to chlorpyrifos were studied over periods of 1 to 4.5 years. They were found to have a heightened immune responses to common allergens and increased antibiotic sensitivities, elevated CD26 cells, and a higher rate of autoimmunity, compared with control groups. Autoantibodies were directed toward smooth muscle, parietal cell, brush border, thyroid gland, myelin, and the subjects also had more anti-nuclear antibodies. Chlorpyrifos methyl The Dow Chemical Company also developed Chlorpyrifos methyl in 1966, which had a lower acute toxicity (WHO class III), but this appears to be no longer in commercial use. The molecule is similar to Chlorpyrifos ethyl, but with a O,O dimethyl chain. Proposed applications included vector control. Mechanisms of toxicity Acetylcholine neurotransmission Primarily, chlorpyrifos and other organophosphate pesticides interfere with signaling from the neurotransmitter acetylcholine. One chlorpyrifos metabolite, chlorpyrifos-oxon, binds permanently to the enzyme acetylcholinesterase, preventing this enzyme from deactivating acetylcholine in the synapse. By irreversibly inhibiting acetylcholinesterase, chlorpyrifos leads to a build-up of acetylcholine between neurons and a stronger, longer-lasting signal to the next neuron. Only when new molecules of acetylcholinesterase have been synthesized can normal function return. Acute symptoms of chlorpyrifos poisoning only occur when more than 70% of acetylcholinesterase molecules are inhibited. This mechanism is well established for acute chlorpyrifos poisoning and also some lower-dose health impacts. It is also the primary insecticidal mechanism. Non-cholinesterase mechanisms Chlorpyrifos may affect other neurotransmitters, enzymes and cell signaling pathways, potentially at doses below those that substantially inhibit acetylcholinesterase. The extent of and mechanisms for these effects remain to be fully characterized. Laboratory experiments in rats and cell cultures suggest that exposure to low doses of chlorpyrifos may alter serotonin signaling and increase rat symptoms of depression; change the expression or activity of several serine hydrolase enzymes, including neuropathy target esterase and several endocannabinoid enzymes; affect components of the cyclic AMP system; and influence other chemical pathways. Paraoxonase activity The enzyme paraoxonase 1 (PON1) detoxifies chlorpyrifos oxon, the more toxic metabolite of chlorpyrifos, via hydrolysis. In laboratory animals, additional PON1 protects against chlorpyrifos toxicity while individuals that do not produce PON1 are particularly susceptible. In humans, studies about the effect of PON1 activity on the toxicity of chlorpyrifos and other organophosphates are mixed, with modest yet inconclusive evidence that higher levels of PON1 activity may protect against chlorpyrifos exposure in adults; PON1 activity may be most likely to offer protection from low-level chronic doses. Human populations have genetic