New York: Dutton, 2010.

29. Davis D. Cell phones and brain cancer: the real story. Huffington Post 2010 May 22. http://www.huffingtonpost.com/devra-davis-phd/cell-phones-and-brain-can_b_585992.xhtml.

30. Sunstein CR. Laws of Fear. Cambridge: Cambridge University Press, 2005; Cross FR. Paradoxical perils of the precautionary principle. Washington and Lee Law Review 1996;53:851–925.

31. Sunstein. Laws of Fear; Cross. Paradoxical perils.

32. Bioinitiative 2012, Summary for the Public (2014 Supplement). http://www.bioinitiative.org/report/wp-content/uploads/pdfs/sec01_2012_summary_for_public.pdf.

33. Davis. Cell phones and brain cancer; Davis. Disconnect.

34. The INTERPHONE Study Group. Brain tumours risk.

35. Not surprisingly, print and web news stories—I counted ninety hits from my “Google alert” for “INTERPHONE study” between May 15 and August 14, 2010—reported these ambiguous findings in a variety of ways. To some, this largest of studies found no evidence of a hazard, while to others the study provided evidence of a “cancer link.” It is noteworthy, however, that a large proportion of news stories correctly highlighted the lack of any clear-cut evidence of an effect.

36. Saracci R, Samet J. Commentary: call me on my mobile phone… or better not?—a look at the Interphone study results. International Journal of Epidemiology 2010;39:695–698.

37. Frei P, Poulsen AH, Johansen C, Olsen JH, Steding-Jessen M, Schüz J. Use of mobile phones and brain tumors: update of Danish cohort study. BMJ 2011;343:d6387.

38. Inskip PD, Hoover RN, Devesa SS. Brain cancer incidence trends in relation to cellular telephone use in the United States. Neuro-Oncology 2010;12:1147–51.

39. Deltour et al. Time trends in brain tumor incidence rates; Deltour et al. Mobile phone use and incidence of glioma.

40. De Vocht F, Burstyn I, Cherrie JW. Time trends (1998–2007).

41. Little et al. Mobile phone use and glioma risk.

42. SCENIHR. Potential health effects of exposure, 86.

44. Moulder JE, Foster KR, Erdreich LS, McNamee JP. Mobile phones, mobile phone base stations and cancer: a review. International Journal of Radiation Biology 2005;81:189–203.

45. Adair RK. Biophysical limits on athermal effects of RF and microwave radiation. Bioelectromagnetics. 2003;24:39–48.

46. Volkow ND et al. Effects of cell phone radiofrequency signal exposure on brain glucose metabolism. JAMA 2011;305:808–13. doi:10.1001/jama.2011.186.

47. Letters in response to Volkow et al.: Kosowsky A, Swanson E, Gerjuoy E. Cell phone activation and brain glucose metabolism; Davis CC; Nordström C-H; Volkow ND, Tomasi D, Vaska P. JAMA 2011;305:2066–68.

48. Kwon MS et al. GSM mobile phone radiation suppresses brain glucose metabolism. Journal of Cerebral Blood Flow & Metabolism 2011;31:2293–2301.

49. Baan R et al. Carcinogenicity of radiofrequency magnetic fields. Lancet Oncology 2011;12:624–26.

50. Boffetta P, McLaughlin JK, La Vecchia C, Tarone RE, Lipworth L, Blot WJ. False-positive results in cancer epidemiology: a plea for epistemological modesty. Journal of the National Cancer Institute 2008 July 16;100(14):988–95. doi:10.1093/jnci/djn191. Epub 2008 Jul 8; Boffetta P, McLaughlin JK, La Vecchia C, Tarone RE, Lipworth L, Blot WJ. A further plea for adherence to the principles underlying science in general and the epidemiologic enterprise in particular. International Journal of Epidemiology 2009 38(3):678–79. doi:10.1093/ije/dyn362; McLaughlin JK, Tarone RE. False positives in cancer epidemiology. Cancer Epidemiology Biomarkers and Prevention 2012;22:11–15; Kabat G. How activism distorts the assessment of health risks. Forbes 2012 Nov. 20; Kabat G. Behind the World Health Organization’s “cancerous” pronouncement on cell phones. Forbes 2011 Aug. 23. http://www.forbes.com/sites/realspin/2011/08/23/world-health-organization-cancerous-cell-phones/.

51. World Health Organization. International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Preamble, Lyon, France, 2006. http://monographs.iarc.fr/ENG/Preamble/CurrentPreamble.pdf.

52. Wiedemann PM, Boerner FU, Repacholi MH. Do people understand IARC’s 2B categorization of RF fields from cell phones? Bioelectromagnetics 2014;35:373–78.

53. According to Dr. Vijayalaxmi, who was a member of the IARC Working Group on cell phones, in issuing its report IARC wanted to send a message that we still have limited information about the possible effects of prolonged and heavy use of cell phones, especially among users who start as children and adolescents. She is comfortable with the classification and thinks that it will be an “eye-opener for people who abuse the technology, which is meant for benefit, not for overuse and abuse.” Quoted in Kabat. Behind the World Health Organization’s “cancerous” pronouncement.”

54. Associated Press. Cellphones a “possible” carcinogen—like coffee. Seattle Times 2011 June 1. http://www.columbiatribune.com/news/who-panel-lists-cellphones-as-possible-carcinogen-like-coffee/article_75f0a55f-4457–5b8c-8fb7–287010d42027.xhtml.

55. The Cohort Study of Mobile Phone Use and Health (COSMOS) is a cohort study of mobile phone use and health that is in the process of recruiting approximately 250,000 men and women in Denmark, Finland, Sweden, Netherlands, and Great Britain. Participants will be followed for at least twenty-five years, and exposure information will be collected via both questionnaires and objective data from telecommunications providers, which represents an improvement over previous studies. Outcomes will be determined by linkage to disease registries. However, there is a serious problem confronting studies undertaken at this point in time—that is, that exposure to RF from cell phones and other wireless appliances is nearly ubiquitous, and this reduces the ability to detect an effect of exposure.

1. Carlsen E, Giwercman A, Keiding N, Skakkebaek NE. Evidence for decreasing quality of semen during past 50 years. BMJ 1992;305:609–13.

2. Colborn T, Dumanski D, Myers JP. Our Stolen Future. New York: Plume Books, 1997; Krimsky S, Hormonal Chaos: The Scientific and Social Origins of the Environmental Endocrine Hypothesis. Baltimore: Johns Hopkins University Press, 2000.

3. Krimsky. Hormonal Chaos, 48–51.

4. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. New England Journal of Medicine 1971 Apr. 15;284(15):878–81.

5. The central importance of the DES experience as a model for those studying the effects of chemicals in the environment is conveyed by John McLachlan, a scientist who has spent his career studying the biological mechanisms by which early exposure to chemicals, including DES, might set the stage for future disease. In 2001 he wrote, “The universe of chemicals ‘endowed with estrogenic properties’ has grown enormously in the last 30 years. Environmental compounds have also been discovered that are anti-estrogens and anti-androgens. Species as diverse as snails and humans are thought to be affected by endocrine disruption. It is all the more remarkable that the principles used to establish this growing list of hormonally active chemicals were, and continue to be, based on the potent synthetic estrogen DES and the clinical experience first reported 30 years ago.” McLachlan JA, Newbold RR, Burow ME, Li SF. From malformations to molecular mechanisms in the male: three decades of research on endocrine disrupters. APMIS 2001;109:263–72.

6. Environmental History Timeline. http://www.environmentalhistory.org/.

7. Higginson J. Cancer and the environment: Higginson speaks out. Science 1979;205:1363–64.

8. Colborn, Dumanski, Myers. Our Stolen Future, 259–68; Krimsky. Hormonal Chaos, 24–29. For good early discussions of the endocrine disruption hypothesis, see Hollander D. Environmental effects on reproductive health: the endocrine disruption hypothesis. Family Planning Perspectives 1997;29:82–89; Baker VA, Endocrine disrupter—testing strategies to assess human hazard. Toxicology in Vitro 2001;15:413–19.

9. Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet 1993;341:1392–95. Commenting on this hypothesis paper in 2014, Sharpe had the following to say: “It has become a citation classic (hint: to get high citations, never include data!). Yet time and further research has proved that the hypothesis is fundamentally flawed, because human foetal Leydig cells do not express full-length oestrogen receptor alpha (ESR1) as do rodent foetal Lyedig cells, and it is ESR1 that mediates the adverse effects of estrogens on the foetal testis.” Sharpe RM. Lessons learned from andrology. Andrology 2014;2:652–55.

10. Boisen KA, Main KM, Rajpert-de-Meyts E, Skakkebaek NE. Are male reproductive disorders a common entity? Annals of the New York Academy of Sciences 2001;948:90–99.

11. PubMed citations “environmental endocrine disruptors.” http://www.ncbi.nlm.nih.gov/pubmed/?term=environmental+endocrine+disruptors.

12. Krimsky. Hormonal Chaos, 105.

13. Ibid., 2, 3. It’s worth noting that the two successful hypotheses cited by Krimsky were highly focused and specific and led to the identification of a specific mechanism that added clear-cut and important new knowledge. In contrast, the endocrine disruption hypothesis was all-encompassing, incorporating countless distinct phenomena and exposures, and innumerable potential mechanisms. Rather than a specific hypothesis, it was really a vast program of research.

14. Safe HS. Environmental and dietary estrogens and human health: is there a problem? Environmental Health Perspectives 1995;103:346–51; Safe HS. Is there an association between exposure to environmental estrogens and breast cancer? Environmental Health Perspectives 1997;105:675–78; Safe HS. Endocrine disruptors and human health—is there a problem? An update. Environmental Health Perspectives 2000;108:487–493; Joffe M. Are problems with male reproductive health caused by endocrine disruption? Occupational and Environmental Medicine 2001;58:281–87; Hollander. Environmental effects on reproductive health.

15. Particularly Richard Sharpe has embodied this.

16. Two such figures are Richard Sharpe and Stephen Safe.

17. Hollander. Environmental effects on reproductive health.

19. Ioannidis JAP. Contradicted and initially stronger effects in highly cited clinical research. JAMA 2005;294:218–28; Boffetta P, McLaughlin JK, La Vecchia C, Tarone RE, Lipworth L, Blot WJ. False positives in cancer epidemiology: a plea for epidemiologic modesty. Journal of the National Cancer Institute 2008;100:988–95; Kabat. Hyping Health Risks.

20. Safe. Environmental and dietary estrogens; Safe. Is there an association?; Safe. Endocrine disruptors and human health.

21. Hollander. Environmental effects on reproductive health.

22. Longnecker MP et al. An approach to assessment of endocrine disruption in the National Children’s Study. Environmental Health Perspectives 2003;111:1691–97.

23. Colborn, Dumanski, Myers. Our Stolen Future, 67–69; Longnecker MP, Rogan WJ, Lucier G. The human health effects of DDT (dichlorodiphenyltrichloroethane) and PCBs (polychlorinated biphenyls) and an overview of organochlorines in public health. Annual Review of Public Health 1997;18:211–44.

24. Obaid Faroon, Toxicological Profile on DDT. Darby, Penn.: Diane Publishing, 2010. https://books.google.com/books/about/Toxicological_Profile_for_DDT_DDD_DDE_Up.xhtml?id=qWs20foSm_4C&hl=en.

25. Wolff MS, Toniolo PG, Lee EW, Rivera M, Dubin N. Blood levels of organochlorine residues and risk of breast cancer. Journal of the National Cancer Institute 1993;85(8):648–52.

26. Hunter DJ, Kelsey KT. Pesticide residues and breast cancer: the harvest of a silent spring? Journal of the National Cancer Institute 1993;85:598–99.

27. MacMahon B. Pesticide residues and breast cancer? Journal of the National Cancer Institute 1994;86:572–73.

28. Lopez-Cervantes M et al. Dichlorodiphenyldichloroethane burden and breast cancer risk: a meta-analysis of the epidemiologic evidence. Environmental Health Perspectives 2004;112:207–14.

29. A more recent meta-analysis, which included forty-six studies, obtained a similar result. Ingber SZ, Buser MC, Pohl HR, Abadin HG, Murray HE, Scinicariello F. DDT/DDE and breast cancer: a meta-analysis. Regulatory Toxicology and Pharmacology 2013;67:421–33. doi:10.1016/j.yrtph.2013.08.021. Epub 2013 Sept. 8.

30. Institute of Medicine. Breast Cancer and the Environment: A Life Course Approach. Washington, D.C.: National Academies Press, 2012.

31. http://www.niehs.nih.gov/research/supported/dert/programs/breast-cancer/, accessed Dec. 1, 2014.

32. Joffe M. What has happened to human fertility? Human Reproduction 2010;25:295–307.

34. Kolata G. Sperm counts: some experts see a fall, others poor data. New York Times 1996 Mar. 19.

37. Joffe went on to comment that “an odd feature of this literature is the way it has been framed: the hypothesis has been of a global decline in sperm concentration, with an assumption that the level at any given time is the same in all parts of the world…. If this were true it would be unusual, possibly unique, in all epidemiology. This way of posing it means that any item of evidence tends to be regarded either as confirming or refuting a global decline, rather than providing information on the population from which the data were drawn.” Joffe. What has happened to human fertility?, 296.

38. Fisch H. Declining worldwide sperm counts: disproving a myth. Urologic Clinics of North America 2008;35:137–46.

40. Ibid.; Joffe. What has happened to human fertility?

41. Joffe M, Holmes J, Jensen TK, Keiding N, Best N. Time trends in biological fertility in Western Europe. American Journal of Epidemiology 2013;178:722–30.

42. Joffe, What has happened to human fertility?; Safe S. Clinical correlates of environmental endocrine disruptors. Trends in Endocrinology and Metabolism 2005;16:139–44.

43. Paulozzi LJ. International trends in rates of hypospadias and cryptorchidism. Environmental Health Perspectives 1999;107:297–302.

44. Fisch H, Hyun G, Hensle TW. Rising hypospadias rates: disproving a myth. Journal of Pediatric Urology 2010;6:37–39; Safe. Clinical correlates.

45. Joffe. What has happened to human fertility?, 302.

46. Dodds EC, Lawson W. Synthetic oestrogenic agents without a phenanthrene nucleus. Nature 1936;137:996–97.

47. The journalist Trevor Butterworth has chronicled the BPA saga since it became a high-profile story, explaining the scientific issues, pointing out the weaknesses of many published studies that received media attention, interviewing key researchers, and holding media coverage to account for its lax standards. Forbes.com. http://www.forbes.com/sites/trevorbutterworth/.

48. Nagel SC, vom Saal FS, Thayer KA, Dhar MG, Boechler M, Welshons WV. Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environmental Health Perspectives 1997;105:70–76.

49. Goodman JE et al. Weight-of-evidence evaluation of reproductive and developmental effects of low doses of bisphenol A. Critical Reviews in Toxicology 2009;39(1):1–75. doi:10.3109/10408440903279946.

50. Ibid.; Kamrin MA. The “low dose” hypothesis: validity and implications for human risk. International Journal of Toxicology 2007;26:13–23.

51. Rhomberg LR, Goodman JE. Low-dose and nonmonotonic dose-responses of endocrine disrupting chemicals: has the case been made? Regulatory Toxicology and Pharmacology 2012;64:130–33. Kamrin. The “low-dose” hypothesis.

52. vom Saal FS, Nagel SC, Timms BG, Welshons WV. Implications for human health of the extensive bisphenol A literature showing adverse effects at low doses: a response to attempts to mislead the public. Toxicology 2005;212:244–52. Tyl RW. Basic exploratory research versus guideline-compliant studies used for hazard evaluation and risk assessment: bisphenol A as a case study. Environmental Health Perspectives 2009;117:1644–51. doi:10.1289/chp.0900893.

53. Elswick BA, Welsh F, Janszen DB. Effect of different sampling designs on outcome of endocrine disruptor studies. Reproductive Toxicology 2000;14:359–67.

54. Ibid.; Kamrin. The “low dose” hypothesis; Owens JW, Chaney JG. Weighing the results of differing “low dose” studies of the mouse prostate by Nagel, Cagen, and Ashby: quantification of experimental power and statistical results. Regulatory Toxicology and Pharmacology 2005;43:194–202; Tyl. Basic exploratory research.

55. Teeguarden JG et al. Twenty-four hour human urine and serum profile of bisphenol A during high dietary exposure. Toxicological Science 2011;123:48–57.

56. Doerge DR, Twaddle NC, Woodling KA, Fisher JW. Pharmacokinetics of bisphenol A in neonatal and adult rhesus monkeys. Toxicology and Applied Pharmacology 2010 Oct 1;248(1):1–11. doi:10.1016/j.taap.2010.07.009. Epub 2010 Jul 23; Fisher JW, Twaddle NC, Vanlandingham M, Doerge DR. Pharmacokinetic modeling: prediction and evaluation of route dependent dosimetry of bisphenol A in monkeys with extrapolation to humans. Toxicology and Applied Pharmacology 2011 Nov. 15;257(1):122–36. doi:10.1016/j.taap.2011.08.026. Epub 2011 Sept. 2.

57. Teeguarden et al. Twenty-four hour human urine.

58. Teeguarden J, Hanson-Drury, Fisher JW, Doerge DR. Are typical serum BPA concentrations measurable and sufficient to be estrogenic in the general population? Food and Chemical Toxicology 2013;62:949–63.

60. Vandenberg LN et al. Regulatory decisions on endocrine disrupting chemicals should be based on the principles of endocrinology. Reproductive Toxicology 2013;38:1–15. doi:10.1016/j.reprotox.2013.02.002; Vom Saal FS, Welshons WV. Evidence that bisphenol A (BPA) can be accurately measured without contamination in human serum and urine and that BPA causes numerous hazards from multiple routes of exposure. Molecular and Cellular Endocrinology 2014;398:101–13. http://dx.doi.org/10.1016/j.mce.2014.09.028.

61. Bergman A, Heindel JJ, Jobling S, Kidd KA, Zoeller RT, eds. Endocrine Disrupting Chemicals 2012: The State of the Science. Geneva: World Health Organization and United Nations Environment Programme, 2013. http://www.who.int/ceh/publications/endocrine/en/. Written by a group containing a number of endocrine disruption advocates, this three-hundred-page document presented an enormous amount of information, accompanied by graphs, charts, and maps, to dramatize the potential impact on wildlife and human health from exposure to endocrine disrupting chemicals worldwide. However, the document confused two issues: one that is not controversial and for which there is abundant, strong evidence—that is, effects of pollution on the environment in the broadest sense (ocean acidification, pollution of waterways with runoff, destruction of habitat, extinction of species, etc.); and one for which there is no clear or consistent evidence—namely, the effects of exposure to trace amounts of these chemicals on human health and development. This obliges the authors to imply that endocrine disruption might be playing a role in a wide range of health outcomes: cancers of the breast, prostate, testicles, and endometrium; birth defects; sperm count; fertility; and obesity. But they use selective citation to make their case and ignore evidence that does not support their thesis. The report trades on this basic confusion in its appeal to politicians and a concerned public. For systematic critiques of the State of the Science report, see Lamb JC IV et al. Critical comments on the WHO-UNEP State of the Science of Endocrine Disrupting Chemicals—2012. Regulatory Toxicology and Pharmacology 2014;69:22–40; Testai E, Galli CL, Dekant W, Marinovich M, Piersma AH, Sharpe RM. A plea for risk assessment of endocrine disrupting chemicals. Toxicology 2013;314:d51–59.

62. Dietrich D et al. Open letter to the European Commission: scientifically unfounded precaution drives European Commission’s recommendation on EDC reduction, while defying common sense, well-established science, and risk assessment principles. Food Chemistry and Toxicology 2015;62:A1–A4.

63. Bergman A, et al. Science and policy on endocrine disrupters must not be mixed: a reply to a “common sense” intervention by Toxicology journal editors. Environmental Health 2013;12:69. http://www.ehjournal.net/content/12/1/69; Bergman A et al. The impact of endocrine disruption: a consensus statement on the state of the science. Environmental Health Perspectives 2013;121:A104–A106; Gore AC et al. Policy decisions on endocrine disruptors should be based on science across disciplines: a response to Dietrich et al. European Journal of Endocrinology 2013;169:E1–E4.

64. Cressey D. Journal editors trade blows over toxicology: debate flares around European regulation of bisphenol A and other endocrine disrupters. Nature News 2013 Sept. 20.

65. Teeguarden et al. Twenty-four hour human urine.

66. Smith OW, Smith GV. Use of diethylstilbestrol to prevent fetal loss from complications of late pregrancy. New England Journal of Medicine 1949;241:562–68.

67. Testai et al. A plea for risk assessment.

68. Ibid.; Lamb et al. Critical comments; Goodman et al. Weight-of-evidence evaluation.

69. Sharpe RM. Is it time to end concerns over the estrogenic effect of bisphenol A? Toxicological Science 2010;114:1–4. doi:10.1093/toxsci/kfp299; Butterworth T. The scientists, the scare, the 100-million dollar surge. Forbes 2014 Apr. 9. http://www.forbes.com/sites/trevorbutterworth/2014/04/09/bpa-the-scientists-the-scare-the-100-million-dollar-surge/.

70. Wilcox A, Herbst A. http://www.ncbi.nlm.nih.gov/pubmed/?term=wilcox+aj%2C+herbst+diethylstibestrol.

71. Interview with Allen Wilcox, Oct. 20, 2014.

72. Joffe. What has happened to human fertility?, 301.

73. Interview with Richard Sharpe, Aug. 21, 2014.

75. Interview with Daniel Doerge, Jan. 2, 2015.

77. Interview with Richard Sharpe.

78. Interview with Daniel Doerge. I should mention that a number of the researchers I interviewed regarding endocrine disruption asked that certain comments about specific researchers or institutions not be quoted. This is an important reminder of how even the most independent-minded scientists have to get along in the very small world of their specialized research area.

1. Vanherweghem JL et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimes including Chinese herbs. Lancet 1993;341:387–91.

2. Cosyns JP et al. Chinese herbs nephropathy: a clue to Balkan endemic nephropathy? Kidney International 1994;45:1680–88; van Ypersele de Strihou C, Vanherweghem JL. The tragic paradigm of Chinese herbs nephropathy. Nephrolology Dialysis Transplantation 1995; 10:157–60.

3. Cosyns et al. Chinese herbs nephropathy.

4. Jadoul M, de Plaen JF, Cosyns JP, van Ypersele de Strihou C. Adverse effects from traditional Chinese medicine. Lancet 1993;341:892–93.

5. Cosyns JP, Jadoul M, Squifflet JP, van Cangh PJ, van Ypersele de Strihou C. Urothelial malignancy in Chinese herbs nephropathy. Lancet 1994;344:188.

6. Nortier JL et al. Urothelial carcinoma associated with the use of Chinese herb (Aristolochia fangchi). New England Journal of Medicine 2000;342:1686–92.

7. van Ypersele de Strihou, Vanherweghem. The tragic paradigm of Chinese herbs nephropathy.

8. Scarborough J. Ancient medicinal use of Aristolochia: birthwort’s tradition and toxicity. Pharmacy in History 2011;53:3–21; Grollman AP, Scarborough J, Jelaković B. Aristolochic acid nephropathy: an environmental and iatrogenic disease. Advances in Molecular Toxicology 2009;3, chap. 7:211–27.

9. Kluthe R, Vogt A, Batsford S. Double blind study of the influence of aristolochic acid. Arzneimittel-Forschung 1982;32:443–45.

10. Mengs U, Lang W, Poch J-A. The carcinogenic action of aristolochic acid in rats. Archives of Toxicology 1982;51:107–19.

11. Schmeiser HH, Schoepe KB, Wiessler M. DNA Adduct formation of aristolochic acid I and II in vitro and in vivo. Carcinogenesis 1988;9:297–303.

12. Schmieser HH, Bieler CA, Wiessler M, van Ypersele de Strihou C, Consyns JP. Detection of DNA adducts formed by aristolochic acid in renal tissue from patients with Chinese herbs nephropathy. Cancer Research 1996;56:2025–28.

13. Nortier et al. Urothelial carcinoma.

14. International Agency for Research on Cancer. Some Traditional Herbal Medicines, Some Mycotoxins, Naphthalene and Styrene. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 82. Lyon, France: 2002.

15. Marcus DM, Grollman AP. Botanical medicines—the need for new regulation. New England Journal of Medicine 2002;347:2073–76.

16. Marcus DM, Grollman AP. Ephedra-free is not danger-free. Science 2003;301:1669–71.

17. The lecture is now incorporated into the online edition of the leading textbook of pharmacology, Goodman and Gilman’s The Pharmacological Basis of Therapeutics.

18. Hranjec T et al. Endemic nephropathy: The case for chronic poisoning by Aristolochia. Croatian Medical Journal 2005;46:116–25.

19. Čeović S, Miletić-Medved M. Epidemiological features of endemic nephropathy in the focal area of Brodska Posavina. In Endemic Nephropathy in Croatia, ed. Čorišćec D, Čeović S, Stavljenić-Rukavina A, 7–21. Zagreb, Croatia: Academic Croatica Scientarium Medicarum, 1996.

21. Markovic B. Balkan nephropathy and urothelial cancer (in French). Journal d’urologie (Paris) 1990;96;349–52.

22. World Health Organization. Memorandum: the endemic nephropathy of south-eastern Europe. Bulletin of the World Health Organization 1965;32:441–48.

23. There was another important bit of misleading evidence: namely, the observation that ochratoxin causes cancer in the kidney—but not the urothelium—in one strain of male mice—and in fact is the most potent nephrocarcinogen ever reported in this test species. Although widely cited, this observation is irrelevant to human exposure since different tissues are involved.

24. Ivić M. The problem of aetiology of endemic nephropathy. Acta Facultatis Medicae Naissensis 1969;1:29–38.

25. Grollman AP et al. Aristolochic acid and the etiology of endemic (Balkan) nephropathy. PNAS 2007;104:12129–34. The kidney Grollman retrieved was that of a 39-year-old aerobics instructor from Cranston, Rhode Island, who, according to an article in Consumer Reports, had been prescribed over half a dozen Chinese herbs by her acupuncturist for health conditions, including endometriosis. She had been on the herbs for more than two years. At least one of the products contained Aristolochia as an ingredient, even though the FDA had issued a nationwide safety warning regarding Aristolochia in 2001.

26. Hranjec T, Brzić I. Eighty years of agricultural evolution: farming in Slavonski Brod. Unpublished report, May 1, 2006.

28. Grollman et al. Aristolochic acid.

29. Grollman, Scarborough, Jelaković. Aristolochic acid nephropathy.

30. Holstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 1991;253:49–53.

31. Moriya M et al. TP53 mutational signature of aristolochic acid. International Journal of Cancer 2011;129:1532–36.

32. International Agency for Research on Cancer. IARC TP53 database. http://p53.iarc.fr/RefsDBanalysis.aspx.

33. Grollman, Scarborough, Jelaković. Aristolochic acid nephropathy.

34. Hoang ML et al. Mutational spectrum of aristolochic acid exposure as revealed by whole-exome sequencing. Science Translational Medicine 2013;15:197 197ra102.

35. Lai MN, Wang SM, Chen PC, Chen YY, Wang JD. Population-based case-control study of Chinese herbal products containing aristolochic acid and urinary tract cancer risk. Journal of the National Cancer Institute 2010;102:179–86.

36. Chen CH et al. Aristolochic acid-associated urothelial carcinoma in Taiwan. PNAS 2012;109(21):8241–46. doi:10.1073/pnas.1119920109. Epub 2012 Apr. 9.

38. Laing C, Hamour S, Sheaff M, Miller R, Woolfson R. Chinese herbal uropathy and nephropathy. Lancet 2006;368:338.

40. Personal communication with Arthur Grollman, Oct. 30, 2015.

41. Totoki Y et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nature Genetics 2014;46:1267–73. doi:10.1038/ng.3126; Scelo G et al. Variation in genomic landscape of clear cell renal cell carcinoma across Europe. Nature Communications 2014;5. doi:10.1038/ncomms6135.

42. Cohen PA. Hazards of hindsight—monitoring the safety of nutritional supplements. New England Journal of Medicine 2014;370:1277–80.

43. Offit PA. Do You Believe in Magic? The Sense and Nonsense of Alternative Medicine. New York: HarperCollins, 2013.

44. Cohen. Hazards of hindsight.

46. Ibid.; Offit. Do You Believe in Magic?, 91.

47. Adulteration of supplements with unapproved, banned, or untested drugs is a major problem, documented in more than five hundred instances. The contaminants include stimulants, anabolic steroids, antidepressants, weight-loss medications, and Viagra analogues (Cohen. Hazards of hindsight). Both adulterants and legal ingredients present in supplements have been linked to a wide range of potential adverse reactions, from arrhythmias, cancer, and liver damage to heart attacks and strokes (ibid.).

48. Marcus DM, Grollman AP. The consequences of ineffective regulation of dietary supplements. Archives of Internal Medicine 2012;172:1035–36.

50. Cohen. Hazards of hindsight.

51. Acute hepatitis and liver failure following the use of a dietary supplement intended for weight loss or muscle building—May–October, 2013. MMWR Morbidity and Mortality Weekly 2013;62:817–19.

52. Cohen. Hazards of hindsight. Grollman explained something that was not mentioned in the news reports, or even in medical articles, discussing the OxyElitePro incident. For OxyElitePro to qualify as an herbal supplement, the manufacturer USPLabs added a natural ingredient, aegeline, derived from the bael fruit, which is popular in China and India. However, the concentration used in OxyElitePro was many times higher than in the bael fruit. In effect, aegeline was being used as a drug. Unbelievably, an earlier formulation of OxyElitePro and another product, Jack3d, that contained the stimulant DMAA were linked to one hundred cases of illness and six deaths. After destroying the stocks of these products, USPLabs reformulated OxyElitePro and rereleased it. A month later the first reports of liver toxicity turned up in Hawaii.

53. Navarro VJ et al. Liver injury from herbals and dietary supplements in the U.S. drug-induced liver injury network. Hepatology 2014;60:1399–1408.

54. Geller AI et al. Emergency department visits for adverse events related to dietary supplements. New England Journal of Medicine 2015;373:1531–40.

55. Offit. Do You Believe in Magic?; Singh S, Ernst E. Trick or Treatment: The Undeniable Facts About Alternative Medicine. New York: Norton, 2009.

56. Another argument used by supporters of dietary supplements is that there are well-documented cases in which medications approved by the FDA have been shown to cause harm. But this argument doesn’t stand up since, first, in order to be approved, medications have to have some evidence of effectiveness, and, second, due to regulation, drugs that show adverse effects are removed from the shelves. In fact, this argument favors tighter oversight of supplements.

1. Kevles, DJ. Pursuing the unpopular: a history of courage, viruses, and cancer. In Hidden Histories of Science, ed. Silver RB. New York: New York Review of Books, 1996; Stebbing J, Bower M. Epstein-Barr virus in Burkitt’s lymphoma: the missing link. Lancet Oncology 2009:430.

2. Coakley D. Denis Burkitt and his contribution to haematology/oncology. British Journal of Haematology 2006;135:17–25. My account of Burkitt’s work and Harald zur Hausen’s early work on Epstein-Barr virus is based on the primary literature by Burkitt, zur Hausen, and their colleagues. After this chapter was written, The Cancer Virus: The Story of Epstein-Barr Virus, by Dorothy H. Crawford, Alan Rickinson, and Ingolfur Johannessen, was published. The early chapters of that book give a detailed account of the seminal research on the first human cancer virus.

3. Burkitt D. A Sarcoma involving the jaws of African children. British Journal of Surgery 1958;46:218–23.

4. Burkitt D. Determining the climatic limitations of a children’s cancer common in Africa. BMJ 1962;2:1019–23; Burkitt D. A “tumor safari” in East and Central Africa. British Journal of Cancer 1962;16:379–86.

5. Burkitt. Determining the climatic limitations.

6. In “A ‘Tumor Safari,’” Burkitt credited his colleague J. N. P. Davies for this insight.

7. Smith O. Denis Parsons Burkitt CMG, MD, DSc, FRS, FRCS, FTCD (1911–93) Irish by birth, trinity by the grace of God. British Journal of Haematolology 2012;156:770–76. Epstein A, Burkitt D. Sir Anthony Epstein, CBE FRS in conversation with Dr. Denis Burkitt, CMG, FRS, Oxford, 20 March 1991. Royal College of Physicians and Oxford Brookes University Medical Services Video Archive MSVA 059, Oxford Brookes University, Oxford, UK.

8. Coakley. Denis Burkitt.

9. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphocytes from Burkitt’s lymphoma. Lancet 1964; Mar. 28:702–3. This highly cited paper, half of which is taken up by two electron micrographs, is less than two pages long.

10. DeThé G et al. Epidemiological evidence for causal relationship between Epstein-Barr virus and Burkitt’s lymphoma from Ugandan prospective study. Nature 1978;274:756–61.

11. Molyneux EM et al. Burkitt’s lymphoma. Lancet 2012;379:1234–44. Molyneux points out that the story of Burkitt’s lymphoma includes a number of important firsts. “Burkitt’s lymphoma has had an important role in the understanding of tumorigenesis. It was the first human tumour to be associated with a virus, one of the first tumours shown to have a chromosomal translocation that activates an oncogene, and the first lymphoma reported to be associated with HIV infection. Burkitt’s lymphoma is the fastest growing human tumour, with a cell doubling time of 24–48 h, and was the first childhood tumour to respond to chemotherapy alone. It is the most common childhood cancer in areas where malaria is holoendemic—e.g., equatorial Africa, Brazil, and Papua New Guinea. The so-called Burkitt’s lymphoma belt stretches across central Africa 15° either side of the equator where the climate is hot and wet (more than 50 cm annual rainfall). The epidemiological maps of malaria and Burkitt’s lymphoma overlap.”

13. Stebbing, Bower. M. Epstein-Barr virus in Burkitt’s lymphoma; Harald zur Hausen, Nobel lecture.

14. W. Henle papers, National Library of Medicine.

15. Castellsagué X, Bosch FX, Muñoz N. Environmental cofactors in HPV carcinogenesis. Virus Research 2002;89:191–99.

16. Hulka BS. Risk factors for cervical cancer. Journal of Chronic Disease 1982;35:3–11.

18. Schiffman MH, Hildsheim A. Cervical cancer. In Cancer Epidemiology and Prevention, ed. Schottenfeld D, Fraumeni JF Jr., 1044–67. New York: Oxford University Press, 2006.

20. Rotkin ID. A comparison review of key epidemiological studies in cervical cancer related to current searches for transmissible agents. Cancer Research 1973;33:1353–67.

21. Zur Hausen H. Papillomaviruses in the causation of human cancers—a brief historical account. Virology 2009;384:260–65.

22. Ibid.; Franco EL, Schlecht NF, Saslow D. The epidemiology of cervical cancer. Cancer Journal 2003;9:348–359.

23. Zur Hausen H. On the case (interview). Nature 2012;488:S16.

26. Stebbing, Bower. M. Epstein-Barr virus in Burkitt’s lymphoma.

27. Zur Hausen. On the case.

28. Zur Hausen H. Roots and perspectives of contemporary papillomavirus research. Journal of Cancer Research and Clinical Oncology 1996;122:3–13. Koutsky L. The epidemiology behind the HPV vaccine discovery. Annals of Epidemiology 2009;19:239–244.

29. Hulka. Risk factors for cervical cancer.

30. Zur Hausen. Roots and perspectives.

31. Zur Hausen H. Cervical carcinoma and human papillomavirus: on the road to preventing a major human cancer. Journal of the National Cancer Institute 2001;93:252–253.

32. Schiffman M, Wentzensen N. Human papillomavirus infection and the multistage carcinogenesis of cervical cancer. Cancer Epidemiology Biomarkers and Prevention 2012;22:553–60.

35. Ho GYF, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. New England Journal of Medicine 1998;338:423–28.

36. Interview with Robert Burk. Burk pointed out that in the early days herpes virologists “basically populated the scientific network of HPV research.” Herpes is a latent virus—once infected with herpes, always infected with herpes. “So they brought with them the collective consciousness of continual persistence.” Burk himself had worked on hepatitis B virus before turning to HPV. “The hepatitis B virus actually gets cleared from the body and is gone.”

37. de Sanjosé S et al. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infectious Disease 2007;7:453–59; Bosch FX et al. Epidemiology and natural history of human papillomavirus infections and type-specific implications in cervical neoplasia. Vaccine 2008;26S:K1–K16.

38. Bosch et al. Epidemiology and natural history; Ho et al. Natural history.

39. Schiffman, Wentzensen. Human papillomavirus infection.

40. Bosch et al. Epidemiology and natural history.

41. Schiffman, Wentzensen. Human papillomavirus infection.

42. Interview with Burk.

43. Schiffman, Wentzensen. Human papillomavirus infection.

44. Muñoz, N. Human Papillomavirus and cancer: the epidemiological evidence. Journal of Clinical Virology 2000;19:1–5.

45. Ibid.; Wallboomers JMM et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. Journal of Pathology 1999;189:12–19.

46. Franco, Schlecht, Saslow. Epidemiology of cervical cancer. Although the IARC study had an important impact, providing strong evidence for a causative role of HPV in cervical cancer, the decision to retest only those samples that were negative for HPV was shocking to those who are methodologically inclined. If you retest the negatives, the results can only get better! According to Burk, his epidemiologist colleagues “went nuts, went ballistic because that was just the wrong way to do it.”

48. Castellsagué, Bosch, Muñoz. Environmental cofactors.

49. Tommasino M. The human papillomavirus family and its role in carcinogenesis. Seminars in Cancer Biology 2014;26:13–21.

50. Franco, Schlecht, Saslow. Epidemiology of cervical cancer.

52. Schiffman, Wentzensen. Human papillomavirus infection.

53. Zur Hausen. Papillomaviruses.

56. Scudellari M. Sex, cancer, and a virus. Nature 2013;503:330–32.

58. O’Connor A. Throat cancer link to oral sex gains notice. New York Times 2013 June 3.

59. STATBITE. Number of HPV-associated cancer cases per year in the United States (2004–2008). Journal of the National Cancer Institute 2013;105:998.

60. Peto J, Gilham C, Fletcher O, Matthews FE. The cervical cancer epidemic that screening has prevented in the UK. Lancet 2014;364:249–56.

61. Pollack A. F.D.A. panel recommends replacement for the Pap test. New York Times 2014 Mar. 18.

62. Interview with Burk.

63. Koutsky. Epidemiology behind the HPV vaccine discovery; Moscicki AB. HPV vaccines: today and in the future. Journal of Adolescent Health 2008;43 (Suppl):S26–S40.

64. Koutsky. Epidemiology behind the HPV vaccine discovery; Moscicki. HPV vaccines.

65. CDC. Teen Vaccination Coverage. 2014. http://www.cdc.gov/vaccines/who/teens/vaccination-coverage.xhtml.

67. Carroll A. Good talks need to combat HPV vaccine myth. New York Times 2015 Nov. 9.

68. National Cancer Institute. Gardasil 9 vaccine protects against additional HPV types. http://www.cancer.gov/types/cervical/research/gardasil9-prevents-more-HPV-types; Guliano AR, Kreimer AR, de Sanjosé S. The beginning of the end: vaccine prevention of HPV-driven cancers. Journal of the National Cancer Institute 2015;107:djv128. doi:10.1093/jnci/djv128.

69. Tota JE, Chevarie-Davis M, Richardson LA, deVries M, Franco EL. Epidemiology and burden of HPV infection and related diseases: implications for prevention strategies. Preventive Medicine 2011;53:S12–S21.

71. Arbyn M et al. Worldwide burden of cervical cancer in 2008. Annals of Oncology 2011;22:2675–86.

72. de Sanjosé et al. Worldwide prevalence.

73. Schiffman M, Castle PE. The promise of global cervical-cancer prevention. New England Journal of Medicine 2005;353:2101–04.

74. Mills A. Health care systems in low- and middle-income countries. New England Journal of Medicine 2014;370:552–57.

75. Ibid.; Cohen SA. A long and winding road: getting the HPV vaccine to women in the developing world. Guttmacher Policy Review 2007;10:15–19; Bharadwaj M, Hussain S, Nasare V, Das BC. HPV and HPV vaccination: issues in developing countries. Indian Journal of Medical Research 2009;130:327–33; Agosti JM, Goldie SJ. Introducing HPV vaccine in developing countries—key challenges and issues. New England Journal of Medicine 2007;356:1908–10; Bello FA, Enabor OO, Adewole IF. Human papilloma virus vaccination for control of cervical cancer: a challenge for developing countries. African Journal of Reproductive Health 2011;15:25–30.