By Chris Lane
By Jeff Balke
By Aaron Reiss
By Angelica Leicht
By Dianna Wray
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By Camilo Smith
By Craig Malisow
So far, the FDA isn't listening, and until it does, the drug manufacturers see no reason to change their ways.
Alcohol -- specifically, ethyl alcohol or ethanol -- has been a key ingredient in nonprescription drugs since before the temperance movement, when snake-oil salesmen went from dry town to dry town, peddling Lydia Pinkams and other "magic elixirs" with a wink and a nod. But ethanol has a practical purpose as well: It does what water cannot -- dissolve active ingredients and disperse them uniformly throughout a mixture that can be taken orally. The alcohol also dissolves the flavoring oils that make liquid medications taste better.
In 1990, Wilson was awarded two patents that would render obsolete the use of ethanol or any other liquid solvent in mouthwashes and drugs. The technology incorporates surface-acting agents, or surfactants. Explained in the simplest terms possible, these surfactants allow the blending of water and oil -- or in the case of drugs, water and active ingredients that are otherwise soluble only in alcohol. Wilson has, indeed, found a way for mouthwash, as well as just about any medication, to be carried about in powdered form and then mixed with water like Kool-Aid.
To say the invention is revolutionary is something of an understatement. Imagine never having to swallow another pill or foul-tasting concoction. Imagine encouraging your children to take their medicine by mixing it with a few ounces of water and telling them it's fruit punch.
"We can give you a drug and make it taste like fresh-squeezed orange juice," says Wilson, a 46-year-old former investment banker whose first patent was for a dry, nonalcoholic mouthwash flavored with essential oils from fruits and flowers. "A lot of people, especially the elderly, take multiple drugs -- big pills, nasty-tasting liquids. Why do they have to have a bad experience reinforced every day?"
And, Wilson asks, why should they risk their health by taking medication laced with alcohol? In the past decade, the hazards of consuming alcohol with nonprescription pain relievers such as acetaminophen have been well documented. The federal Food and Drug Administration has acknowledged as much by ordering drug manufacturers to reduce the level of ethanol in their over-the-counter, or OTC, products and by mandating stronger warning labels on ethanol-based medications.
So, it would seem that a so-called "drug-delivery system" that eschews alcohol is an idea whose time has come.
Not so, at least according to the FDA. The agency's "dirty little secret," says Wilson, is that drug manufacturers have replaced the ethanol in their OTC medications with another solvent, propylene glycol, a substance that was banned from use in cat foods by the FDA in May 1996.
Moreover, the FDA has apparently refused to acknowledge what is taught in any high school chemistry class: Propylene glycol is an alcohol. In what may come as a shock to parents who are careful about what nonprescription drugs they administer to their children, the agency has allowed OTC medications loaded with propylene glycol to be sold as "alcohol-free."
"It's a bait and switch, a canard," Wilson argues. "The FDA says that for something to be called sugar-free, it has to be sugar-free, and it is. But the drug manufacturers just took out one alcohol and replaced it with another."
Wilson readily acknowledges that he has a vested interest in the propylene glycol issue. As long as the FDA continues to allow its use, drug manufacturers will see no reason to switch to a nonalcoholic process, for which his company, Argyll Scientific, owns worldwide patents.
There are, however, questions about how much propylene glycol -- which is also prominent in foods and cosmetics, as well as being the central ingredient in aircraft deicing fluid -- can safely be consumed. Interestingly, for propylene glycol, unlike many FDA-approved food and drug additives, the agency has no scientific research that proves it safe.
"If you give me an ounce of ethylene glycol, or antifreeze, I will go into kidney failure," says Wayne Snodgrass, a pediatrician and toxicologist who is medical director of the Texas State Poison Center at the University of Texas Medical Branch in Galveston. "But the government hasn't put a number on how much propylene glycol, per body weight, per day, the general population can take without a problem. If that number exists, I'm not aware of it."
Meanwhile, the FDA has ignored studies that suggest propylene glycol may cause seizures, central nervous system depression and severe metabolic acidosis. Several of these studies have concluded that the substance should be re-examined for use as a drug solvent.
Yet, Ivy Kupec, an FDA spokesperson, says the agency's position is that propylene glycol is not an alcohol and that "there is no safety concern at this time that warrants any further review on its use as an inactive ingredient in OTC drugs."
Propylene glycol is a clear, viscous liquid derived from cracked petroleum. Though it is a synthetic substance, its chemical makeup puts it squarely in the same class of compounds as ethanol. And while widely believed to be less toxic, propylene glycol is absorbed and processed by the human body in the same way as ethanol, meaning that both substances cause similar reactions.
"The bottom line is," says Mark Wilson, "does the consumer have the right to know that the products they are buying are not as they are advertised? I'm not a toxicologist. I'm only saying that if it quacks like a duck, waddles like a duck and looks like a duck, why isn't it a duck?"
In 1993, when Antonio Benedi was a 37-year-old aide to former President George Bush, he had wine with his dinner one evening. Over the next four days, he took ten extra-strength Tylenol tablets. On the fourth day, he went into a coma and nearly died. A liver transplant saved his life. Benedi sued Johnson & Johnson, Tylenol's manufacturer, and won $8 million.
During the lawsuit, it was revealed that, in 1986, Johnson & Johnson had polled several hundred people, including physicians, on how they would react to an alcohol-warning label on Tylenol. About 70 percent said such a warning would damage their faith in the product's safety. Benedi's lawyers also trotted out internal Johnson & Johnson memos that advised the company's salespeople to avoid any discussion with physicians about studies that linked liver damage to the use of acetaminophen and alcohol.
Following other, similar lawsuits, Johnson & Johnson agreed to adopt alcohol-warning labels on its liquid Tylenol products. Yet, to this day, liquid Children's Tylenol contains propylene glycol as a solvent, as do other brands of acetaminophen for children. While it's uncertain if propylene glycol was a factor, acetaminophen products formulated for children were blamed for nearly 105,000 poisoning cases between 1993 and 1995, according to the American Association of Poison Control Centers.
Toxicologists say there simply isn't enough published data to know how toxic propylene glycol is. Unlike most FDA-approved chemical additives, propylene glycol has no known LD 50 -- the amount of a substance that would be lethal to 50 percent of the population.
"Take acetic acid, or vinegar," says Andrew R. Barron, a professor of chemistry and materials science at Rice University. "We know what its LD 50 is, we know what concentrations are safe to drink. Vinegars are not more acidic than they are for the simple reason that pure acetic acid is very dangerous.
"In the case of things like propylene glycol, it would be nice to know the reason it's not a problem, rather than the FDA saying, 'Oh, we just don't think it's an issue.' Well, it might be someday, so let's work it out now, not only for the consumer, but so the people who make Children's Tylenol know how much to put in and how much not to put in."
But, as Barron probably knows, he's talking about a federal agency that, though supposedly looking out for the best interests of consumers, is not known for decisive action.
In March 1984, the American Academy of Pediatrics released a policy statement noting that, while more than 700 pharmaceutical liquids contained ethanol, little was known about how the alcohol content of those medications affects children. The academy pointed out that, even though ethanol had been known to cause neuronal dysfunction, some liquid OTC medications, such as cough medicines and teething preparations, contained as much as 68 percent alcohol.
The academy concluded that while "efforts should be made to have alcohol removed from liquid preparations for children," the Food and Drug Administration should limit the amount in OTC drugs to no more than 5 percent.
Despite the academy's compelling advice, the FDA didn't establish alcohol limits in OTC products until 1995 -- 11 years later. It is impossible to know how many ethanol-induced poisonings could have been prevented had the FDA acted sooner; data on adverse drug reactions is recorded only by the active ingredients of a particular product.
But, according to the American Association of Poison Control Centers, more than 29,000 people, including two who died, were poisoned by ethanol-based mouthwash between 1993 and 1995, when the agency finally stepped in. The 1995 rule on ethanol limits its content in OTC products to 10 percent for adults, 5 percent for children under 12, and 0.5 percent for children under six.
"Apparently, there is more than a one decade delay in the FDA doing its job," says Mark Wilson. "Conservatively, there are probably tens of thousands of poisonings that occurred during that time. No one really knows."
Wilson has been butting heads with the FDA over the propylene glycol issue for years now, with little success. The FDA has never even bothered to respond to the dozens of letters Wilson has written since 1994 requesting an explanation for why the government will not recognize the substance as an alcohol.
If the feds thought Wilson would grow frustrated and quit, they were wrong. He spends 12 to 14 hours a day, seven days a week, researching propylene glycol, consulting with scientists and other experts and hounding the FDA for information he never receives. While, admittedly, he has quite a future as a manufacturer of alcohol-free drugs if the FDA ever reclassifies propylene glycol, the issue has become for him an all-consuming crusade to protect children. Pity the mother who gets into a conversation with Wilson; she's sure to get an earful about the FDA.
Nothing in Wilson's past suggests that he was destined to become a consumer advocate, unless you count his days as a longhaired, somewhat radical student-body president at Arizona State University in the early '70s. He does, however, descend from a long bloodline of inventive, if somewhat whimsical, imaginations.
Wilson's grandfather, for instance, came to America from Scotland in 1901, and immediately set out on a seven-year quest to find a place where the landscape was rumored to resemble the Island of Skye. Wilson's father was an engineer and an inventor who decided he wanted to live in the Amazon, so he did. Wilson still has no idea why.
After college, Wilson started accumulating a working knowledge of basic chemistry that would come in handy later. He worked for Allied Chemical and as a field representative for Shell Oil, where he learned about surface-acting agents, the backbone of his new technology.
"The human body has hundreds of surfactants," he says. "Surfactants are things that your body makes. The human body does not make alcohol."
A compulsive scribbler, Wilson keeps a little black book for ideas and musings that come to mind during the course of a day. He had it with him in 1981, when, in a hotel room somewhere in Wyoming, he opened his suitcase to find that a bottle of mouthwash had broken, soaking his belongings in a tacky green liquid.
There, amid the sickly sweet odor and his stained boxer shorts, Wilson pondered with some annoyance the rhetorical question, "Why can't you just mix this crap like (powdered) Kool-Aid?"
The answer didn't come until several years later, but it has changed Wilson's life. In 1987, he chucked a promising career with Kidder, Peabody to put all his energy into developing a dry, nonalcoholic mouthwash. He was 36.
"I just started thinking about making a change, about what I could do," he says. "I thought, at my age, if I didn't go for the brass ring then, I never would."
It didn't take much time at the research library to discover that alcohol was everywhere -- in foods, drugs, cosmetics, even on kitchen countertops. The turning point was the day Wilson read an article about a four-year-old girl who was accidentally poisoned by mouthwash. At the time, many mouthwashes contained upward of 60 percent alcohol, and they all lacked childproof caps and warning labels. (Wilson was among a consortium of individuals, physicians and consumer groups that pushed the FDA to require child-resistant caps on mouthwashes in 1995.)
Angry, but imbued with a sudden sense of life-and-death purpose, Wilson spent the next three years at his kitchen table perfecting a nonalcoholic mouthwash. In 1988, he formed Spectrum Consumer Products and filed for his first patent. But even then, he understood there was more to what he'd learned than mouthwash.
"I knew I was going to pursue a drug-delivery company," he says. "I was prepared to bet the ranch from day one, from the day I quit my job. My sense was that we had a pretty good idea and we were going to make it."
But for the FDA, people around the world might now be taking their medicine mixed with water rather than propylene glycol. But, just as the agency was slow to respond to the problems caused by ethanol, the FDA seems reluctant to consider the possibility that propylene glycol might have adverse effects as well.
In fact, the FDA seems opposed to even revealing the substance's presence in medications. The agency has chosen to limit its definition of alcohol to ethanol, which allows drug manufacturers to freely use other alcohols, such as benzyl alcohol and propylene glycol, as solvents and preservatives. While benzyl alcohol pretty much describes itself, you'd almost have to be a chemist to know that propylene glycol is an alcohol. Moreover, thanks to the FDA's narrow definition, a cold medication could be comprised of 15 or 20 percent propylene glycol and still legally be labeled "alcohol-free."
Clouding the issue further, the FDA has classified propylene glycol as an inactive ingredient, which means manufacturers are currently not required to list it on product labels.
All this from an agency that, in 1995, stated that its goal was "to provide important and truthful labeling to consumers who may be interested in total avoidance of alcohol for personal, religious or medical reasons."
Says Andrew Barron: "The issue to me is not that propylene glycol is this horribly toxic chemical; it's not. But it should be labeled for what it is, and if you ask a chemist, propylene glycol is an alcohol. As for truth in advertising, saying something is alcohol-free is wrong if it's got propylene glycol in it."
While the substance is not horribly toxic --it's estimated to be about one-third as potent as ethanol -- studies have shown that propylene glycol can cause significant health problems, particularly because of how it reacts with some active ingredients.
How humans handle the substance hasn't been studied extensively, but when it has been studied, the results haven't been especially encouraging. In 1987, for example, an article in a British publication, Journal of Pharmaceutical Pharmacology, reported that propylene glycol may compromise the human immune system. In concentrations as small as 0.5 percent, researchers found that propylene glycol inhibits cytotoxicity, or the ability of red blood cells to defend themselves. The study concluded that drug manufacturers "would be wise to consider [propylene glycol's] potential immunosuppressive effects in the evaluation of drug formulations."
A number of studies, dating back to 1980, suggest that propylene glycol may be damaging to the kidneys. In 1994, scientists at the Louisiana State University Medical Center reported that propylene glycol in concentrations as low as 0.5 percent can be toxic to cultured kidney cells and that its use as a drug solvent could accelerate the damage. Like the British in 1987, the LSU researchers recommended that manufacturers exercise caution in using propylene glycol as a drug-delivery device.
Likewise, a team of German scientists recommended that propylene glycol be replaced as a solvent in drugs after finding that concentrations of the substance in the bloodstream actually increase over time. They recommend diluting propylene glycol in saline "to minimize the undesirable effects of this solvent."
To put these studies, which evaluate the effects of relatively low levels of propylene glycol, into the proper context, consider a 1993 report from the University of Missouri-Kansas City. Researchers there administered over-the-counter Dramamine --which is 50 percent propylene glycol -- to female rabbits, and found that the solvent significantly reduced the rabbits' ability to metabolize, or process and eliminate, the active ingredient.
Wayne Snodgrass says the FDA and drug manufacturers need to examine more closely the kinetics of propylene glycol -- in other words, how it is handled by the human body. Snodgrass says that alcohol has "zero-order kinetics," which means that each subsequent dose may increase the concentration in the bloodstream three, four or even five times.
"At some point, any substance will build up, but the question of propylene glycol is, when does it happen?" Snodgrass says. "What is the dose that generates that effect in the general population? If you're a public-health official, you have to ask, 'What is the safety factor so the general population can have some dose, but not any more?'
"Well, there are no controlled, random studies in humans, so to do that, you have to go on what you know from animal studies."
The most significant animal study on propylene glycol actually led the FDA to ban the substance in cat foods in 1996. Once again, the federal agency was well behind the scientific curve. In 1976, 20 years earlier, researchers in Europe reported that propylene glycol increased the presence of Heinz bodies in cat hemoglobin, an indication of red blood cell damage. Those results led to the formation of a group of pet-food researchers in the U.S., who found that, in addition to the damage propylene glycol causes to red blood cells, the substance accumulates in the liver and causes heart and kidney lesions in cats.
After the U.S. research was published in 1994, the FDA took only two years to pull propylene glycol's status as a substance "generally regarded as safe," or GRAS, and ban it from cat food. Compare that to the ten- or 12-year lag in how the FDA reacted to the documented dangers of ethanol, and it's little wonder that, as time goes by, Mark Wilson is increasingly worried about propylene glycol's continued use in children's medications.
"I think the FDA ought to consider its own history," he says. "The original incident that strengthened the Food and Drug Act happened in 1938 --about a hundred people died after they were poisoned by ethanol that had been used as a solvent in cough and cold medicine. Now here we are, 60 years later...."
After almost eight years of inaction by the federal agency, Wilson took his crusade to Capitol Hill. In a long, pointed letter to U.S. Senator Phil Gramm of Texas, he expressed frustration at the FDA's lack of response, not only to Wilson's repeated inquiries about propylene glycol, but to the troubling scientific data on the substance. He asked Gramm to contact the FDA to see if a U.S. senator could get an answer.
It took two letters from Gramm's office over a six-month period to finally get a response from the agency in late February. The four-page letter from an FDA legislative liaison is interesting because it's really the first defense the agency has offered for the use of propylene glycol, to Wilson or anyone else.
According to the FDA, the substance has been in use in drugs for more than 50 years and in foods since at least 1920. Its GRAS status dates back to 1959. The FDA also notes that propylene glycol, in addition to its ability to dissolve active ingredients, is effective as a solvent and "plasticizing agent" in food.
But, as to why propylene glycol is not classified as an alcohol, the FDA's explanation is less than compelling: "Although propylene glycol is, as a matter of scientific nomenclature, a member of the class of hydroxyl compounds identified as alcohols, propylene glycol is not alcohol as the word is commonly understood. As commonly understood, 'alcohol' means ethyl alcohol, i.e., the type found in alcoholic beverages."
Presumably, the job of a watchdog organization like the FDA is to help distinguish what is "commonly understood" from what people don't know, but probably should. Just as questionable is the FDA's assertion that it has "considered the available body of evidence, and concluded that, in the amounts that propylene glycol is commonly used in drug products, the chemical poses no unacceptable risks."
Chemists and toxicologists like Wayne Snodgrass and Andrew Barron say that statement ignores two very important variables: First, no one knows what constitutes a lethal dose, apparently because it's not entirely understood how the human body metabolizes propylene glycol; and second, right now, no one knows how much propylene glycol is in a product because it's not required to be listed on the label.
That second variable will likely be changed later this year, when the Food and Drug Modernization Act of 1997 goes into effect. Among its proposed statutes is a requirement that all inactive ingredients in OTC products be listed on the label. Interestingly, another new requirement seems to bolster Wilson's contention that there is, in fact, more than one alcohol.
According to Section 704 of the new law, drug manufacturers will have to list the proportion of each active ingredient, "including the quantity, kind and proportion of any alcohol...."
"The key word there is 'kind,' " Wilson says. If they put the word 'kind' in, it must mean ethanol isn't the only kind of alcohol."
But, to others, relying on the semantic nuances of a federal law few people will actually read shouldn't be necessary. Common sense and a little scientific evidence ought to be plenty.
"You've gotta wonder," says Andrew Barron of Rice University, "if you can't feed it to your cat, what's it doing to you?"
E-mail Brian Wallstin at firstname.lastname@example.org.