Advanced NIOSH Research on Neurotoxicity Opens New Avenues Toward Preventing Job Risks

Contact: Fred Blosser (202) 401-3749
April 2, 2003

Recent research findings by the National Institute for Occupational Safety and Health (NIOSH) point to new leads for studies that will help to protect individuals from the risk of nervous system impairments from work-related exposures to certain chemicals.

The findings also illustrate the practical application of new laboratory technologies for identifying and understanding subtle biochemical changes in the nervous system, at levels of analysis that would have been impossible a few years ago. Such changes may be very early precursors of serious impairments in the ability to think, move, or communicate. As such, they might lead to new and faster ways of recognizing hazards from occupational exposures in time to avert serious risks.

In recently published studies based on laboratory experiments and reviews of the latest scientific literature, NIOSH found that:

• Obesity may increase susceptibility to neurotoxic chemicals, based on comparisons between two groups of laboratory mice, an obese group and a lean group, that were exposed to two compounds. The comparisons focused on changes in certain cellular and biochemical features that are fundamentally similar to those of humans.
• Progressive weakness and other potential long-term effects associated with exposure to organophosphate chemicals, whether employed as nerve gas or in their more common usage as pesticides, may not begin with chemical changes in an enzyme known as "NTE," as scientists have widely believed. Based on new molecular data that throw conventional wisdom into question, certain other leads show more promise for better explaining the ways in which these effects may be initiated.

"The NIOSH findings do not provide final answers, nor are they intended to do so in this exploratory phase of the science, but they show that the questions are worth pursuing, and they provide new clues that can help scientists fill key gaps in current knowledge," said NIOSH Director John Howard, M.D. "For example, would the results found in the laboratory studies be the same in humans? If subtle changes may predict or lead eventually to clinical symptoms, how does that progression occur, what steps may be involved, and what does this suggest for early intervention and prevention?"

In the NIOSH study of obesity as a potential risk factor, the comparison groups of obese and lean mice received equivalent doses of two compounds that are commonly used in neurotoxicological studies and are representative of chemicals that are neurotoxic in different ways. The study was published in the journal Neuroscience, Vol. 115, No. 4 (2002). Results included these:

• Systematic administration of the neurotoxic compounds to lean mice resulted in an increase in a brain protein known as GFAP. NIOSH research has shown that areas of the brain that show such increases in GFAP represent areas of brain damage, and the larger the increase in GFAP, the larger the degree of damage. When these same compounds were administered to obese mice, the increase in GFAP was much greater—findings which suggest that brain damage was greater for obese mice for a given dosage of the neurotoxic agent.
• Systematic administration of one compound resulted in greater decrease of the protein striatal dopamine in the obese subjects than in the lean ones. Striatal dopamine is the neurotransmitter (or nerve signal transmitter) affected in Parkinson's disease. These observations in mice are similar to recent findings in humans that indicate that mid-life adiposity, or a mid-life increase in skin-fold thickness in the area of the triceps, is a risk factor for Parkinson's disease.
• Following administration of the other compound, the obese group showed a greater degree of degeneration of neurons in specific brain areas than the lean group did.
• Both compounds produced greater activity of the gene UP-2 in both groups, but the increase was much greater in the obese group. The UP-2 gene is associated with a type of stress in brain cells that has been implicated in the development of nervous system degenerative disorders such as Parkinson's.

"Although much remains to be learned from these findings, we know in the meantime that some agents such as lead and mercury pose a fundamental risk of neurotoxicity, and that there are practical ways to reduce occupational exposures," Dr. Howard said. "Similarly, we also know that excess body weight is a risk factor for many diseases and can be controlled by appropriate physical activity and nutrition."

In the other recent study, NIOSH noted that for more than 30 years, scientists have widely believed that "delayed neuropathy," or progressive weakness and paralysis of the limbs, was initiated by a modified or "aged" form of a protein and enzyme called neurotoxic esterase or neuropathy target esterase (NTE). The process that modifies the enzyme is associated with exposure to organophosphates. The theory that the "aged" NTE enzyme is the key culprit in triggering the neurotoxic process was largely based on circumstantial evidence, rather than on actual observations at the molecular levels at which the changes would occur. Until recently, scientists were limited in their ability to study changes at those very minute levels.

However, a newly reported laboratory study by a team of scientists in California found that mice with less NTE enzyme and less NTE biochemical activity were more sensitive to the effects of an organophosphate compound than mice with more NTE. This indicates that lower levels of NTE and lower NTE activity, not the presence of the modified form of NTE, seem to be the key factors in the initiation of neurotoxic effects, NIOSH said. In conjunction with other factors, it further suggests that other proteins should also be investigated as "candidates" for initiating those effects, NIOSH suggested.

The NIOSH analysis was published in Nature Genetics (advance online publication), March 17, 2003. The NIOSH studies are part of a program of health effects laboratory research on neurotoxicity. In this program, NIOSH scientists are developing new "biomarkers" or ways to identify subtle cellular, molecular, and biochemical changes that may signal the potential onset of neurotoxic effects, and are applying those biomarkers to better understand how exposure to certain chemicals may lead to the development of symptoms. The application of this knowledge will lead to timely identification of neurotoxic agents, as well as development and implementation of early intervention and prevention strategies.

For further information about NIOSH research, visit the NIOSH web site or call the toll free NIOSH information number, 1-800-35-NIOSH (1-800-356-4674).