Volume 21 | Issue 10 | Page 77

By Jack Woodall

COLUMN Poisoning the Poison

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

Jack Woodall Despite using only 25% of the world's pesticides, developing countries are home to 99% of pesticide-related deaths

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