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The Ramazzini study was conducted with 1,900 rats, as opposed to the 280 to 688 rodents used in Searle's studies, and the rats lived for up to three years instead of being sacrificed after two, which is the human equivalent of age 53. "Cancer is a disease of the third part of life," Dr. Soffritti said. "You have 75 percent of cancer diagnoses for people who are 55 years old or older. So if you truncate the experiments at 110 weeks and the rats are supposed to survive until 150 to 160 weeks, it means you avoid the development of cancer at the time when cancer would be starting to arise."

Others have also challenged Searle's studies. Documents from the F.D.A. and records from the Federal Register indicate that, in the years before the F.D.A. approved aspartame, the agency had serious concerns about the accuracy and credibility of Searle's aspartame studies. From 1977 to 1985 ? during much of the approval process ? Searle was headed by Donald H. Rumsfeld, who is now the secretary of defense; Searle was acquired by Monsanto in 1985. Monsanto later spun Searle's assets out into two companies: Merisant, which owns the brands Equal and Canderel, and NutraSweet, which is owned by J. W. Childs Equity Partners, an investment firm in Boston.

A 1976 report from an F.D.A. task force, for example, found that Searle's studies on aspartame and several of the company's pharmaceutical drugs were "poorly conceived, carelessly executed, or inaccurately analyzed or reported." It cited what it called a lack of training by the scientists analyzing tissue samples, a "substantial" loss of information because of tissue decomposition and inadequate monitoring of feeding doses.

In response to the report, the F.D.A. asked the Justice Department to open a grand jury investigation into whether two of Searle's aspartame studies had been falsified or were incomplete. In a 33-page letter in 1977, Richard A. Merrill, the F.D.A.'s chief counsel at the time, recommended to Samuel K. Skinner, then the United States attorney for the Northern District of Illinois, that a grand jury investigate the company, which was based in the Chicago suburb of Skokie, for "concealing material facts and making false statements in reports of animal studies conducted to establish the safety of the drug Aldactone and the food additive aspartame."

A grand jury was never convened, however. Shortly after the letter was sent, Mr. Skinner left the Justice Department to join Sidley & Austin, a law firm that represented Searle. After 12 years at that firm, now Sidley, Austin, Brown & Wood, Mr. Skinner was appointed to be President George H. W. Bush's transportation secretary; later he became his chief of staff. In 1978, a year and half after Mr. Skinner left the United States attorney's office in Chicago, his deputy, William F. Conlon, also left to work at Sidley & Austin.

Mr. Skinner, now a lawyer at Greenberg Traurig LLP, said that as soon as he began looking for a new job and interviewing with Sidley & Austin, he recused himself from the Searle investigation. Mr. Conlon, who is still at Sidley & Austin, did not return phone calls.

Over the next few years, Searle's petition for aspartame approval led to much disagreement within the F.D.A. The commissioner at the time, Alexander M. Schmidt, convened a three-member public board of inquiry, which concluded that one of Searle's studies on rats showed an increase in brain tumors from aspartame. The board members ? all of them scientists at universities ? voted to withhold approval of aspartame until more studies were done.

But yet another F.D.A. review, this one of Searle's tumor tissue slides ? paid for by Searle and conducted by an academic group that is now defunct ? concluded that Searle's studies had demonstrated that aspartame was safe. In 1981, a new F.D.A. commissioner, Arthur Hull Hayes, concurred with this assessment and granted approval to aspartame shortly after President Ronald Reagan appointed him to run the agency.

And in a move that fueled the conspiracy theories, Mr. Hayes left the F.D.A. a little more than a year after approving aspartame and took a job as a consultant to Burson-Marsteller, which at the time was Searle's public relations agency. Mr. Hayes did not return calls seeking comment.

Ms. Nabors of the Calorie Control Council said that suggestions or innuendoes that Searle was trying to influence government officials with lucrative job offers were baseless. Artificial sweeteners are unfairly targeted for suspicion, she said, citing the government's decision to ban the sweetener cyclamate in 1969 after studies showed that it caused cancer in animals. "Cyclamate was banned, saccharin was required to have a warning label for a while, and there's all these conspiracy theories on aspartame," she said.

She added that there were more than 100 published scientific studies showing no adverse effects from aspartame, and said that in 2002, the European Commission reviewed many of these studies and reaffirmed the sweetener's safety. The bulk of the studies investigated neurological effects; none were animal cancer studies, which are lengthy and expensive.

In any case, critics say that most of these studies were financed either directly or indirectly by manufacturers of aspartame, and that the results of aspartame studies tend to depend on who paid for them. In an analysis of 166 articles published in medical journals from 1980 to 1985, Dr. Ralph G. Walton, a professor of psychiatry at Northeastern Ohio Universities College of Medicine found that all 74 studies that were financed by the industry attested to sweetener's safety.

Of the 92 independently funded articles, 84 identified adverse health effects. "Whenever you have studies that were not funded by the industry, some sort of problem is identified," said Dr. Walton, adding that he has not looked at studies performed since 1985. "It's far too much for it to be a coincidence."

Dr. Walton, who, like some other psychiatrists, has studied aspartame from a neurological perspective, said he had also seen problems from the sweetener firsthand. At Safe Harbor Behavioral Health, a mental health facility in Erie, Pa., where he is clinical director, Dr. Walton said he had observed that for many people with mood disorders, such as depression or bipolar disorder, aspartame exacerbates the condition. "For people with panic disorders, for instance, we've seen that when we eliminate aspartame, it's much easier to control their illness," he said. "The number of panic attacks goes down."

Dr. Walton and others say that this is probably attributable to aspartame's phenyalanine component. (Aspartame is made up of two amino acids, phenyalanine and aspartic acid.) He said that an excess of phenyalanine could upset the body's balance of neurotransmitters, causing a range of neurological symptoms.

Defenders of aspartame often point out that phenyalanine is naturally present in many protein-intensive foods. But Dr. William M. Pardridge, a professor of endocrinology at the David Geffen School of Medicine at the University of California, Los Angeles, says that when it comes from food, phenyalanine is absorbed into the brain more slowly.

"If your blood phenyalanine level was increased five times, in my view there would be a safety concern," Dr. Pardridge said. "The question is whether aspartame use could ever increase levels that much, and the answer is yes. We've known that for 20 years."

Dr. Soffritti said he had not studied the effects of phenyalanine. He theorized that the tumors in his study were related to the methanol, or wood alcohol, that is produced as the body metabolizes aspartame. When the body breaks down methanol, the result is formaldehyde, a known carcinogen. "I know that when I treat animals with methanol, you end up with lymphomas and leukemias," he said.

BUT Dr. Kenneth E. McMartin, a methanol expert and professor of pharmacology, toxicology and neuroscience at the Louisiana State University Medical Center, said he believed that it was unlikely that someone could consume enough aspartame to let harmful levels of formaldehyde build up in the body.

Dr. Soffritti said he thought that more research and open debate were needed on whether aspartame was a carcinogen. "It is very important to have scientists who are independent and not funded by industry looking at this," he said.

Michael F. Jacobson, executive director of the Center for Science in the Public Interest, a nutrition advocacy group, said he did not think that Dr. Soffritti's study could be considered definitive, but that it should prompt an "urgent re-examination.

"For a chemical that is used by hundreds of millions of people around the world, it should be absolutely safe," Mr. Jacobson said. "There shouldn't be a cloud of doubt."

Dr. Soffritti's journal article on his findings is at nytimes.com/business.