In early 2006 a self-styled “naturopathic” doctor, Chad Livdahl, pleaded guilty in Arizona to mail fraud and conspiracy to engage in mail and wire fraud, to misbrand a drug and to defraud the U.S. He was sentenced to nine years in prison. His wife and business partner in Toxin Research International, Inc., in Tucson, Zarah Karim, pleaded guilty to the same charges and received a six-year sentence. Both also paid heavy fines and restitution because, according to prosecutors, the couple had made at least $1.5 million in just more than a year by peddling tiny vials of fake Botox to doctors across the U.S.
Botox, which is injected in minute amounts to smooth frown lines or relax muscle spasms, is far from the only medical product that inspires illicit manufacture and trade. The world market in counterfeit pharmaceuticals is estimated to be worth some $75 billion annually. But the active ingredient in Botox and related products differs from the constituents of other pharmaceuticals in a profound way: in its pure form, it is the deadliest substance known to science. In fact, botulinum neurotoxin (BoNT) is grouped with the world’s most lethal potential biological weapons agents, sharing “Select Agent” status with the pathogens that cause smallpox, anthrax and plague. This biowarfare potential puts the existence of illicit laboratories churning out the toxin and of shady distributors selling it worldwide through the Internet into a more disturbing light than most pharmaceutical fraud.
As security analysts, we undertook two years ago to explore the size and nature of this illicit global trade and have come away gravely concerned that a deadly, but once relatively inaccessible, weapons agent is now becoming as easy to get or to make as a roadside bomb. We also believe concrete steps that are inexpensive and without risk could begin to reduce this threat and should be taken as soon as possible.
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A Multitiered Market
Since 1989, when the U.S. Food and Drug Administration licensed Allergan in Irvine, Calif., to sell Botox for medical uses, the company has garnered the major share of the legitimate market for botulinum toxin products, worth some $2 billion in sales in 2009. Other manufacturers of licensed BoNT products, particularly Ipsen, based in France, Merz Pharma in Germany and Lanzhou Institute of Biological Products in China, are making inroads, however, and in some countries outselling Allergan. The FDA approved cosmetic applications of BoNT in 2002, and today a total of only seven companies in the world have licenses to produce pharmaceutical-grade botulinum toxin for use in people. Many other companies, three of them in the U.S., supply laboratories with so-called reagent-grade BoNT, which is not approved for human use but rather for industrial and scientific applications, such as vaccine research.
Counterfeit products are sometimes mislabeled to resemble an authentic pharmaceutical brand or more often are given a sound-alike name, such as “Butox” or “Beauteous.” Some are fakes in every sense, lacking any detectable BoNT, but one study published last year by Ipsen investigators Andy Pickett and Martin Mewies found that about 80 percent of the illicit BoNT products they tested did contain some of the toxin, albeit in widely varying amounts. The primary customers for these bootleg BoNT products, which typically sell for less than the legitimate versions, are unscrupulous doctors and cosmetologists who buy from illicit producers or middlemen, often via the Internet, hoping to pocket the price difference. Makers of genuine BoNT products estimate that this counterfeit market costs them hundreds of millions of dollars a year in lost sales.
The cost to people who receive counterfeit products is potentially much higher, as a 2004 incident in Florida illustrates. Vials of counterfeit cosmetic BoNT landed four people in the hospital for months, near death with severe botulism and in need of mechanical ventilation. A doctor with a suspended license had purchased the BoNT from a licensed reagent-grade producer, then injected three patients and himself with a massive overdose of toxin. Exactly how much toxin each person received is unclear, but the doctor had made the grave mistake of confusing units (one unit is equivalent to 4.8 nanograms of BoNT, or 4.8 billionths of a gram) with micrograms (µg), or millionths of a gram.*
Other cases of reagent-grade material illegally resold for human use have also been documented, and some evidence suggests that legitimate pharmaceutical-grade product has on rare occasion been stolen or diverted to the black market. The great majority of counterfeit products, however, have mysterious origins, mainly in Asia, and are offered by illicit sellers who may or may not also be making their own ingredients.
In China alone we found 20 entities—they represent themselves as companies—that claim on their Web sites to be “certified” suppliers of BoNT and to offer cosmetic products for sale. The addresses provided on the sites often proved to be nonexistent locations or small offices that appeared to be empty fronts. Whatever the real nature of the entities behind these Web sites, they have access to genuine botulinum toxin, as the Ipsen analyses demonstrated.
Evidence suggests that the manufacture of counterfeit BoNT products has also spread to the former Soviet Union and that criminal gangs may be involved. Counterfeit pharmaceuticals have been a common problem in Russia for some time, so we were not surprised to learn from experts there that an estimated 90 percent of Russian cosmetology clinics are using counterfeit BoNT products at least some of the time. One security consultant described a purveyor of counterfeit BoNT products that has been operating in Russia for more than three years. The source of these products is reportedly located somewhere in Chechnya, and its representative flies regularly to St. Petersburg carrying suitcases filled with vials bearing labels almost identical to legitimate Botox packaging. When one client asked how much product could be purchased, the representative is alleged to have replied that any quantity, even 1,000 vials, could be supplied.
We believe there is a danger that India’s counterfeit drug producers, if not already involved in the illicit BoNT business, soon will be as well. The country has a legitimate producer of a BoNT product called BOTOGenie, launched in 2007, and a vibrant domestic market for both cosmetic and therapeutic BoNT products. The Indian medical tourism industry catering to foreigners seeking inexpensive care is also expanding rapidly, which is likely to entice the country’s well-documented pharmaceutical counterfeiting rings to cash in.
From a security perspective, this booming market is troubling because, for manufacturer-distributors it is only a small step from selling counterfeit BoNT products for cosmetic uses to selling the botulinum toxin itself in bulk quantities directly to subversive interests. Indeed, as the Russian example illustrates, such distinctions may already be blurred. And there is little to stop counterfeiters or criminals from setting up a manufacturing facility, because making botulinum toxin requires no exotic equipment and only moderate expertise in microbiology.
Easy to Make, Harder to Deploy Clostridium botulinum, the bacterium that produces BoNT, exists naturally in soil, but it is anaerobic, meaning that it thrives only in oxygen-free conditions. In the past, the most common source of botulinum toxin poisoning—botulism—in the U.S. was food, such as damaged or unsterilized canned goods. The more common form in adults today is wound botulism, which occurs mostly among addicts who infect themselves with C. botulinum while injecting drugs.
The pure toxin that the microbes generate is, on its own, the most potent poison in the world. And manufacturing the minuscule amounts of it that are required to kill takes only equipment standard in biology laboratories worldwide. In less than a month, someone with the equivalent of a master’s degree in biology could probably accomplish the necessary steps to produce enough toxin to cause mass casualties.
BoNT is so potent that a single molecule of toxin is believed to be capable of incapacitating one nerve cell. The toxin particles block receptors on nerve endings, silencing the nerves and paralyzing surrounding muscles. When pure BoNT is injected into a vein or muscle, just 0.09 to 0.15 µg can kill a 70-kilogram person. Although inhalation delivers the toxin to nerve fibers less efficiently, a mere 0.70 to 0.90 µg of inhaled toxin can be deadly to an adult. Ingesting BoNT is actually the least effective method of poisoning oneself, requiring 70 µg. Put another way, one gram of BoNT potentially contains more than 14,000 lethal doses delivered orally or about 1.25 million lethal doses if inhaled.
All C. botulinum strains found in nature are capable of producing BoNT, although the strains used by legitimate manufacturers are naturally occurring hyperproducers of toxin. One in particular, known as the Hall strain, is also widely employed in academic labs and stored in national cell culture collections. A would-be toxin manufacturer with access to the bacterium would have no problem finding out how to use it because instructions have been widely published in the scientific literature over the past 50 years.
The process begins with a small colony of C. botulinum, suspended in a common nutrient broth and allowed to multiply in incubators and fermenters for a total of three to four days. This mixture is then removed from the fermenter and centrifuged or filtered to separate out the liquid containing concentrated toxin. Of course, the pharmaceutical industry performs additional purification steps to ensure the quality and stability of their final product, which is sold as a fine powder packaged in a small vial. When the end user is ready to reconstitute the material, adding 10 milliliters of saline to the vial dissolves the powder in seconds. This liquid formulation must then be used within a few hours, because it quickly loses potency.
The relative fragility of the toxin once it is exposed to the environment has been a substantial obstacle in past efforts to weaponize BoNT. The U.S. and U.S.S.R. nonetheless succeeded in developing weapons that dispersed BoNT as an aerosol. Iraq developed BoNT-containing bombs, which would probably have been next to useless. The only well-documented attempt by a nonstate actor to deploy botulinum toxin as a weapon occurred in the early 1990s. The apocalyptic Japanese cult Aum Shinrikyo, whose membership included medical doctors and a scientist, attempted several times to disperse aerosolized BoNT through sprayers hidden in briefcases. These attacks failed, but only because the strain of C. botulinum the group’s scientist used was a poor toxin producer, sprayer nozzles got clogged and some guilt-ridden operatives failed to activate their devices.
The most plausible scenarios for terrorist use of BoNT involve sabotage of food or beverages. One study published in the Proceedings of the National Academy of Sciences USA in 2005 analyzed possible strategies for introducing the toxin at key points in the cow-to-consumer milk supply chain. The paper provoked controversy for identifying a sabotage method that might succeed. Yet its authors, Lawrence M. Wein and Yifan Liu of Stanford University, could not have known five years ago that terrorists attempting this kind of attack today would be able to purchase the toxin needed for their plan from an anonymous Internet source instead of having to manufacture it themselves. Their hypothetical plot now seems that much easier to carry out.
Assessing the Threat
Attempts by the international security community to prevent the proliferation of biological and chemical weapons usually focus on limiting demand by pressuring countries not to engage in weapons development and constraining supply by tightly controlling traffic in weapons-making equipment and know-how. Export controls and treaties, such as the 1972 Biological and Toxin Weapons Convention and the 1993 Chemical Weapons Convention, were developed by governments for governments, however. The international proliferation of illicit botulinum toxin products creates an entirely new and perplexing situation because the toxin-making supplies are not sought by governments but by individuals and because demand for the toxin is not driven by governments but by consumers.
The unique and important role of the Internet in both facilitating supply and in driving demand also makes the proliferation of the botulinum toxin threat more immediate than is the case for any other potential biological or chemical weapon. Our study documented a substantial increase in Internet vendors in the past two years, yet the possibility that these sellers represent a comparable proliferation in illicit BoNT manufacturers has not yet garnered much attention from agencies charged with preventing bioterrorism or suppressing the counterfeit pharmaceutical trade. Instead it is falling into the cracks between the two jurisdictions.
Indeed, some traditional weapons-interdiction strategies are likely to be ineffective against this novel threat. Attempting to affect the supply side of this equation by limiting equipment or information, for example, cannot seriously deter would-be BoNT manufacturers because the commonplace materials needed to make the toxin and the bacterium itself are too widespread.
Limiting demand for counterfeits might help discourage illicit manufacturers. Producers of pharmaceutical-grade toxin are employing advanced labeling technologies, such as holograms and verifiable serial numbers on packages so that doctors and cosmetologists can be assured they have genuine products. To educate end users about the dangers of counterfeits, Ipsen researchers have also made parts of their analyses of counterfeit products available to the public in lectures, poster sessions and scientific articles.
Allergan has taken quiet and selective steps toward stemming counterfeiting, including collaborating with investigators in China to close down one illicit BoNT operation in Shanxi Province. Because the number of illegal BoNT laboratories is large and likely to increase, however, companies have neither the expertise, the resources nor the authority needed to track down and prosecute these criminals.
A different example of pharmaceutical counterfeiting may offer a more effective approach. Only a few years ago the antimalaria drug artesunate had become the object of a robust counterfeit market. By 2007 one third to one half of all artesunate sold in Southeast Asia was actually counterfeit product, most of it therapeutically useless. As a result, licensed artesunate manufacturers were not only losing money, malaria victims were dying and the disease was spreading because so many patients were going untreated. That same year, a relatively complex international cooperative effort code-named Operation Jupiter was mounted for the specific purpose of suppressing this counterfeit artesunate trade. Collaborators in the offensive included representatives from the Wellcome Trust, Interpol, the Royal Canadian Mounted Police, the Australian Therapeutic Goods Administration, the Intellectual Property Division of the Chinese Ministry of Public Security, the World Health Organization, the U.S. Centers for Disease Control and Prevention, and several other smaller agencies and nongovernmental organizations.
Although Operation Jupiter holds many lessons for attempts to suppress counterfeit drugs, one of the project’s most notable and important activities was the collection of hundreds of samples of counterfeit artesunate sold at five different sites in Cambodia, Laos, Myanmar (Burma), Thailand and Vietnam. These samples were transported to high-quality reference laboratories and subjected to detailed analyses that constructed a “product signature” for each sample. These unique profiles allowed analysts to deduce how many different illicit artesunate producers were operating, and with that information in hand, law-enforcement agents could begin matching the products sold by intermediaries to the original manufacturers and sketching the outlines of distribution networks. In this way, at least some of the counterfeit products were traced to southeast China, enabling officials there to break up that criminal operation.
We do not delude ourselves about how difficult it would be to convince governments to partake in such an effort against counterfeit botulinum toxin producers. We do believe the Operation Jupiter example is relevant because it offers a scientific approach to at least beginning to understand the scope of the problem. If law-enforcement agencies took just the first step of setting up phony clinics to buy illicit BoNT products, then laboratory analyses could begin to establish how many illegal producers are operating. The data could later be used to pursue the criminals or could point to possible toxin sources in the event of an attack.
As security analysts, we know there are myriad theoretical threats to public safety. Only very few biological and chemical agents can be used by nonstate actors to cause mass casualties, however, and now none is as easy to procure as BoNT, because of illicit manufacturing and Internet trade. Vanity is currently driving the highly profitable market for counterfeit BoNT products, but it would be folly to assume that subversives have not noticed that booming business, too.
*Erratum (8/13/10): The correct conversion is 100 units equals 4.8 nanograms.