The Cancer Chronicles (15 page)

While epidemiologists kept watch for the appearance of a delayed
epidemic,
Bruce Ames, the inventor of
the
Ames test, was also coming to question whether synthetic substances were a significant threat. It was Ames who, back in 1973, had used experiments with bacteria to show that carcinogens, most of them anyway, caused cancer by inducing genetic mutations. (Not all carcinogens are mutagens. Some can work more indirectly.
By killing esophagus cells and increasing their rate of replacement, alcohol raises the odds of random copying errors.) As his test became established, Ames worried at first about the hazards of what modern man was releasing into the
world. His early
research helped lead to bans on carcinogens that were being used as flame retardants in children’s pajamas and in hair dyes. He helped persuade California to strengthen its regulation of an agricultural fumigant. He became something of an environmental hero. Then he began testing chemicals that occurred in nature, finding that a surprising number also appeared to damage DNA.

It made good
evolutionary sense. Throughout time plants have evolved the ability to synthesize chemicals that ward off predators—bacteria, funguses, insects, rodents, and other animals. Ames described some of these natural pesticides in
a paper in
Science
in 1983. The black pepper used to spice our food contains safrole and piperine and causes tumors in
mice. Edible mushrooms carry hydrazines that are carcinogenic. Celery, parsnips, figs, and parsley have carcinogenic furocoumarins. In chocolate there is theobromine, and pyrrolizidine alkaloids are found in various herbal teas. Over the years Ames continued to keep count.
In 1997, he reported that of sixty-three natural substances found in plants, thirty-five tested as carcinogenic. His most striking example was a cup of
coffee—nineteen different carcinogens, including acetaldehyde, benzene, formaldehyde, styrene, toluene, and xylene. Altogether, he estimated, people were imbibing ten thousand times as many natural pesticides as manufactured ones. Those seeking chemical causes of
cancer, he said, were looking in the wrong place.

In fact he doubted that nature’s poisons were really causing much cancer. Often forgotten is that his paper in
Science
also listed numerous antioxidants and other elements in plants that might conceivably provide some protection. It was possible, Ames proposed, that the good outweighed the bad, that on balance eating fruits and vegetables might reduce the incidence of cancer. But no one really knew.

Ultimately Ames’s message was that we were worrying too much about both kinds of chemicals, natural and artificial.
Half of everything tested, he wrote, was registering as carcinogenic, but that didn’t necessarily mean that the substances were dangerous. Suspected carcinogens are administered to rodents using what is called
the maximum tolerated dose—as much as the animals can take without debilitating effects. This is many times the exposure that people might receive in the world. There is a logic to this approach. Suppose that exposing 10,000 people to some chemical results in a single instance of cancer. For a population of 10 million that is 1,000 potentially preventable cases. To demonstrate the danger you would have to give the chemical to tens of thousands of mice—
an experiment costing tens of millions of
dollars. The alternative is to give megadoses to many fewer animals and see if a significant portion of them are affected. The problem, Ames said, was that big concentrations of any foreign substance can throw an animal into physical turmoil. Sensing the damage to its tissues, the body reacts as though it has been wounded, unleashing the healing process. That involves the acceleration of
mitosis—rapidly generating new cells to replace damaged ones. With so much DNA being duplicated, the odds of random mutations would be higher and so would the possibility of acquiring one of the deadly combinations. In technical terms,
mitogenesis increases
mutagenesis.

Toxicologists defended the tests as a reasonably good compromise. And like Doll and
Peto, Ames was condemned by his harsher critics for giving comfort to polluters and
diverting attention from a genuine problem. Perhaps environmental poisons are collecting in the human bloodstream—barely noticed but still adding incrementally to the background cancer rate. A
recent report by a White House advisory group suggested that animal tests are actually understating carcinogenicity—the opposite of what Ames has long contended. The tests are generally done on adolescent rodents that are sacrificed when the experiment is over. That would miss the effects of prenatal and childhood exposures as well as late-developing tumors.
The alternative would be to administer chemicals to pregnant animals and follow the health of their babies as they grow into adults and die of their own accord. Also overlooked would be
synergistic interactions. It has been estimated that more than eighty thousand novel substances have been introduced into the world in modern times. The number of combinations is endless. Only a small fraction of
new compounds are tested—after they have already been suspected of causing
cancer. Taking these factors into consideration, the panel gravely concluded that the number of cancer cases associated with industrial carcinogens “
has been grossly underestimated.”

While
many scientists criticized the report for seriously exaggerating the threat of synthetic
chemicals and giving unwarranted credence to a maverick view, few would disagree that toxicology testing needs to be improved.
The
National Academy of Sciences has described how advances in cellular biology and computer science are opening the way to rapid high-throughput assays allowing many more chemicals and combinations of chemicals to be analyzed. Instead of animals, the tests can be done on cells kept alive in laboratory dishes. The hope is that new carcinogens will be identified quickly and measures taken to reduce their prevalence. If all that should come to pass then cancer rates might be lowered further. That can only be good. But it is hard to make the case that the effect would be very large.

As the years have passed, no epidemic has appeared. Adjusted for the aging of the population, the statistics amassed by
SEER show that
death rates from cancer did rise gradually by half a percentage point a year from 1975 to 1984—smoking no doubt was a factor—and at a slower pace until 1991, but then they
began decreasing modestly and have been doing so ever since.
Incidence rates tell a similar story, though the picture is a bit more complex. Like death rates they gradually rose from 1975 until the early 1990s with a burst of newly reported cases from 1989 to 1992, when the rate increased by 2.8 percent a year. The biggest driver for the spike appears to have been more assiduous screening for two of the most common cancers. The number of cases of prostate cancer that were detected shot up by 16.4 percent per year before sharply dropping and breast cancer by 4.0 percent. Then incidence rates, like death rates, began their slow
decline.

Every year when the
National Cancer Institute publishes the
“Report to the Nation on the Status of
Cancer,” the story has been the same. Evidence that a large percentage of cases can be attributed to
lifestyle has also prevailed. Opinion continues to vary on just which elements are the most important, with specific foods—how much red and processed
meat is bad, how many fruits and vegetables are good—giving way to the suspicion that
lack of
exercise and excess weight are far more to blame.
A twenty-five-year retrospective on “The
Causes of Cancer” still attributed 30 percent of cancer to tobacco. Obesity and inactivity were believed to account for 20 percent, diet for 10 to 25 percent, alcohol for 4 percent, and
viruses for 3 percent. A study by the
World Health Organization’s
International Agency for Research on Cancer
found comparable numbers in France. Far down on the lists are occupational exposure and pollutants. Other studies have shown similar proportions in the United Kingdom and other industrialized countries.

Throughout all of this,
neighborhood
cancer clusters, like the ones I’d read about in
Los Alamos and on Long
Island and saw fictionalized in
Erin Brockovich,
continue to be reported. But in almost every instance they turn out to be statistical illusions, more examples of the Texas sharpshooter effect. Of those that do not, only a rare few have been associated with an environmental contaminant. Over the decades unusual occurrences of cancer among workers have led to the identification of some carcinogens—the link between
mesothelioma and
asbestos, for example, and between
bladder cancer and
aromatic amines (substances also found in cigarette smoke). But
even occupational clusters are uncommon.

As the rest of the world develops,
the same patterns are appearing as those in the West. Poorer countries tend to be dominated at first by cancers that spread through
sexual intercourse and overcrowding—those induced by viruses. There is human
papillomavirus and
cervical cancer,
hepatitis B and C and
liver cancer,
Helicobacter pylori
and
stomach cancer. With better hygiene and the growing use of Pap smears (and more recently HPV vaccine), cervical cancer may begin to recede. But then new cancers will arise to take its place. As women
choose to have fewer children and their better nourished daughters begin
menstruating at an earlier age, there may be more estrogen-driven
cancers of the uterus and breasts. Education, vaccines, better sanitation—these also push down cancers of the liver and stomach, but at the same time colorectal cancer increases as more people move from the fields to the cities and become slothful. They go from being undernourished to overnourished with all the nutritional imbalances that can come with a modern diet. The cancers of poverty give way to the cancers of affluence.
Prostate cancer, a disease of old men, becomes a problem when life expectancy rises into the seventies and eighties.
Lung cancer increases as the cigarette companies migrate to less discriminating markets. Industrialization brings with it new dangers of occupational exposure.

Everything doesn’t fit into a neat picture. Cancer rates might appear higher in one country than another because of the availability of screening tests. Cancer in urban areas is more likely to be noticed than cancer in the countryside. Beyond the statistical uncertainties, a mix of ingredients—diet, genetics, and cultural practices—can cause surprising variations. The prevalence of mouth cancer in
India may come from the chewing of betel nuts and, of all things,
reverse smoking—with the lit end of the cigarette inside the mouth. Drinking scalding hot maté may explain the high rates of esophageal cancer in some
South American countries.
Japan, an affluent society, still leads the world in the rate of
stomach cancer. The reason is often laid to diet—a cultural preference for salty fish.
Breast cancer in Japan is low for such a developed nation but it is rapidly catching up.

One day, trying to absorb all of this, I holed up in my office and began
unpacking the most recent
SEER statistics. Concentrating on overall cancer rates can smear over some interesting details, and I wondered what might be lurking underneath. The prime mover in driving down the numbers has been
a decline or leveling off in what
are by far the most common
cancers—cancer of the prostate in men, cancer of the breast in women, and lung and colorectal
cancer in both women and men. At the same time, the cancers that appear to be rising—melanoma, for example, and cancer of the pancreas, liver,
kidney, and
thyroid—are among the rarest. The annual
incidence of
pancreatic cancer is
12.1 cases per 100,000, compared with 62.6 cases for lung and bronchial. Year by year the figures fluctuate ever so slightly. With numbers so low, it can be difficult to tell if the increases are real or illusory—artifacts created by better reporting and
early detection.

That is one of the gnawing difficulties of epidemiology. The scarcer the cancer the more subject the numbers are to random fluctuations, the statistical equivalent of noise.
Childhood cancers are among the very rarest, ranging in incidence from 0.6 cases per 100,000 for
Hodgkin’s lymphoma to 3.2 for brain and nervous system cancer and 5.0 for
leukemia.
Death
rates from these malignancies have fallen to about half of what they were just a few decades ago—one of medicine’s great
triumphs. But trends in incidence—how many
children get cancer in the first place—are almost impossible to decipher. While there is slight evidence of an overall increase, it’s very hard to tell. A
rise from 11.5 total cases per 100,000 in 1975 to 15.5 in 2009 looks scary. But for the years in between
the numbers jump all over the place. The rate was nearly the same, 15.2, back in 1991. The following year it was down to 13.4 and eleven years later, in 2003, it was 13.0. The year after that it was 15.0, then 16.4, then 14.2. What will it be next? You might as well flip a coin.

Every cancer tells a different story. For many years lung cancer
declined among men because of the delayed effects of giving up cigarettes. Women started smoking later in the century and so their rates continued to climb. Only recently have they taken a downward turn. A spike in breast cancer in the last quarter of the twentieth century—including the tiny, slow-growing in situ tumors that some doctors don’t think should be classified as cancer—may be explained both by better diagnosis and earlier menarche. The recent improvement
in the numbers may be partly because of a drop in the use of
hormone replacement therapy during menopause. Rising rates of melanoma, which began long before the discovery of the ozone hole, is often attributed to the popularity of sunbathing, tanning salons, and skimpier clothing that protects less flesh from ultraviolet rays. Another reason may be
international travel. People from northern climes with lighter
skin are now more likely to spend time in sunnier places.
What may appear to be a climb in childhood malignancies, the National
Cancer Institute suggests, is probably because of better imaging technologies and the reclassification of some benign tumors as malignant. Childhood obesity may conceivably be involved.