Issue Date: October 31, 2011
Detecting Pesticide Exposure
The only diagnostic routinely used by clinicians to confirm a pesticide poisoning case is a test that measures inhibition of the enzyme cholinesterase. The assay works well for diagnosing patients exposed to organophosphate pesticides, which dominated the pesticide market in the 1990s. But the use of organophosphate pesticides has been declining over the past decade as less toxic alternatives, such as pyrethroids, have become available. There are no diagnostic tests for these increasingly common alternatives.
The key reason for the absence of diagnostic tests for pesticide exposure is a lack of biomarkers. This makes it difficult for physicians, who typically have little training in environmental health, to diagnose acute cases of pesticide poisoning. Epidemiological studies and pesticide risk assessments are also being hobbled by this lack of biomarkers.
These problems came to light last month at a stakeholder workshop hosted by the Environmental Protection Agency’s Office of Pesticide Programs (OPP). Experts from the pesticide community congregated at the meeting to discuss opportunities and challenges associated with advancing toxicology in the 21st century and developing biomarker-based tests for pesticide exposure.
Workshop participants agreed that new tools for monitoring pesticide exposure are needed, and they grappled with how to prioritize which pesticides to study. They also questioned how to deal with the variability of biomarkers over time and the instability of biomarkers in blood and urine samples.
The test for cholinesterase inhibition, the gold standard in pesticide exposure, is old and nonspecific. It measures exposure to pesticides that bind the cholinesterase enzyme—any of the organophosphate and carbamate pesticides—not exposure to one particular pesticide.
“Unfortunately, cholinesterase inhibition is the only test we have for pesticide exposure,” said Matthew C. Keifer, a senior research scientist with the Marshfield Clinic Research Foundation’s National Farm Medicine Center in Wisconsin. Physicians regularly order the test when it isn’t appropriate, such as in the cases of herbicide poisoning, he said.
Keifer highlighted the importance of pesticide biomarkers for identifying worker protection practices that have failed. He and others also pointed out the need for biomarkers to confirm pesticide exposures in worker compensation claims.
“In mild to moderate pesticide overexposure, a nonspecific clinical presentation is common,” said Amy K. Liebman, director of environmental and occupational health at the Migrant Clinicians Network, a group dedicated to health care for migrant farmworkers. The availability of a diagnostic biomarker could provide objective confirmation of a work-related illness, she said.
Biomarkers and diagnostics are also needed for pesticide risk assessments and to help interpret and design epidemiological studies, OPP Director Steven Bradbury said. Biomonitoring tools are a critical part of EPA’s long-term vision to integrate molecular and exposure science into its pesticide risk assessments, but EPA doesn’t have the tools to get an in-depth understanding of what exposure information means, he said.
In terms of where to start developing those tools, Dana Boyd Barr, a researcher at Emory University’s Rollins School of Public Health, recommended that EPA focus on pesticides that are the most toxic and have the highest potential for human exposure. Pyrethroids and pyrethrins are some of the most widely used pesticides, yet no clinical test is available for them, said James R. Roberts, associate professor of pediatrics at the Medical University of South Carolina. Many other commonly used pesticides, including organochlorines, neonicotinoids, chlorophenoxy herbicides, and chloropicrin, also don’t have diagnostics, he noted.
Other people suggested a more holistic approach. “Individuals are not exposed to a single compound. We want to come up with a comprehensive view of the individual environment,” said David M. Balshaw, a program administrator at the National Institutes of Health’s National Institute of Environmental Health Sciences. Balshaw described a program on exposure biology led by NIEHS to develop new technologies and biomarkers to characterize the entire personal environment, including chemical exposures as well as dietary intake, physical activity, and psychosocial stress.
Balshaw also highlighted an NIEHS effort to improve the way biomarkers are measured. “Biomarkers in this case are not a single gene or protein,” he said. NIEHS is coming up with new ways of detecting biomarkers, focusing on arrays and other techniques to understand how the entire biological pathway responds, Balshaw noted.
Along similar lines, Dean P. Jones, a medical biochemist and professor at Emory University, pointed out that his lab can measure approximately 10,000 chemicals—including 1,500 to 2,000 metabolites—in a drop of blood in 20 minutes using high-resolution mass spectrometry. The analysis provides a “relatively complete understanding of metabolic pathways,” he said.
So far, high-resolution mass spectrometry hasn’t found its way into the clinic for routine medical exams. But Jones predicts that it might not be too long before that happens. “The methodology has been around for about 30 years,” he said, adding that it took about that long for nuclear magnetic resonance—NMR—spectrometry to go from being a basic lab research tool to the clinical imaging technique called MRI.
Jones referred to the concept of the exposome—all of the exposures of an individual over a lifetime and how those exposures relate to disease. “If we had a system where we could collect samples and collect exposure information throughout life, then we would really have a new opportunity in terms of epidemiology to be able to look at disease associations,” he said. The biggest limitations right now are in the informatics side, he noted.
In addition to debating what to measure, workshop participants pondered how often to take samples. Biomarker concentrations vary over time, so a single spot sample doesn’t provide the whole picture, said Lesa L. Aylward, principal at the Colorado-based consulting firm Summit Toxicology. Variation is often significant within one person and within one day, she noted.
For biomarkers related to chemical exposures, interpretation of the results “is not as simple as higher concentration equals higher exposure,” Aylward said. “If you understand the pharmacokinetics of the compound, you can improve how you use biomonitoring for patients,” she added.
In the end, there are many different needs for pesticide-specific diagnostic tools. Public health advocates are pushing EPA to require the pesticide industry to develop such tests for their products as part of the approval process. Without such requirements, diagnostic tests will not be created, the advocates say.
“If industry can’t come up with a test for pyrethroids, surely they are not going to come up with a test for the newer nicotinoids or fipronil,” a chemical used on dogs to control fleas, South Carolina’s Roberts said. “Coming up with it on their own,” he warned, “is just not going to happen.”
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