The Long Winding Road of Research Proving Smoking Causes Cancer

In 1964, the United States Surgeon General published a landmark report confirming that smoking causes lung cancer and other diseases. But proving that causal link definitively took over 50 years of tenacious research spanning epidemiological studies, clinical observations, laboratory experiments, and more across multiple continents.

Early History of Tobacco

Indigenous peoples in the Americas cultivated and used tobacco for medicinal, ceremonial, and social purposes for centuries before Europeans arrived. Tribes like the Taino in the Caribbean were observed using tobacco smoke ritualistically and treating ailments by applying tobacco poultices to skin infections or consuming it as an enema.

When Columbus arrived in the late 15th century, he and other European explorers returned home with vivid stories of tobacco’s cultural importance and potential health benefits. By the 1600s, tobacco had spread through Europe and Asia with glowing endorsements as a panacea. Scholars proclaimed tobacco’s ability to cure everything from wounds to tumors without needing proof.

The scientific method was still in its infancy, so medicine was not yet rigorously evidence-based. Two popular but misguided medical theories contributed to tobacco’s mystique: the humoral theory and the miasma theory.

Humoral theory stated that health depends on balancing four bodily fluids. Treatments aimed to restore balance. Miasma theory blamed diseases on foul “bad air.” Fragrances like tobacco could supposedly counteract the vapors’ ill effects.

Despite wild claims about tobacco’s benefits, risks also emerged. In the early 1700s, doctors noted throat irritation and “smoker’s cough” in users. Menthol cigarettes soothed the throat. Filters further reduced irritation when they were developed in the 1930s.

Rise of Lung Cancer

By the late 1800s, cigarettes were popular, and physicians began reporting increased mouth, lip, and throat cancers in smokers. However, lung cancer was still uncommon and poorly understood. Lung cancer diagnoses were extremely rare since confirming cases required an autopsy. X-rays eventually improved clinical detection in the early 1900s.

Additionally, most tobacco users still preferred pipes, chewing tobacco, and cigars over cigarettes at this time. These products delivered tobacco differently than cigarette inhaling. Smoking did not substantially increase until the late 1800s after cigarettes became mass-produced and affordable.

Once smoking became pervasive, lung cancer rates rose dramatically. Between the 1920s and 1940s, lung cancer deaths increased 15-fold in Britain and 9-fold in the U.S. Scientists debated the causes. Was it rising auto pollution? Dust from industrial workplaces? The 1918 influenza pandemic? Finding the reason required research free from outdated theories.

Early Observational Studies

In the 1920s and 30s, case-control studies compared lifestyle factors between lung cancer patients (cases) and similar healthy individuals (controls). Researchers surveyed participants about potential risks like smoking, hoping to pinpoint differences.

By the 1930s, multiple studies found higher smoking rates among lung cancer cases compared to controls. For example, a 1928 study found 96.5% of lung cancer cases were heavy smokers versus 73.7% of controls. However, these retrospective observational studies had limitations. Confounding factors and recall bias were difficult to rule out.

Prospective cohort studies that tracked outcomes forward over time would be more powerful. But few cohorts existed, and lung cancer’s long lag time between exposure and disease made prospective studies challenging.

The Threshold of 1950

In 1950, four higher-quality epidemiological studies emerged using improved statistical methods and larger samples. Though still case-control or retrospective, these studies came to similar conclusions on smoking and lung cancer:

  1. Wynder and Graham found 96.5% of 684 male lung cancer patients were heavy smokers versus 73.7% of controls.
  2. Levin et al. reported similar findings from hospital chart data on 605 patients.
  3. Mills and Porter showed 85.4% of 155 veteran lung cancer patients smoked versus 76.1% of 522 cancer controls.
  4. Doll and Hill found the only smokers among lung cancer patients and a dose-response relationship between smoking and lung cancer risk in their 789-patient case-control study.

The consistency across these more rigorous studies from both the U.S. and Britain was convincing. The dose-response relationship, meaning more smoking led to more cancer, lent further credibility. But skepticism lingered.

The British Doctors Study

To generate more definitive prospective evidence, Doll and Hill launched an ambitious cohort study of British physicians in 1951. They sent questionnaires to inquire about smoking habits to all registered UK doctors, receiving over 40,000 responses.

The researchers followed the doctors forward in time, periodically contacting them again to update their status. Over four decades, they observed disease rates and deaths correlating to participants’ smoking behaviors.

The study included over 34,000 men under age 75 at baseline. Participants were grouped by smoking amount, type, duration, and quitting. Controlling for subjects’ similar SES and gender avoided confounding.

Early results in 1954 found zero lung cancers among non-smokers but high rates among heavy smokers with clear dose-response trends. Critics expressed skepticism over the preliminary findings. But by the 1964 report, the study had followed participants for 13 years, accumulating irrefutable evidence through its prospective design.

Other prospective cohort studies lent further support. The 1956 Hammond-Horn Study of over 187,000 American men showed similar dose-dependent mortality relationships between smoking and lung cancer. Evidence mounted until causality could not be reasonably disputed.

Animal and Laboratory Evidence

Epidemiological studies linked smoking to lung cancer in people statistically, but scientists also wanted to know if tobacco could biologically cause cancer.

Argentine scientist Angel Roffo led pivotal early animal experiments in the 1920s-40s. He extracted tar from cigarette smoke and applied it to rabbits’ ears to induce tumors, proving tobacco alone had carcinogenic potential.

Later cellular and genetic research revealed how benzopyrene and other cigarette chemicals mutate lung cells, triggering uncontrolled growth. Combined with population data, the biological plausibility sealed the causative conclusion.

From Science to Policy

The 1964 Surgeon General’s report synthesized over 7,000 existing studies linking smoking to lung cancer and other diseases. This landmark review meant the science was no longer controversial, though acceptance took time. The report provided an evidence basis for public health action to curb smoking.

In 1965, warning labels appeared on cigarette packs. Advertising restrictions, public smoking bans, and youth prevention programs followed over subsequent decades due to strong scientific evidence that smoking causes cancer.

By the 21st century, declining smoking rates demonstrated the success of science-based policies. But the battle is not over. Over 40 million American adults still smoke, and tobacco use remains the leading preventable cause of death in the U.S. Ongoing research continues furthering our understanding of tobacco’s risks so society can save more lives.