Chlorpyrifos is moderately toxic to humans, and exposure has been linked to neurological effects, persistent developmental disorders, and autoimmune disorders. Exposure during pregnancy retards the mental development of children, and most use in homes has been banned since 2001 in the U.S. In agriculture, it remains "one of the most widely used organophosphate insecticides", according to the United States Environmental Protection Agency (EPA).
Chlorpyrifos is produced via a multistep synthesis from 3-methylpyridine, eventually reacting 3,5,6-trichloro-2-pyridinol with diethylthiophosphoryl chloride.
Chlorpyrifos is used around the world to control pest insects in agricultural, residential, and commercial settings, although its use in certain residential applications has been restricted in several countries. According to the Dow Chemical Company, chlorpyrifos is registered for use in nearly 100 countries and is applied to approximately 8.5 million crop acres each year. The crops with the most intense chlorpyrifos use are cotton, corn, almonds, and fruit trees including oranges, bananas and apples.
The U.S. EPA estimated that between 1987 and 1998 about 21 million pounds of chlorpyrifos were used in the United States each year. In 2007, chlorpyrifos was the most commonly used organophosphate pesticide in the United States, with an estimated 8 to 11 million pounds applied.
Chlorpyrifos is normally supplied as a 23.5% or 50% liquid concentrate. The recommended concentration for direct-spray pin point application is 0.5% and for wide area application a 0.03 – 0.12% mix is recommended (US).
History of regulation
First registered in 1965 and marketed by Dow Chemical under the tradenames Dursban, Lorsban and Renoban, chlorpyrifos was a well known home and garden insecticide, and at one time it was one of the most widely used household pesticides in the US.
In the U.S. in 1995, Dow was fined US$732,000 for not sending the U.S. EPA reports it had received on 249 chlorpyrifos poisoning incidents.
Facing impending regulatory action by the U.S. EPA, Dow agreed to withdraw registration of chlorpyrifos for almost all use (except child-proof containerized insect baits) in homes and other places where children could be exposed, and severely restricted its use on crops. These changes took effect on Dec 31, 2001. It is still widely used in agriculture, and Dow continues to market Dursban for home use in developing countries. Dow's sales literature claimed Dursban has "an established record of safety regarding humans and pets."
In 2003, Dow agreed to pay US$2 million – the largest penalty ever in a pesticide case – to the state of New York, in response to a lawsuit filed by the Attorney General to end Dow's illegal advertising of Dursban as "safe".
On July 31, 2007, a coalition of farmworker and advocacy groups filed a lawsuit against the EPA seeking to end agricultural use of chlorpyrifos. The suit claims that the continued use of chlorpyrifos poses an unnecessary risk to farmworkers and their families. The suit was still pending as of August 2012.
In August 2007, Dow's Indian offices were raided by Indian authorities for allegedly bribing officials to allow chlorpyrifos to be sold in the country.
In 2008 in the US, the National Marine Fisheries Service (NMFS) imposed 1000 ft buffer zones around salmon habitat to protect endangered salmon and steelhead species. Aerial applications of chlorpyrifos will be prohibited within these zones.
Toxicity and safety
Chlorpyrifos exposure may lead to acute toxicity at higher doses, persistent health effects following acute poisoning or from long-term exposure to low doses, and developmental effects in fetuses and children even at very small doses.
Persistent health effects
Effects from exposure during pregnancy, infancy, and childhood
Epidemiological and experimental animal studies suggest that infants and children are more susceptible than adults to effects from low exposure to chlorpyrifos. This susceptibility derives in part because the very young have a decreased capacity to detoxify chlorpyrifos and its metabolites and in part from disruption, observed in animal experiments, in normal developmental processes in the nervous system.
Human studies: In the growing number of epidemiological studies, exposure to chlorpyrifos during pregnancy or childhood has been potentially linked with lower birth weight and neurological changes such as slower motor development and attention problems. Exposure to organophosphate pesticides in general has been increasingly associated with changes in children's cognitive, behavioral, and motor performance.
Animal experiments: In experiments with rats, short-term low-dose exposure to chlorpyrifos early in life has resulted in lasting neurological changes, with larger effects on emotional processing and cognition than on motor skills. Such rats can also exhibit behaviors consistent with depression and reduced anxiety. In rats, low-level exposure during development to chlorpyrifos has its greatest neurotoxic effects during a window in which sex differences in the brain develops, and exposure leads to reductions or reversals of normal rat male-female differences.
In laboratory rats, exposure to low levels of chlorpyrifos early in life or as adults also appears to affect metabolism and body weight. These rats show increased body weight as well as changes in liver function and chemical indicators similar to prediabetes, likely associated with changes to the cyclic AMP system.
Effects from exposure during adulthood
Adults may develop lingering health effects following acute exposure or repeated low-level exposure to chlorpyrifos. Among agricultural growers, use of chlorpyrifos has been associated with slightly increased risk of wheeze, a whistling sound while breathing due to obstruction in the airways.
Among 50 farm pesticides studied, chlorpyrifos was associated with higher risks of lung cancer among frequent pesticide applicators than among infrequent or non-users. Pesticide applicators as a whole were found to have a 50% lower cancer risk than the general public, likely due to their nearly 50% lower smoking rate. However, chlorpyrifos applicators had a 15% lower cancer risk than the general public, which the study suggests indicates a likely link between chlorpyrifos application and lung cancer.
A 2011 study on the neurotoxic effects of chlorpyrifos showed that chlorpyrifos and its more toxic metabolite, chlorpyrifos oxon, altered firing rates in the locus coeruleus. These results indicate that the pesticide may be involved in Gulf War Syndrome and other neurodegenerative disorders.
Acute health effects
For acute effects, the World Health Organization classifies chlorpyrifos as Class II: moderately toxic. The oral LD50 for chlorpyrifos in experimental animals is 32 to 1000 mg/kg. The dermal LD50 in rats is greater than 2000 mg/kg and 1000 to 2000 mg/kg in rabbits. The 4-hour inhalation LC50 for chlorpyrifos in rats is greater than 200 mg/m3.
Symptoms of acute exposure
Acute poisoning with chlorpyrifos results mainly from interference with the acetylcholineneurotransmission pathway (see Mechanisms of Toxicity), leading to a range of neuromuscular symptoms. Relatively mild poisoning can result in watering of the eyes, increased saliva and sweating, nausea, and headache. More intermediate exposure may lead to muscle spasms or weakness, vomiting or diarrhea, and impaired vision. Symptoms of severe poisoning include seizures, unconsciousness, paralysis, and suffocation from inability of the lungs to operate.
Children may exhibit different symptoms than adults. Children are more likely to experience muscle weakness rather than twitching; excessive saliva rather than sweat or tears; seizures; and sleepiness or coma.
Frequency of acute exposure
Acute poisoning with chlorpyrifos is probably most common in agricultural areas in Asia, where many small farmers have access to pesticides. Poisoning may be due to occupational or accidental exposure or intentional self-harm. Precise numbers of chlorpyrifos poisonings globally are not available. Pesticides are estimated to be used in over 200,000 deaths by suicide annually, organophosphate pesticides are thought to contribute two-thirds of ingested pesticides in rural Asia, and chlorpyrifos is among the pesticides commonly used for self-harm in some areas.
In the United States, the number of incidents of chlorpyrifos exposure reported to the U.S. National Pesticide Information Center reduced sharply from over 200 in the year 2000 to less than 50 in 2003 following the U.S. ban on chlorpyrifos for residential use.
Poisoning by chlorpyrifos and other organophosphate pesticides has been treated with atropine and simultaneously with oximes such as pralidoxime. Atropine blocks acetylcholine from binding with muscarinic receptors, which clearly reduces the impact of organophosphate poisoning. However, atropine does not affect acetylcholine at nicotinic receptors and thus is a partial treatment. Pralidoxime is intended to reactivate acetylcholinesterase, but the benefit of oxime treatment is questioned. A small randomized controlled trial supported the use of higher doses of pralidoxime rather than lower doses. A subsequent small randomized, controlled, double-blind trial treating patients who self-poisoned with organophosphates found no benefit of treatment with pralidoxime, including specifically in patients poisoned by chlorpyrifos.
In news coverage
Chlorpyrifos poisoning has been described by New Zealand scientists as the likely cause of death of several tourists in Chiang Mai, Thailand who developed myocarditis in 2011. Thai investigators have come to no conclusion as to what caused the deaths, but maintain that chlorpyrifos was not responsible and that the deaths were not linked.
Mechanisms of toxicity
Primarily, chlorpyrifos and other organophosphatepesticides interfere with signaling from the neurotransmitteracetylcholine. One metabolite of chlorpyrifos, chlorpyrifos-oxon, binds permanently to the enzymeacetylcholinesterase, 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.
Chlorpyrifos may also 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.
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 variation in the sequence of PON1 and its promoter region that may influence the effectiveness of PON1 at detoxifying chlorpyrifos oxon and the amount of PON1 available to do so. Some evidence indicates that children born to women with low PON1 may be particularly susceptible to chlorpyrifos exposure. Further, infants produce low levels of PON1 until six months to several years after birth, likely increasing the risk from chlorpyrifos exposure early in life.
Several studies have examined the effects of combined exposure to chlorpyrifos and other chemical agents, and these combined exposures can result in different effects during development. Female rats exposed first to dexamethasone, a treatment for premature labor, for three days in utero and then to low levels of chlorpyrifos for four days after birth experienced additional damage to the acetylcholine system upstream of the synapse that was not observed with either exposure alone. In both male and female rats, combined exposures to dexamethasone and chlorpyrifos decreased serotonin turnover in the synapse, for female rats with a greater-than-additive result. Rats that were co-exposed to dexamethasone and chlorpyrifos also exhibited complex behavioral differences from exposure to either chemical alone, including lessening or reversing normal sex differences in behavior. In the lab, in rats and neural cells co-exposed to both nicotine and chlorpyrifos, nicotine appears to protect against acetylcholinesterase inhibition by chlorpyrifos and reduce its effects on neurodevelopment. In at least one study, nicotine appeared to enhance chlorpyrifos detoxification.
In 2011, EPA estimated that, in the general U.S. population, people consume 0.009 micrograms of chlorpyrifos per kilogram of their body weight per day directly from food residue. Children are estimated to consume a greater quantity of chlorpyrifos per unit of body weight from food residue, with toddlers the highest at 0.025 micrograms of chlorpyrifos per kilogram of their body weight per day. People may also ingest chlorprifos from drinking water or from residue in food handling establishments. The EPA’s maximum acceptable daily dose is 0.3 micrograms/kg/day.
Before chlorpyrifos was restricted from residential use in the U.S., data from 1999-2000 in the national NHANES study detected the metabolite TCPy in 91% of human urine samples tested. In samples collected between 2007 and 2009 from families living in Northern California, TCPy was found in in 98.7% of floor wipes tested and in 65% of urine samples tested. For both children and adults, the average concentrations of TCPy in urine were lower in the later study. A 2008 study found dramatic drops in the urinary levels of chlorpyrifos metabolites when children in the general population switched from conventional to organic diets.
Certain populations with higher likely exposure to chlorpyrifos, such as people who apply pesticides, work on farms, or live in agricultural communities, have been measured in the United States to excrete levels of the metabolite TCPy in their urine that are 5 to 10 times greater than levels in the general population.
Air monitoring studies conducted by the California Air Resources Board (CARB) have documented chlorpyrifos in the air of California communities. Analyses of the CARB data indicate that children living in areas of high chlorpyrifos use are often exposed to levels of the insecticide that exceed levels considered acceptable by the EPA. Advocacy groups monitored air samples in Washington and Lindsay, CA, in 2006 with comparable results. Grower and pesticide industry groups have argued that the air levels documented in these studies are not high enough to cause significant exposure or adverse effects, but a follow-up biomonitoring study in Lindsay, CA, has shown that people there have higher than normal chlorpyrifos levels in their bodies.
Effects on wildlife
Among freshwater aquatic organisms, crustaceans and insects appear to be more sensitive to acute exposure than are fish or the aquatic life stages of amphibians, although little data may exist for amphibians. Aquatic insects and animals appear to absorb chlorpyrifos directly from water rather than ingesting it with their diet or through contact with sediment.
When concentrated chlorpyrifos has been released into various rivers, it has killed insects, shrimp, and/or fish. In Britain, the rivers Roding (1985), Ouse (2001), Wey (2002 & 2003), and Kennet (2013) all experienced insect, shrimp, and/or fish kills as a result of small releases of concentrated chlorpyrifos. The July 2013 release along the River Kennet poisoned insect life and shrimp along 15 km of the river, potentially from several teaspoonsful of concentrated chlorpyrifos washed down a drain.
Acute exposure to chlorpyrifos can be toxic to bees, with an oral LD50 of 360 ng/bee and a contact LD50 of 70 ng/bee. Guidelines for the State of Washington indicate that chlorpyrifos products should not be applied to flowering plants such as fruit trees within 4-6 days of blooming to prevent bees from directly contacting the residue.
Risk assessments have primarily considered acute exposure, but more recently researchers have begun to investigate the effects on bees of chronic exposure to low levels of chlorpyrifos through residue in pollen and components of bee hives. A review of studies in the U.S., several European countries, Brazil, and India found chlorpyrifos in nearly 15% of hive pollen samples and just over 20% of honey samples. Because of its combined high toxicity to bees and prevalence in pollen and honey, bees are considered to have higher risk from chlorpyrifos exposure via their diet than from many other pesticides.
When exposed in the laboratory to chlorpyrifos at levels roughly estimated from measurements in hives, bee larvae experienced 60% mortality over 6 days, compared with 15% mortality in controls. Adult bees exposed to sub-lethal effects of chlorpyrifos (0.46 ng/bee) exhibited altered behaviors: less walking; more grooming, particularly of the head; more difficulty righting themselves; and unusual abdominal spasms. Chlorpyrifos oxon appears to particularly inhibit acetylcholinesterase in bee gut tissue as opposed to head tissue. Other organophosphate pesticides have impaired bee learning and memory of smells in the laboratory.
^Cao, Jun-li , Varnell, Andrew, and Cooper, Donald.(2011) Gulf War Syndrome: A role for organophosphate induced plasticity of locus coeruleus neurons. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2011.6057.1> (2011)
^Eaton, David L.; Daroff, Robert B.; Autrup, Herman; Bridges, James; Buffler, Patricia; Costa, Lucio G.; Coyle, Joseph; McKhann, Guy; Mobley, William C.; Nadel, Lynn; Neubert, Diether; Schulte-Hermann, Rolf; Spencer, Peter S. (2008-01). "Review of the toxicology of chlorpyrifos with an emphasis on human exposure and neurodevelopment.". Critical Reviews in Toxicology. 38 Suppl 2: 1–125. doi:10.1080/10408440802272158. ISSN1547-6898. PMID18726789.Check date values in: |date= (help)