Recognizing the Health Effects of Pesticides

By MMS Committee on Environmental and Occupational Health members Brita Lundberg, MD, and Michael B. Bader, MD, with input from Committee member Caren Solomon, MD, MPH, and Philip J. Landrigan, MD, MSc

In May 2022, the MMS approved a new policy to prioritize educating the public about the health effects of pesticides. Here we summarize the latest data regarding health sequelae of pesticides and share recommendations for diagnosis, treatment, and prevention.

Pesticides defined

Produced mainly from coal, gas and oil, pesticides are synthetic chemicals that are designed to kill living organisms. They represent an under-recognized but ubiquitous environmental exposure. According to the EPA, pesticides are defined as “chemicals used to destroy or control weeds (herbicides), insect pests (insecticides), rodent pests (rodenticides), or fungi (fungicides);” they may be grouped by class, use, the type of pest they target, or place of use. The most common pesticide chemical classes include the pyrethroids (permethrin, deltamethrin), organophosphates (glyphosate, chlorpyrifos, parathion), carbamates (aldicarb, 2,4 D), organochlorines (DDT, dieldrin), and neonicotinoids (imidacloprid, clothianidin). In the US, according to EPA 2012 estimates, over 1.1 billion pounds of pesticide are applied annually.

Pesticides are important but insufficiently appreciated causes of disease, subclinical disability and premature death. Although 70-90% of the risk of developing a chronic disease is tied to environmental factors rather than genetic or dietary ones environmental causes of disease receive substantially less attention than the latter in the lay press and in medical training. Multiple pesticides have been detected in US groundwater systems and in agricultural produce, as well as in the US population at large. According to Professor Daniel Faber, Professor of Sociology and Director of the Environmental Justice Research Collaborative at Northeastern, babies are now born pre-polluted, with more than 200 chemicals — many of them pesticides — found in cord blood at birth.

A casual acquaintance: how and where people can be exposed

Most pesticide exposure is not advertised by the presence of yellow flags! Rather, it occurs via often unrecognized inhalation, skin contact (direct or via contact with contaminated clothing), or ingestion of contaminated water, soil, or food. The dose and route of exposure determine the rapidity of symptom onset, with inhalation exposure the most rapid, then ingestion, then topical.

Moreover, patients may be exposed to the chemicals present in pesticides via other routes: organophosphates and carbamates, for example, are also present in fertilizers, fire retardants, plasticizers, pet shampoos, building materials and medications. These other avenues of exposure to these chemicals can serve to magnify their health effects.

Rates of degradation in the environment of pesticides can vary from months to years: according to the EPA, pesticides can degrade quickly initially and then more slowly with the passage of time. Many degradation products are more toxic than the parent compound and may have a greater propensity to bioaccumulate; this bioaccumulation can also exert additive and compounding health effects on patients.

In addition, many pesticides are mixed with solvents that enhance cytotoxicity. One such chemical is benzene, which is associated with childhood leukemia. Another is piperonyl butoxide, a P450 inhibitor that can interfere with the degradation of medications and chemicals that are metabolized through this pathway — which includes pesticides. Thus, because of the solvents they are dissolved in, many pesticides may inhibit their own metabolism, increasing their toxicity.

Mechanism of action determines spectrum of toxicity

Many pesticides and virtually all insecticides are neurotoxic. Toxicity depends on the specific action of the pesticide as it binds to its target. There are, generally, two chief mechanisms of action: irreversible acetylcholinesterase inhibition and sodium channel disruption that results in modification of gating kinetics.

Several pesticide groups, including the neonicotinoids, organophosphates (chlorpyrifos, glyphosate) and carbamates, irreversibly bind acetylcholinesterase, leading to accumulation of acetylcholine at receptors in the CNS, peripheral nerves and neuroendocrine cells. Organophosphates and carbamates stimulate both the sympathetic and parasympathetic nervous systems by acting at both nicotinic and muscarinic acetylcholine receptors; the neonicotinoids irreversibly bind acetylcholinesterase at the nicotinic acetylcholine receptor only. Since these receptors are located on the sympathetic and parasympathetic arms of the autonomic nervous system as well as on the adrenal medulla, toxicity of neonicotinoids, like the organophosphates, is also characterized by both sympathetic and parasympathetic symptoms.

The organochlorines (DDT, dieldrin, paraquat) and the pyrethroids are sodium channel agonists; clinical symptoms that are related to sodium channel inactivation include paresthesias, seizures, cardiac symptoms like chest pain, tremors and if severe, respiratory failure. All agents lead to the repetitive firing and irreversible membrane depolarization of nerves. Moreover, many pesticides, such as paraquat, exert important effects on the human microbiota, decreasing colonization with beneficent flora fundamental to the homeostasis of the oral cavity, nasopharynx and GI tract.

Diagnosis

The symptoms of poisoning are nonspecific and often misdiagnosed. In one case of organophosphate poisoning, a patient was misdiagnosed at five different hospitals; his illness was alternately labeled acute pancreatitis; gastroenteritis; respiratory arrest; and PTSD. An astute resident eventually made the diagnosis of intentional poisoning (a political group later accepted responsibility); the other 249 patients intentionally poisoned with minute amounts of organophosphate in the patient’s cohort were not so fortunate; none was accurately diagnosed and all died.

There are few data on how frequently pesticide poisoning occurs without being diagnosed, but it is plausible that these Lancet case numbers — a correct diagnosis in only 1/250 patients — are representative. The fact that exposures are often unrecognized and that symptoms are nonspecific makes recognizing key symptoms and taking an occupational and environmental exposure history regarding important epidemiologic risk factors critical.

What history does the doctor need to collect?

There are several important occupational and recreational risk factors for pesticide exposure. Elevated risk is associated with occupational exposures to pesticides or with living or working near farming communities where pesticides are applied to crops; living downwind from golf courses; and home pesticide use. Persons whose occupation puts them at increased risk of pesticide exposure include landscapers; airline crews; veterinarians; lawn and pest providers, and greenhouse and farm workers, according to CDC.

Signs and Symptoms of acute pesticide exposure

While most physicians have memorized the classic symptoms of organophosphate poisoning for the purposes of board certification (these so-called “SLUDGE” symptoms include: salivation, lacrimation, urination, defecation, GI distress, and emesis), other more commonly used pesticides like the pyrethroids may, in addition to GI distress, lacrimation and sweating manifest different neurologic sequelae including anosmia, tremor, arrhythmias, seizures and rarely, auditory hallucinations as well as cutaneous symptoms like localized itching and erythema. Neonicotinoid intoxication, like the organophosphates, is characterized by cholinergic symptoms such as sweating, salivation, tremors, ataxia, fasciculations and, if severe, hypoxia due to diaphragmatic paralysis.

In general, the physician must maintain a high level of clinical suspicion when no history of exposure or ingestion is elicited but key signs and symptoms of exposure are present. The signs and symptoms may be protean since sodium channels for intracellular communication are abundantly expressed in both the central and peripheral nervous system and in neuroendocrine cells. Initially, the symptoms of pesticide poisoning may be subtle and more closely resemble an acute gastroenteritis, with nonspecific symptoms like lethargy, nausea, vomiting, diarrhea and abdominal cramps predominating.

Unusual features that may be helpful to differentiate pesticide toxicity from a GI illness include the unique neurologic signs that may accompany it: muscle fasciculations, tremor, muscle weakness, ataxia (and in more severe cases, seizure) and behavioral changes, as well as parasympathetic symptoms like increased salivation, sweating, miosis, urinary frequency and increased lacrimation. These symptoms, particularly in the setting of respiratory failure and mental agitation, should trigger a high suspicion of pesticide poisoning. A distinctive garlic, fruity, or petroleum breath odor, if present, may also aid in diagnosis.

Some experts have recommended categorizing pesticide exposure according to early, intermediate, and late stages, since signs and symptoms that may occur several days following pesticide exposure are also important to recognize. So-called “intermediate syndrome” consists of neurologic symptoms that typically occur 24 to 96 hours after exposure and can include prominent weakness of neck flexors, muscles of respiration, and proximal limb muscles; it can manifest as tracheal or laryngeal paralysis, decreased deep tendon reflexes, cranial nerve abnormalities, proximal muscle weakness, and, in severe cases, respiratory insufficiency.

A late complication that may be seen two or more weeks following exposure is peripheral neuropathy (notable particularly with chlorpyrifos poisoning), which may manifest as stocking-glove paresthesia that progresses to symmetric polyneuropathy with flaccid paralysis. Peripheral neuropathy may start in the lower extremities and progress to include the upper extremities. Late neurologic sequelae may also include diaphragmatic paralysis, cerebellar ataxia and hearing loss.

Other sequelae include pancreatitis, not uncommon in organophosphate poisoning, and metabolic complications like hyperglycemia and glycosuria; pesticide poisoning has been known to present as diabetic ketoacidosis.

With the exception of the organophosphates, diagnosis is primarily clinical, due to lack of diagnostic tests. Therefore pesticide exposure should be considered whenever an alternative cause of such signs or symptoms cannot be definitively established.

Diagnostic testing

Testing remains limited; the only tests are available now are the same ones first developed in the 1960s. Organophosphate poisoning is assessed by testing for red blood cell and total plasma acetylcholinesterase levels. For pesticides other than organophosphates, there are few direct biological markers that can indicate poisoning. Urine and blood tests may be able to detect pesticide residues or metabolites (like p-nitrophenol) to confirm acute exposures. But for the most part, there are no available clinical diagnostic tests for other common pesticides. While in an experimental laboratory approximately 10,000 chemicals — including 1,500 to 2,000 metabolites — can be detected in a drop of blood in 20 minutes using high-resolution mass spectrometry, that technology is not available in the clinic or emergency room.

Other laboratory tests in addition to cholinesterase activity that may be helpful include increased serum amylase, urinary p-nitrophenol, serum phosphorus, and occasionally serum or urine glucose.

Treatment

Although diagnostic testing is limited, rapid diagnosis and treatment (within minutes) of pesticide poisoning is essential to prevent hypoxic brain damage and can improve long term prognosis.

If a source of poisoning exposure has been identified, that source (clothing, food, etc) should be safely destroyed/mitigated and never re-used. Recurrent poisoning has been described due to repeated exposure; subsequent episodes of poisoning tend to be more severe and, if due to organophosphate poisoning, more difficult to reverse.

To treat organophosphate, neonicotinoid and carbamate poisoning – and even if such exposures are on the differential but not confirmed – a trial of atropine may be employed. Atropine is also used to treat carbamate overdose from common medications like donepezil. If symptoms resolve after atropine, this increases the likelihood of an acetylcholinesterase inhibitor poisoning. The use of pralidoxime is no longer uniformly recommended due to lack of benefit in clinical trials and increased incidence of intermediate syndrome.

There is no specific treatment for any other pesticide exposure (DDT, 2,4 D or the pyrethroids) other than supportive care. Dermal decontamination, including removing clothing and washing the skin with soap and water should be carried out to protect the patient and health care workers; it is recommended that this be performed in the field. Patients may be observed in the ER, and if symptoms of central nervous system [CNS], heart, lung, liver failure occur they should be admitted.

With supportive care, patients may recover normal neurologic function within two to three weeks. There may, however, be long-term complications.

Chronic health sequelae of pesticide exposure

Unfortunately, those who survive pesticide poisoning, even if neurologic function returns to normal, may develop “late” sequelae, two or more weeks following exposure. These include neuropsychiatric deficits like confusion, memory impairment, lethargy, psychosis, irritability and Parkinson-like extrapyramidal symptoms, including dystonia, resting tremor, bradykinesia, mask-like facies, chorea, and cog-wheel rigidity.

In addition, there are well-described health effects linked to chronic and low-level pesticide exposure that are well described. Epidemiologic studies indicate that Parkinson’s disease is strongly associated with chronic exposure to chlorpyrifos and paraquat. Indeed, Parkinson’s disease in the US has risen exponentially since the 1970s — mirroring the exponential increase in the use of those pesticides.

Many pesticides act as endocrine disruptors and are associated with diabetes mellitus and reproductive disorders, including decreased sperm count and mammary enlargement in men. According to CDC, pesticides are also associated with increased miscarriage risk and birth defects. Many studies show associations between pesticide exposure and cancer: glyphosate exposure has been shown to be associated with a 30-41% increase in non-Hodgkin’s lymphoma (meta-RR = 1.41, 95% CI, confidence interval: 1.13–1.75); and pesticide exposure, especially prenatally, has been shown to increase the risk for leukemia in children (OR: 2.83). Cardiotoxicity has also been well described, including conduction defects, hypertension, hypotension, arrhythmias, heart attack and increased risk of cardiovascular mortality due to pesticide exposure in the US general adult population; all-cause mortality is also increased. Pesticide exposure among farm workers is associated with a higher incidence of sleep disruption. Recent studies have found that DDT and the organochlorines appear to be associated with Alzheimer’s disease (OR 4.18; 95% CI, 2.54-5.82; P < .001).

Pesticides represent a greater health threat to children because children have greater exposure proportionate to their body mass. In addition, children can be in closer contact with their environment and frequent hand-to-mouth activities.

Children’s diminished ability to detoxify many chemicals leaves them at a heightened biological vulnerability. They also have more years of future life in which to experience the long -term negative health outcomes. Even at levels below the threshold for systemic toxicity, pesticide exposure is associated with neurodevelopmental disorders like learning or developmental disabilities; autism (aOR: 1.6) and lower IQ. Low IQ is also closely associated with exposure to chlorpyrifos and organochlorine pesticide exposure: according to NHANES, between 1999 and 2004 organophosphate exposure led to loss of 16.9 million IQ points.

Preventing pesticide exposure

Patients should know not to store pesticides in the refrigerator or in containers used for common beverages. Using gloves, mask and boots during pesticide application may protect users from the health effects of some pesticides but not all. It is prudent to avoid using pesticides in unventilated or poorly ventilated spaces and to keep pets and children away following application. Patients should be aware that pesticide residues may linger for several months; in some cases (chlorpyrifos), the breakdown products are far more toxic than the original pesticide, and do not fully reach their toxic potential for several years. Moreover, pesticides can be taken home on workers’ shoes and clothing: CDC offers the following guidance on how to reduce take-home exposure.

An Equity issue: Exposure is highest in low-income communities

Pesticide exposure occurs at more than just the point of application. This is an important equity issue since many pesticides are heavily used in urban and low-income communities and exert a disproportionate impact on populations already exposed to more air, water and soil pollution. Moreover, pesticides are more likely to be manufactured in these communities and to be placed in landfills or incinerated there. In California, pesticide use is closely associated with the zip codes with the highest percentage of people of color. Fifteen or more pesticide metabolites are found in more than 50% of the US population and are more commonly found among nonwhites.

A saturated system

Modeling shows that the planet has now exceeded its ability to absorb the ever escalating number of chemicals being introduced into it. Although there may be a public perception that chemicals on the market are “safe” because they have been approved, this belief is not supported by data: less than 1% of chemicals approved for use in the US, including pesticides, have ever been tested for safety, according to the EPA.

In sum

The concept of a safe pesticide is somewhat of an oxymoron because pesticides by their essence are designed to kill and cause damage to living organisms; the problem is that their intended target is never their only target. Humans and other non-target species suffer potentially harmful effects all too often, with significant consequences for the health of communities and society at large.

Doctors represent an important resource for patients regarding knowledge about both treatment and prevention– how to avoid pesticide exposure in the first place and when to seek medical attention for potential exposure. The most successful form of prevention is to avoid using and manufacturing pesticides in the first place; and to ban the most toxic pesticides, as many other countries, including the European Union, China and Brazil, have done. Since pesticide exposure disproportionately affects minority communities and communities of color, this is an important health equity issue.

We as physicians can work to be better aware of the symptoms of acute and chronic pesticide toxicity, to educate our patients about the dangers of pesticide exposure for them and their children and to suspect pesticide exposure and test patients for potential pesticide toxicity in compatible clinical scenarios.

The scope of the problem is substantial, with spraying and use particularly concerning when it occurs near schools, since children have unique vulnerabilities. Implementing science-based control strategies based on effective regulation is proven to be protective of health and cost-effective. A first step towards a solution is recognizing the extent of the problem.

Additional References

The Massachusetts Attorney General sued the US Environmental Protection Agency to ban a toxic pesticide (chlorpyrifos) because epidemiological studies showing the pesticide causes neurological damage to prenatal/infants/children.
https://www.mass.gov/news/ag-healey-sues-epa-for-failing-to-protect-children-and-the-public-from-known-toxic-pesticide

The Harvard Environmental Law & Policy Clinic’s 2/5/2021 letter and previous two amicus briefs to the 9th Circuit regarding the misguided approval of chlorpyrifos, a neurologically damaging health threat to prenatal/infants/children and older adults.
https://clinics.law.harvard.edu/environment/2021/02/05/clinic-submits-comments-on-proposed-interim-registration-review-decision-for-chlorpyrifos-and-revised-draft-human-health-risk-assessment/