Background

Paraquat, also known as methyl viologen or N,N′-dimethyl-4,4′-bipyridinium dichloride, is a bipyridyl quaternary ammonium compound first described in 1882, and later noted to be an oxidation-reduction indicator in 1933.¹ The compound’s utility as an herbicide was first observed in 1955, and production for market use was implemented in 1962 in the United Kingdom by Imperial Chemical Industries (ICI), now Syngenta.¹ The leading paraquat product, Gramoxone, is sold by Syngenta, with other manufacturers producing paraquat under trade names including Crisquat, Dextrone X, and Esgram.²

Currently banned in over 50 countries, including the EU, China, and Brazil, more than 10 million pounds of paraquat was used in the United States annually as of 2017, though use was restricted to that applied by licensed applicators.^2,3 Additional restrictions on use in the United States were proposed by the U.S. Environmental Protection Agency (EPA) in late 2020, which included the prohibition of aerial application except for use in cotton desiccation, prohibition of handheld and backpack spray application, introduction of a residential area drift buffer for use in cotton desiccation, a minimum 48 hour restricted entry interval (REI) for all applications and seven-day REI for cotton desiccation uses, and mandatory addition of spray drift management language to product labels.⁴ The EPA did not make any reference to a complete paraquat ban in its updated guidance and noted that there were “presently no direct alternatives” to the product.⁴

The continued use of paraquat is attributed to a number of factors, including: 1) its non-selective nature, which allows broad-spectrum weed control at low cost; 2) its inactivation and immobilization at the soil surface, which leaves roots intact to avoid erosion, allows rapid planting of treated areas, limits the effects of overspray, and prevents it from contributing to cumulative ecosystem effects; 3) its spray diameter being too large (>100 µm) for penetration of human alveoli, which prevents substantial inhalation effects; and 4) its hydrophilic nature, which limits absorption through intact skin.^1,2

Practically, paraquat is a fast-acting contact herbicide that kills a diversity of grasses and dicot weeds.¹ It is also used as an agricultural dessicant.² Herbicidal activity occurs via reactive oxygen species interference with plant intracellular electron transfer systems, causing destruction of plant organelles and cell death.² However, when bound to soils, particularly clay minerals such as bentonite, paraquat is unavailable for herbicidal or ecotoxicological action, microbial degradation, and photodecomposition, making it nearly completely biologically inactive in such circumstances and yielding an environmental half-life of approximately 6.6 years.¹ Commercial paraquat formulations generally contain 10% to 30% paraquat as an aqueous solution, while it is recommended that it be diluted to 0.05% to 0.2% paraquat when used in spray applications.¹

Along with other widely used herbicides, paraquat is known to have very high acute toxicity, though potential chronic effects in humans, if they occur at all, are poorly described. Notably, paraquat has been implicated in acute poisoning cases, both accidental and intentional (i.e. suicides), across the globe.⁵ Similar to plants, acute toxicity in humans involves production of reactive oxygen species (ROS) that deplete NADPH.² Once absorbed, paraquat accumulates most readily in the lungs and kidneys, with adverse effects noted in other target organs including the eyes, skin, heart, liver, gastrointestinal tract, and respiratory system.² Paraquat is poorly metabolized in humans and excreted in the feces and urine, with an elimination half-life of approximately 84 hours.⁵ Various studies found no production of metabolites associated with paraquat.¹

Paraquat is poorly absorbed via the gastrointestinal system, with 76 to 90% and 11 to 20% of oral doses found in the feces and urine, respectively.¹ Acute, low-level human ingestions of 20 to 30 mg paraquat/kg body weight may be survivable if treatment is provided rapidly; however, higher doses between 30 and 50 mg paraquat/kg body weight have been shown to elicit vomiting, diarrhea, abdominal pain, and mouth and throat ulceration within hours. Similarly, exposure to 30 to 50 mg paraquat/kg body weight doses elicit renal failure, hepatic impairment, and hypotension within one to four days of exposure, while pulmonary fibrosis and impaired lung function become apparent one to two weeks post-exposure and death often occurs due to pulmonary failure two to three weeks post exposure. Doses of 40 to >50 mg paraquat/kg body weight generally elicit cardiogenic shock and multi-organ failure, leading to death one to four days post exposure.⁵ Prognosis following acute ingestion of paraquat in humans can be derived via plasma paraquat concentrations, and cases with concentrations below 2.0, 0.6, 0.3, 0.16, and 0.1 mg/L paraquat at 4, 6, 10, 16, and 24 hours post exposure generally survive.¹ A semiquantitative urine test for paraquat is predictive of prognosis when urine concentrations exceed 1 µg/ml.¹ Specifically, the intensity of blue color seen on addition of 10 ml of urine to 2 ml of a 1% sodium dithionite in 1 N sodium hydroxide solution is predictive of outcome, with dark blue colors predictive of fatal urine paraquat concentrations of > 10 µg/ml, and pale blue colors predictive of survivable urine paraquat concentrations of < 1 µg/ml.¹ In humans, the estimated lethal dose of a 40% paraquat solution is 14 ml.⁷ While poorly absorbed via intact skin, direct contact with paraquat solutions may yield burns and dermatitis.²

Acute oral LD₅₀ values of 189 and 125 mg paraquat/kg body weight have been derived for male and female rats, respectively.⁶ Oral LD₅₀ values of 25, 30, 35, 120, 262 mg paraquat/kg body weight have been derived for dogs, guinea pigs, cats, mice, and chickens, respectively.⁷ Acute oral LD_Lo (lowest published lethal dose) values of 171 to 1690 mg paraquat/kg body weight have been observed in humans based on respiratory, urinary, and gastrointestinal effects.⁷ In solution, LD_Lo values of 0.071 to 1.49 ml paraquat/kg body weight have been described in humans.⁷ Further, dermal LD₅₀ values of 80 to 90 and 236 mg paraquat/kg body weight have been found in rats and rabbits, respectively, while intraperitoneal LD₅₀ values are 30, 16 to 39, and 25 mg paraquat/kg body weight in mice, rats, and rabbits, respectively.¹

Paraquat is not demonstrated to be carcinogenic or mutagenic across numerous animal and human studies.⁶ However, it is classified as a category C, or possible human carcinogen, by the EPA due to paraquat induced production of squamous cell carcinoma in the head region of Fischer 344 rats in a study with an NOAEL of ≥ 10.9 mg paraquat/kg body weight per day.⁸ Cancerous skin lesions were also noted in workers of paraquat manufacturing facilities, though no carcinogenic effects have been observed in the respiratory system of rats.² Paraquat has not been analyzed for carcinogenicity by IARC. Few non-carcinogenic chronic effects have been described following paraquat exposure. Various studies of cohorts occupationally exposed to paraquat on a chronic basis found no effects on respiratory health.^9,10 However, some evidence suggest that, while chronic paraquat exposure may not influence rates of asthma, COPD, and allergic rhinitis, such exposure may marginally impair forced vital capacity and forced expiratory volume.¹¹ Recently, though, some epidemiological and animal studies have noted a potential association between paraquat exposure and Parkinson’s disease.^2,12,13 Many such studies are founded on the structural similarity between paraquat and MPTP, a metabolite of which (MPP+) is used to produce Parkinson’s like symptoms in animal studies.² While few, studies finding a positive association between paraquat exposure and population-level rates of Parkinson’s disease have gained much attention.

One proposed mechanism by which paraquat induces neurodegeneration centers on N-methyl-D-aspartate (NDMA) receptor activation induced excitotoxicity.¹⁶ Such excitotoxicity later results in glutamate-induced, RNS-mediated cytotoxicity, effecting the dopaminergic terminals and resulting in long-lasting dopamine overflow and a reduction in dopamine synthesis.¹⁶ An additional proposed mechanism involves paraquat induced decrease in mitochondrial complex I activity, which is associated with onset and rapid progression of neurodegenerative diseases including Parkinson’s disease.¹⁶ Further, a final mechanism proposed for paraquat’s effects on Parkinson’s etiology relates to induction of alpha-synuclean up-regulation and aggregation, which contribute to the formation of protein clumps in the brain termed Lewy bodies.¹⁶ The mechanistic origin of paraquat-induced Parkinson’s, if such a relationship exists at all, likely involves some combination of the aforementioned pathways, which cumulatively may lead to nigrostriatal damage and an impaired dopaminergic pathway between the substantia nigra pars compacta in the midbrain and dorsal striatum in the forebrain.¹⁶ Importantly, paraquat is demonstrated to cross the blood brain barrier (BBB).¹⁶ This allows both penetration of and accumulation in the brain, and potential origination of the aforementioned disease pathways. Maximal brain paraquat levels occur at approximately 24 hours post exposure.¹⁶ Some evidence indicates that developmental exposure to paraquat may disrupt formation of the BBB, resulting in enhanced neurological vulnerability to toxic insults, including paraquat, later in life.¹⁷ 

While the above mechanisms are well-founded, arguments that paraquat exposures lead to Parkinson’s disease have numerous flaws. First, many studies examining paraquat exposure do not examine the effects of paraquat independently, and instead analyze health outcomes on the basis of exposure to paraquat in concert with other herbicides and pesticides, often maneb, rotenone, and MPTP.^{2,12,13,14,15} Such analyses do not provide an accurate representation of paraquat’s independent effects, and numerous epidemiological studies have found that, when paraquat exposures are examined in isolation, no association between exposure and Parkinson’s etiology exists.^12,13 Second, Parkinson’s disease is diagnosed on the basis of symptomology, with no biomarkers indicative of disease available and exact date of disease onset subject to conjecture.¹² Given this, studies rely on prevalent, rather than incident, cases of Parkinson’s disease, and incident cases are difficult to recruit given varying treatment scenarios, no centralized disease registry, and low pesticide exposures in the general population, resulting in positive-selection bias in most studies.¹² Third, many, if not most, studies finding positive associations between paraquat exposure and Parkinson’s disease rely on occupational exposure histories provided by identified cases.^12,13 Such histories are notoriously imprecise and subject to nondifferential and differential misclassification due to inabilities to recall past exposures or product attributes.¹² All told, these difficulties make any observed link between paraquat exposure and Parkinson’s disease tenuous at best, though such a link is most likely absent altogether. Questions of potential disease latency have not been widely addressed, perhaps due to the aforementioned variability in symptomatic expression.

In occupational environments, paraquat is most likely encountered by workers applying paraquat in agricultural scenarios either directly (such as with a backpack or handheld applicator) or indirectly (such as via mechanized equipment or airplanes/crop dusting). Though recent changes in EPA regulations on paraquat use will preclude some of these exposure pathways, they remain relevant to individuals with historic exposures, including those alleging potential paraquat-induced Parkinson’s disease.⁴ Given use restrictions in the United States, workers handling paraquat are primarily certified pesticide applicators, though other workers may assist with transport and mixing of paraquat formulations. The ACGIH threshold limit value (TLV) for occupational exposure to paraquat salt/dust is 0.1 mg/m³ and 0.5 mg/m³ for respirable and non-respirable conditions, respectively.² Similarly, the OSHA permissible exposure limit (PEL) and NIOSH recommended exposure limit (REL) are both 0.1 mg/m³ for respirable paraquat, while the NIOSH immediately dangerous to life or health (IDLH) value for paraquat is 1 mg/m³.² The EPA publishes a reference dose for oral exposure (RFD) of 4.5 x 10^-3 mg paraquat/kg body weight per day.⁸ Non-occupational exposures to paraquat may arise from overspray during agricultural application, though such exposures would be orders of magnitude lower than those experienced by applicators. As consumer uses are restricted, and since paraquat becomes highly immobile shortly after application, other routes of non-occupational exposure are of minimal significance in the United States.

Though paraquat is a well-known, widely used herbicide, its health effects, specifically as they pertain to Parkinson’s disease, more work is needed to understand the plausibility of this association.  Further animal and epidemiological studies that examine paraquat specifically, rather than in concert with other compounds, are needed to fully elucidate the potential effects of chronic exposures to this economically important herbicide.

Technical Approach

Paustenbach and Associates recently attended Harris Martin’s Webinar Series on paraquat herbicide litigation on May 10, 2021. This meeting provided a general background on paraquat and its uses, outlined scientific literature finding a potential association between paraquat exposure and Parkinson’s disease, and reviewed the current global regulations for the substance. In addition, the meeting presented potential legal approaches for supporting plaintiff claims regarding paraquat exposures and potential health effects.

Our View

Specific to a risk assessment of paraquat, analyses should be based on factors including the timing, frequency, and duration of an alleged paraquat exposure; the route of alleged exposure (e.g., respiratory, dermal, oral ingestion, environmental); potential for co-exposure to other herbicides and agricultural chemicals; and the latency between exposure period and alleged onset of disease, particularly Parkinson’s disease.

With individual exposure and disease parameters identified, a risk assessment approach should be considered. As in many cases which go to court, dose-reconstruction to examine the potential magnitude of paraquat exposure can be quite informative.  The estimated doses are then compared to those that are believed associated with adverse health effects.  Additionally, exposures should be compared relative to published occupational exposure guidelines, EPA guidance, international guidelines, and other risk criteria for paraquat.  Comparing the estimated doses for the plaintiff to doses alleged to increase the risk of Parkinson’s (if there is such a hazard) is, perhaps, among several major challenges in this litigation.

References

1. Dinis-Oliveira, RJ, Duarte, JA, Sanchez-Navarro, A, et al. 2008. Paraquat Poisonings: Mechanisms of Lung Toxicity, Clinical Features, and Treatment. Critical Review in Toxicology, 38:13-71.
2. Tsai, WT. 2013. A review on environmental exposure and health risks of herbicide paraquat. Toxicological and Environmental Chemistry, 95(2):197-206.
3. USGS. 2017. Pesticide National Synthesis Project. Estimated Annual Agricultural Pesticide Use.
4. EPA. EPA Proposes New Safety Measures for Paraquat. Press Release, October 22, 2020.
5. Kim, JW, and Kim, DS. 2019. Paraquat: toxicology and impacts of its ban on human health and agriculture. Weed Science, 68:208-213.
6. EPA. 2006. Appendix K: summary of Human Health Effects Data for Paraquat (Tables from HED New Use Risk Assessment 2006).
7. PubChem. 2021. Compound Summary: Paraquat.
8. EPA. 1987. IRIS Evaluation: Paraquat; CASRN 1910-42-5.
9. Dalvie, MA, White, N, Raine, R, Myers, JE, London, L, Thompson, M, Christiani, DC. 1999. Long Term respiratory health effects of the herbicide, paraquat, among workers in the Western Cape. Occupational and Environmental Medicine, 56:391-396.
10. Castro-Gutierrez, N, McConnell, R, Andersson, K, Pacheco-Anton, F, Hogstedt, C. 1997. Respiratory symptoms, spirometry, and chronic occupational paraquat exposure. Scandinavian Journal of Work, Environment, and Health, 23:421-427.
11. Cha, ES, Lee, YK, Moon, EK, Kim, YB, Lee, Y, Jeong, WC, Cho, EY, Lee, IJ, Hur, J, Ha, M, Lee, WJ. 2012. Paraquat application and respiratory health effects among South Korean farmers. Occupational and Environmental Medicine, 69:398-403.
12. Mandel, JS, Adami, HO, and Cole, P. 2012. Paraquat and Parkinson’s disease: An overview of the epidemiology and a review of two recent studies. Regulatory Toxicology and Pharmacology, 62:385-392.
13. Costello, S, Cockburn, M, Bronstein, J, et al. 2009. Parkinson’s Disease and Residential Exposure to Maneb and Paraquat from Agricultural Applications in the Central Valley of California. American Journal of Epidemiology, 169(8):919-926.
14. Berry, C, La Vecchia, C, and Nicotera, P. 2010. Paraquat and Parkinson’s disease. Cell Death and Differentiation, 17:1115-1125.
15. Nistico, R, Mehdawy, B, Piccirilli, S, et al. 2011. Paraquat- and Rotenone-Induced Models of Parkinson’s Disease. International Journal of Immunopathology and Pharmacology, 24(2):313-322.
16. Dinis-Oliveira, RL, Remiao, F, Carmo, H, Duarte, JA, Navarro, AS, Bastos, ML, Carvalho, F. 2006. Paraquat exposure as an etiological factor of Parkinson’s disease. NeuroToxicology, 27:1110-1122.
17. Thiruchelvan, M, Richfield, EK, Goodman, BM ,Baggs, RB, Cory-Slechta, DA. 2002. Developmental Exposure to the Pesticides Paraquat and Maneb and the Parkinson’s Disease Phenotype. NeuroToxicology, 23:621-633.