Poisoning the poison!

Poisoning the Poison

A new biologic could save the thousands of people killed by pesticides every year.

http://www.the-scientist.com/article/home/53619/


In the year 2000, hospitals in six Turkish cities were flooded by 2,000 students with poisoning symptoms after eating hazelnuts. Fortunately, nobody died. The nuts had been stored for a long time in a grain depot disinfected with an organophosphate (OP) pesticide.

The problem of pesticide poisoning is most acute in developing countries, where workers mix OP pesticides and spray fields without using gloves, goggles, or protective clothing, and then enter sprayed areas without waiting a safe interval. Despite using only 25% of the world's pesticides, these countries are home to 99% of pesticide-related deaths.

It's not just a problem in the developing world: In 1998 in California, all 34 workers fell ill after returning to weed a crop sprayed with an OP pesticide without waiting the recommended 48 hours. One was hospitalized. (Eating food treated with OPs is, of course, not nearly as harmful as swallowing heavily contaminated nuts or walking in newly-sprayed areas.)

A 2005 report on the International Workshop on Secure Access to Pesticides in conjunction with the Annual Congress of the International Association for Suicide Prevention, Durban, South Africa, estimated that there were 3 million cases of pesticide poisoning resulting in as many as 300,000 deaths per year, more than 100,000 of them in China. There's another risk: In rural areas, a significant percentage of people attempting suicide (up to 90%, in Malaysia) use pesticides, and close to 80% of all pesticide-related attempted suicides use OPs. This is a situation that needs some kind of a solution. Enter the military.

OPs are also used as nerve gases such as Sarin, of the infamous Tokyo metro attack. In this context, OPs act as powerful pesticides for people. OPs are cholinesterase inhibitors, interfering with the transmission of signals between nerve cells. Molecularly, all OPs are generally quite similar. Before the first Gulf War, Saddam Hussein converted the Muthanna, Iraq, pesticide factory into a production unit for the OP nerve gases Sarin, Tabun, and VX. The US military currently deploys an atropine-2PAM (2-pyridine aldoxime methylchloride) combination for preexposure prophylaxis and postexposure therapy for OP nerve agents. (Some of you may recall Nicolas Cage stabbing himself in the heart with a syringe-full of antidote after being exposed to Sarin in the 1996 movie, "The Rock"). But this combination has various undesirable side-effects, such as breathing and vision problems.

So researchers are turning to butyrylcholinesterase (BChE), a naturally occurring protein found in human blood that counters the anticholinesterase activity of organophosphates, including those used for agriculture, biowar, and bioterror. Before, BChE could be recovered only in microgram amounts from human blood, but in September 2006 the Annapolis, MD-based biotech PharmAthene was awarded a contract of up to $213 million from the Department of Defense for production of kilogram quantities of recombinant human butyrylcholinesterase (rHuBChE) from the milk of transgenic goats. (I have no ties to PharmAthene, financial or otherwise.)

Preliminary in vivo research suggests that the product's biochemical properties are similar to HuBuChE (Chem Biol Interact, 363:157-8, 2005). Material from PharmAthene does not mention its potential for prophylactic treatment of pesticide workers and for treating poisoned people. The basic mechanism is generic, however, so if the product works against OP nerve gases, could it not also protect people against poisoning from OP pesticides?

Could the benefits be even bigger? New research presented in April at the 8th International Conference on Alzheimer's and Parkinson's Diseases in Salzburg, Austria, from the Hebrew University of Jerusalem, in collaboration with PharmAthene, showed that rBChE dramatically suppresses the formation of intermediary fibrils, believed to play a crucial role in the development of the neurotoxic amyloid plaques that occur in patients with Alzheimer disease. Anticholinesterases are already being used in treating Alzheimer disease; rBChE could be more effective.

In my view, the potential of rHuBChE for prevention and treatment of accidental or intentional exposure to OP pesticides, and of Alzheimer disease, is likely to produce tangible benefits far outweighing its putative military use. It'll take time and money to test the product's effectiveness against pesticides and plaques, and there are obvious challenges associated with making it available to the millions who would need it in developing countries. But wouldn't all that be worth it if it worked?

Jack Woodall is former director of the Nucleus for the Investigation of Emerging Infectious Diseases in the Institute of Medical Biochemistry at Brazil's Federal University of Rio de Janeiro.

jwoodall@the-scientist.com