Never say "never again" is something you learn in FDA. Worthless or dangerous products have an annoying way of cropping up time after time. Even drugs thought to have been banned forever have come back from the dusty pages of history to afflict an unsuspecting public.
The chemical 2,4-dinitrophenol is a case in point. Described in a chemical dictionary as "highly toxic" and a "severe explosion hazard when dry," this substance has been used in dyes, wood preservatives, weedkillers, photographic developers, explosives and, astonishingly, in weight-reducing products for human use.
Before 1938 it was legal under federal law to sell dinitrophenol (as it was commonly called) as a diet potion. At that time, drug makers were not required to prove that their products were safe before they put them on the market. Dozens of weight-reducing preparations containing dinitrophenol and other dangerous drugs were being sold.
But reports were multiplying that dinitrophenol could maim and kill. It was included in the "Chamber of Horrors" exhibit prepared by FDA for hearings held by a Senate committee considering a bill that became the Federal Food, Drug, and Cosmetic Act of 1938.
Even though it was some 50 years ago that the chemical made headlines and helped toughen federal drug laws, dinitrophenol is by no means merely of historical interest. In April 1986, a Texas court issued an injunction to stop a doctor from using the deadly chemical in a weight-loss program in that state. Less than three months later, the doctor was again in court for violating that injunction.
The doctor, Nicholas Bachynsky, operates a chain of "Physicians Clinics" throughout Texas and in several other states. Until last December the mainstay of his weight-loss program in Texas was dinitrophenol, which he dispensed under the trade name Mitcal. According to his advertising brochures, Russian-born Bachynsky learned of dinitrophenol in 1963 while translating Russian medical journals for the U.S. government. The Russians used it to keep soldiers warm in winter, he learned. The main side effect reported was weight loss.
This is not as far-fetched as it may seem. Even in small doses dinitrophenol accelerates metabolism of the cells, increasing their consumption of oxygen. To meet the increased need for fuel, the body burns up fat. The body's temperature rises, and heat radiation increases.
Bachynsky's advertising promised weight loss of up to 15 pounds a week under his program. Increased body heat is the only side effect mentioned. The brochure claimed that no deaths had been associated with Mitcal. (However, in 1984 FDA documented a suicide associated with an overdose of Mitcal by a professional weight lifter burdened with a number of emotional problems.)
The history of dinitrophenol tells a story far different from that portrayed in Bachynsky's brochure.
Before the turn of the century, European and American scientists studied the effects in laboratory animals of food dyes containing dinitrophenol and related compounds. They found the chemicals caused a rise in temperature, stimulated respiration, and hastened the onset of rigor mortis upon death. As a result, these dyes were banned in a number of countries, including the United States.
Dinitrophenol next surfaced during World War I when French munitions workers experienced loss of appetite, nausea, vomiting, diarrhea, loss of weight, night sweats, weakness, headaches, and high fever. These symptoms improved when the workers were off the job for a few days.
The effects were most severe among alcoholics and those with liver and kidney problems. They developed extremely high temperatures, profuse sweating, and intense thirst. Death followed in a few hours.
A commission set up by the French Ministry of Munitions pinpointed dinitrophenol as the cause of the problem. (France was the only country using the compound in explosives.) The ministry took steps to protect its workers from dinitrophenol.
In the late 1920s, scientists started looking into possible therapeutic uses of dinitrophenol. In the July 15, 1933, issue of the Journal of the American Medical Association (JAMA), three Stanford University researchers reported that patients receiving daily oral doses of 3 to 5 milligrams of dinitrophenol per kilogram of body weight experienced steady weight reduction without demonstrable side effects. However, since their studies were short term -- no longer than three months -- the researchers warned that they could not be sure that toxic effects might not appear after longer use. They urged that "for the present, dinitrophenol be used only as an experimental therapeutic procedure in carefully selected patients under close observation by the physician."
In the same issue of the journal, AMA's Council on Pharmacy and Chemistry echoed that advice. An editorial warned, "A drug with the potency and effects of dinitrophenol is a two-edged sword with appalling possibilities for harm as well as good."
This warning was soon borne out. In the Sept. 30, 1933, issue of JAMA, three San Francisco physicians described a severe skin reaction in a woman who had taken dinitrophenol for 14 days. They concluded the chemical was not as safe for weight reduction as other methods in common use. Then San Francisco newspapers reported the bizarre death of a Viennese doctor who took an overdose of dinitrophenol to achieve quick weight loss and, as one newspaper put it, "literally cooked to death." His temperature had reached 110 degrees Fahrenheit.
In a report on this death, JAMA predicted, "It is to be expected that, with the craze that has in the past few years affected the American public, and especially the feminine contingent thereof, for shortcuts to the sylph figure, proprietary products will begin to appear having for their essential drug dinitrophenol."
During the next 15 months an estimated 100,000 persons took the drug for weight reduction. More than 1,200,000 capsules were dispensed from a single clinic in San Francisco. More than 20 drug houses supplied both dinitrophenol and mixtures containing the drug. Proprietary products with such names as Nox-Ben-ol, Nitroment, Nitraphen, Redusols, Formula 17, Slim, Dinitrenal and Dinitrole were freely sold in drugstores without a prescription and with no warnings or adequate directions for use. Only in New Jersey, Louisiana and California was a prescription required.
It was assumed that the chief danger from this drug lay in the careless use of over-the-counter products. But physicians were reporting serious toxic reactions, including severe skin rashes, agranulocytosis (a potentially fatal blood disorder), jaundice, and disturbances of smell and taste even in patients under their care. Some deaths also were reported. Unfortunately, there was no way to predict who might suffer these reactions.
In August 1934, the Food and Drug Administration issued the first of a series of warnings, pointing out that sales of dinitrophenol fat reducers were booming, despite the reports of deaths, but the 1906 Food and Drugs Act did not cover products of this type. All FDA could do was to warn the public.
Nevertheless, the agency was preparing for action -- to test the law if nothing else. Chemists at FDA's Chicago district laboratory were involved in a crash project analyzing a broad range of reducing products. Dinitrophenol was found in products that did not reveal their contents on the label. An official method of analysis for dinitrophenol was developed and sent out to cooperating enforcement agencies in the states.
At the same time, the E. I. DuPont de Nemours Company informed FDA that it was trying to restrict its sales of dinitrophenol to industrial users.
In April 1935, a virtual epidemic of cataracts began to occur, predominantly in young women who had been taking dinitrophenol. Some cases showed up months or years after the last dose of the drug had been taken. Tragically, once started, changes in the eye's lens progressed rapidly until vision was obscured. Dr. Warren D. Homer, a San Francisco ophthalmologist and one of the first to report dinitrophenol-related cataracts, estimated that more than 164 people were affected. Newspaper headlines proclaimed "Blinded By Drug To Reduce Weight," "Anti-Fat Drug May Cause Blindness," and "Women Blinded In Reducing Try."
On July 6, 1935, the AMA's Council on Pharmacy and Chemistry reported dinitrophenol would not be included in its quasi-official list of acceptable remedies.
In September 1935, FDA Commissioner Walter Campbell repeated the previous year's warning against dinitrophenol, this time stressing the danger of blindness: "The eye cataracts develop with a rapidity and malignancy hitherto unknown, and result in total blindness within a comparatively short time."
Campbell pointed out that existing federal law was "silent with respect to the control of dangerous drugs," and that the only possible application of the law would be through "some misstatement of fact or fraudulent curative claim in the labeling." In any event, he said, "the law can be invoked only when the product has been transported across a State line." He said the agency, contrary to its usual policy, "would take advantage of any legal technicality in proceeding against all products containing dinitrophenol."
Such technicalities were found in two cases against a product called "Slim." The reducing pills were labeled as "safe to use," whereas medical opinion was unanimous to the contrary. Three shipments were seized -- two in Pittsburgh and one in Fort Wayne, Ind. The seizures were not contested in court and the products were destroyed.
Though dinitrophenol made headlines in the papers and news reports on radio, it took another experience to demonstrate effectively the need for a stronger drug law -- the 107 deaths in 1937 from a poisonous elixir of sulfanilamide. In this disaster, a popular sulfa drug had been dissolved in diethylene glycol, a deadly poison. The chemist tested the solvent for flavor, appearance and fragrance but, unfortunately, not for safety.
The only remedy for such a situation, said FDA Commissioner Campbell, was a law "which will require that all medicines placed upon the market shall be safe for use under the directions for use, and for potent drugs and new drugs a federal licensing system is probably the answer."
In 1938, the Federal Food, Drug, and Cosmetic Act was enacted, giving FDA the power to take action against drugs that are dangerous even when used in the recommended dosage. Subsequently, the agency included dinitrophenol in a list of drugs potentially so toxic that they should not be used even under a physician's supervision.
Apparently manufacturers had already gotten the message. Reducing potions containing dinitrophenol disappeared from the marketplace. FDA's Annual Report for 1940 was able to state: "Again, as in 1939, no articles containing dinitrophenol were encountered."
Since that time no drug containing this dangerous chemical has been approved by FDA for any use in humans.
Dinitrophenol's notorious history was not unknown to Dr. Bachynsky; he cited the medical reports of the 1930s in a paper he hoped to publish and which he made available to FDA. But that did not stop him from using the chemical in his weight-loss clinics. In fact, his brochure stated that his was the only program in the nation using this substance. In addition, he claims to have discovered that dinitrophenol "decreases useful energy production, and thus makes an over-efficient metabolism very inefficient," so subjects can burn off unwanted fat. Treatment at Bachynsky's clinics was not cheap -- in the neighborhood of $1,300.
Although Bachynsky's brochure stated, "There have been no fatalities associated with Mitcal," the consent form patients were asked to sign lists among the potential risks of his treatment "blood clots in veins and lungs; cataract formation; hemorrhage; allergic reactions; and even death." This apparently wasn't enough to dissuade prospective patients. As many as 14,000 people were treated at Bachynsky's clinics, according to court papers.
FDA first learned of the clinics in late 1982 when some of Bachynsky's customers started calling the agency's Houston office to complain of adverse reactions, including fever, shortness of breath, dizziness and sweating.
FDA investigators went to Bachynsky's Houston clinic and to the pharmacy next door, also owned by Bachynsky, where they observed bulk containers of dinitrophenol from the Eastman Kodak Co. labeled "For chemical purposes, not for drug use." The pharmacy appeared to be using this material to compound Mitcal. The FDA investigators warned Bachynsky that he was using a dangerous, unapproved drug in violation of federal law.
In March 1983 Bachynsky wrote to FDA's Houston office that since Mitcal was not for sale, distribution or transportation across state lines, the clinic was not breaking any laws. Mitcal was not sold to patients at the clinic or anywhere else; it was part of the total treatment. Since the raw material in Mitcal had been shipped across state lines, FDA did have jurisdiction but, in the agency's opinion, a case against Bachynsky for use of an unapproved new drug was better handled by the state; federal law does not regulate the practice of medicine.
In 1985 Bachynsky opened a new clinic in Dallas. Soon complaints of adverse reactions to his treatment began to come in to the agency's Dallas office and to a local poison control center. FDA wrote to Bachynsky on Aug. 19, 1985, pointing out again that dinitrophenol is a "new drug" needing FDA approval. In addition, the letter explained that under the Texas Food, Drug, and Comestic Act new drugs cannot be sold, or even given away, unless they have been approved by FDA or have been tested and found safe, and an application for marketing has been filed with the Texas commissioner of health. This had not been done, according to the commissioner.
Such approval was not necessary, Bachynsky responded, since the Texas law does not apply to a drug sold in the state before the enactment of the 1938 Federal Food, Drug, and Cosmetic Act. In support of his claim that dinitrophenol is safe for weight control, he enclosed his paper describing clinical trials with the drug. Furthermore, he said a "pre-IND" submission had already been sent to FDA headquarters. (An IND is a request for an exemption to federal drug laws and is filed to permit testing of an investigational new drug on humans. Bachynsky's submission was, in effect, a "testing of the waters.'')
Texas authorities were not convinced by Bachynsky's response to FDA that his use of dinitrophenol was legal. In November 1985, the Texas attorney general brought suit against the doctor and his clinics. The state charged that, among other things, Bachynsky failed to advise his patients that the drug is not generally recognized as safe for weight loss, that it is highly toxic, and that it is not approved by FDA.
Supporting the state's case were a written affidavit and a videotaped deposition by Dr. Robert Temple, director of the Office of Drug Research and Review in FDA's Center for Drugs and Biologics. In both, Dr. Temple discussed the toxicity and the adverse effects of dinitrophenol. He pointed out that although it was widely used in the 1930s, there have been no published reports of adequate, well-controlled clinical studies showing that the drug is safe.
The case against Bachynsky came to trial on March 10, 1986, in Dallas. On March 21 the jury found him guilty of drug law violations and ordered him to pay $86,000 in fines and attorney's fees. The presiding judge, Leonard Hoffman, immediately issued an injunction prohibiting Bachynsky from dispensing dinitrophenol to any patients. The final judgment, handed down on April 10, provides that the defendants may use dinitrophenol only if it is approved by FDA or if FDA allows its use under an IND.
Bachynsky apparently was not deterred by the orders of the court any more than he was by the history of dinitrophenol. In July, the doctor and his Dallas clinic were charged with violating the April injunction by continuing to solicit patients with the intent of dispensing dinitrophenol, by representing that the drug is safe for use in a weight-loss program, and by failing to advise patients that the drug is a highly toxic herbicide (weedkiller).
Because of the large amount of money Bachynsky made from his Texas customers (in excess of $8 million), the court decided the penalty would not be meaningful unless it was substantial. Therefore, Bachynsky and the clinic were fined a total of $100,000, with interest at the rate of 10 percent a year beginning Aug. 1, 1986, the day the judgment was signed.
Bachynsky continues to operate the Physicians Clinics, though he is now using substances other than dinitrophenol for weight reduction. The clinic program has been expanded to include treatments for impotence and smoking cessation. Dinitrophenol has not been abandoned completely, however. Bachynsky presented the results of his studies with the chemical to an FDA advisory committee in September 1986. He said he hoped that the committee would have an open mind if he submits an IND in the future.
Committee members felt that if the question of whether dinitrophenol is an effective treatment for obesity is reopened, it should be done in the classic fashion with rigorous testing of the drug in animals first and then with very carefully monitored studies in people under hospital conditions.
This article was published in the February 1987 issue of FDA Consumer. At the time it was written, Ms. Hecht was a member of FDA's public affairs staff and Mr. Janssen is FDA's historian. In 1990, Bachynsky's Texas medical license was canceled after he was sentenced to prison in a case involving insurance fraud.