Pamela J. Lein at the University of California, Davis discusses the evidence suggesting that pesticides are risk factors for asthma
Asthma is a chronic inflammatory lung disease, characterised by episodic and reversible bronchoconstriction (contraction of the smooth muscles that line the airways), excessive secretion of mucus in the airways and airway hyperreactivity (an exaggerated reaction of airway smooth muscle to contractile stimuli). All of these effects interfere with breathing.
Worldwide asthma prevalence and severity has increased markedly over the past two decades, especially in urban settings. Many hypotheses have been proposed to explain the increased asthma in urban residents, including exposure to allergens, air pollution, differences in healthcare and stress. However, an environmental factor associated with agricultural asthma that is beginning to receive increased attention in the context of urban asthma is exposure to organophosphorus pesticides (OPs).
OPs are the most widely used class of pesticides worldwide and are applied extensively in not only agricultural but also in suburban and urban settings to control insects. Although residential uses of OPs are being phased out in the United States and many European countries, OPs are still used heavily in agricultural, industrial and commercial settings and OPs are widely detected in the general human population in all countries in which this has been assessed.
Occupational exposures associated with the production, distribution and application of OPs occur primarily via dermal absorption, with more limited exposure via inhalation. The general population is exposed to OPs via ingestion of food and water contaminated with OPs and by dermal and inhalational exposure to pesticide drift and “overspray”. The latter is not an insignificant source of exposure as extensive OP contamination has been documented in the air, homes and urine from pregnant women and children living in communities near agricultural fields sprayed with OPs
OPs inhibit the enzyme acetylcholinesterase, which functions to inactivate the neurotransmitter acetylcholine. Acetylcholinesterase inhibition significantly increases acetylcholine levels at the synaptic junction between nerves that secrete acetylcholine and their target tissues, causing excessive stimulation of target tissues.
Acetylcholinesterase activity is functionally important in not only insects, but also humans. It is well established that OPs cause neurotoxicity in humans by inhibiting this enzyme, a medical condition referred to as the cholinergic crisis. Acute exposures to OPs that inhibit acetylcholinesterase by more than 80-90% of control levels can cause death in humans, typically by inhibiting the respiratory centres in the brain that control breathing. Thus, many regulatory agencies have identified safe levels of OPs as those that do not inhibit acetylcholinesterase.
Case reports published in the 1960’s provided the first indication that exposures to OPs at levels that do not cause cholinergic crisis may trigger asthma in adults. Subsequent cross-sectional studies of farmers and their families, farmworkers and commercial pesticide applicators in multiple countries around the world provided further evidence that occupational exposures to OP pesticides are associated with adult-onset asthma.
More recent epidemiologic data suggest that not only occupational exposures, but also exposures to environmentally relevant levels of OPs, such as might be experienced by the general public, are associated with increased risk of asthma and asthmatic symptoms in adults and adolescents. OP-induced asthma may not be limited to these age groups, as indicated by emerging data from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), the longest-running longitudinal birth cohort study of pesticide effects on children’s health, which has been studying children in a farmworker community in the Salinas Valley of northern California. Data from the CHAMACOS study suggests that OP exposures during pregnancy and the first year of life, as determined by analysis of urinary OP metabolites in pregnant women and their infants, are associated with respiratory symptoms in children at five and seven years of age.
While systematic reviews of the published epidemiologic literature generally support an association between OP pesticide exposure and asthma, it is difficult to establish a cause-effect relationship based on human data. This is due in large part to the fact that it is extremely challenging to accurately quantify OP exposure in humans. Thus, studies in animal models are critical for determining whether OPs are causally linked to asthma. The animal studies published to date support the hypothesis that OPs directly cause airway hyperreactivity, a key symptom of asthma.
Importantly, OP-induced airway hyperreactivity is observed at levels that do not inhibit acetylcholinesterase. Several different OPs, including chlorpyrifos, parathion and diazinon, can induce airway hyperreactivity in guinea pigs following subcutaneous injection, a route of exposure that mimics dermal exposure in humans. In contrast, pyrethroids, a class of pesticides structurally and mechanistically distinct from OPs, do not induce airway hyperreactivity in guinea pigs, suggesting that the airway response to OPs is not a generalised property of all pesticides.
Interestingly, the effect of OPs on airway hyperreactivity was not evident immediately after exposure, but rather were manifest 24 hours later and persisted for at least seven days after a single injection of the OP. Further studies in the guinea pig model suggest that OPs cause airway hyperreactivity by interfering with neural mechanisms that normally function to limit the release of acetylcholine from airway nerves onto airway smooth muscle. This effectively increases the amount of acetylcholine available to cause contraction of the airway smooth muscle.
How OPs cause dysfunction of airway nerves remains an outstanding question, although preliminary data suggest that the mechanism may vary depending on the allergic status of the individual. Answering this question will be critical for identifying susceptible subpopulations and for designing more effective therapeutic interventions for preventing or reversing OP-induced airway hyperreactivity. More immediately, these findings raise significant questions regarding the use of acetylcholinesterase activity as a point of departure for regulatory action. Furthermore, these findings suggest the possibility that the increased prevalence of asthma is related less to the insects that we live with than to the chemicals we use to kill them.
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Pamela J. Lein
University of California, Davis
Tel: +1 530 752 1970
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UC Davis Department of Molecular Biosciences
The Department of Molecular Biosciences serves as the academic home for all nutritional, physiological chemistry, and pharmacologic and toxicologic programs of the School of Veterinary Medicine at UC Davis. The goal of the Department of Molecular Biosciences is to study fundamental biological processes and their perturbations by mutations, nutrition, drugs and xenobiotics and the application […]