Synergistic Effects of Chemicals in the Nervous System

Dr. Abou-Donia / CIIN MCS Conference Lecture 27aug01

CONARCH Number 3
August 13,2001
CIIN MCS Conference
Sante Fe, NM
Mohamad B. Abou-Donia, Ph.D Neurotoxicology Laboratory of Duke University Medical Center.

Synergistic Effects of Chemicals in the Nervous System.  Dr. Abou-Donia is an experienced toxicologist , certified since 1981, whose mission as a researcher with limited grant money, is to: 1) do studies to help the largest number of people and 2) understand chemical effects of neurodegenerative disorders. He laments that Duke med students only get 2 hours of toxicology in 4 years of med school. His message to them is "CHEMICALS CAN CAUSE DISEASE. Environmental exposure and personal habits are very important in disease! "

Trying to sort out which of two chemicals (liptophos and hexane) in a factory exposure caused symptoms resulted in his getting a grant in which he discovered chemical--chemical interactions. While FDA requires studies on drug-drug interactions before a pharmaceutical gets to market, NO drug/pesticide and/or pesticide/pesticide interactions are required before commercialization. Such interactions are important and can be:

1) Additive 1+1=2 2) Synergistic 1+1=3

3) Negative 1+1=0 HOW They Work? 1) Molecular basis--the chemical(s) get modified

2) Affect trarget site--affect absorption or metabolism

3) Increased permeability of BBB--blood/brain barrier For the past 3 years, he has been working on GWS (Gulf War Syndrome)

It is known from sensitivity to OP (organophosphate) poisoning that plasma acetyl-cholinesterase levels are critical and 4% of the population has decreased levels.

Many Gulf War veterans were exposed to 4 chemicals.

1) Sarin Nerve Gas-- similar to any OP pesticide.

The other 3 seemed OK used separately but when all used together the test animals: some rats were killed. These 3 chemicals compete for liver Cytochrome P 450 enzymes and plasma cholinesterases.

(*a=plasma b=brain cholinesterase)

2) PB Pills--Pyridostigmine Bromide--temporarily inhibits

*acetyl-cholinesterase

3) DEET--insect repellent

4) Permethrin--insecticide & anti-lice agent A new study is published in Toxicology Science: 60,305,2001 . This study compares the effects for 28 days on rats exposed to: 1) chemicals

2) stress 3) chemicals + stress 4) controls While all the rats gained weight and looked OK, there were dramatic effects on locomotion,coordination (balance beam) & sensimotor tests (grip strength) in the chemically exposed rates.

While chemicals caused disease, chemicals and stress cause more disease.

Stress augments the effects of the 3 chemical combo.

Dr. Abou-Donia explained that the integrity of the BBB-blood brain barrier is crucial. When the cellular junctions to the endothelial cells are tight junctions, water soluble and/or positive charged chemicals normally don't penetrate. His group did 4 separate tests of the integrity of the BBB in these rats: 3H hexamethonium, horseradish peroxidase, and BYSMI71 (a monoclonal antibody specific for the BB endothelium), and a muscarinic receptor. In all 4 tests, the permeability of the BBB is breached!

* Degeneration in layers 3 & 5 of the motor cortex lead to weakness and decreased strength.

* Loss in the hippocampus is associated with progressive loss of memory.

* Purkinje cell death in the cerebellum leads to tremor and problems with coordination and movement.

A current concern is the New York and Maryland recommendations for dealing with the risk of the West Nile Virus from mosquitos. A 3 chemical combination of DEET, permethrin and malathion spraying is occurring. Dr.

Abou-Donia is trying to get funding to study this. He would also like to study aspirin, tylenol with other chemicals in combinations that many people usually take.

No one wants to know about the canaries! Funding is not given to study old rats, female rats, pregnant rats and the young. Only healthy adult male rats are studied.

Notes of: Constance L. Holbrook, M.D. conarch@aol.com
Thanks to Steve Tvedten for these notes