Don’t Sweat the Small Stuff

By Anne Fairbrother

How worried should you really be about whether eating red meat or drinking coffee will cause cancer? Will using your cell phone too much result in brain tumors? Can the use of plastic water bottles containing the chemical bisphenol A, commonly known as BPA, cause male infertility or reproductive disorders?

Faced with the continued proliferation of online news outlets and scientific journals, all under the same pressure to publish new, eye-catching findings, sorting the truly alarming revelations about health and environmental risks from those that may be interesting but don’t pose actual danger is increasingly difficult. This challenge of understanding and prioritizing risks is compounded by the media’s tendency to conflate hazard and risk, particularly when advocating for regulatory change. (Hazard is simply a measure of the potential for something, such as a chemical, to cause harm, while risk is the probability that a hazard will actually result in some adverse effect under a specific use scenario.)

Geoffrey C. Kabat addresses these issues in his new book, Getting Risk Right: Understanding the Science of Elusive Health Risks. This is the latest of several books and magazine articles that he has written in an effort to educate both scientists and the general public about the practice of risk assessment, hoping to alleviate growing anxieties about low-level environmental risks that are likely to have minimal or no health effects but consume large amounts of regulatory agencies’ scarce resources.

The book begins by introducing the concept of critical thinking when looking for patterns and associations in large datasets and how thinking outside the box—in his words, “being open to new ways of seeing to look for answers in places where we might not immediately think to look”—can lead to breakthroughs in understanding causal relationships. Next comes an examination of how correlation is often misinterpreted as causality, resulting in misleading and erroneous conclusions. Kabat asserts that such behavior results from scientists interpreting data within what he calls a “biased worldview,” coupled with the need to find alarming associations between environmental hazards and adverse health outcomes to ensure publication of results and a steady funding stream.

Kabat provides multiple examples of how a biased worldview can constrain scientific progress. These include the belief that environmental chemicals are causing global declines in fertility, even after the initiating study was repudiated; believing in an endogenous or dietary cause for all cancers, which limited the search for viral etiologies that proved to be the case in cervical cancers; and continuing to think that electromagnetic fields cause adverse health effects, despite two decades of research showing such effects to be nonexistent. To avoid these biases, Kabat warns strongly against the dangers of using the “court of public opinion” to gain support for a particular hypothesis rather than using the totality of the evidence to subject a favored hypothesis to rigorous testing, a theme found throughout the book.

Though Kabat provides a good discussion of the pitfalls of observational epidemiological studies, how to differentiate a good study design from a faulty one, and key concepts of statistical power and significance, sample size, and preconceived biases, the writing is uneven. At times, he seems to assume the reader is totally new to the subject, while at other times he assumes at least a basic level of scientific understanding. For example, he carefully explains the difference between observational and case-control epidemiological studies, but spends very little time describing the process required for quantitative risk analysis, which is central to his arguments about wrongful assumptions of causality. And sometimes Kabat discusses the same topics in multiple locations within a section, causing the reader to circle back in an attempt to put the pieces together rather than following a linear argumentative approach.

Kabat explores how societal pressures influence research in the field of biomedicine. He highlights the power of the media to amplify scientific findings, resulting in regulatory action furthering political or advocacy agendas—often before a true causal association between exposure and health is determined. For example, a high level of public concern over the use of BPA in thermal printing paper or food containers resulted in its ban in certain consumer products by various states. The ban was implemented despite the US Food and Drug Administration’s conclusion, based on extensive research, that BPA is safe at the current levels occurring in food. Kabat asserts that this kind of premature regulatory action due to fears of endocrine disruption or of cancer is becoming increasingly common. This in turn feeds back into the scientific community and influences funding streams and research pressures in certain fields.

Interspersed throughout these topics is a continuing discourse on why positive associations are published much more frequently than negative (or nonexistent) associations, why even small risks can become magnified when taken out of context, and how certain types of risks raise greater fears than others. Kabat touches on the role of science in the sphere of public policy, arguing that scientists must be aware of how their advocacy of a particular policy approach can pose a serious threat to their ability to conduct truly independent and unbiased research. He cautions that the peer-review system is susceptible to public pressures and biases, and that researchers need to be aware of their tendency to want to find any plausible explanation for observed phenomena. He admonishes scientists to focus on the next experiment or observation needed to critically examine a causal hypothesis, rather than conducting a study with a high level of public appeal.

The meat of the book comprises four in-depth case studies, each examining an instance where research has been applied to identify factors affecting health and disease. The first two studies explore examples where researchers had hypothesized significant health effects resulting from miniscule environmental exposures, yet little progress had been made in studying them in spite of abundant public attention and large amounts of funding. The next two studies turn to examples where scientifically rigorous approaches determined the causes of seemingly intractable health problems. But even as all four chapters are well written and thoroughly documented, they lack sufficient introductory or conclusory material to inform the reader of how they illustrate the primary thesis of the book: that scientists should avoid the biases and pitfalls that arise from becoming vocal public advocates of a hypothesized risk before it has been subjected to rigorous testing or an in-depth analysis of prior work.

The first case study provides a thorough review of the epidemiological research conducted on the safety of mobile telephones and their hypothesized connection to brain cancers. These studies, mostly conducted in the 1990s and early 2000s and summarized in a multiauthored review paper in 2010, stem largely from the very public concerns raised by one vocal man whose wife talked incessantly on her cell phone while holding it primarily against one ear, and ultimately died of a brain tumor on the same side of her head. Kabat documents the numerous shortcomings of research on this topic, including significant recall bias between brain tumor cases and controls, selective and slanted presentation of results, and failure to report on weaknesses and limitations of the studies. He notes that data correlating the (small) number of brain tumors with the (huge) number of people using cell phones, along with animal studies that showed the lack of health effects associated with cell phones, were underrepresented in the public and scientific debate of this issue. Kabat summarizes his use of this example by stating that it “has provided ample occasions for the play of bias in many forms and at many different levels in the interpretation of the results of scientific studies and the translation of these results to the public.”

The next case study presents the lack of scientific consensus on endocrine disruption, a research topic on which large amounts of research dollars have been spent. Kabat describes the research and subsequent significant regulatory pressure brought to bear on identifying chemicals that cause—or have the potential to cause—measurable changes in the human endocrine system that result in disease, reproductive impairment, or both. This work was based on an observational paper published by Danish researchers in 1995. The paper purported to find decreased quality of semen in men during the prior 50 years, and expressed concern that this might be due to “estrogens or compounds with estrogen-like activity or other environmental factors.” Kabat meticulously describes the ensuing research that eventually discredited the initial report and revealed regional differences in male fertility over time without being able to document a widespread causal factor. He illustrates the role that public pressure played, following the publication in 1996 of the sensationalist book Our Stolen Future: Are We Threatening Our Fertility, Intelligence, and Survival? in pushing federal governments and regulatory agencies to identify “endocrine disrupting chemicals” as a special regulatory class. Kabat points out that how a science-based question is posed can significantly affect the type of research and public discourse conducted. Asking the question now enshrined in regulatory language—“What chemicals cause deleterious endocrine-based health effects?”—leads to the study of a multiplicity of weakly active compounds present in the environment. Asking, instead, “What exogenous factors might impact reproductive development via hormonal perturbations?” would focus research more usefully on the potential reproductive effects of potent pharmaceuticals.

The next two case studies describe how researchers build on each other’s successes to understand mechanisms of disease, which can lead to major breakthroughs in diagnosis and prevention. This is interesting, but it is not clear how they illustrate the principles of risk analysis, public awareness, and potential bias that are the focus of the book. In the chapter “Deadly Remedy: A Mysterious Disease, a Medicinal Herb, and the Recognition of a Worldwide Public Health Threat,” Kabat documents the detailed epidemiological work that identified the cause of terminal renal failure in Belgian women during the 1990s and in rural families in the Balkan countries from the 1950s to the 1990s. Both episodes resulted from exposure to aristolochic acid, a powerful kidney toxin and carcinogen found in various Aristolochia plant species. Aristolochia fangchi was mistakenly substituted for the herb Stephania tetrandra and used as a supplement in Belgian weight-loss clinics. Aristolochia clematitis grows wild within wheat fields in the Balkans in a just-sufficient amount to be considered not worthy of removal but toxic if ingested repeatedly over 10 years or more.

The book’s final case study, of viruses and cancer, illustrates how researchers followed their intuition and built on each other’s work to describe the epidemiology of various cancers, identify the causal viral agents, and develop diagnostic and preventative approaches. This is the story of how, in the late 1950s, the surgeon Denis P. Burkitt established the distribution of facial (Burkitt’s) lymphoma in equatorial Africa, from which he concluded that an infectious agent was implicated in its transmission. The pathologist Anthony Epstein at the Bland Sutton Institute in London subsequently isolated the inciting virus, now known as the Epstein-Barr virus. Others, most notably the virologist Harald zur Hausen, followed in the 1970s with similar research to identify the specific human papilloma viruses that cause cervical cancer. These findings radically changed the medical view of cancers, broadening the potential causal agents to include a wide range of viruses and resulting in better diagnostics and life-saving vaccines.

Kabat concludes his book with a short chapter reiterating points made earlier and admonishing readers to realize that important advances in the biomedical field occur through the persistence and collaboration of researchers building objectively on previous work. He argues that such advances are rarely achieved by “following some fashionable but ill-defined idea” based on “over-stated claims, implausible findings, and appeals to irrational fear.” This book presents important topics for consideration and four fascinating and well-documented epidemiological case studies. It is well suited for use in an introductory epidemiology class, where sections or chapters could be assigned as introductory reading followed by in-depth discussion, additional readings on particular topics, or both. And general readers are likely to find the four detailed case studies to be an interesting read.