Since 2001, hundreds of African-American men have come to the Markstein Cancer Education and Prevention Center at Alta Bates Summit Medical Center in Oakland, Calif., for a blood draw and physical exam to test for prostate cancer. While there, they've answered detailed questions about how frequently they eat chicken, beef, pork and fish, in what quantities, using which cooking methods, and to what degree of doneness.

The 600 men, ages 50 to 70, are part of an ongoing study that may provide answers to a grim mystery: Why do African-American men have the highest prostate cancer rate of any group of men in the world?

"We're increasingly confident that we're onto something," said Kenneth Bogen, an environmental scientist at Lawrence Livermore National Laboratory and head of the Oakland research project. "The hope is that we will really be able to tell people how to lower their risk."

The HCA connection

Bogen launched the study to test an intriguing hypothesis: African- American men are at high risk of prostate cancer because they consume very high quantities of carcinogens formed in cooked meats.

The hypothesis stemmed from decades of research conducted by James Felton, co-leader of UC Davis Cancer Center's Cancer Etiology, Prevention and Control Program and division leader of the Biosciences Directorate at Lawrence Livermore National Laboratory. Felton and Bogen are among the 40 Lawrence Livermore scientists who work as members of UC Davis Cancer Center's Integrated Cancer Research Program, the first formal research partnership uniting a major cancer center and a national laboratory.

Back in the late 1970s, Felton, as well as researchers in Japan, began discovering a range of carcinogens in cooked meats. Eventually, they identified 20 such compounds – known as heterocyclic amines or HCAs – and learned how the compounds form during cooking. In 2002, Felton received a five-year, $1.5 million P01 grant from the National Cancer Institute to explore the human cancer risk posed by these mutagens, employing science and technology originally developed for national security uses.

"As soon as you get over 350 degrees Fahrenheit – in the frying pan, the broiler or on the barbecue – these compounds show up," Felton said.

Making the case

Animal studies, meanwhile, were showing that HCAs consumed in food could cause tumors in mice and rats. An HCA called PhIP turned out to be one of the most potent carcinogens ever tested, and it specifically caused prostate cancer in rats. Parallel evidence – nearly 30 epidemiological studies in all – was implicating HCAs in cooked meats as a cause of human cancer.

But to make the case against HCAs, Felton's research team needed more precise estimates of people's typical dietary exposures, particularly to PhIP. So the scientists cooked meats in the lab, made fine-scale measurements of HCAs, and created charts of the kinds and amounts generated.

"At the same temperature, steak has more than hamburger, and chicken has more than either," according to Garrett Keating, a Lawrence Livermore toxicologist who works on the project.

In general, HCAs form more readily when meats are cooked for long periods of time and dry out, Keating said. Fast-food burgers have low amounts, probably because fast-food operations, for the sake of speed and efficiency, try to cook meat as long as necessary to kill E. coli and appeal to customers, but no longer than necessary.

Implicating PhIP

With their HCA data in hand, Bogen and Keating next turned to a U.S. Department of Agriculture diet survey of 25,000 Americans that contained detailed data on meat consumption and doneness preferences. The combined information allowed them to determine that the predominant HCA compound Americans consume is PhIP, primarily from pan-fried meats, such as chicken.

But the big surprise was their finding that African-American males were typically consuming two to three times more PhIP than white males.

"A light went on," Keating said. "We thought maybe this would explain their high rates of prostate cancer."

That finding, published in the Journal of Exposure Analysis and Environmental Epidemiology in 2001, fit with other dietary surveys suggesting African Americans eat more meat in general, particularly chicken, and prefer it well done.

Cause and effect

To demonstrate that a diet heavy in well-done meats can cause prostate cancer, the researchers next needed to show a dose-response effect: that men who eat more PhIP have more prostate damage.

Preliminary results from the Oakland study suggest there is indeed a significant dose-response: Not only did the study participants have high PhIP intakes, but the higher their intakes, the higher their PSA levels. PSA, for prostate-specific antigen, is a bloodstream marker for prostate damage and early prostate cancer. The findings were published online in the Jan. 16 issue of Prostate Cancer and Prostatic Diseases.

Specifically, the researchers found that men in the study consumed an average of 17 nanograms of PhIP per kilogram of body weight per day – about double the consumption estimates reported for age-matched white men in the United States. Moreover, the Oakland men who consumed 30 ng/kg per day or more were 30 times more likely to have a highly elevated PSA, defined as 20 nanograms per milliliter of blood or more, when compared to those in the study who consumed less than 10 ng/kg per day. A PSA of less than four is generally considered normal. The association remained significant even after adjusting for family history, saturated fat intake and total calories consumed, and it was strongest for men over age 50.

Type of meat and cooking method explained about 89 percent of the differences in PhIP intake among study participants. Doneness preference explained the remaining 11 percent.

Study volunteers with high PSA levels, suspicious physical exams, or both were referred for appropriate follow-up care.

Other suspects

But while PhIP is emerging as an important prostate cancer risk factor, it isn't the only one.

Genes are another. Michael Malfatti, another Lawrence Livermore researcher, found that PhIP is detoxified in the body primarily by an enzyme known as UGT1A. As a group, African Americans tend to have low amounts of this enzyme.

"So not only are African-American men eating more HCAs, they may also have a genetic makeup that means they can't get rid of it – it might be a double whammy," Felton said.

To date, Bogen's Oakland work has been funded by the NCI P01 and a three-year, $600,000 grant from the U.S. Department of Defense Cancer Research Program. Now he is seeking funding for a second phase of the study. In it, he hopes to expand the number of volunteers, extend his investigation to include geneenvironment interactions, and find a way to eliminate the excess prostate cancer burden borne by African-American men.