In the experiment, two researchers working at Oxford, Isaac Berenblum and Philippe Shubik, assembled a group of mice, clipped a patch of hair on each rodent’s back, and painted the patches with DMBA, a cancer-linked chemical that was found in coal tar. Yet only one animal in thirty-eight developed a malignant lesion. When the researchers added some slicks of croton oil to the same area, the results were startlingly different. (Croton oil, a blistering, inflammatory liquid extracted from the seeds of an Asian tree, was used as an emetic and as a skin-sloughing exfoliant.) Now malignant tumors bloomed, appearing on more than half the mice. The sequence mattered. Reverse the schedule of application—croton oil first, tar after—and there were no tumors.
It was as though the known carcinogen, DMBA, had primed the cell and the croton oil had catapulted it toward malignancy. Berenblum and Shubik saw croton oil as a “promoting” agent: here was a new kind of carcinogen that, it appeared, acted through an inflammatory response. The idea that inflammation could lead to cancer wasn’t new. In the eighteen-seventies, the Viennese surgeon Alexander von Winiwarter had proposed that cancer was a consequence of an incompletely healed wound. But in what sense was croton oil a carcinogen? The mice painted only with croton oil hadn’t developed tumors. It passes a standard Ames test on bacteria, and a more sensitive version of the Ames test that uses fruit-fly cells. It’s negative even with animal cells. There’s no evidence, in short, that it causes DNA mutations.
So what was its contribution, and why did it do its malign work only after the coal-tar chemical was applied? Yes, it caused inflammation, but plenty of things do. A staph infection in the skin produces a potent inflammatory state, and yet it doesn’t cause skin cancer. The mystery perplexed cancer biologists for decades. What if this mechanism wasn’t an incidental curiosity but a major source of disease which we were only starting to understand? And, if so, what kind of substance irritates its victims to death?
Scientific investigations, like detective stories, take place within an epistemological system, a way of knowing. To identify the murderer, we might need to first identify the method of murder. But sometimes this presents a more complicated puzzle than we might anticipate; the weapon may involve a confluence of factors. In Arthur Conan Doyle’s “The Adventure of the Speckled Band,” Sherlock Holmes is on guard for a mysterious killer who can seemingly slip through doors. He sits awake in a room, waiting nervily by a ventilation shaft. The weapon turns out to be a venomous snake; it climbs through the shaft via a rope and poisons its victim. Yet the snake isn’t the singular cause: it’s necessary but not sufficient. The murderer has to whip the snake into a frenzy—inflame it—before it will attack. In “The Hound of the Baskervilles,” the titular creature doesn’t maul its victim but frightens him to death. The hound is lethal because it has been painted with a phosphorescent substance, and because of a specific context: the victim is terrified by a legend that says his ancestors were haunted by a supernatural monster. Conan Doyle was drawn to these additive scenarios because they expanded the complexity of a mystery.
For decades, chemical irritants presented carcinogen hunters with a structurally similar problem. These agents may work only in combination with other chemicals; like a hound on the moor, they, too, might depend on the victim’s history of prior exposure (DMBA first, croton oil next). And, as with Conan Doyle’s creaturely killers, they may also depend on multiple causes: the irritant promotes the development of tumors, but only after an initiator has been applied. How, then, might we devise a test for a substance when it acts only in concert and in context?
Not long after Berenblum and Shubik published that paper, a doctor named Irving Selikoff opened a medical clinic in Paterson, New Jersey, a largely working-class city. His was a blandly modern office: veneer panels, a curved Formica-topped desk, a few chairs. In the postwar years, factories were starting to close, but Paterson’s Union Asbestos and Rubber Company factory, which produced asbestos insulation material, was still operating. And members of an asbestos-workers union enrolled in his practice.
Selikoff was particularly attuned to lung diseases. By the early fifties, he had learned to treat tuberculosis using the antibiotic isoniazid (for which he and a couple of colleagues would win a Lasker Award). Soon, he began to notice lung problems—most prominent, deposits of calcium in scarred, inflamed lesions—in patients with asbestos exposure. “These men came home each day covered with the whitish fibers of asbestos—on their clothes, in their hair, in their lunch pails,” the Times later reported. “Sometimes they brought home samples of the fireproof product they made for their children to play with.”
As the years passed, the cases took a more ominous turn. Selikoff, confirming research done in Britain and Germany, noted that the workers were succumbing to a rare, lethal form of cancer that typically spread through the lining of the lung: mesothelioma. X-rays lit up the white shadow of the cancer coursing through the back and the bottom of the lung. The tumors often invaded the spine and the chest wall, and led to agonizing deaths. By the early sixties, Selikoff had collected data on a cohort of six hundred and thirty-two men who had worked in the insulation factory, some for many years. Among these men, Selikoff documented forty-five cases of lung cancer and mesothelioma—seven times more than the expected number. The incidence of stomach, colon, and rectal cancer was three times higher than expected.
Even as asbestos was identified as a major occupational carcinogen, however, scientists struggled to understand how it might cause cancer. The research remains inconclusive. In a study published in 1977, researchers exposed various strains of bacteria to asbestos fibres, and didn’t find that the fibres were associated with mutations. The toxicologists persisted. In one study, researchers added several other chemicals to asbestos and finally found bacterial mutants. In another, asbestos-induced chromosomal abnormalities were detected in animal cells. Yet another study found that mice injected with asbestos developed cancer, but with a latency period that seemed inexplicably long, given the material’s potency as a human carcinogen. And a study of a cohort of Turkish villagers exposed to one type of asbestos came to the opposite conclusion: sensitive tests revealed no increase in DNA damage. It was obvious that asbestos exposure raised your risk of cancer; it wasn’t obvious how. Like croton oil, asbestos seems to act as a promoter. Generate a mutation first, and then add an irritant, and a cell is propelled toward becoming a tumor.